REVISTA BOLIVIANA DE QUÍMICA VOLUMEN 22, No.

1 - 2005

THE ORGANIC CHEMISTRY NOTEBOOK SERIES,

A DIDACTICAL APPROACH,® (I)
A THEORETICAL MECHANISTIC APPROACH TO DIASTEROSELECTIVE
SYNTHESIS OF CIS-1,2-DIALKENYLCYCLOPROPANOLS AND
SUBSEQUENT OXY-COPE REARRANGEMENT BY JIN KUN CHA ET AL.
José BRAVO
joseabravo2004@yahoo.com.mx

Department of Chemistry, Universidad Mayor de San Andrés, P.O. Box 303, La Paz Bolivia

Key Words: Kulinkovich hydroxycyclopropanation, cis-1,2-dialkenylcyclopropanols, oxy-Cope

rearrangement, hydroazulenic sesquiterpenes, theoretical reaction mechanism

Scheme by J. K. Cha et al.1

ABSTRACT RO
OR
CO2Me
Kulinkovich Oxy-Cope
The Organic Chemistry Notebook Series, A (CH2)n (CH2)n (CH2)n

Didactical Approach,® has a reviewing character and 1 2

it is intended to meet the needs of students debuting
in studies of synthesis, in order to increase their
capabilities to understand in an explicit manner,
synthesis works already published. This discussion
analyzes the article published by Prof. Jin Kun Cha
(former Professor at the University of Alabama at
Tuscaloosa, currently Professor at Wayne University,
Detroit) entitled: Diasteroselective Synthesis of cis-
1,2-Dialkenylcyclopropanols and Subsequent Oxy-
Y
3 H Y
X X
cis-1,2-dialkenylcyclopropanols
An approach to such reaction scheme will take us to
first depict the oxy-Cope rearrangement of cis-1,2-
dialkenylcyclopropanols, leaving the first part of the
scheme (the Kulinkovich reaction) for afterwards. In
this sense the oxy-Cope rearrangement of the cis-1,2-
dialkenylcyclopropanols can be explained as follows:
RO
OR
OR x
H OR

Cope Rearrangement. 1 Oxy-Cope

y
y H y
x H H
x x y
ANALYSIS AND MECHANISTIC PROPOSALS
To better understand this oxy-Cope rearrangement we
Prof. Cha and his collaborators became interested in will review some related examples extracted from the
this subject due to the wide occurrence of literature. The preceding process of the oxy-Cope
hydroazulenic sesquiterpenes and related bicyclic rearrangement is the well-known Cope [3,3]-
natural products.1 The synthesis method chosen by sigmatropic rearrangement of 1,5-hexadienes. 2 A
Cha and col., used the Cope rearrangement of cis- revised version uses a catalytic amount of palladium
divinylcyclopropanes. On such basis they reported the chloride bis(benzonitrile) complex, 3 which avoids the
diasteroselective synthesis of cis- high temperature often required, being thence
dialkenylcyclopropanols (2: R=H and tert- performed at room temperature. An example of this is
butyldimethylsilyl) and subsequent oxy-Cope the treatment of 2-methyl-3-phenyl-1,5-hexadiene that
under palladium catalyst conditions affords the cis and
rearrangement (2 Æ 3). Cha and col. adopted a
trans dienes shown below.
convenient assembly of cis-1,2-
dialkenylcyclopropanols according to the already C6H5
CH3 CH3
C6H5 CH3
published Kulinkovich hydroxycyclopropanation. The H +
global process can be envisaged according to the C6H5

sequence in the following scheme. thermal Cope rearrangement Cl

C6H5CN
Pd C H CN The Pd catalized reaction
6 5
Cl

The oxy-Cope rearrangement of 1,5-hexadienes with a

hydroxyl substituent at C-3 provides, under thermal

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REVISTA BOLIVIANA DE QUÍMICA VOLUMEN 22, No.1 - 2005

conditions, a useful route to δε-unsaturated aldehydes undergoes the oxy-Cope rearrangement to afford the
and ketones. final monoterpene.
O
OH O H O
1 +
3 2 CN OH2 O H
220°C
Cl H2O + Cl-
4
5 6 CN + Cl-
Cl C N +
Cl
- C NH
(1,5)-dienes H
H

+
+H
O + -
If there is an extra hydroxyl group at C-4 of the diene, C
-
N
+
+ Cl- HCN +HCl O Li C CH

1,6-dicarbonyl compounds are produced. Bicyclo[2.2.2]octa-2-ene-6-one

H

- +
- + - + O Li
- + O Li
O O Li + - O Li
OH O H Li AlH4 . . .
o .
3 1 H .. .. Li
H3C 2
190°C Me C CH . + .
Me Me . .
H3C 4
5 6 Me . - Li+ H
.
H
OH O H O o H
H H
+ -
Li Al
H H

