Brodford P. Mundy
Montana State University Bozeman, 59715
Alkylations in Organic Chemistry
The concept of alkylation is very important in organic synthesis. In a simple view of this process, the a-position of a ketone is allcylated by way of a carbanionic intermediate. There are, however, many subtle factors involved in alkylations, and some of these will now be considered.
Table 2.
Alkylation of Representative Ketones ( 7 )
Alkylations via Enolotes
Initiation of alkylation reactions frequently requires a base, and the choice of this reagent can be a critical factor in the ultimate success of the reaction (1). The reagent must have reasonable solubility in the reaction solvent. This allows the bese to enter into the reaction quickly. Frequently the base is added rapidly to a solution of the alkylating agent and substrate to be allcylated. This process often minimizes crotonization. The extent of crotonization can be seen in some relative rates of self condensation (Table 1). The alkylating agent's leaving group can have some effecton the rate of the process. However, this is not generally an important factor to be considered. Table 1. Relative Rates of Condensation of Some Re~resentativeKetones ( 7 )
Ketones ZMethylcyclohexanone 3-Methylcyclohexanone 4-Met,hylcyclohexanone Cyclohexanone Acetone
Cyclopentanone
3-Methvlcvclo~ent-Zenone
Rel. rate 1 3 6 7 1,050 14,000
20.000
Although the reactivity of various systems is of importance, the synthetic chemist is frequently more concerned with where the alkylation will occur, and the stereochemistry of the resulting product. The chemist can frequently control the position of alkylation by judicious use of blocking groups. However, without these groups a chemist can still make some apriori predictions on alkylations. For many simple aliphatic ketones, the position of alkylation can be predicted by a simple consideration of enolate stability which corresponds to the stability of the resulting alkenes. Table 2 analyzes the alkylation of some representative ketones. At first glance a few of the examples seem inconsistent with the general rule of "alkene stability" governing enolate stability. Steric affects can occasionally ac-
count for the apparent anomalies. Consider, for example, the two enolates of IV (from Table 2) R
R R /C=C\ R 0IVa.
0IVb
The steric effects in IVa are considerably greater than IVb, thus favoring the latter. A very interesting argument can be applied to VIII and X. Brown, Brewster, and Shechter considered the exo- and endo- cyclic olefinic bonds associated with cyclopentane and cyclohexane and made the suggestion that an exocyclic bond is more favorable than an endocyclic bond for cyclopentyl derivatives, while the exocyclic bond is less favorable for the cyclohexyl derivatives (8). This is also born out in the observation that cyclohexane is reduced to the alcohol considerably faster than-cyclopentanone to cyclopentanol. Thus, the enolate of VIII favors the "double bond" exocyclic to the ring, while this process in not favorable for the cyclohexane ring. For simple cyclohexanone derivatives, the thernzodynamic stabilities of the enolate ions have to be conVolume 49, Number 2, February 1972
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91
sidered. Generally, the most highly substituted enolate is the more stable. From these considerations, one might predict that methylation of 2-methylcyclohexanone would give predominately 2,2-dimethylcyclohexanone as the product; this is indeed observed (1). n
Table 3.
Orientotion of Alkylation Compared to Alkene Stabilitv (11
n
Alkylation of 3-methylcyclohexanone has resulted in the observation that only one product is formed (1).
Alkylation of cyclopentanone and its derivatives follow the same general trend (1). 0
0 Dimethyletion
0
&x
+
CH~,&CH.
CHI
The problem of controlling monoalkylation has always been of interest. Tardella has investigated the use of tin and aluminum organometallics for this (5). If it is accepted that the problem of polyalkylation is simply a problem of how to control enolate equilibration, a reasonable control is to make the metal-oxygen bond more covalent. This has been found to be true in examples using the metals potassium, sodium, and lithium. .R'
H
q
correlates well with the stability of the corresponding alkene (Table 3). Frequently in the course of synthetic operations one generates an enone system (4)
*a
0
This, in fact, almost always results after annelation
With these metals, the Li-0 bond is more covalent and less polyalkylation is observed. Addition of either tributyltinchloride or triethylaluminum to a previously generated lithium enolate prior to alkylation results in considerably increased yields of monoalkylated product. For the more complex ring systems, the site of alkylation 92
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lournd o f Chemical Education
I
IJB-
I
p-x
I
p-x
p-x
procedures. Alkylation of these systems generally results in addition of the alkyl group to "a". The only requirement for this reaction is that a y-hydrogen be available. As was pointed out earlier, polyalkylation of ketones is not an unexpected process. Because of the ease of dialkylation it is not unusual to find diakylated products and alkene isomerization. Since many triterpenes are characterized by a dimethyl function in the A-ring, this can sometimes be of synthetic utility.
