New reactions of γ-halocarbanions: Underestimated reactive intermediates in organic synthesis

Article abstract of DOI:10.1007/s11172-005-0043-8

Short-lived γ-halocarbanions can be trapped by active electrophiles such as aldehydes, imines, and Michael acceptors to give anionic adducts, which undergo intramolecular substitution to give substituted tetrahydrofurans, pyrrolidines, and cyclopentanes. This has underlain a new method for the synthesis of these valuable ring systems. We have determined the acidity of the γ-halocarbanion precursors and have shown that the halogen atoms in the γ-position relative to the carbanion center exert a significant stabilizing effect on the carbanion.

Full text of DOI:10.1007/s11172-005-0043-8

1
846
Russian Chemical Bulletin, International Edition, Vol. 53, No. 9, pp. 1846—1858, September, 2004
New reactions of γꢀhalocarbanions: underestimated reactive
intermediates in organic synthesis*
ꢀ
М. Barbasiewicz , M. Judka , and M. M kosza
Institute of Organic Chemistry, Polish Academy of Sciences
ul. Kasprzaka 44, 01ꢀ224 Warsaw 42, POB 58, Poland
Fax: +48 22 632 6681. Eꢀmail: ichoꢀs@icho.edu.pl
Shortꢀlived γꢀhalocarbanions can be trapped by active electrophiles such as aldehydes,
imines, and Michael acceptors to give anionic adducts, which undergo intramolecular substiꢀ
tution to give substituted tetrahydrofurans, pyrrolidines, and cyclopentanes. This has underlain
a new method for the synthesis of these valuable ring systems. We have determined the acidity
of the γꢀhalocarbanion precursors and have shown that the halogen atoms in the γꢀposition
relative to the carbanion center exert a significant stabilizing effect on the carbanion.
Key words: carbanions, tetrahydrofurans, pyrrolidines, cyclopentanes, cyclizations,
pK values of carbanion precursors.
a
Introduction
Carbanions containing halogen substituents are imꢀ
sulting in the departure of the halogen anion to give
carbenes. This reaction, often termed αꢀelimination, usuꢀ
ally does not proceed with αꢀhalocarbanions stabilized by
electronꢀwithdrawing groups.
4
portant intermediates in organic synthesis. Due to the
presence, in one molecule, of a strongly nucleophilic carꢀ
banion center and an electrophilic center connected to a
leaving group, such carbanions are able to enter into a
variety of reactions. Particularly, αꢀhalocarbanions are
widely used as reactive intermediates in numerous proꢀ
cesses. The addition of αꢀhalocarbanions to electronꢀdeꢀ
ficient double bonds creates systems with an 1,3ꢀarrangeꢀ
ment of the nucleophilic and electrophilic active centers,
which usually undergo intramolecular substitution to proꢀ
duce threeꢀmembered rings (Scheme 1). Thus, the haloꢀ
hydrin anions formed in the reaction of αꢀhalocarbanions
with aldehydes and ketones cyclize to give oxiranes (the
The only known transformation of βꢀhalocarbanions
is rapid elimination of the halide anion to give alkenes.
Therefore, βꢀhalocarbanions generated by deprotonation
of βꢀhaloꢀnitriles, ꢀketones, ꢀsulfones, etc., are shortꢀlived
intermediates in the βꢀelimination reaction proceeding
5
according to Elcb mechanism. These carbanions can also
be generated via the addition of anionic nucleophiles to
βꢀhalovinylꢀnitriles, ꢀketones, etc., being the intermediꢀ
ates in the vinylic nucleophilic substitution proceeding
6
via the addition—elimination route (Scheme 2).
γꢀHalocarbanions can be generated by three major
routes:
(1) deprotonation of appropriate precursors, namely,
γꢀhalonitriles, sulfones, esters, etc. by the action of a base;
1
Darzens reaction ). A similar reaction of αꢀhalocarbanions
with Michael acceptors gives substituted cyclopropanes
(
2) alkylation of the carbanions formed by methylenic
via initial adducts, γꢀhalocarbanions, which undergo intraꢀ
2
CH acids with 1,2ꢀdihaloalkanes, the initial alkylation
products, 2ꢀhaloethyl derivatives being rapidly deprotonꢀ
ated to the corresponding γꢀhalocarbanions; and
molecular substitution. The addition of αꢀhalocarbanions
to electronꢀdeficient arenes, mainly nitroarenes, gives
σ ꢀadducts that undergo baseꢀinduced βꢀelimination, the
H
(
3) the addition of αꢀhalocarbanions to Michael acꢀ
ceptors.
Irrespective of the way of generation, γꢀhalocarbanions
process known as vicarious nucleophilic substitution of
3
hydrogen (see Scheme 1).
Some αꢀhalocarbanions are able to undergo uniꢀ
once formed enter into rapid intramolecular substitution
leading to threeꢀmembered rings, mainly cyclopropanes;
this process is often referred to as γꢀelimination.7
γꢀHalocarbanions generated via deprotonation of
αꢀhalodialkyl ketones cyclize to cyclopropanones, which
undergo ring opening in the presence of nucleophiles;
this process is known as the Favorsky rearrangement
molecular dissociation at the carbon—halogen bond, reꢀ
*
Based on the report presented at the International Conference
"
Modern Trends in Organoelement and Polymer Chemistry" dediꢀ
cated to the 50th anniversary of the A. N. Nesmeyanov Institute
of Organoelement Compounds of the Russian Academy of Sciꢀ
ences (Moscow, May 30—June 4, 2004).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1771—1783, September, 2004.
066ꢀ5285/04/5309ꢀ1846 © 2004 Springer Science+Business Media, Inc.
1