E. J. Corey and X. M. Cheng present an illustration of - +

O Li
2H2O
OH
4 OH
Li H oxy-Cope 3
+2OH-+2 Li+
5
the oxy-Cope rearrangement in the retrosynthetic C C
H
C C
H
H H 2

sense thus giving rise to the corresponding oxy-Cope 2 LiOH

H 1

transform. 4 Although this transform does not belong 4

3
OH
H

5
to the most crucial structurally simplifying transforms, 2
H H H o
it can facilitate molecular disconnection through the H 1
H O H H O H

rearrangement of the skeleton. This type of

transforms, effect an essentially unchanged molecular Let us examine now the procedure to effect the
complexity being however useful because they modify Kulinkovich hydroxycyclopropanation which involves
a target structure to allow the subsequent application treatment of a carboxylic ester with an excess (3
of simplifying transforms. A frequent application of equiv) of Grignard reagent at –78° to 0°C in the
such transforms is to generate the retron for some presence of Ti(O-iPr)4 (1 equiv), to afford 1-
other transform that can thus operate to simplify the alkylcyclopropan-1-ols. 5 Among the various
structure.4 The oxy-Cope is a disconnecting but not a experiments of hydroxycyclopropanation by
removing transform. The decalyn-ene-one target Kulinkovich and col., the example followed by Cha
structure can be disconnected by applying first an oxy- and col. consists of a catalytic process of 2 equiv of
Cope transform, followed by a functional group Grignard reagent, 5-10 mol % of Ti(O-iPr)4, ether, at
removing transform. A final disconnecting and 20 °C. This experiment shows the attractive
simplifying Diels-Alder transform finishes the mechanistic loop which involves the “double
retroanalysis. alkylation” of titanocyclopropane intermediate 5 as
H
O shown below.
OH
H O
H
O
Scheme by J. K. Cha et al. 1
o H
RCO2R"
H H R'CH2CH3 R'
2 R'CH2CH2MgX
Cl CN
(i-PrO)2Ti
(i- PrO)4Ti
5 R'
2 i-PrOMgX H

(i-PrO)
R' Ti OR"
The oxy-Cope rearrangement is the last step of the (i-PrO)2Ti
(i- PrO) O
6 R

synthesis which starts with the formation of the Diels- R'

4 R'
H
H R'
Alder adduct from the diene 1,3-ciclohexene and the R"OMgX +
R
dienophile chlorocianoethylene, followed by a R
(i-PrO)2Ti O
XMg O 8 7
nucleophilic substitution of the better departing group OR"
2 R'CH2CH2MgX
Cl- at expense of a water residue. Protonation of the
avid nitrogen of the ciano group generates the
departing of the :CNH+ group and the formation of the To depict this Kulinkovich hydroxycyclopropanation
ketone group. This carbonyl group undergoes a scheme we start with our 2 equiv of Grignard reagent
nucleophilic attack by the basic lithium acetylene. or 2 R’CH2CH2MgX or 2 R’CH2CH2-+MgX. A first
Reduction of the resulting alkyne group by means of interaction occurs between Grignard reagent and the
lithium aluminum tetrahydride and subsequent titanium tetraisopropoxy derivative. Titanium is
hydrolysis affords the gem-hydroxyethylene linked to the four alkoxy substituents. The reaction
substituted bicyclo[2.2.2]octa-2-ene. This intermediate provokes the expulsion of two alkoxy residues to

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REVISTA BOLIVIANA DE QUÍMICA VOLUMEN 22, No.1 - 2005

leave a Ti 2+(IV) (OiPr)2 species. The metal di-cationic carbonium ion) species that neutralizes the charged
charge is used by two carbanions each from 1 equiv of extremes into a substituted cyclopropane or
the Grignard reagent, to obtain a dialkoxy-dialkyl intermediate 7.
titanium derivative (4).
iPrO R H iPrO H C¨ - H iPrO H C ¨- H
2 R 2
Ti OR"
R' Ti Ti
OiPr OiPr OiPr R' + R'
iPrO iPrO iPrO C
Ti +2
2 R'CH2CH2:- +MgX + Ti (IV) -
+ 2 R'CH2CH2: +2 -OiPr
O
OR" O
+
O R
OiPr 6 ¨ OR"
OiPr OiPr
OiPr R'
iPrO OR" H H OiPr H
O Ti
Ti
R' R' OR"
iPrO R
O R R'
R'CH2CH2 CH2CH2R' R' R' R
Ti Ti
(iOPr)2Ti + 2 iPrO- +MgX (iPrO)2Ti O 7

OiPr OiPr OiPr OiPr R' OR"

4

Titanium receives temporarily an extra electron from It is now time for two more equiv of Grignard reagent
an alkyl methylene to afford the Ti-1(IV) and for intermediate 7 to interact to afford species 8,
(iPrO)2(CH2CH2R’) species and the carbonium ion closing thus our looping cycle. This meeting takes
R’CH2CH2+. A reductive nucleophilic attack by the place by means of cationic interchange, or the cationic
anionic titanium leads to the apparition of the moiety of Grignard MgX+ that replaces cationic
titanocyclopropane intermediate (5). Ti+(OiPr)2(OR”) through the temporary apparition of
an anionic oxygen. The remaining Ti2+(OiPr)2 species
R'
H
- H neutralizes the two anionic moieties liberated by the 2
(iOPr)2Ti:
- H
+ CH3CH2R' equiv of Grignard reagent to form two new equiv of
H (iPrO)2Ti R'
+
R' the species 4 to continue the cycle.
4 5

