MAGNESIUM

1

Magnesium

1

Mg

[7439-95-4]

Mg

(MW 24.31)

InChI = 1/Mg
InChIKey = FYYHWMGAXLPEAU-UHFFFAOYAI

(formation of organomagnesium compounds; reduction of metal

halides; reduction of organic functional groups)

Physical Data:

mp 651

◦

C; bp 1107

◦

C; d 1.74 g cm

−3

.

Preparative Methods:

widely commercially available in forms

(most commonly turnings and powders) and in purity (98–
99.95%) suitable for many applications in organic synthesis.
For some applications magnesium powder or activated mag-
nesium is freshly prepared via the reduction of a magne-
sium(II) salt or the evaporative deposition of magnesium metal.
The commercially available magnesium–anthracene adduct
[86901-19-1]

also provides a highly reactive form of magne-

sium metal.

Handling, Storage, and Precautions:

most freshly prepared

magnesium powders and organomagnesium compounds are
pyrophoric.

Original Commentary

James M. Takacs
University of Nebraska-Lincoln, Lincoln, NE, USA

Formation and Reactions of Organomagnesium Com-

pounds. The carbon–carbon bond forming reactions of organo-
magnesium (Grignard) reagents via their reaction with carbon
electrophiles constitute one of the cornerstones of organic synthe-
sis (eq 1). Much is known about this most famous of organometal-
lic reactions. The mechanisms of Grignard formation

2

–

13

and

reaction

14,15

have been studied extensively. Structural

16,17

and

thermochemical

18

data of the organomagnesium compounds have

been reported.

RX

+

Mg

E

+

RE

(1)

[RMgX]

Many novel organomagnesium compounds have been prepared.

These include dimetallic species

19,20

such as methylenedimag-

nesium dibromide (see also Magnesium Amalgam)

21

and 1,n-

(dimagnesio)alkanes such as 1,4-bis(bromomagnesio)pentane, an
intermediate which has been used for the stereoselective conver-
sion of esters to trans-1,2-disubstituted cyclopentanols (eq 2).

22

Remarkably, even a soluble trimagnesium compound was recently
prepared under relatively routine reaction conditions (eq 3).

23

96% trans

OH

MgBr

MgBr

(2)

+

MeCO

2

Et

77%

Br

Br

Br

BrMg

MgBr

MgBr

(3)

Mg

The form of the magnesium metal employed is often criti-

cal to the successful formation of the organomagnesium reagent.
For simple primary or secondary alkyl bromides or iodides, and
simple aryl or vinyl bromides or iodides, commercially available
magnesium turnings or powders of modest purity (>98%) are
often suitable. If necessary, activating the surface of the mag-
nesium with iodine,

1,24

dibromoethane,

1,25

or ultrasound

26

treat-

ment, or employing ultrapure magnesium metal,

27

is usually suffi-

cient to facilitate Grignard reagent formation with such substrates.
In the case of many organochlorine or organofluorine compounds,
as well as unreactive bromides and iodides, a more reactive form
of magnesium must be employed. Three practical methods have
been developed for the preparation of highly reactive magnesium
(active magnesium) for use in organic synthesis. A highly re-
active magnesium slurry is prepared via the evaporative depo-
sition of magnesium in THF using a relatively simple prepara-
tive apparatus.

28

–

30

Magnesium halides are reduced by Potas-

sium metal,

31,32

or better Lithium Naphthalenide,

33,34

to afford

an active magnesium powder often referred to as ‘Rieke mag-
nesium’. Magnesium metal can be activated by treatment with
anthracene,

35

or the magnesium–anthracene adduct,

36

which is

in equilibrium with the finely divided metal powder, can be used
directly.

The formation of allyl or benzylic Grignard species is often

accompanied by dimerization of the allylic or benzylic halide. In-
deed, this reductive dimerization can be preparatively useful using
the classical Grignard-forming reaction conditions,

37

but to avoid

it, an active magnesium is typically employed.

38,39

Oppolzer

40

reported a comparison of the three methods discussed above in a
1984 study of the metallo–ene reaction. The magnesium variant of
the metallo–ene reaction

41

features the formation and subsequent

cycloisomerization of an allylmagnesium chloride from an al-
lylic chloride. As shown in eq 4, magnesium-mediated cyclization
and trapping with the electrophilic oxygen source Oxodiperoxy-
molybdenum(pyridine)(hexamethylphosphoric triamide) (i.e.
MoOPH) proceeds in 55% yield with magnesium slurry prepared
by evaporative deposition, in 55% yield with Rieke magnesium,
and in 56% yield with magnesium–anthracene.

Cl

(4)

OH

1. Mg*, –65 °C

2. MoOPH

55–56%

The extent to which these activated forms of magnesium have

expanded the range of substrates suitable for formation of organo-
magnesium species cannot be overemphasized. For example,
alkyl fluorides are very poor substrates for the classical Grignard
conditions. In contrast, treatment of octyl fluoride with Rieke
magnesium

32,34

affords the corresponding organomagnesium

reagent which reacts with Carbon Dioxide in 89% yield (eq 5).
The chloride shown in eq 6 is benzylic, thus prone to dimeriza-
tion with classical magnesium sources, and requires formation
of a dianionic intermediate. Magnesium powder is reported to

Avoid Skin Contact with All Reagents

2

MAGNESIUM

afford the diorganomagnesium species in only 43% yield. In con-
trast, the dichloride reacts with magnesium–anthracene in 92%
yield.

