REVISTA BOLIVIANA DE QUMICA

Bolivian Journal of Chemistry

Received 12 01 2014

Vol. 31, No.2, pp. 61-67, Jul./Dic. 2014

31(2) 61-67, Jul./Dec. 2014
Published 12 31 2014

Accepted 12 15 2014
Bravo et Vila

MECHANISTIC VIEWS OF STEREOSELECTIVE SYNTHESIS OF TRIAND TETRA-SUBSTITUTED ALKENES, PART I; THE ORGANIC
CHEMISTRY NOTEBOOK SERIES, A DIDACTICAL APPROACH, N 3
Jos A. Bravo*, Jos L. Vila
Department of Chemistry, Instituto de Investigaciones en Productos Naturales IIPN, Universidad Mayor de San
Andrs 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: jabravo@umsa.bo
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 -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 stereoselectively and from the side less hindered by R1 and R2 groups, on the -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.
O

R1
O

R2
-

+ R4 MgBr
R3

R2

O- MgBr+
R2

R3

R3

R4

R1

R3
R4

R1

Cl

Cl

OH
H2 O

R2
R1

Cl

Cl

R-4

Figure 1. Halohydrin by nucleophilic attack (R4) over C=O of -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).
O

R1
O

R2
4-

+ R MgBr
R3

Cl

R2

O- MgBr+2
R

R3

R3

R1

Cl

H2O

OH

R3

R1

Cl

R1
Cl

R4 -

Figure 2. Synthesis of (E)-3-methyl-pentene as reviewed by W. Carruthers [3]

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REVISTA BOLIVIANA DE QUMICA

Bolivian Journal of Chemistry
Received 12 01 2014

Vol. 31, No.2, pp. 61-67, Jul./Dic. 2014

31(2) 61-67, Jul./Dec. 2014
Published 12 31 2014

Accepted 12 15 2014
Bravo et Vila

CH3

O- MgBr+
CH3

CH3

CH3

Et

H
Cl

OH

Et

+ Na OH

Me
H
Cl
Na+

Cl

Cl
-

OEt
Me

CH3

CH3

H2O

Et MgBr

+ CH3CO2

O
Et
Me

HO+

NaI, CH3CO2H

Na+

Et
Me

H
Me

Me
O
H Cl P
+
+ Sn2 2 Cl+
Cl Cl
I
Cl + O
P
Cl Cl

HO
Et
Me

H
Me
I-

HO+

Sn+ Me
H

Et
Me

Et

Me
Cl

SnCl2 + HOI

+
Me

HOSnCl-

Cl + O
I+ +
P
+ Cl
Cl Cl

(Sn(OH)Cl)

Sn+Cl-

HO

IOPCl4

HO- Sn+2 Cl- + I+

O- P+Cl3 Cl-

O
P

Cl

Cl

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.
IMg+
Cl

O
+

Me IMg

O-

CH3

H 2O

Me

Cl

OH

CH3
Me

H
Cl

CH3
H

Cl

Me-IMg+

OH
Me
Et

Me
H

HO+

+ Sn+2
SnCl2 +

+ NaOH

Me
Et

Cl
Sn

Me
Et
IOH

+ O

HO+

Me
H

Na+O -

+ H + H2O + NaCl + Na I + CH3COOH

Me

Me
Et

Cl

Me
Et

H
Me

HO
Me
Et

Me
H
I

I-

Me
H

Me

Et

Me

I+ + O- P+Cl3

SnOHCl + Cl

Sn+1OH-1 +2 Cl-

+
SnCl2 + IOH + O P Cl3

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 - or -iodoallylic alcohols with aluminium hydride
reagent (modified) and ulterior reaction of the reduction product with iodine [3,5], Figure 5.
R
(1) LiAlH4,
(2)

I2

CH3ONa,

THF

H
C C

Li(CH3)2Cu

CH2OH

R
CH3

H
C C

CH2OH

-78 C

R C C CH2OH
(1) LiAlH4,
(2) I2

AlCl3,

THF

-78 C

R
H

I
C C

Li(CH3)2Cu

CH2OH

R
H

CH3
C C

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]