OiPr R'
OiPr H
The next step in this pathway consists of the H
O
- +
Ti + +MgX H
O MgX
OR" + R'CH2CH2-
condensation of intermediate 5 with a carboxylic ester +
MgX + R'CH2CH2
- R
R' R'
RCO2R”. The carbonyl group of this ester drives the R R
R'
XMg O
8
reaction by interacting with the titanocyclopropane in OiPr
OiPr -
2+ + 2 R'CH2CH2 R"OMgX + (OiPr)2Ti
a transition state that implies a co-planarity of both Ti

4 R'
species. A nucleophilic attack by the nucleophile
carbonylic oxygen over titanium dispatches the two
electrons of the bond Ti-CH(R’)(CH2) over that Cha and col. oriented their initial efforts to the
carbon. Hence the titanocyclopropane splits therefore application of this Kulinkovich reaction to the
to afford a carbanion and a cationic oxygen over the cyclopropanation of commercially available methyl-1-
same molecule. A nucleophilic attack over the cyclohexene-1-carboxylate (9). The addition of
carbonylic carbon (with an exacerbated electrophilic EtMgBr or n-BuMgCl in the presence of Ti(OiPr)4
character) leads to the formation of a titanium furanoid under catalytic conditions afforded the expected
ring. cyclopropanols 10a and 10b respectively.

H -
H -
H Scheme by J. K. Cha et al.1
5 C: C:
(iPrO)2Ti R' (iPrO)2Ti R R' O
(iPrO)2Ti
R O
R'
+
R O
R" O
+ HO
O
R" O
O EtMgBr or
R" OMe n-BuMgCl
iPrO R H
Ti
R' Ti(OiPr)4 R1
iPrO
O
OR" 9 10a : R1 = H
6
10b : R1 = Et

An intramolecular nucleophilic attack by the ethereal

oxygen of the α -O-R” substituent group over the However these products did not accomplish the
electrophilic titanium dispatches the two electrons of requirements to effect an ulterior oxy-Cope
the Ti-CH2- bond on intermediate 6 to afford the rearrangement. Hence, the use of
corresponding split species bearing a carbanion and a CH2=CHCH2CH2MgBr was assayed with no success
cationic oxygen, which in turn recovers neutrality by (a mixture of unidentified products was obtained).
splitting the four-membered, di-oxygenated (oxirane- Also, no cyclopropanols could be obtained by the use
type) ring. The result is the dipolar (a carbanion and of (2-(3’furanyl)ethyl))magnesium bromide or 2-
phenethylmagnesium bromide. If the reactions with

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REVISTA BOLIVIANA DE QUÍMICA VOLUMEN 22, No.1 - 2005

these substrates had been successful, this procedure iPrO R H iPrO H

would have provide a one-step synthesis of the Ti
H
R= Ti
H
iPrO if iPrO
required substrates for the subsequent oxy-Cope O
OR"
R" = Me O
:O:
Me

rearrangement.

Scheme by J. K. Cha et al.1

As described above, cyclopropanation comes out as a
R2 = CH2=CH,
result of the intra-molecular nucleophilic attack of the
O
HO TMSCC, methylether residue oxygen over titanium to form an
R2CH2CH2MgBr
OMe
Ph,
3'-furanyl α-methylene carbanion. The 4-membered diether
R2 cycle formed is broken by the methylated cationic
Ti(OiPr)4 or
ClTi(OiPr)3
oxygen which recovers neutrality by means of
capturing one extra electron from a cyclic bond. The
two emerging opposing charges neutralize each other
Let us now focus on a more detailed scope on the
affording the expected cyclopropane.
mechanistic procedure to obtain cyclopropanols 10a
and 10b by Kulinkovich’s hydroxycyclopropanation.
iPrO H iPrO H C¨ - H iPrO H C ¨- H
Following a parallel route to the already examined for Ti
2
Ti
2
OMe
H Ti H + H
the cyclopropanation loop cycle, we confront the iPrO
O
:O:
Me iPrO
O
iPrO
O
C
+
tetraoxyisopropyl titanium derivative with the OMe

OiPr H
currently used Grignard reagent or ethyl magnesium iPrO
OMe
H H OiPr H
O Ti
bromide to obtain a dialkyl-dialkoxy titanium iPrO
Ti
H OMe
O
derivative. H
(iPrO)2Ti O