New reactions of γꢀhalocarbanions
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 9, September, 2004
1847
Scheme 1
B– is a base
7
Scheme 2
(Scheme 4, reaction (1)). Similarly, treatment of αꢀhaloꢀ
dialkyl sulfones with a base results in the formation of
threeꢀmembered dioxathiiranes upon intramolecular reꢀ
placement of γꢀhalocarbanions. The dioxathiiranes lose
SO to give alkenes; the overall process is known as the
2
8
Ramberg—Bäcklund reaction (Scheme 4, reaction (2)).
Intermolecular reactions of γꢀhalocarbanions
i. fast.
By analogy with the reactions of αꢀhalocarbanions,
the addition of γꢀhalocarbanions to electronꢀdeficient
C=O, C=N, and C=C double bonds is expected to proꢀ
duce systems with 1,5ꢀarrangement of the active nucleoꢀ
philic and electrophilic centers, which would cyclize to
give fiveꢀmembered rings (Scheme 5).
Scheme 3
These processes, namely, the reactions of γꢀhaloꢀ
carbanions with aldehydes, imines, and Michael accepꢀ
tors, should produce tetrahydrofurans, pyrrolidines, and
cyclopentanes, thus being of high value for organic synꢀ
thesis (Scheme 6).
The major problem in the realization of these attracꢀ
tive opportunities is the high rate of intramolecular subꢀ
stitution of γꢀhalocarbanions (γꢀelimination); as a conseꢀ
quence, the intermolecular addition to external electroꢀ
philic partners is disfavoured and usually does not occur.
Due to the high rate of γꢀelimination, only very few
studies on intermolecular reactions of γꢀhalocarbanions
have been reported, the known reactions being limited to
the γꢀhalocarbanions whose specific structural features
decelerate the γꢀelimination.
The only reported example of intermolecular transꢀ
formation of γꢀhalocarbanions susceptible to fast γꢀelimiꢀ
–
B is a base

1848
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 9, September, 2004
Barbasiewicz et al.
Scheme 4
B– is a base
Scheme 5
nation is the baseꢀpromoted reaction of bis(chloroꢀ
methyl) sulfone with aldehydes and ketones.9 Deꢀ
pending on the carbonyl component and the conditions,
the initially formed aldol type adducts are converted
into threeꢀ or fiveꢀmembered rings via 1,3ꢀ or 1,5ꢀnuꢀ
cleophilic substitution. Apparently, intramolecular subꢀ
stitution (γꢀelimination) in the α,γꢀdichlorocarbanion
derived from bis(chloromethyl) sulfone is decelerꢀ
ated by the SO2 group vicinal to the leaving group9
(Scheme 7).
EWG = ArSO , CN, COOR, ...
2
Y = O, NTs, CꢀEWG´
X = Cl, Br, ...
Scheme 6