Reduction is done with presence of NaOMe and the final product is only -iodoallylic alcohol. If reduction is
carried out with LiAlH4 in the presence of AlCl3, final iodination gives final -iodoallylic alcohol exclusively.
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REVISTA BOLIVIANA DE QUMICA

Bolivian Journal of Chemistry
Received 12 01 2014

Vol. 31, No.2, pp. 61-67, Jul./Dic. 2014

31(2) 61-67, Jul./Dec. 2014
Published 12 31 2014

Accepted 12 15 2014
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 -iodinated,
allylic alcohol.
H Al-H3 + Li+

AlH3
R

H
R C

C C:-

H
OH

Li+

Li

Cl3Al

R
C C:-

Li+
H

HO

HO

R
C

HO

HO

R
C C:-

Li+
H

HO

CH2OH
Al (C CHR)3

H
OH

Li+
H

HO

Cl3Al
I

R
I+

C C:-

HO

CH2OH
+
+ Li + Al (C CHR)3

Cl3Al

Cl3Al

CH2OH

CH2OH
Al (C CHR)2

H
OH

CH2OH

Cl3Al

H
R C

Cl3Al CH2OH
Al (C CHR)3

H
R C

Cl3Al

Li+ CH2OH
Al- (C CHR)3

CH2OH

H Al-H (C CHR)2 Li+

Li
H Al- (C CHR)3

Li+ CH2OH
Al-H (C CHR)2

Cl3Al

Cl3Al

CH2OH

HO

HO

AlH (C CHR)2
Li+
H

Li+ CH2OH
Al-H2 C CHR

Cl3Al

C C:-

Cl3Al

CHR

Cl3Al

AlH3

CH2OH

AlH2 C

H
OH

HO

Cl3Al

Cl3Al
CH2OH
Li+
H Al-H2 C CHR

Al-H3

Li

HO

R C

HO

R
I+

C C:-

I+
H

HO

CH2OH

+
+ Al (C CHR)2

Al+ C

R
C

HO

CHR

I+

HO

Cl3Al
Al+2

CH2OH

C C

Al+2 C CHR

C C

I+

+3
+ Al +3I-

H
H

HO

AlI3 + AlCl3

HO H
-iodo allylic alcohol

Figure 6. Synthesis of -iodinated allylic alcohol, mechanistic view

For the -iodinated allylic alcohol, NaOCH3 is employed (Figure 5) [3,5]. The corresponding mechanism is
shown in Figure 7.
+

H Al-H3 + Li+

R C

:-C C

HO

HO

Li+

HO
C

H
C C

HO

Na

+ AlH2 CR CH(CH2OH)
+
+ MeO + Na

H + Li+
H
H
H
OH

:-C C

H
C C

H2Al-

H
OH

AlH3

MeOLi + Na+

H
R C

+
+ MeO + Na

AlH3

R
Li+

MeOLi + Na+
R

:-C C

:-C C

HO

HO

H
C C

HO

Na

Figure 7. Synthesis of -iodinated allylic alcohol, mechanistic view

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R
C C

HAl-

R C

HO
C

Al-

+
+ MeO + Na

H + Li+

Li+

HO

R C

:-C C

HO

HO

H + Li

Li+

CR=CH(CH2OH)

HO

C C

HO

HO

HO

Al+2

HO

+
+ I

Li+

:-C C

HO

:-C C

HO

HO

HO

R
+

Al

H
C C

HO

C C

HO

[CR CH(CH2OH)]2
I

R
+ Al

+2

CR CH(CH2OH)
I

+
+ I

Li+

+
+ I

Li+

H
C C

HO

Na

I+

H
C

H
:-C C

H
C

HO

H
:-C C

Al+

Li+

Al+2 CR CH(CH2OH)