OMe

iPrO OiPr OiPr

- + Ti +2 -
The substituted titanocyclopropane interacts now with
2CH3CH2: MgX + Ti (IV) + 2CH3CH2: +2 -OiPr
iPrO OiPr OiPr +2 +MgX two additional equiv of Grignard reagents to afford a
CH3CH2 CH2CH3
cyclopropane oxymagnesium bromide.
Ti Ti
(iOPr)2Ti Ti
OiPr OiPr OiPr OiPr iPrO OiPr OiPr
OiPr OiPr
H OiPr H - +
O Ti O Ti + +MgBr
OMe + CH3CH2-
OMe
Again, the titanium intermediate undergoes an H
+ 2EtMgBr
H
+
MgBr + CH3CH2
-

excision to afford a carbonium ethyl and the Ti–1(IV)

species which at its turn experiments an electronic re-
accommodation through an intramolecular oxidative H
H H
(dispatching a hydride) nucleophilic attack by Ti-1 to O MgBr OiPr
OiPr
+ -
+ 2 CH3CH2 MeOMgBr+ (OiPr)2Ti
the methyl extreme carbon. The hydride and the ethyl H
2+
Ti

carbonium neutralize mutually. BrMg O

H - H A protic medium as pure water is sufficient to destroy

- H H
(iOPr)2Ti:
+ CH3CH3
+
H (iPrO)2Ti H this magnesium bromide derivative (a kind of
Grignard r.) to afford cyclopropanol 10a.

H
Let us consider now the condensation of the H H
HO
H HO
titanocyclopropane derivative with a carboxylic ester, +
H (H2O)
HOMgBr +
which our case corresponds to compound 9. The result
BrMg O
is the furane-type cycle titanium derivative. OH 10a

The cyclopropanol 10b can be obtained by the use of

H
H -
H -
C:
n-BuMgCl containing Ti(OiPr)4. The mechanistic
C:
(iPrO)2Ti R H
(iPrO)2Ti
R O
H (iPrO)2Ti
+
R O H
R" +
O
proposal remains identical to the one already proposed
R" O
O O
for 10a as follows.
R"

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REVISTA BOLIVIANA DE QUÍMICA VOLUMEN 22, No.1 - 2005

unprotected for both protecting groups (TIPS and

iPrO OiPr OiPr
- + Ti +2 THP).
2 CH3CH2CH2CH2: MgCl + Ti (IV) + 2 CH3CH2CH2CH2: -
+2 -OiPr
OiPr OiPr +
+2 MgCl Scheme by J. K. Cha et al.1
iPrO
MgCl
R 3O
HO HO
11a : R3 = TIPS
11b : R3 = THP
iPrO OiPr OiPr 9
- + Ti +2
ClTi(OiPr)3
2 CH3CH2CH2CH2: MgX + Ti (IV) + 2 CH3CH2CH2CH2:- +2 -OiPr
OiPr OiPr
iPrO
14
OR3
CH3CH2CH2CH2 CH2CH2CH2CH3
Ti Ti 12a : R3 = TIPS (77% for 11a;
OiPr
(iOPr)2Ti Ti TBAF (75%) 12b : R3 = THP 46% for 11b)
OiPr OiPr OiPr iPrO OiPr or PPTS
(60%) 13 : R3 = H
O
- H
(iOPr)2Ti:
- H H 1. Swern oxidation
+ CH3CH2CH2CH3 + OMe
H (iPrO)2Ti Et 2. TBSOTf, Et 3N
+
OR4

H R4O
H H -
- C:
C:
(iPrO)2Ti R Et
D, PhH
(iPrO)2Ti Et (iPrO)2Ti R O Et
R O +
+ R" O
R" O (76-81%
O O H
TBSO from 13) OTBS
R"
iPrO H iPrO H 15a : R4 = TBS 16a : R4 = TBS
R
Ti R= Ti
15b : R4 = MeSCH2 16b : R4 = MeSCH2
Et Et
iPrO if iPrO
O R" = Me O Me
OR" :O:

R3O
12a : R3 = TIPS
OMe
iPrO H C¨ - H iPrO H C ¨- H iPrO H H 12b : R3 = THP
2 2 H TIPS: triisopropylsilyl Si
OMe O H
Ti Ti
Ti Et + Et Et
iPrO iPrO C iPrO
O O O
+
OMe THP: Tetrahydropyranyl
H O
OiPr OR3
Et O
H OiPr H
O Ti
- +
OMe + 2CH3CH2CH2CH2: MgCl
All mechanisms for protection or removal of the
(iPrO)2Ti O installed protective group, are nucleophilic
OMe
substitutions taking place over the electrophilic
OiPr
H
OiPr
OiPr H +
OiPr oxygenated carbon bearing the hydroxyl group (if
- Ti + +MgCl
O Ti O
OMe
OMe + CH3(CH2)3- protecting) or the silyl or tetrahydropyranyl group (if
+ 2BuMgCl +
MgCl + CH3(CH2)3
-
removing the protective group). Let us examine the
protection mechanism by TIPS first. TIPS is bonded to
Et
a leaving group (LG) besides the three isopropyl
H H
O MgCl OiPr groups. A nucleophilic attack by the alkoxy group
+ OiPr
Et
2+
Ti + 2 CH3CH2CH2CH2- MeOMgCl
+(OiPr)2Ti over silicon provokes the departure of the leaving
ClMg O group. The conditions of the protective reaction must
be taken into account in order to prevent the
Et
environment from protic species to avoid damaging
H Et
H HO HO the magnesium chloride moiety of the Grignard
+
H (H2O)
HOMgCl + reagent.
Et Et
ClMg O
OH
10b iPr iPr
Si - +
iPr HO CH2: Mg Cl
iPr + - + LG
-
LG iPr + iPr O CH2: Mg Cl +
Disappointed by these results Cha and col. employed H
a 4-alkoxybutyl Grignard reagent.
iPr
Reagents 11a,b (see scheme by Cha and col. below)
iPr - +
originated the desired cyclopropanols 12a,b in 77% iPr O CH2: Mg Cl + LGH

