William P. Weber University of Southern California Los Angeles. 90007 and George W. Gokel The Pennsylvania State University University Park, 16802
Phase Transfer Catalysis Part 11: Synthetic applications
In the first half of this article,' we discussed the general principles of phase transfer catalysis and closely related phenomena. In this second part, we have catalogued a number of illustrative examples so that the range of applicability of phase transfer catalysis will he clear.
leads to ring expanded products as illustrated in eqns. (4) and (5).
Carbene Reactions
Phase transfer catalvsis " (ntc) . is now recoenized as a aeneral and versatile techniqur Rpplicahle to many organic renctions. I'TC WRS little mure than a curiosity in the late 1960's when Makosza first published his two-phase method for the generation of dichlorocarbene ( I ) . Usina a reservoir of 50% aqueous sodium hydroxide, a cosolve& of chloroform and olefin, and a catalytic amount of henzyltriethyl ammonium chloride, Makosza was able to achieve high yields of cyclopropaoation products. Dichlorocyclopropanation had previously been a difficult reaction ta conduct and the ease and economy of the new method attracted broad interest in the organic chemical community. It should he noted that this reaction, sometimes called the Makosza reaction, was simultaneously discovered by Starks and examples are reported in a patent (2) which is contemporaneous with Makosza's paper. The dichlorocyclopropanation of olefins can be achieved bv mine 50% aaueous sodium hvdroxide. chloroform. and a phase transfer catalyst. Yields in simple cases generally range uoward from 70%. Cvclohexene has been so treated usine a variety of catalysts; when BTEAC is used the yield is 72% (see eqn. (1) ( 1 ) .
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Alpha- and beta-haloalkylferrocenes are generally unstable. One of the few examnles t o the contrarv is ferrocenvldichlo" ---. rocyclopropanes, butsynthetic approacf;es ta these molecules have been difficult. The ~ h a s transfer e catalvtic method nllowed these molecules to he synthesized in high yield with relative ease (eqn. (2)) (3). Likewise, the phase transfer method facilitates the synthesis of the highly strained 1,ldichloro-2-phenylspiropentaneshown in eqn. (3) (4).
The facilitv with which dichlorocarhene can be eenerated under phase transfer catalytic conditions invariahh led to a search for new reactions of dichlorocarbene. Amone these new reactions was the insertion of dichlorocarbene into tertiary C-H bonds. The reaction of Dhase transfer eenerated dichlorocarhene with adamantani(7) (see eqn. (6)) is a high-yield reaction although such reactions are not aenerallv so satisfactory. The efficiency and economy of &is process make what might otherwise have been a marginal reaction a useful one.
The observation that dichlorocarhene gives stereospecific cis-insertion into one of the tertiary C-H bonds in cis-decalin precludes the possibility that the reaction involves free ion pairs (see eqn. (7)) 18). CHO,
The reactions of dichlorocarhene with substrates containine heteroatoms can he understood in terms of initial coordination of the electro~hilicspecies with heteroatom lone nairs of electrons. Dichlorocarbene reacts, for example, with &ohoh to give an intermediate alkoxychlorocarbene which then collapses to an alkyl chloride by the mechanism shown in eqn. (8) (9,10).
In some cases, the dichlorocyclopropanationproduct is not isolated but undergoes secondary reactions and rearrangement. The dichlorocarhene adducts of norhornene ( 5 ) and 3-methylindole (6) are examples. In both cases, the intermediate adduct loses chloride by ionization and simultaneous opening of the cyclopropane ring to an allylic carbonium ion
This is the second of a two-part Resource Paper. Part I appeared on p. 350 of the June issue. This series of Resource Papers is intended primarily for college and university teachers and is supported in part by a grsnt from the Research Corporation. Volume 55, Number 7, July 1978 1 429
11-OH
+ lCCl,l
-
I
-
[R-Wl,l
H.
[~+ra,l
CI
LR+FC.-CII
IR*WV//
k.,
(81
+ R--TI + R--n
+ C0 The reaction of dichlorocarbene with primary amines has been known for over a hundred years to give low yields of isonitriles (Hofmann carbylamine reaction). Application of the phase transfer technique to this reaction makes it preparatively useful (eqn. (9)) (11). Numerous other examples of dichlorocarhene reactions have also been reported (12). CO
~-CIHS-NH~+ :CCh
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t-CdHg-NC (66%)
Hydrocyanation of a,&unsaturated ketones has also been accomplished under phase transfer catalytic conditions. The a,&unsaturated ketones add cyanide ion under the influence of 18-crown-6, yielding an enolate anion. This enolate ion is protonated by acetone cyanohydrin, also present in the reaction mixture, regenerating cyanide ion and acetone as a by-product (see eqn. (13)) (28).
191
In addition to dichlorocarbene, dibromo- (13-15), chlorofluoro- (16), bromofluoro- (I7), fluoroiodo- (18),chloroiodo(19). and diiodocarbenes (19) have all been eenerated under plelsc transfer catal!.ric conditions, while attempts LOgenerate difluonsarhene have been ~ ~ n s u r c e s s Of f ~ ~these l . dihalocarbenes, only dihrnrnorarhene has bren extensively studied. It has twen found that rood 5ields of dibrmnocarhene from the relatively expensive l;n,m&rrn ran he obtained u.hen asmall amount of alcohol (preierahl\, n-hutanol, is added to the reaction mixture (14fand the best catalyst for the reaction is not a quaternary salt, but tributylamine (15). Dihalocarbenes generated under phase transfer catalytic conditions are formed by alpha-elimination of H-X from a haloform. The intermediate trihalomethyl anion is formed first by deprotonation, and this species may itself react with a substrate if the latter is highly electrophilic. Rather than adding dichlorocarbene, for example, acrylonitrile cyanoethylates the trichloromethyl anion as shown in eqn. (10) (20). Likewise, the reaction of bromoform with carvone (see eqn. (11)) leads to the product of Michael addition followed by ring closure and not to the product of direct cyclopropanation, although either is obviously possible (21,22).
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Esters Esters are ordinarily formed by the reaction of a carhoxylic acid with excess alcohol in the presence of a mineral acid catalyst. Although esters can he formed by the alkylation of silver carboxylates, this method has not found wide use. The phase transfer technique offers a significant advantage in this regard. A large number of esters have been synthesized under phase transfer conditions (29-34) and two examples are shown in eqns. (14) (30) and (15) (35). Note that in the latter case, nucleophilic substitution occurs without a significant amount of elimination. Elimination should be a particularly favorable process because dehydrohalogenation would lead to cyclohexadienone, the tautomer of phenol. That substitution rather than elimination is the favored process in this reaction indicates that the nucleophilicity of acetate is favored over the basicity, the same trend observed in the reactions of crownactivated t-butoxide ion (36).
&
p0-"
CO,-N~+ .c~a