HO

[CR=CH(CH2OH)]2 C
Al

HO

Al+ [CR CH(CH2OH)]2

:-C C

Al [CR CH(CH2OH)]3

H + Li+

Na

:-C C

Al-

H
H
H
OH

MeOLi + Na+
R

H
C

+
+
+ MeO + Na
+

[CR=CH(CH2OH)]3 C C

Al [CR CH(CH2OH)]3

:-C C

MeOLi + Na+
R

H
H
H
OH

R
[CR=CH(CH2OH)]2 C C

+ AlH [CR CH(CH2OH)]2

CR=CH(CH2OH)

Vol. 31, No.2, pp. 61-67, Jul./Dic. 2014

31(2) 61-67, Jul./Dec. 2014
Published 12 31 2014

HO

C C

Al+3 + 3 Li-

-iodo allylic alcohol

Figure 7. Synthesis of -iodinated allylic alcohol, mechanistic view (Cont.)

The -iodinated and -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.
HO
I

C C H
H

R
+

+ Li (Me )2Cu

HO H
-iodo allylic alcohol

C:- C

C:- C

120o

CH3

R
Me
OH

C C

+
- +
+ Li Me I Cu

H
HO H
2-alkylated allylic alcohol

C C H

R
rotate

I
Me

C C:-

+
+
+ Li (Me )2Cu

C C

Me HO

HO
-iodo allylic alcohol

H
+
- +
+ Li Me I Cu

CH3
HO H
3-alkylated allylic alcohol

Figure 8. Transformation of -, -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.
1.

(CH2)2C CCH2OH

LiAlH4, CH3ONa, THF

2. I2

CH2OH
3.

(CH3)2CuLi
(54%, 97% E)

Figure 9. Key step in the synythesis of dl-C18 Cecropia juvenile hormone; reviewed by W. Carruthers [3]

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Bolivian Journal of Chemistry
Received 12 01 2014

Vol. 31, No.2, pp. 61-67, Jul./Dic. 2014

31(2) 61-67, Jul./Dec. 2014
Published 12 31 2014

Accepted 12 15 2014
Bravo et Vila

Figure 10 is the mechanism corresponding to the key step in the synthesis of dl-C18 Cecropia juvenile hormone.
C

H2C

CCH2OH
H2C

CH2

CH3
+

AlH3

H
OH

:-C C

:-C C

HO

HO

Li+

AlH3

MeOLi + Na+

+ MeO + Na
H

H
C

CH3

H3C

H Al-H3 + Li+

CCH2OH

R C
CH2

CH CH2

R C

=R

CH CH2

H
C C

HO

Na

Etc.
Continue with the rest of steps illustrated in Figure 7 until obtaining of the -iodinated allylic alcohol and then proceed to the alkylation process of Figure 8.
R

C C

HO

R
C

C H

HO
-iodo allylic alcohol

C:-

C C

Me HO

-iodo allylic alcohol

R
C

+
+
+ Li (Me )2Cu

+
- +
+ Li Me I Cu

CH3
HO H
3-alkylated allylic alcohol

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 -dialkylacrylic esters by reaction with -acetylenic
esters (Figure 11) [3]. The structure of each stereoisomer depends on the temperature and the solvent [3]. High yield
of ,-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+

R1
C
R2

CO CH
2
3
C
+
H

R1

C C

R2

H
CO2CH3

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.

R1

R1

C:O

R2

R1

H+

H+

R2

H+
R1

C
O

O
R2

Li+(R2-)2Cu+

R1

H3O+

Infraplanar nucleophilic attack

R1

R2

R1

C:-

CO2Me

R2

OMe

R1

H3O+

H
C

C
O

R2
O

Li+(R2-)2Cu+
Infraplanar nucleophilic attack

Figure 12. Trisubstituted alkenes stereoselectively obtained from alkynes by addition of organocuprates; mechanism