and 46% respectively. The mechanistic approach is

identical to that already extensively explained to The reaction for uninstalling the protecting group to
obtain of 10a,b out of compound 9. regenerate the alcohol function, in the protected
Removal of the protective group provided alcohol 13 product (12a) or the cyclopropane derivative that
as a single isomer. The hydroxyl function of the 4- evolves (by expelling the protecting group) to
alkoxy Grignard reagent can be set as protected or cyclopropanol, implies the use of TBAF (tetra-n-
butylamine fluoride) or PPTS.

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REVISTA BOLIVIANA DE QUÍMICA VOLUMEN 22, No.1 - 2005

difficulty being finally circumvented by the

H
O H H application of a Swern oxidation of alcohol 13 or the
H Me O H
Me formation of the silyl enol ether. Subsequent treatment
+
N N
+ + H3O +
+
+ +
with TBSOTf and triethylamine afforded almost
O
iPr
Si +
H2O iPr
O exclusively the (Z)-silyl enol ether 15a (J = 5.9 Hz)
iPr O S O Si
iPr
12a
PPTS O
-
O S
-
O
iPr
iPr
along with a small amount of 15b.1 Swern oxidation
O
(pyridinium-p-toulensulfonate) consists of oxidizing primary and secondary alcohols
to aldehydes an ketones by action of a base on the
H
O
OH
H
O H
H
O H derived alkoxysulphonium salt. 6 7 The conditions of
+ PPTS
reaction are mild and high yields of carbonyl
H2O
O
+ + O
compounds are generally obtained. One of these
iPr O N
iPr
Si H H H H 13 procedures involved reaction of the alcohol with
iPr +
HOSi(iOPr)3 dimethyl sulphoxide and dicyclohexylcarbodiimide in
the presence of a proton source.7 8 The mechanism of
With respect to the protecting by using THP, the use the reaction involves initial formation of a sulphoxide-
of a Lewis acid catalyst can be envisaged to promote a carbodiimide adduct which reacts with the alcohol to
nucleophilic attack by the protective group give the alkoxysulphonium ion. This then undergoes
tetrahydropyrane (here the protecting procedure proton abstraction to form an ylid which collapses into
implies attacking the electrophilic oxygenated carbon the aldehyde and dimethyl sulphide by an
of the alcohol function under catalysis by Mg). Mg2+ intramolecular concerted process. This process can be
from Mg Cl2 can be mixed with the magnesian visualized by the oxidation of the sensitive natural
Grignard reagent thus avoiding a destructive protic product 3’-O-acetylthymidine.
catalyst. The resulting protected 4-alkoxy-n-butyl
O
magnesium bromide, acquires a double cationic CH3 dicyclohexylcarbodiimide
H C6H11
N̈ H11C6
character that can be neutralized by the two chloride H
¨
N CH3
N C N + -
N
C
N
O H B ¨
anions. This, however, can hinder its solubility. O
HO + O:
+
O
O
HO H S
Tetrahydropyrane thus displaces the better leaving ¨H Me
S
Me Me Me
3'-O-acetylthymidine DMSO
MgClOH species.
O
H C6H11 O CH3
H11C6 CH3 H C6H11
N N H11C6 N
¨ C N̈ N N N CH3
Cl
- O N¨ CH3 C H
MgCl 2 + - + O O
HO CH2: Mg Cl Mg H - + +
+ - + +
HO
O O O O
Cl O CH2: Mg Cl S H O
Me Me O + HO H
O Me s ¨H
HO H Me
H ¨H

H O
OH CH3
Cl
- Kulinkovich H
+ H C6H11 H C6H11 N
O - + H11C6 H11C6 N H CH3
CH2: Mg Cl + MgClOH N N N N H NEt 3
C C + O
H O
O
+ O H O O
Cl O HO
- + H
12b Me s H
Me

O
CH3
Removal of the tetrahydropyrane moiety from the N H
N CH3
cyclopropane derivative (12b) can be achieved by H
O B
-
+
adding TBAF to the solution containing 12b to O + N HEt 3 NEt 3 + BH
O
O
generate the alcohol 13. HO H + Me2S
H

H H Applying this reaction mechanistic scheme to our

OH OH
+ + -
N (C4H9)4F + H2O - +
OH + FH + N (C4H9)4Cl
-
+
O
Kulinkovich product (alcohol 13) to oxidize it
TBAF H TBAC
OH according to Swern, we obtain the following pathway.
+
O O
-
Cl H
13
+
12b O
H11C6
C6H11 H
H11C6 C6H11
N C N + -
¨-
N N N C N
H B H
¨ C O ¨ + OH
+ S
O: O Me
Unfortunately, several attempts by Cha and col. to S
Me
HO
Me Me S
Me Me
convert 13 into olefin 14 were unsuccessful, a 13