New reactions of γꢀhalocarbanions
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 9, September, 2004
1849
Scheme 7
Examples of intermolecular reactions of γꢀhalocarbꢀ
anions unable to undergo γꢀelimination due to structural
features are reported for 3ꢀbromoꢀ2ꢀmethylenepropyl pheꢀ
nyl sulfone. Obviously the rigid methylene moiety with
Scheme 9
2
the sp carbon atom keeps the carbanion apart from the
electrophilic centers, thus preventing cyclization. In this
situation, the carbanion derived from this γꢀbromosulfone
was successfully trapped by Michael acceptors. The subꢀ
sequent intramolecular substitution in the resulting adꢀ
1
0
duct anions gave methylenecyclopentane derivatives
Scheme 8).
(
Scheme 8
L = HMPA
nitropropane anion reacts with imines to give substituted
1
3
nitropyrrolidines (Scheme 10).
Scheme 10
The possibility of an intermolecular reaction also exꢀ
ists for those γꢀhalocarbanions that are weak nucleophiles
inactive in S 2ꢀtype substitution. Thus the reaction of tin
N
enolate of γꢀchlorobutyrophenone with aldehydes results
in the formation of substituted tetrahydrofurans, whereas
lithium enolate undergoes γꢀelimination to give benzoylꢀ
cyclopropane11 (Scheme 9).
The nitronate anions generated from γꢀhalonitroꢀ
propanes belong to this category. Due to the low nucleoꢀ
philicity of the nitronate anions, only γꢀiodonitropropane
slowly cyclizes to nitrocyclopropane when treated with a
base.12 Recently, it was reported that the γꢀmesyloxyꢀ
i. slow.
–
B is a base

1850
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 9, September, 2004
Barbasiewicz et al.
Novel reactions of γꢀhalocarbanions
protocol for the synthesis of substituted tetrahydrofurans
via the reaction of 4ꢀchlorobutyronitrile (1), 3ꢀchloroꢀ
propylphenylsulfone (2), and tertꢀbutyl 4ꢀchlorobutyrate
Our interest in reactions of γꢀhalocarbanions came
from the observation of facile cyclization of γꢀchloroꢀ
butyronitrile under conditions of phase transfer catalysis
50% aqueous NaOH and tetraalkylammonium (TAA)
1
6
(3) with aldehydes. The reactions were carried out using
t
Bu OK to generate carbanions in the presence of aldeꢀ
o
(
hydes in 0.5 M THF solutions at –30 C. Relatively conꢀ
1
4
catalyst, whereas intermolecular alkylation of butyroꢀ
nitrile with benzyl bromide does not proceed under these
conditions. These results can be rationalized in two ways:
either the Cl atom in the γꢀposition of butyronitrile exerts
a stabilizing effect on the αꢀcyanocarbanion and, hence,
γꢀchlorobutyronitrile can be deprotonated by the aqueous
NaOH, or the cyclization (γꢀelimination) does not reꢀ
quire the formation of kinetically free carbanions. In orꢀ
der to clarify this point, we have carried out the reaction
of γꢀchlorobutyronitrile under the PTC conditions in the
presence of benzaldehyde. Apart from cyanocyclopropane,
this reaction gave 3ꢀcyanoꢀ2ꢀphenyltetrahydrofuran. We
have, therefore, concluded that the halogen atom in the
γꢀposition increases the CHꢀacidity of γꢀchlorobutyroꢀ
nitrile and that the intermediate γꢀchlorocarbanion is
trapped in the fast intermolecular reaction with benzꢀ
aldehyde.1
centrated solutions were used in order to promote the
intermolecular reactions (Scheme 11).
The effect of the concentration on the competition
between the intraꢀ and intermolecular reactions is shown
in Scheme 12.
Scheme 12
5
t
i. PhCHO, Bu OK, –30 °C, THF.
Reactions of γꢀhalocarbanions with aldehydes
C/mol L–1
Yield (%)
and ketones
Ia
IIb
Further studies based on the unprecedented finding
that shortꢀlived γꢀhalocarbanions can enter into intermoꢀ
lecular reactions resulted in the development of a general
0
0
0.05
.5
.1
0
17
22
95
79
74
a
Substituted cyclopropane. b Substituted tetrahydrofuran.
Scheme 11
Under these conditions, the formation of tetrahydroꢀ
furans was the major process, although some amounts of
substituted cyclopropanes resulting from competing intraꢀ
molecular substitution were always formed. Since the reꢀ
actions of the carbanions of 1 and 2 with aldehydes gave
good results, compound 2 was used in further studies as
the standard γꢀhalocarbanion precursor.
2
,3ꢀDisubstituted tetrahydrofurans can be formed as
cisꢀ and transꢀisomers. The reaction of 4ꢀchlorobutyroꢀ
nitrile (1) with aldehydes gives mixtures of transꢀ and
cisꢀisomers in ~4 : 1 ratio; it was shown that the stereoisoꢀ
mer ratio is under thermodynamic control. Only the
transꢀisomers of tetrahydrofurans containing more bulky
phenylsulfonyl and tertꢀbutoxycarbonyl substituents are
formed in the reactions of aldehydes with the correspondꢀ
ing sulfone 2 and ester 3. Estimation of the rates of inꢀ
tramolecular substitution in γꢀhalocarbanions, their addiꢀ
tion to the carbonyl group, and intramolecular substituꢀ
tion within the aldol type adducts to produce tetrahydroꢀ
furans are shown in Scheme 13.
t
i. ArCHO, Bu OK, –30 °C, THF.
Compound
EWG
Ar
Yield (%)
IIb
Ia
c
1
CN
CN
CN
Ph
11
78
82
76
95
88
83
64
61
c
c
d
d
d
d
d
1
1
2
2
2
3
3
pꢀMeC H
PhCH=CH
Ph
14
15
0
6
4
SO Ph
2
SO Ph
pꢀMeC H
8
2
6
4
SO Ph
pꢀClC H
15
15
32
2
6
4
t
t
COOBu
COOBu
Ph
pꢀMeC H
6
4
t
a
c
b
The addition of Bu OK to a solution of nitrile 1 or
sulfone 2 in THF at –70 °C followed immediately
Substituted cyclopropane. Substituted tetrahydrofuran.
trans/cis = 4 : 1. Only the transꢀisomer.
d

