Bravo et Vila .
MECHANISTIC VIEWS OF STEREOSELECTIVE SYNTHESIS OF TRI-
AND TETRA-SUBSTITUTED ALKENES, PART I; THE ORGANIC
CHEMISTRY NOTEBOOK SERIES, A DIDACTICAL APPROACH, Nº 3
José A. Bravo*, José L. Vila
Department of Chemistry, Instituto de Investigaciones en Productos Naturales IIPN, Universidad Mayor de San Andrés UMSA, P.O. Box 303, Tel. 59122792238, La Paz, Bolivia
Keywords: Organic Chemistry, Stereoselective synthesis, Alkenes, Addition reaction, Mechanisms of Reactions.
ABSTRACT
As underlined in two previous papers in: “The Organic Chemistry Notebook Series, a Didactical Approach”, the presentation of synthesis works in a verbal and graphical succinct manner, needs a didactical approach. Isomerically pure tri- and tetra-substituted alkenes are difficult to obtain as shown in several publications. We used a series of reactions to synthesize tri- and tetra-substituted alkenes as reviewed by W. Carruthers, and we have proposed didactical and mechanistic views for the reviewed reactions.
*Corresponding author: [email protected]
ANALYSIS AND MECHANISTIC PROPOSALS
As academics we are concerned with the didactical importance of covering the needs of debutant students in organic synthesis. This is a third study in: “The Organic Chemistry Notebook Series, a Didactical Approach” [1,2]. The present article is an analytical and didactical approach to stereoselective synthesis of tri- and tetra-substituted alkenes as reviewed by W. Carruthers [3]. Tri- and tetra-substituted alkenes are difficult to obtain. Authors [3,4] signaled that the substrate α-chloro-aldehyde or –ketone, in its way to alkene, finds its critical step when reacting with Grignard reagent. Also, the most reactive conformation for the substrate is when the carbonyl group and the carbon-chlorine are antiparallel dipoles [3,4]. This conformation allows an addition of Grignard reagent very stereo-selectively and from the side less hindered by R1 and R2 groups, on the α-carbon atom with respect to carbonyl [3,4]. The nucleophilic attacking group R4 orients itself in an anti disposition with respect to the most hindering group between R1 and R2 [3,4]. The derived chlorohydrin is then submitted to stereoselective reactions to afford the alkene where three of the double bond substituents come from the alfa-chloro-aldehyde, -ketone and the fourth one comes from Grignard reagent [3,4]. Figure 1 shows the corresponding mechanistic view.
R3
O
R2
Cl R1
+ R4-MgBr+
O R3
Cl R2
R1
R-4
O- MgBr+
R3
Cl R2
R1
R4
OH R3
Cl R2
R1
R4
H2O
Figure 1. Halohydrin by nucleophilic attack (R4) over C=O of α-chloro-aldehyde, -ketone
As an example let us examine the synthesis of (E)-3-methyl-2-pentene [3,4] (Figure 2), and let us propose the corresponding mechanistic view (Figure 3).
R3 O
R2
Cl R1
+ R4-MgBr+
O R3
Cl R2
R1
R4
O- MgBr+ R3
Cl R2
R1 R4
OH R3
Cl R2
R1 R4 H2O
Bravo et Vila .
O CH3
Cl CH3
H
Et-MgBr+
O- MgBr+
CH3
Cl CH3
H Et
OH CH3
Cl CH3
H Et H2O
Na+OH
-+
O
-Cl Me Et
Me H
Na+
O
Me Et
MeH
NaI, CH3CO2H HO+
Me Et
MeH + CH3CO2
-I
-Na+ HO
I Me Et
Me H
+ +
Cl P Cl Cl
O Sn2+2Cl
-Cl P+
Cl Cl O
-HO+
I Me Et
Me H Sn+
H
Me Et
Me
+ HOSn+Cl- + + (Sn(OH)Cl)
I+
+ Cl
P+
Cl Cl O
-Cl
-IOPCl4 HO Sn +
Cl- HO-Sn+2
Cl- O- P+Cl 3 Cl
-I+
SnCl2 +HOI + Cl
P Cl Cl
O
+
Figure 3. Synthesis of (E)-3-methyl-pentene, mechanistic view
Similarly, a series of stereo-selective reactions with methylmagnesium iodide (Grignard reagent) onto substrate 2-chloropentane-3-one gave rise to (Z)-3-methyl-2-pentene [3,4] as shown in the mechanism of Figure 4. These reaction series are an elegant way to obtain pure stereo-isomers.