Organocopper(I) reagents add readily to terminal alkynes giving rise to 1-alkenylcopper(I) compounds [3].
These organocopper(I) reagents are RCu.Alkyl copper(I) compounds that can be obtained from Grignard reagents
and an equimolar quantity of copper(I) bromide or copper(I) bromide-dimethylsulphide complex [3]. Copper adds to
the alkyne on the terminal carbon, adding the alkyl group of the alkylcopper(I) reagent, in a syn manner [3]. This kind
of products, alkenylcopper(I) compounds, react with electrophiles like alkyl halides, -unsaturated ketones and
epoxides to afford trisubstituted alkenes with almost complete retention of configuration [3,7,8]. See Figure 13. The
elaborated mechanism is shown in Figure 14.
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REVISTA BOLIVIANA DE QUMICA

Bolivian Journal of Chemistry
Received 12 01 2014

Vol. 31, No.2, pp. 61-67, Jul./Dic. 2014

31(2) 61-67, Jul./Dec. 2014
Published 12 31 2014

Accepted 12 15 2014
Bravo et Vila

RMgBr + CuBr.(CH3)2S

ether

RCu.(CH3)2S.MgBr2

CH

RC

-45 C

-25 C

Cu(CH3)2S.MgBr2

R1

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- + CH3SCH3

..

[H3C :S+ CH3][Br-] + R- MgBr+

Cu

MgBr2

..
..S

RCu + MgBr2 + [H3C

CH3]

..
..S

[H3C

R-

CH3]

Cu+.(CH3)2S.MgBr2

RCu
R

R1

R
C C:-

R- + Cu+.(CH3)2S.MgBr2 ;

RCu.(CH3)2S.MgBr2

Cu.(CH3)2S.MgBr2
C C

R1

R1

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
o
ether
-45 C

CH3Cu.(CH3)2S.MgBr2

C6H13C

H3C

CH

CH3

Cu(CH3)2S.MgBr2

Br
H13C6

-25 C

H13C6

CH3

H
CH3

O
Cu.(CH3)2S.MgBr2

H7C3

(81%)

OH

H7C3
(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

..

[H3C :S+ CH3][Br-] + CH3- MgBr+

CH3MgBr + Cu+Br- + CH3SCH3

..

Cu

MgBr2
CH3Cu + MgBr2 + [H3C

..
..S

CH3]

[H3C

..
..S

CH3]

MgBr2

MgBr2
CH3Cu

..
..S

[H3C
-

..
..S

CH3- + [H3C

CH3Cu.(CH3)2S.MgBr2

CH3] ;

Cu

CH3] ;

CH3

Cu

CH3
H

CH3

C
C:-

C Cu

[H3C

Br

..
..S

CH3]

MgBr2
MgBr2

CH3
C
C

[H3C

..
..S

CH3] ;

BrCu

Figure 16. Trisubstituted alkenes stereoselectively obtained from alkynes by addition of organocopper(I) reagents, other
examples; mechanistic views
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REVISTA BOLIVIANA DE QUMICA

Bolivian Journal of Chemistry
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31(2) 61-67, Jul./Dec. 2014
Published 12 31 2014

Accepted 12 15 2014
Bravo et Vila

MgBr2
MgBr2

..
..S

[H3C

CH3]

..

Cu

C:-

[H3C S+ CH3]
Cu O

H
+

CH3

..
..S

[H3C

H 2O

CH3]

CH3

CH3
+

Cu

HO

+ (CH3)2S.MgBr2 + CuOH
CH3

Figure 17. Trisubstituted alkenes stereoselectively obtained from alkynes by addition of organocopper(I) reagents, other
examples; mechanistic views

Alkenyl iodides also react in the presence of Pd(PPh3) as catalyst to give conjugated dienes [3,9], Figure 18.
H3C

Cu.MgBr2

C5H11

catalytic Pd[P(C6H5)3]4

H3C

THF, 25oC

C2H5

C5H11
C2H5

(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.

Ph3P
PPh3

Ph3P

+ Pd[P(C6H5)3]4
H

Cu.MgBr2

:
: Br
..

Pd

Ph3P
PPh3

Mg

Pd
Ph3P

: Br
.. :
H

Cu

C:-

:
: Br
..
Ph3P Mg

: Br
.. :
Cu+

H
C5H11

C5H11

=
CH3

CH3

CH3

CH3

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 Andrs, for bibliographic support.
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