New reactions of γꢀhalocarbanions
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 9, September, 2004
1851
Scheme 13
Conditions: –70 °C, THF.
(
after 1—2 s) by the addition of benzaldehyde gave only
are deprotonated under the reaction conditions. Thereꢀ
fore, the reaction proceeded satisfactorily only with
pivalaldehyde to give tertꢀbutyltetrahydrofuran in a good
yield.
t
cyclopropanes. The addition of Bu OK to a THF solution
of nitrile 1 or sulfone 2 and benzaldehyde followed by the
addition of MeI or Me SiCl gave only tetrahydrofurans.
3
Thus, the rates of the reactions under consideration are
very high and the carbanions should be generated in the
presence of aldehydes.
The extension of this reaction to aliphatic aldehydes is
limited because they are relatively strong CHꢀacids and
Due to the lower electrophilicity of the carbonyl group
in ketones and some steric hindrance, the reactions of 1
and 2 with ketones are less efficient, although they still
can be carried out (Scheme 14).
The intramolecular variant of this reaction was perꢀ
formed for the substrate whose molecule contained siꢀ
multaneously a γꢀhalocarbanion fragment and an aldeꢀ
hyde carbonyl group* (Scheme 15).
Scheme 14
Scheme 15
t
i. Bu OK, –30 °C, DMF.
The attempts to extend the reactions of carbanions
generated from compounds 1 and 2 to other electrophilic
partners such as imines and Michael acceptors in the
expectation to develop a synthesis of pyrrolidines and
cyclopentanes gave initially negative results. The carbanꢀ
ion precursors were mostly converted into cyclopropanes,
t
i. Bu OK, –30 °C, THF.
* Unpublished results obtained by our research group.