Cl
O +
Me-IMg+
O
Cl CH3
H
Me-IMg+
O
-Cl CH3
H Me
IMg+
H2O
OH
Cl CH3
H Me
OH
Cl Et Me
Me H
+ NaOH
Na+O
-Cl Et Me
Me H
O
Et Me
Me
H + H2O+ NaCl + Na+I- + CH 3COOH
HO+
Et Me
MeH
I
-HO
I Et Me
Me H
+ Sn+2 HO +
I Et Me
Me H Sn+
H
Me Me
Et
I++ O- P+Cl3 +
Sn+1OH-1
+2 Cl- SnOHCl + Cl- SnCl
2+ IOH + O - P+Cl
3
SnCl2 + IOH + O PCl3
Figure 4. Synthesis of (Z)-3-methyl-2-pentene, mechanistic view
A different reaction to afford the stereo-specific obtaining of 2- or 3-alkylated allylic alcohol from a propargylic alcohol is achieved by reduction of propargylic alcohol into β- or γ-iodoallylic alcohols with aluminium hydride reagent (modified) and ulterior reaction of the reduction product with iodine [3,5], Figure 5.
R C C CH2OH
(1)
(2)
LiAlH4, CH3ONa, THF I2 -78OC
(1)
(2)
LiAlH4, AlCl3, THF
I2 -78OC
R C C
H
I CH2OH
Li(CH3)2Cu R C C
H
CH3 CH2OH
R C C
I
H CH2OH
Li(CH3)2Cu R C C
CH3
H CH2OH
Figure 5. Synthesis of 3- or 2-alkylated allylic alcohols where the susbtituents, originally present in the propargyl alcohol, are
trans to each other; reviewed by W. Carruthers [3]
Bravo et Vila .
The resulting iodo compounds with LiR2Cu afford the corresponding substituted allylic alcohol, where the
original substituents of the propargyl alcohol, are now trans to each other (Figure 5) [3,5]. The explicit mechanism for these reactions are shown on Figure 6 and 7. Figure 6 shows the mechanism for the synthesis of β-iodinated, allylic alcohol.
H Al-H 3 + Li+
C C: -R
H HO
H H
Cl3Al
Li+ AlH3 C C H R HO H H
Cl3Al
Li
AlH3 C C
H R
HO H H
Cl3Al
Al-H3
Li+
C OH H
H
Cl3Al
C R
H Al-H2C CHR
CH2OH
Li+
C OH H
H
Cl3Al
C
R C C:
-H R
HO H H
Cl3Al
Li+
AlH2C CHR
CH2OH
C C H R HO H H
Cl3Al
Al-H 2C CHR
CH2OH
Li+ H Al
-H (C C-HR)2
CH2OH
C OH H
H
Cl3Al
C R
Li+
C C: -H
R
HO H H
Cl3Al
Li+ AlH (C CHR)2
CH2OH
C C H R HO H H
Cl3Al
Al-H (C CHR)2
CH2OH
Li+ H Al- (C CHR)3
CH2OH
Li+
C OH H
H
Cl3Al
C
R C C:
-H R
HO H H
Cl3Al
Li+ Al (C CHR)3
CH2OH
C C H R HO H H
Cl3Al
Al
-(C CHR)3
CH2OH
Li+
C C: -H
R
HO H H
Cl3Al
Li+
Al (C CHR)3
CH2OH
I+ C C H R HO H H I Li+
+ Al (C CHR)3
CH2OH
+ C C H R HO H H Al (C CHR)2
CH2OH
C C:
-H R
HO H H
Cl3Al
I+ I
+
+ Al+ (C CHR)2
CH2OH
C C H R HO H H Al+C CHR
CH2OH
I+ C C H R HO H H I C C H R HO H H Al+2 I+ C C H R HO H H I Al+3 + +3 β γ + I
-AlI3 AlCl3
β-iodo allylic alcohol Al+2
C CHR CH2OH
Figure 6. Synthesis of β-iodinated allylic alcohol, mechanistic view
For the γ-iodinated allylic alcohol, NaOCH3 is employed (Figure 5) [3,5]. The corresponding mechanism is
shown in Figure 7.