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REVISTA BOLIVIANA DE QUÍMICA VOLUMEN 22, No.1 - 2005

H H
H C6H11
H
OH OH OH The obtained compound was azulene 19 in 53 %
H11C6
N
C
N
H
N̈Et3 overall yield by means of cyclopropanol 181 (a similar
+ H H NEt 3
H
O
-
+ O H mechanistic approach to the one already developed
H O + O
+ S Me
S Me
Me
- +
+ B HN Et 3 + SMe2
until now can be applied to 17 by the reader).
Me

The sylil enol ether is obtained through a nucleophilic Scheme by J. K. Cha et al. 1
1. TBAF
attack by the quaternary ammonium salt from which R 3O
MgCl
2. Swern Oxid.
OTBS
11a : R3 = TIPS HO 3. TBSOTf, Et 3N
the enol nucleophile interacts over tri-ter-butylsilyl- CO2Me 4. Δ, PhH
ClTi(OiPr)3
oxy-triflate (TBSOTf) replacing the -OTf group. (53%)
(60%)
H
17 OTBS
O CF3 OTIPS 19 : R4 = TBS
S HOSO2CF3
Si O O

H H
¨
O H OR4 Once developed a convenient synthetic method for
O CF3
Et 3NH O
+ - S fused bicyclic systems 16a and 19, Cha and col.
Si O O
H O
(tBu)3Si
H +
+ N HEt 3 OSO2CF3
-
examined subsequent elaborations of the
H H
TBSOTf cycloheptadiene functionality. Simmons-Smith
15a: R4 = TBS cyclopropanation (CH2I2, Et2Zn) of 16a gave
cyclopropane 20 as a single diastereomer (75%). 9
Simultaneously, the other hydroxyl moiety is replaced
by a tri-ter-butylsilyl ether extremity to afford Scheme by J. K. Cha et al. 1

derivative 15a. The Z stereochemistry of the enol ether 1. H2, Pd/C

OTBS (95%) O
double bond could be established by the protons’ Et2Zn
2. HF Me
CH2I2 MeCN/H2O
coupling constant of 5.9 Hz. At this stage the PhH (73%)
16a
apparition of a synthetic companion (15b) could be (75%)
explained by the formation of the species H H
OTBS OH
methylmethylene carbonium sulphide. In a 21
20
competitive
process to the protection of the hydroxyl moiety, this This reaction (S-S) is widely used for the synthesis of
could be distracted by a electrophilic species other cyclopropane derivatives from alkenes by reaction
than the protecting group TBSOTf namely a with methylene iodide and zinc-copper or, better, zinc-
methylmethylene carbonium sulphide. silver couple. This valuable method permits to not to
δ
-
affect many functional groups when forming the
H
H
H SCH3
H
H
H SCH
3 H
H SCH
3 cyclopropane moiety. 10 11 Stereo-specifically, cis-
O + H O
δ O
H H
- +
H -
H addition of methylene to the less hindered side of the
+ H
+ H2
O H O H
(tBu)3SiO H
double bond occurs. The reactive intermediate is
(tBu)3Si (tBu)3Si
H H
H
believed to be an iodomethylenezinc iodide complex
15b
which reacts with the alkene in a bimolecular process
to give a cyclopropane and zinc iodide. When a
A nucleophilic attack over a carbon of dimethyl neighboring hydroxyl group is present (allylic or
sulphide is conceivable due to the positive polar homoallylic alcohol or ether) in 5- or 6-membered
attraction of this carbon itself developed by the rings, the product with a cis-cyclopropane to the
electronegative sulfur. The strongly basic hydride hydroxyl group is formed stereo-specifically. The
dispatched is immediately compensated by the acid H+ transition state involves a co-ordination of oxygen to
escaped from the acidic oxygen of the now DMSO+H the zinc with subsequent transfer of the methylene
moiety. Next in the reaction is the advent of the oxy- group to the nearer face of the adjacent double bond.10
Cope rearrangement of the adducts 15a and 15b when As an example of the S-S reaction let us evoke the
heated at reflux in benzene. The enol ethers underwent following reaction.
the oxy-Cope rearrangement to provide bicyclic
cycloheptadiene 16a (72% overall yield from 13) and Scheme by W. Carruthers 10
16b (4%).1 The mechanistic view for the oxy-Cope
CH3 CH3
rearrangement was exposed at the beginning of this
paper (first page). Cha and col. tried the identical CH2I2, Zn-Cu

synthetic sequence on methyl 1-cyclopentene-1- ether

OH OH
carboxylate (17).