1852
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 9, September, 2004
Barbasiewicz et al.
whereas electrophiles decomposed or polymerized under
the reaction conditions. It appears that intramolecular
replacement of the halogen in the highly nucleophilic
carbanions derived from 1 and 2 proceeds faster than the
intermolecular addition to these moderately active elecꢀ
trophilic partners.
Scheme 16
The outcome of the reactions of γꢀhalocarbanions with
electrophilic partners, viz., aldehydes, ketones, imines,
electronꢀdeficient alkenes, etc., depends on the relationꢀ
ship between the rates of intramolecular substitution
(
γꢀelimination), the addition to an external electrophilic
partner, and the rate of intramolecular 1,5ꢀsubstitution in
the anionic adducts formed. Since the addition is reversꢀ
ible, the final outcome can also be affected by the equilibꢀ
rium position in the addition reaction.
The effect of the leaving group on the reactions
of γꢀhalocarbanions
t
i. Bu OK, –30 °C, DMF, <2 min.
The relationship between the rates of intramolecular
substitution and intermolecular addition to an external
electrophile depends on the type of the leaving group, the
nature of the carbanionꢀstabilizing group, which dictates
the precursor deprotonation rate and carbanion nucleoꢀ
philicity, the substituents in hydrocarbon chain, etc. It
can be expected that intramolecular substitution would be
much faster in γꢀbromocarbanions than in γꢀchloroꢀ
carbanions; nevertheless, the former can be trapped by
+
oxirane ring is activated by a Lewis acid, e.g., by Li
2
0
cations. This is not a fast reaction, as the intermediate
carbanions are relatively longꢀlived species and can add
to aldehydes giving aldol type adducts, which can be isoꢀ
lated upon protonation or converted in situ into hydroxyꢀ
methyltetrahydrofurans. This process also requires actiꢀ
vation of the oxirane ring with Lewis acids. Since this
reaction gives rise to three chiral centers, the tetrahydroꢀ
furans are formed as mixtures of four diastereomers. We
have elaborated conditions that ensure a high overall yield
and reasonably high diastereoselectivity of the synthesis
of 5ꢀhydroxymethyltetrahydrofurans by the reaction
of 3,4ꢀepoxyꢀ1ꢀphenylsulfonylbutane with aldehydes*
benzaldehyde taken in an excess to form the correspondꢀ
ing tetrahydrofurans.16 The nucleophilic replacement of
the tetraalkylamonium group usually proceeds more slowly
1
7
than the replacement of chlorine. Therefore, we have
tested reactions of the carbanions derived from 3ꢀcyanoꢀ
propyl(trimethyl)ꢀ and 3ꢀphenylsulfonylpropyl(trimeꢀ
thyl)ammonium chlorides. Treatment of these compounds
with a strong base does not induce noticeable intramoꢀ
lecular substitution to form the corresponding cycloproꢀ
panes; apparently, the uncontrolled Hoffmann type degꢀ
radation takes place. Nevertheless, the expected carbanꢀ
ions can be generated and trapped by benzaldehyde, alꢀ
though aldol type anions do not replace trimethylꢀ
ammonium group and give only traces of tetrahydrofurans.
Meanwhile, aldol anions can enter into the intermolecuꢀ
(
Scheme 17)
Scheme 17
lar reaction with MeI (or MeSO Cl) followed by eliminaꢀ
2
tion of MeOH (or MeSO OH) and Me N yielding substiꢀ
2
3
tuted butadienes. This could serve as a useful route to
substituted butadienes1 (Scheme 16).
8
The ring opening in epoxides on treatment with nuꢀ
R
Yield (%)
Diastereoselectivity (%)
cleophiles, which can be considered as an S 2 type reacꢀ
N
Ph
87
90
61
74
77
23
13
19
47
tion, usually proceeds more slowly than the replacement
of chlorine.1 Thus, the 3,4ꢀepoxybutyl phenyl sulfone
carbanion should be a good, slow reacting analog of the
γꢀhalocarbanion. Indeed, treatment of this sulfone with a
strong base results in intramolecular ring opening to
produce hydroxymethylcyclopropane provided that the
pꢀMeC H4
2ꢀthienyl
But
87
81
53
6
9
t
t
i. RCHO, Bu OK, Bu OLi, –78 °C, THF; ii. –15 °C, 10 h.
* Unpublished results obtained by our research group.

New reactions of γꢀhalocarbanions
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 9, September, 2004
1853
Scheme 18
Although the initial formation of aldol type adducts is
not diastereoselective, fast equilibration caused by reꢀ
versibility of the addition followed by slower cyclization
results in the preferential formation of one diastereomer.
replacement of the halogen atom bound to the secondary
carbon atom and, hence, intramolecular substitution is
disfavored in competition with the intermolecular addiꢀ
tion to benzaldehyde. Therefore, the addition proceeds
quantitatively, and, since the intramolecular 1,5ꢀsubstiꢀ
tution of the aldol type anion for secꢀhalogen is also a
slow process, the corresponding alcohol can be isolated
upon protonation.* In this situation, the final outcome
depends on the interplay of the rates of the 1,3ꢀ and
The effect of substituents in the carbon chain
Substituents in the C(1)—C(3) carbon chain of the
γꢀhalocarbanions should exert a substantial influence on
their reactivity. An excellent example of this influence is
the carbanion derived from 2ꢀmethyleneꢀ3ꢀbromopropyl
phenyl sulfone, which is unable to cyclize to methyleneꢀ
cyclopropane.1 The phenyl group in 4ꢀchloroꢀ2ꢀphenylꢀ
butyronitrile provides additional stabilization of the corꢀ
responding carbanion and decreases its nucleophilicity.
This effect is expected to decelerate both competing proꢀ
cesses, namely, intramolecular substitution and the interꢀ
molecular addition to aldehydes. The additional phenyl
group in the αꢀposition to the carbanion center causes
steric hindrance, which should affect more appreciably
the latter process and, hence, hamper the formation of
tetrahydrofurans. Indeed, the reaction of 2ꢀphenylꢀ4ꢀ
chlorobutyronitrile with benzaldehyde under the standard
conditions gave mostly cyclopropane. Some amounts of
tetrahydrofurans are formed when benzaldehyde is used
in a large excess.16
1
,5ꢀintramolecular substitution and the position of the
addition equilibrium. It was possible to trap the aldol
anion with a reactive external electrophile, methyl iodide.
The methylation followed by double elimination gave subꢀ
stituted butadiene (Scheme 18).
0
Allylic halides can react with nucleophiles according
to S 2 and S 2´ mechanisms. On the basis of the vinylogy
N
N
principle, we can consider that the carbanions formed
from 1ꢀchloroꢀ5ꢀphenylsulfonylpentꢀ2ꢀene and similar
structures are analogs of γꢀhalocarbanions when particiꢀ
pate in S 2´ reactions. Due to the stereoelectronic effect,
N
the intramolecular S 2´ substitution in these carbanions
N
is not fast; therefore, the intermolecular addition to aldeꢀ
hydes would compete successfully with intramolecular
1
,3ꢀ and 1,5ꢀsubstitution, the latter being feasible only in
the case of Zꢀgeometry of the double bond. The intramoꢀ
lecular 1,3ꢀ and 1,5ꢀsubstitution in this type of carbanion,
proceeding according to the S 2´ and S 2 mechanisms,
N
N
The carbanions generated from 2ꢀmethylꢀ and 3ꢀmeꢀ
thylꢀ3ꢀchloropropyl phenyl sulfones readily cyclize to give
the same methylcyclopropane. The cyclization rate of the
latter sulfone is substantially lower, because it involves
respectively, was observed when methylenic carbanions
were alkylated with Zꢀ1,4ꢀdichloroꢀ2ꢀbutene, producing
* Unpublished results obtained by our research group.