H Al-H 3 + Li+
Li+ : -C -C R HO H H H AlH3 C OH H H C R
+ MeO- Na+
+ MeOLi Na+
+ : -C -C R HO H H H C C R HO H H Na H AlH3 C C R HO H H H2Al
-H
H
+ Li+
C OH
H H C
R Li+
:-C C
R
HO H
H H
AlH2CR CH(CH2OH)
+ MeO- Na+ + MeOLi Na+
+
:-C C
R HO H H H C C R HO H H Na H + +
Bravo et Vila .
C C R
HO H
H HAl
-H
H
CR=CH(CH2OH)
+ Li+
C OH
H H C
R Li+
:-C C
R
HO H
H H
AlH [CR CH(CH2OH)]2
+ MeO- Na+
+ MeOLi Na+ +
:-C C
R
HO H
H H
C C R
HO H
H Na
H +
C C R
HO H
H Al
-H
H
[CR=CH(CH2OH)]2 + Li+
C OH
H H C
R Li+
:-C C
R
HO H
H H
Al [CR CH(CH2OH)]3
+ MeO- Na+
+ MeOLi Na+ +
:-C C
R
HO H
H H
C C R
HO H
H Na
H +
C C R
HO H
H Al
-H [CR=CH(CH2OH)]3
+ Li+
Li+
:-C C
R
HO H
H H
C C R
HO H
H H
I I+
Al [CR CH(CH2OH)]3 C C
R
HO H
H Al
H [CR=CH(CH2OH)]2
=
Li+
:
-C -C R
HO H
H H
+ Al+ [CR CH(CH2OH)]2
+ I+ I
C C R
HO H
H H
Al+
[CR CH(CH2OH)]2 C C
R
HO H
H Al+
H
CR=CH(CH2OH)
=
Li+
:-C C
R
HO H
H H
+ Al+2 CR CH(CH2OH)
+ I+ I
C C R
HO H
H H
Al+2 CR CH(CH
2OH) C C
R
HO H
H Al+2
H
=
Li+ :
-C -C R
HO H
H H
+ I+ I
C C R
HO H
H H
Al+3 Li
-3 + +
γ-iodo allylic alcohol
β γ
Figure 7. Synthesis of γ-iodinated allylic alcohol, mechanistic view (Cont.)
The γ-iodinated and β-iodinated allylic alcohols are easily transformed by action of lithium dimethylcuprate over substrates to afford 2-, 3-alkylated allylic alcohols as shown in Figure 8.
C C H
R
HO H
H I
β γ
β-iodo allylic alcohol
+ Li+(Me-) 2Cu+
C:- C
H R
HO
I Me
C:- C
H
R I
Me OH rotate 120o
C C H
R
HO H
H CH3
2-alkylated allylic alcohol + Li+Me-I-Cu+
C C I
R
HO H
H H
β γ
γ-iodo allylic alcohol
+ Li+(Me-)
2Cu+ C C:
-I R H
Me HO
C C CH3
R
HO H
H H
3-alkylated allylic alcohol + Li+Me-I-Cu+
Figure 8. Transformation of β-, γ-iodinated allylic alcohols into 2-, 3-alkylated allylic alcohols; mechanisms
This method found application in the stereo-specific C=C bond formation in the synthesis of trisubstituted derivatives. This was the case for the key step in the synthesis of the dl-C18 Cecropia juvenile hormone, as reviewed by W. Carruthers [3,6], Figure 9.