-+
-t
0
R-X
R-X
R
Other unsaturated ketones can also be alkylated. A 0-r unsaturated ketone is alkylated like the a,p isomer. The r,8 unsaturated ketone behaves like the corresponding saturated system.
An interesting, but not entirely tested, method of alkylation concerns the enolates derived from zinc reduction of a-bromo ketones (6)
The procedure has been effective only with rings larger than cyclohexanone. Although there are problems associated with this process at present, one of the interesting potentials of this reaction is in the fact that the entering alkyl . group - - maintains the stereochemistry of the bromine. General examples of well-known reactions initiated by an enolate anion include Aldol condensation 2CH3-C-H
1 I
+ OH--
CHs-CH-CH-C-H
I
OH
0
-
1 I
0
Claisen condensation (Note: The aldehyde should have no a-hydrogen) ETO-
R4-H
Because alkylation reactions are no more than an extension of the nucleophilic substitution reaction, the stereochemistry can be considered in terms of both stereo and electronic effects. The initial attack of R-X will occur in an axial position; the R group adding from the side of lesser steric effects.
a
+ CHI-C-OET
R-CH-CH1-C-OET
-H10
d
AH
R-CH=CH-C-OET
c!
Perkin reaction 0
$4-H
8
cd-o-
--
+ CH8-C-0-CCHa
K 8
Darzens reaction Cl-CH2-COOEt
Steric effects and alkylations can be best demonstrated by one example (6)
OEC
CI-CH-COOE~
R-C-R'
II
0
-.
Stobbe condensation
R'
COOEt
I I R-C-CH
I I
"I* 7 C=O I
OEt Volume 49, Number 2, February 1972
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93
R'
-
COOEt
I I R-C-CH
R'
COOEt
I I R-DCH
EtO-
, OEt 0
Malonic ester synthesis ETOOC--CH*--COOET
'
1)
OET-
a) RX
The 1,3-axial shielding in alkylation of fused ring systems is apparently quite important. This is readily reflected by the observation that the reversed specificities of a-cyano and a-carbomethoxy groups is not observed in other compounds
ETOOdH--COOET
Sterie shield of methylgroup
w _ _ - --. _
-
0 COOH
R'
IR'
I LC-CH-C-0-H OH COOH
R,>c=c\ ' I
-
H
H
Alkylationr via Enamines
The enamine (vinylamine) is a useful protective and directive group. Primary interest in this organic II 0 intermediate is concerned with its directive effects in alkylation reactions. A simple analogy with the S%+ R ' \ ~ = ~ ~ - ~enolate ~ ~ ion ~ suggests how the enamine affects alkylation
C-0-H
II
-H,O
d
0
Using fused systems, some stereoselective control in methylations has been observed (7). Enamines are easily generated by acid-catalyzed condensation of an aldehyde or ketone with a secondary amine. It is critical that the water he removed from the reaction mixture as it is formed. Commonly used amines are pyrrolidine, piperidine and morpholine.
These results are particularly interesting in light of the relative acidities of the cyano and carbomethoxy enolates. Although the carbomethoxy compounds are less acidic, and form enolates less readily, they are more reactive to competitive methylation. It is thought that the less nucleophilic an enolate ion, the more likely that it will favor axial alkylation.
Enamine formation of alkylated ketones was noted to generally give the lesser substituted enamine.
This had been attributed to steric interactions. However, recent work questions this interpretation (9). 94 / Journal of Chemical Education
Enamines can be effectively alkylated
Stork has pointed out that enamines can best be alkylated by two groups of alkylating agents (1) electrophilic olefins; and ( 2 )alkyl halides (10). The electrophilic olefins are best exemplified as or,@-unsaturated aldehydes, ketones, esters or other acid derivatives. Consider the addition of acrylonitrile to the pyrrolidine enamine of cyclopentanone
Simple monoalkylation of enone systems, contrary to the dialkylation usually observed, is possible with enamine intermediates.
A recent and exciting aspect of enamine chemistry is the observation that asymmetric synthesis can be carried out by proper choice of anamines (11). Esters of L-proline have been, a t this time, most thoroughly investigated; and because of the accessability of this naturally occurring amino acid it is a logical choice. In general, the degree of asymmetric synthesis is enhanced by increasing the size of the ester group. Nonpolar aprotic solvents frequently give lower product yields, but higher optical yields.
o An obvious advantage of this process is that the reaction is run under essentially neutral conditions. The conditions frequently associated with alkylations-particularly the strong bases-tend to cause polymerization of electrophilic olefins as well as crotonization of the carbonyl compound. With enamines these problems are avoided. Enamine alkylation with unactivated alkyl bromides and iodides generally give only fair yields of product. It is of interest to note that the enamine procedure offers another annelation method. An extreme example of the special effectiveness of the enamine procedure can be obtained in the following sequence (10)
n.a
One of the problems associated with the general use of enamines is that the method does not apply itself well to the use of unactivated halides. To circumvent this problem, Stork introduced the method of alkylating the carbon of imine salts (It). The general characteristics of the process can be &mplifiedby the conversion of cyclohexanone to 2-butylcyclohexanone.