17
REVISTA BOLIVIANA DE QUÍMICA VOLUMEN 22, No.1 - 2005

The intermediate iodomethylenezinc iodide complex
that reacts with the alkene can be described as follows.
Scheme by W. Carruthers 10
Zn I Zn
cyclopropane moiety will be formed also in an α
position. The stereochemical assignment was firmly
established by Cha and col. on the basis of the NOE
difference experiment.
I

H2C CH2 + ZnI2

+ Zn
+2
2 -CH2CH3 + CH2I2 H2C: + I. + I. 2 I.
+
2I + 2e
- +2
Zn + 2 e
-
Zn°
I
I

2 -CH2CH3 + 2 I+ 2 I+ -CH2CH3 2 ICH2CH3 2I. + 2 .CH2CH3 2CH3CH2CH2CH3

As a surface catalyst, the Zn offers to the medium

avilable unpaired electrons which will incite ..I
Zn
.
2I. + CH 2: + Zn: .
homolytic excision of covalent bonds in CH2I2. CH2
..
I
H H OR OTBS
I Zn . .I Zn . .I OR H RO
Zn . H
. .C. I..I + :CH2 +Zn:
. H . . .I
I H I + ZnI2
H H
RO
RO R : TBS I
Zn RO H
H
..I Zn I H . H Zn
I
I OTBS
Zn . . Zn I H
. I
. C. . 20
I. + I. +Zn: + :CH2 + CH2 .
CH2 I
.. H
I
I
The derivative 21 was obtained by treatment with
H
. .. C
+
Zn
+ ZnI2
H2/Pd, to saturate the only remaining double bond,
. I I
H and subsequent oxidation by HF (MeCN-H2O) to
afford the ketone function. Removal of the OTBS
For the 6-membered cyclic system we can picture the protecting group by an acid agent followed this partial
corresponding transition state as the one developed by stepwise procedure.
coordination of Zn with the allylic alcohol hydroxyl
RO
function thus defining the formation of the RO RO

cyclopropane moiety also in a β position (just as the H H2

.
. .
.
Pd
Pd . . .
OH group position). RO H
Pd
RO .
.
.
.
.
. RO .
.
.
.
.
H . H . H
H H H. H. H H
R:TBS H. H.
20
I
CH3 CH3 CH3 CH3
CH3 CH3 Zn I
H2C CH3

RO RO H
. RO
OH OH OH H.
H3C H3C H3C OH H
. .
H H H H H H .
. Pd
Pd
H H + H2 + Pd°
. . . . . .
RO . . . RO . . . RO
H
H H . H
. . . H
. H .H
Applying these mechanisms to 16a, we obtain its H H H

cyclopropanation by Simmons-Smith or compound 20.

tBu
O O O
Si O Me
tBu tBu
tBu + - Me tBu
H F Me +F Si
OTBS + -
H F + F Si
Et 2Zn O O tBu tBu
RO tBu tBu tBu H H
CH2I2 R:TBS
H H OH
H tBu tBu
PhH 21
16a
(75%)
H Next in this structural elaboration by Cha and col., the
OTBS
20 treatment of 16a with dichlorocarbene to afford
In this reaction, Zn appears as Zn2+, thus we must dichlorocyclopropane 22 was reported. Hydrogenation
reduce this oxidized state by means of procuring 2 on Pd of 22 and subsequent submission to silver
electrons. Iodomethylene affords carbene and two nitrate (in aqueous acetone) gave rise to a 1 C ring
iodine atoms which can oxidize to afford two expansion or ketal 23. In a parallel reaction , they
Scheme by J. K. Cha et al. 1
electrons. The two cationic iodine atoms neutralize
with carbanion species from diethyl zinc (II). The Zn° Cl 1. H2, Pd/C
OTBS
OTBS (100%) Cl OTBS
species thus obtained can act catalytically when Cl3CCO2Et Cl H
2. AgNO3
NaOMe Me2CO/H2O
adding carbene to the corresponding double bond 16a
(99%) (70%) O
following the already exposed mechanism. The H
H H
coordinating agent (Zn), acts in this case with a TBSO OTBS OTBS
23 24
group situated in an α position (equatorial), thus 22

giving rise to a transition state that involves a obtained a full reduction of unsaturated bonds or
homoallylic alkoxy group. As expected, the compound 24. A variety of methods is available for

18
REVISTA BOLIVIANA DE QUÍMICA VOLUMEN 22, No.1 - 2005

the generation of carbenes. 12 Accordingly, PhHgCl. The already existing trichloromethane

dihalogenocarbenes can be obtained by action of a carbanion as already mentioned, came out not from
base on a haloforme or also by the halophenylmercury the haloform/potassium ter-butoxide couple, but in our
compounds PhHgCXYZ (X, Y, Z = halogens). Such case from the trichloroacetic ethyl ester residue as
compounds can be prepared from phenylmercury (II) shown above. Following the mechanism described
halide interacting with haloform and potassium t- above for the interaction between the carbanion and
butoxide as follows. the phenylmercury halide we obtain the following.