(CH2)2C CCH2OH
1. LiAlH4, CH3ONa, THF 2. I2 3. (CH3)2CuLi
CH2OH
(54%, 97% E)
Bravo et Vila . Figure 10 is the mechanism corresponding to the key step in the synthesis of dl-C18 Cecropia juvenile hormone.
C CCH2OH
H Al-H 3 + Li+
Li+
:-C C R
HO H
H H AlH3
C OH H
H C
R
+ MeO- Na+ + MeOLi Na+ +
:-C C
R
HO H
H H
C C R
HO H
H Na
H AlH3
+
R C CCH2OH
C H3C
CH2
CH CH2
H2C C
CH2
CH CH2
CH3
CH3
H2C =R
Continue with the rest of steps illustrated in Figure 7 until obtaining of the γ-iodinated allylic alcohol and then proceed to the alkylation process of Figure 8.
Etc.
I C C R
HO H
H H
γ-iodo allylic alcohol
β γ
C C I
R
HO H
H H
β γ
γ-iodo allylic alcohol
+ Li+(Me-) 2Cu+
C C:
-I R H
Me HO
C C CH3
R
HO H
H H
3-alkylated allylic alcohol + Li+Me-I-Cu+
Figure 10. Key step in the synthesis of dl-C18 Cecropia juvenile hormone; mechanism
Organocopper and organoborane reagents are employed to obtain stereoselectively tri- and tetra-substituted alkenes by addition on alkynes [3,7]. Organocuprates lead to ββ-dialkylacrylic esters by reaction with αβ-acetylenic esters (Figure 11) [3]. The structure of each stereoisomer depends on the temperature and the solvent [3]. High yield of β,β-dialkylacrylic ester is achieved at -78oC in THF [3]. Contrasting with reactions employing propargyl alcohols, this reaction produces alkenes in which the substituents in the acetylenic precursor are cis to each other in the alkene [3].
R1 C C CO2CH3
1. Li(R2)2Cu
2. H3O+
C C R1 CO2CH3
R2 H
+ C C R1 H
R2 CO2CH3
β α
Figure 11. Trisubstituted alkenes stereoselectively obtained from alkynes by addition of organocuprates; reviewed by W. Carruthers [3]
The mechanistic views conducting to alkenes by this method are exposed in Figure 12.
Li+(R 2-)2Cu+
C O
O C
R1
Infraplanar nucleophilic attack
C C:
-R1
R2
O O
=
R1R2
O O
-H3O+
H+
Li+(R 2-)2Cu+
C O
O C
R1
Infraplanar nucleophilic attack
C C:
-R1
R2 CO2Me
=
R1
R2
O
OMe
-H3O+
H+
C C
R1
R2
H
O O H+
C C
R1
R2 H
O
O
Figure 12. Trisubstituted alkenes stereoselectively obtained from alkynes by addition of organocuprates; mechanism
Bravo et Vila .
RMgBr + CuBr.(CH3)2S ether
-45oC
RCu.(CH3)2S.MgBr2
R1C CH
-25oC
Cu(CH3)2S.MgBr2 R
R1 H
Figure 13. Trisubstituted alkenes stereoselectively obtained from alkynes by addition of organocopper(I) reagents; reviewed by
W. Carruthers [3]
RMgBr + CuBr.(CH3)2S = RMgBr + Cu+Br- CH+ 3SCH3 [H3C :S+ CH3][Br-]
Cu
+ R- MgBr+
RCu MgBr+ 2 + [H3C S.. CH3]
..
[H3C S.. CH3]
.. MgBr2
RCu
=RCu.(CH3)2S.MgBr2
.. ..
Cu+.(CH3)2S.MgBr2
R
-+ ;
C H
C R1
R
-C -C: -R
R1 H
Cu+.(CH3)2S.MgBr2
C C
R
R1 H
Cu.(CH3)2S.MgBr2
Figure 14. Trisubstituted alkenes stereoselectively obtained from alkynes by addition of organocopper(I) reagents; mechanistic view
The method was employed as shown in the examples of Figure 15.