1854
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 9, September, 2004
Barbasiewicz et al.
1
,1ꢀdisubstituted 2ꢀvinylcyclopropanes and 1,1ꢀdisubstiꢀ
intermolecular reactions only to highly reactive electroꢀ
philes such as aldehydes. Although structural modificaꢀ
tions of the aboveꢀmentioned γꢀhalocarbanions influence
the relationship between the rates of the competing intraꢀ
and intermolecular processes, the range of this changes is
insufficient for our purpose. We have suggested that a
moderate change in the acidity of the carbanion precurꢀ
sors should tune the nucleophilicity of γꢀhalocarbanions
and thus enable intermolecular reactions with less active
electrophiles. This tuning may take place upon introducꢀ
tion of electronꢀwithdrawing substituents in the benzene
ring of compound 2.
2
1
tuted cyclopentenes. The aldol type anions resulting
from the addition of such carbanions to aldehydes should
further react according to the S 2´ 1,5ꢀsubstitution patꢀ
tern to give vinyltetrahydrofurans, which was actually obꢀ
served* (Scheme 19)
N
Scheme 19
Our first choice was 3ꢀchloropropyl pentachlorophenyl
sulfone 4, which can be easily prepared by alkylation of
the corresponding thiophenol with 1,3ꢀbromochloroꢀ
propane and oxidation of the resulting sulfide. First, we
have shown that the lifetime of the carbanion generꢀ
ated from this sulfone is indeed much longer and deꢀ
pends substantially on the counterꢀcation, as shown in
2
2
Scheme 20. Thus, the carbanion of 4 can be generated
in advance and subsequently introduced in the reactions
with electrophiles.
t
i. 1) PhCHO, Bu OK, –30 °C, THF, 2) ~20 °C; ii. PhCHO.
Reactions with imines
The effect of the type of the electronꢀwithdrawing group
The relationship between the rates of intramolecular
substitution in γꢀhalocarbanions and intermolecular adꢀ
dition to aldehydes is undoubtedly affected by the type of
group stabilizing the carbanion, as the nucleophilicity of
carbanions is the function of CHꢀacidity of the precursors
and the charge distribution in the carbanion. In the case
of our model compounds 1 and 2, the high nucleophilicꢀ
ity of the corresponding carbanions limits the scope of
Treatment of 4 with LDA produces the lithium salt of
the respective carbanion, which reacts, due to the relaꢀ
tively long lifetime, with Nꢀbenzylideneꢀpꢀtoluenesulfonꢀ
amide to give the expected substituted pyrrolidine in a
good yield. Tosylimines of other aromatic aldehydes beꢀ
have similarly; therefore, this reaction can be regarded as
a general method for the synthesis of substituted pyrꢀ
rolidines* (Scheme 21).
*
Unpublished results obtained by our research group.
* Unpublished results obtained by our research group.
Scheme 20
Cation
Time before treatment
Yield (%)
/s
4
Li+
K+
15
89
78
38
0
11
22
62
2
5
15
2
5
100