- + -1 +2 -1
-1 Cl3C: Na + Ph Hg Cl PhHgCCl3 + NaCl
PhHgX Ph
-1
Hg
+2
X
-1
+ X3C H + tBuO
-1
+ K+1 X3C: K+1 + tBuOH

CL Cl
-1 +2 -1
Cl -1 +2 -1 -1 +2 -1 -1 +2
-1 +1 Ph Hg Cl + :CCl 2
X3C: K + Ph Hg X PhHgCX3 + KX + tBuOH Ph Hg Ph Hg C CL3 Ph Hg C Cl2
CL

This type of compounds are source of The addition of dichlorocarbene to the double bond
halogenocarbenes, according to a mechanism that occurs from an α position to afford the corresponding
involves the moving of a bromide from carbon of the α-gem-dichlorocyclopropane moiety. The α position
haloform moiety to mercury, passing by a transitory of this is obliged by the very hindering β-oriented
mercurobromocarbon tricycle. The transitory state OTBS group.
collapses into a phenylbromomercury adduct and the
expected dibromo carbene.12 OR
H
OR OR RO Cl
Cl
OTBS
H H
Cl
. .
..
Br Br . .
RO C RO C RO ROCl
Br R : TBS H
-1 +2 -1 -1 +2 -1 -1 +2 H Cl
Ph Hg Ph Hg C Br3 Ph Hg C Br2 Ph Hg Br + :CBr2 H Cl Cl Cl H ClCl H OTBS
Br 22
16a

Hypothetically, by using this method, The next transformation is a hydrogenation of

dichlorocarbene could be obtained from the chlorine compound 22 by means of Pd catalyst and a ring
source trichloroacetic ethyl ester. This may take the expansion of it by means of application of silver
place of the haloform. The alkaline alkoxide or nitrate in aqueous acetone to afford compound 23. The
sodium methoxide in this case, acts more as a cationic silver replaces the tri-ter-butylsiliconium ion
nucleophile than as a base in contrast with the role thus generating a silver salt. The anionic oxygen thus
attributed to potassium ter-butoxide as shown above. generated provokes an intramolecular nucleophilic
The competitiveness to go out of the two potential attack over the electrophilic oxygenated carbon
leaving groups after insertion of the methoxy group supporting the protecting group or C-OTBS. As a
over the carbonyl, namely a trichloromethane result, the ether-bridge-containing bicycle is formed.
carbanion and the ethoxy group, is assumed to be The chloride anion is neutralized by thesilver cation.
comparable. The collapse of the negatively charged
oxygen of the sodium salt intermediate into a carbonyl RO H RO H
RO +
Ag NO3
-
RO
Cl Cl Me2CO/H2O
Cl Ag
group could generate on one hand a trichloroacetic H2/Pd Cl Cl
O Cl
O
+
-
O3N

tBu
methyl ester, and/or a trichloromethane carbanion and H
RO Cl
ROCl
H
H
tBu
Si
tBu
H
Si
tBu
tBu
R : TBS H H tBu
a very stressed di-oxygenated carbonyl compound on 22

the other, which must forcefully decarboxylate to give

RO
CO2 and ethylmethyl ether. RO
H
Cl
OR
Cl Cl
- +
Cl- + + NO3 tBu3Si + AgNO3
O Ag O
MeO H R : TBS O
O O H
Cl 3C O + MeO
-1
+ Na +1 Cl3C O H H H
H3C
23
- +1 O
O O Na

- +
Cl 3C: Na + CO2 + CH3OCH2CH3
Cl 3C O
CH3
ACKNOWLEDGEMENT
- +
+ EtO Na
O
The author expresses his gratitude to Prof. Eduardo
Palenque from the Physics Department, Universidad
Thence to go ahead on the generation of the
Mayor de San Andrés, for his bibliographic support.
dichlorocarbene, the use of Hg 2+ must be supposed.
The species to be added to generate a halophenyl
mercury (PhHgCXYZ) is a phenylmercury halide,

19
REVISTA BOLIVIANA DE QUÍMICA VOLUMEN 22, No.1 - 2005

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1
J. Lee; H. Kim; J. K. Cha, J. Am. Chem. Soc., 1995, 117, 9919.
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W. Carruthers, Some Modern Methods of Organic Synthesis, Cambridge University Press, 3rd ed., 1987,
Worcester, U.K., pp. 175-176.
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L.E. Overman, A. F. Renaldo, Tetrahedron Lett. 1980, 24, 3757.
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E .J. Corey, X-M Cheng, The Logic of Chemical Synthesis, John Wiley and Sons, Inc., 1989, New York,
U.S., pp 9-13
5
O. G. Kulinkovich, S. V. Sviridov, D. A. Vaasilevskii, T. S. Pritytskaya, Zh. Org. Khim., 1989, 25, 2244.
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W. Carruthers, Some Modern Methods of Organic Synthesis, Cambridge University Press, 3rd ed., 1987,
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W. W. Epstein, F. W. Sweat, C hem. Rev., 1967, 67, 247.
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J. Furukawa, N. Kawabata, J. Nishimura, Tetrahedron, 1968, 24, 53.
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W. Carruthers, Some Modern Methods of Organic Synthesis, Cambridge University Press, 3rd ed., 1987,
Worcester, U.K., pp. 95-96.
11
H. E. Simmons, T. L. Cairns, S. A. Vladuchick, C. M. Hoiness, 1973, Organic Reactions, 20, 1.
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W. Carruthers, Some Modern Methods of Organic Synthesis, Cambridge University Press, 3rd ed., 1987,
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11