CH3MgBr CuBr.(CH3)2S
ether -45oC
CH3Cu.(CH3)2S.MgBr2
C6H13C CH -25oC
Cu(CH3)2S.MgBr2
H3C
H13C6 H
Br H13C6
CH3
(81%)
H7C3
Cu.(CH3)2S.MgBr2
CH3 O
H7C3
CH3
OH
(78%)
Figure 15. Trisubstituted alkenes stereoselectively obtained from alkynes by addition of organocopper(I) reagents, other
examples; reviewed by W. Carruthers [3]
The corresponding mechanistic views are exposed in Figures 16 and 17.
CH3MgBr + CuBr.(CH3)2S =CH3MgBr + [H3C :S+CH3][Br-]
Cu
+ CH3- MgBr+
CH3Cu MgBr+ 2+ [H3C S.. CH3]
..
[H3C S.. CH3]
..
MgBr2
CH3Cu
=CH3Cu.(CH3)2S.MgBr2 CH3-+ [H3C S.... CH3]; MgBr2
+Cu
H
-CH 3
C:
-H C
CH3
; [H3C S.. CH3]
..
MgBr2
+Cu
C
H C
CH3
Cu
;
[H3C S.... CH3] Cu+Br- CH
3SCH3
+ ....
MgBr2
Br
δ
-δ+
δ
-δ+
C
H C
CH3 + [H3C S.... CH3]; MgBr2
BrCu
Bravo et Vila .
H
CH3
[H3C S.. CH3] ..
MgBr2
Cu
C:- H
CH3
[H3C S.. CH3] ..
MgBr2
+Cu
+
O C
H
CH3 -O
[H3C S+ CH3]
Cu
..
H2O
C H
CH3
HO
+ (CH3)2S.MgBr2 + CuOH
Figure 17. Trisubstituted alkenes stereoselectively obtained from alkynes by addition of organocopper(I) reagents, other examples; mechanistic views
Alkenyliodidesalso reactin the presence of Pd(PPh3) as catalyst to give conjugated dienes [3,9], Figure 18.
Cu.MgBr2
H3C
C2H5
+ C5H11
I catalytic Pd[P(C6H5)3]4
THF, 25oC
H3C
C2H5
C5H11
(78%, 99.5% isomeric purity)
Figure 18. Alkenyl iodide catalyzed by Pd[P(C6H5)3]4 to afford conjugated diene; reviewed by W, Carruthers [3]
The corresponding mechanism is exposed in Figure 19.
H Cu.MgBr2
CH3
=
: .. : ..
Pd[P(C6H5)3]4
+
H Cu
CH3
Br Mg Br
: PPh3
:
Ph3P Ph3P
Pd
: .. : ..
C:
-H
CH3
: PPh3
:
Ph3P Ph3P
Pd Ph3P
Cu+
Br Mg Br
C5H11
I
CH3
C
H C5H11
Figure 19. Alkenyl iodide catalyzed by Pd[P(C6H5)3]4 to afford conjugated diene; mechanism
ACKNOWLEDGEMENTS
Authors express their gratitude to Prof. Eduardo Palenque from the Physics Department, Universidad Mayor de San Andrés, for bibliographic support.
REFERENCES
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(http://www.bolivianchemistryjournal.org, 2013)
3. Carruthers, W. Some Modern Methods of Organic Synthesis, Cambridge University Press, 3rd ed., 1987, Worcester, U.K., pp.
148-156.
4. Conforth, J.W., Conforth, R.H., Mathew, K.K. 1959, J. Chem. Soc., 112.
5. Corey, E.J., Katzenellenbogen, J.A., Posner, G.H. 1967, J. Am. Chem. Soc., 102, 1433.
6. Corey, E.J., Katzenellenbogen J.A., Gilman N.W., Roman, S.A., Erickson, B.W. 1968, J. Am. Chem. Soc., 90, 5618.
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8. Marfat, A., McGuirk, P.R., Helquist, P. 1979, J. Org. Chem., 44, 3888.