New reactions of γꢀhalocarbanions
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 9, September, 2004
1855
Scheme 21
interaction of the bulky arylsulfonyl group with the aryl
substituents of the imines. This new method for the synꢀ
thesis of pyrrolidines corresponds to the recently reported
reaction of in situ generated imines and γꢀiodoenolates
generated in situ by the reaction of cyclopropyl ketones
with metal iodides. In this system, fast intramolecular
reaction of γꢀiodoenolates does not hamper their interꢀ
molecular addition to imines and the subsequent formaꢀ
tion of pyrrolidines, because of the reversibility of the
former process. One can, therefore, consider that the fiꢀ
nal outcome, the formation of the pyrrolidine ring, is due
to the thermodynamic control of the overall multistep
process.
2
3
Reactions with electronꢀdeficient alkenes
Owing to its longer lifetime, the carbanion generated
from sulfone 4 should be a versatile reactive intermediate
in the syntheses of substituted cyclopentanes by reactions
with Michael acceptors. Indeed, treatment of sulfone 4
with LDA in THF at –70 °C followed by the addition of
tertꢀbutyl acrylate to the generated carbanion resulted in
the formation of tertꢀbutyl 3ꢀ(pentachlorophenyl)sulfoꢀ
nylcyclopentanecarboxylate as a mixture of cisꢀ and
transꢀisomers. A variety of other Michael acceptors react
with this carbanion along the same pathway to give
R
Yield (%)
Ia
IIb
Ph
pꢀTol
75
73
5
9
6
0
16
a
Substituted pyrrolidine. b Substituted cyclopropane.
Although the substituted pyrrolidines can be formed
as cisꢀ and transꢀisomers, only the transꢀisomers were
formed in our experiments, perhaps, due to the steric
2
2
cyclopentane derivatives (Scheme 22).
Scheme 22

1
856
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 9, September, 2004
Barbasiewicz et al.
Scheme 23
The origin of the stereochemistry of the resulting
than the intramolecular addition to the electronꢀdeficient
aromatic ring to produce the σꢀadduct. This adduct unꢀ
dergoes further conversion along the Smiles rearrangeꢀ
ment pathway, which is accompanied by expulsion of SO2
and elimination of pentachlorophenol. The overall process
cyclopentanes is rather complicated. On the basis of preꢀ
liminary experiments, it appears that it is determined by
the addition and substitution steps and, hence, the reacꢀ
tion is kinetically controlled. This aspect, however, reꢀ
quires further studies. The carbanion of 4 reacts also with
cyclic Michael acceptors, for instance, with cyclopentꢀ
2
4
is similar to the oneꢀstep variant of the Julia olefination
(Scheme 24).
2
2
enone and cyclohexenone to give fused bicyclic systems
(
Scheme 23).
Determination of the acidity of γꢀhalocarbanion precursors
Thus, mere modification of the aryl substituent in
ꢀchloropropyl aryl sulfone provides attractive and versaꢀ
3
The observation that the halogen atom at the γꢀposiꢀ
tion relative to the potential carbanion site increases the
CHꢀacidity of the carbanion precursor required more rigꢀ
tile possibility for the synthesis of pyrrolidine and cycloꢀ
pentane derivatives. Surprisingly, the reaction of the carꢀ
banion generated from 4 with benzaldehyde followed a
different route to give 4ꢀchloroꢀ1ꢀphenylbutꢀ1ꢀene in high
yield rather than the expected substituted tetrahydrofuꢀ
orous proof. Direct determination of the pK value for
a
these compounds is impracticable due to the short lifeꢀ
time of the carbanions. Thus, only the kinetic acidity can
be measured in these cases. This can be done simply by
determining the rate of baseꢀcatalyzed deuterium exꢀ
ran. Obviously, the intramolecular S 2 1,5ꢀreplacement
N
of chlorine in the intermediate aldolꢀtype adduct is slower
Scheme 24