Particularly noteworthy of this procedure is the fact that alkyl halides which frequently suffer rapid dehydrohalogenation appear to he quite stable to the reaction conditions. Alkylation of Enolates Derived from Reduction of Enone Systems
The reaction has also been used for decalim derivatives A
A consideration of the possible mechanism of lithium amine reduction of enones suggested a new source of enolates for alkylation reactions (13). If the enolate I1 could be trapped by an alkylating agent, a unique method for reduction and alkylation would be available.
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Acid derivatives can also be introduced a t the aposition via the use of the same general procedure. Stork has successfully utilized the enolate from lithiumammonia reduction of an enone in a carbonation reaction (19) The nucleophilicity of the a-carbon wss established by the series of reactions shown below.
1Remove NH, 2. Add Eta 3.AddC0,
0
*
'3s
o
w COOH
Addition of cyanogen chloride to the enolate results in the formation of a-cyano ketones (IS).
Testing the hypothesis of the ability to trap the enolate, the a-alkylation of A1~9-20ctalone was performed. Li+ -0
0
This method has been utilized in research on resin acid (diterpene) synthesis (15).
LIP A
M Final Comments
LOa
2. nBu1
n
The use of lithium rather than sodium or potassium is best understood in light of the observations that this cation-enolate did not undergo rapid equilibration (14). To test this, the highly ionizing solvent DMSO was added to replace the ammonia, before alkylation. Analysis of the product after addition of the wBuI, showed formation of 3-butyl-trans-2-decalone. This is the product expected from equilibration of the enolates.
Literature Cited ( 1 ) Conm, J.-M.,Rcc. Chcm,Prog7.,14,43 (1963). J. H., AND SX&CRTER. H., J. Amel. ( 2 ) (s) Bnows. H . C.. BREWBTER, Cham. Soc., 16, 407 (1954); ( b ) FLECK.B . R,. J. Ow. Chen., 11, 439 (1957); (4 Bnown, H. C.,J . Om. Chem., 11, 439 (1957). P ., A.. Tetrahedron Lett., 14,1117 (1909). (3) TAR~ELU ( 4 ) For background regarding annelation prooedurea, see Hoaan, H. 0.. "Modern Synthetic Reactions," W. A. Benjamin. Ino.. New York, 1965. C h a ~ r 8 . (5) H o u s ~ H. , 0.. o p . cif., Chap. 7 . ( 0 ) S ~ m c e n T. . A,, Barwon, R. W.. A N D Whm, D. S., J. A m w . Chsm. Soo., 89,5727 (1907). (7) K a ~ n rM.E..J. ~. Ovg,Chem.,8n, 171 (1870). EDUO..40, 194 (1903); ( b ) KUEXNE, M.E., ( 8 ) (a) WBBT.J. A,, J. CXEM. S y d h c ~ i s510 , (1970). ( 9 ) G q h y z , W . D., m n JOBEPH,M. A,, Tatrohadron Lcll., 49, 4433
s ~ ,L ~ w o m a l a ~H., ~ . Szlausz~ovror.J., a m (10) S ~ o n x ,G., B n r z ~ o b ~ A,, T e n n e ~B., ~ , J. Amar. Chcnr.Soc., 88,207 (1963). (111 . . Y&UADA. . 8... Hmor.. K... m n Aomw*. K.. Telrohadron Left.. 48. 4233 (1909). (12) Svonu. G., AND Down, 8. R., J. A m , . Chem. Soe., 85,2178 (1963). . ROBEN,P., GOLDMAN, N., COOMBB. R. V.. AND TBUII,J., (13) S ~ o n n G., J . Amer. Chem. Soe., 87,275 (1905). (14) CAINE,D., J.Om. Chem.,29,1868 (1984). J. A,, J . Ew. Cham., 86,101 (1970). (15) KUBHNE,M. E., A N D NELBON, R. E.. "Organic Synthesis, the Foundations of Modern (16) IREZAND, Organic Chemistry Series, Prentioe-Hall. Ino.. Englewood-Cliffs. N. J.. 1969.
0
96
In the preceeding three sections we have tried to review some of the concepts and methods found in alkylation procedures. The choice has been selective rather than exhaustive in an attempt to aquaint the student of organic chemistry with some of the recent advances in methodology and theory of alkylation reactions. The classical orientation procedure involving blocking groups is well reviewed (5,16).
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