New reactions of γꢀhalocarbanions
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 9, September, 2004
1857
change under conditions that ensure much faster reꢀ
protonation (deuteration) compared to the proton abꢀ
straction (Scheme 25).
deuterium exchange for some sulfones and nitriles with
2
5
known pK values.
Using the Brønsted equation (1), which relates the
rate constants to equilibrium constants and the α values
a
2
6
2
7
28
reported for sulfones and nitriles, we calculated the
Scheme 25
approximate pK values for the compounds of interest.
a
logk = αlogK + C
(1)
a
Although the published pK values used in our calcuꢀ
a
lations (Table 1) were determined in an aprotic medium
(
DMSO), while our determination of the isotope exchange
rate was done in a protic solvent, these calculations are
justified, because the deuterium exchange rates of sulꢀ
k2 >> k1
fones and nitriles with known pK were determined under
a
identical conditions; thus, the resulting pK values are
reasonably reliable. These data indicate that the presence
of halogens in the γꢀposition relative to the carbanionꢀ
a
These requirements are met for the deuterium isotope
exchange in a dilute solution of NaOD in a mixture of
D O, EtOD, and DMSO. For convenience, we deterꢀ
2
stabilizing groups (SO Ph and CN) decreases pK by
1
2
a
mined the time of halfꢀexchange using H NMR specꢀ
~
2 units. Using the same approach, the pK values of
a
troscopy. The rates of the isotope exchange for the comꢀ
pounds of interest varied over a broad range; hence, meaꢀ
surements under identical conditions were impracticable.
In order to avoid these difficulties we have controlled the
basicity of the exchange "cocktail" by changing NaOD
concentration and the solvent ratio in such a way as to
keep the time of halfꢀexchange within a range convenient
for measurements. The selected data presented in Table 1
were calculated for identical conditions. From these data,
it is evident that the Cl, Br, and F atoms in the γꢀposition
increase substantially the deprotonation rate of 3ꢀhaloꢀ
propyl phenyl sulfones and 4ꢀhalobutyronitriles. Under
the same conditions, we have measured also the rates of
γꢀhalopropyl aryl sulfones, where Ar is a substituted pheꢀ
nyl or hetaryl group, were also measured and calculated.
Conclusion
We have shown that short lived γꢀhalocarbanions of
nitriles and sulfones can be efficiently trapped by active
electrophilic partners such as aldehydes. The anionic
aldolꢀtype adducts formed initially enter into rapid
1
,5ꢀintramolecular substitution giving substituted tetrahyꢀ
drofurans. This reaction offers a new, convenient and
efficient method for the synthesis of these important hetꢀ
erocycles.
The rate of intramolecular substitution (γꢀelimination)
of the carbanions derived from γꢀchloropropyl aryl sulꢀ
fones can be controlled by varying their nucleophilicity
via modification of aryl groups. A moderate increase in
the acidity of carbanion precursors and, hence, a decrease
in the nucleophilicity of γꢀhalocarbanions increases their
lifetime. Hence, they can be trapped by moderately reacꢀ
tive electrophiles such as imines and Michael acceptors.
On this basis, new methods for the synthesis of substituted
pyrrolidines and cyclopentanes were elaborated.
The isotope exchange rates were measured to deterꢀ
mine the kinetic acidity of a series of γꢀhalobutyronitriles
Table 1. Data of deuterium exchange experiment and calculated
pK values
a
Compound
τ1/2/s
kobs/s–1
pKa
(
DMSO)
EWG
X
PhSO2
PhSO2
PhSO2
PhSO2
PhSO2
H
F
Cl
Br
900
43
22
17
1.2
8
0.11
1.5
0.78
0.094
1.1•10–3
2.3•10
4.5•10–
5.9•10–
31.0
29.4
29.0
28.9
27.5
28.5
26.2
27.6
27.3
26.1
24.8
24.7
32.5
30.0
29.9
28.4
–
2
2
2
+
–1
Me N
8.3•10
*
3
pꢀNO C H SO
H
Cl
Cl
Cl
Cl
Cl
Br
H
1.3•10–1
9.1
6.8•10–1
1.3
2
6
4
2
2
pꢀNO C H SO
2
6
4
and γꢀhalopropyl aryl sulfones and to estimate their pKa
values. The results showed that F, Cl, and Br atoms present
in the γꢀposition relative to the carbanion center have a
significant stabilizing effect on the carbanions.
2
2
2
ꢀPyrimidyl
ꢀPyridyl
,5ꢀCl C H SO
11
140
2
6
2
2
3
2
–
3
C Cl SO
7.1•10
6
5
–
3
C Cl SO
6•10
6500
320
250
13
170
6
5
–
5
3
3
CN
1.5•10
Reference
CN
CN
CN
Cl
Br
3.1•10–
3.9•10–
+
–2
1. (a) M.ꢀC. RouxꢀSchmitt, J. SeydenꢀPenne, and S. Wolfe,
Tetrahedron, 1972, 28, 4965; (b) M. S. Newman and B. J.
Magerlein, Organic Reactions, 1949, 5, 413.
Me N
7.7•10
*
3
*
Salt with the chloride anion.

1858
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Received June 10, 2004;
3
9, 9815.
in revised form August 10, 2004