36,42

Cyclopropylmethyl compounds are prone to rearrange

via ring opening to the n-butenyl isomers. Formation of the Grig-
nard reagent from cyclopropylmethyl bromide under classical
conditions followed by trapping with carbon dioxide affords 4-
pentenoic acid (eq 7). In contrast, treatment of cyclopropylmethyl
bromide at −78

◦

C with the magnesium slurry prepared via evap-

orative deposition affords mostly cyclopropylacetic acid (92% of
the product mixture, 78% yield) after trapping with carbon
dioxide.

28

C

8

H

17

F

[C

8

H

17

MgF]

CO

2

C

8

H

17

CO

2

H

(5)

Mg*

89%

Cl

Cl

ClMg

MgCl

(6)

Mg*

92%

Br

MgBr

MgBr

CO

2

H

CO

2

H

(7)

Mg*

–78 °C

92:8

+

The chemistry of organomagnesium compounds is extraordi-

narily rich and diverse. It is impossible to detail comprehen-
sively their many reactions with classical organic electrophiles
(e.g. aldehydes, ketones, carboxylic acid derivatives, carbon diox-
ide, C–N multiple bonds, epoxides, alkyl halides, etc.) within the
space limitations here. Fortunately, several standard texts give a
good account of these procedures.

43,44

The following paragraphs

highlight several of the many less routine uses of these reagents.
For example, in addition to the reaction with traditional carbonyl
electrophiles, organomagnesium reagents add efficiently to cer-
tain mixed orthoformates to afford acetals. For example (eq 8),
n

-butylmagnesium bromide adds to phenyl diethyl orthoformate

in 90% yield.

45

BuMgBr

+

PhOCH(OEt)

2

90%

(8)

BuCH(OEt)

2

The one-pot combination of alkyl halide, magnesium metal,

and carbon electrophile is often referred to as the Barbier
reaction.

46

This strategy is particularly appropriate for the cy-

clization of substrates containing both reacting partners within
their structure. The intramolecular reaction of halo ketones can
afford cyclized products, but often in only modest-to-good yield
with magnesium.

47

For example (eq 9), the cycloheptanone

derivative cyclizes to the hydroazulene ring skeleton in 54%
yield. Lithium/ultrasound,

48,49

Lithium, Tin(II) Chloride,

50

and

Samarium(II) Iodide

51

may offer suitable alternative reagents for

such cyclizations.

(9)

Mg

O

I

OH

H

cis

:trans = 8:1

54%

The complementary magnesium-mediated cyclizations of

cyanoiodoalkanes can be an efficient reaction. For example,
the iodonitrile shown (eq 10) undergoes magnesium-mediated
cyclization to form the relatively sterically congested 2,2-
disubstituted cyclohexanone in 71% yield.

52

(10)

Mg

O

i

-Pr

i

-Pr

I

NC

Et

2

O

71%

Magnesium is an alternative to zinc metal for effecting the Re-

formatsky reaction and has been used in the synthesis of β-keto
esters.

53

For example (eq 11), t-butyl bromoacetate is condensed

with cyclohexanone in 80% yield.

54

O

O-t-Bu

O

Br

+

OH

O-t-Bu

O

(11)

Mg

Et

2

O

80%

Organomagnesium species can effect the carbometalation of

alkenes and alkynes.

55,56

The more common variants, however,

are the copper-catalyzed reactions, a subject which has been com-
prehensively reviewed by Lipshutz and Sengupta.

57

For exam-

ple (eq 12), the Ethylmagnesium Bromide/Copper(I) Bromide
combination effects net syn addition across 1-octyne. The result-
ing alkenyl metal species can be stereospecifically trapped by a
variety of electrophiles, including Allyl Bromide (85%) and 1-
heptene oxide (94%).

58

This reaction constitutes a useful stereos-

elective alkene synthesis. Dichlorobis(cyclopentadienyl)titanium
also catalyzes the net syn addition of organomagnesium reagent
across alkynes.

59

(See also the corresponding organolithium and

organocopper compounds for alternative reagents.

57

)

(12)

Cu(SMe

2

)MgBr

2

H

C

6

H

13

Et

Et

C

6

H

13

E

H

1. CuBr(SMe

2

)

2. C

6

H

13

C

≡CH

E

+

E = CH

2

CH=CH

2

(85%)

CH

2

CH(OH)C

5

H

11

(94%)

EtMgBr

Organomagnesium reagents undergo efficient copper-catalyzed

conjugate addition reactions.

57

For example (eq 13), n-

butylmagnesium

bromide

undergoes

CuBr–Me

2

S-catalyzed

addition to acrolein in the presence of Chlorotrimethylsilane and
Hexamethylphosphoric Triamide (HMPA) to afford the (E)-silyl
enol ether in 89% yield (96% E).

60

(13)

BuMgBr

+

O

Bu

OTMS

H

H

5 mol % CuBr(Me

2

S)

2 equiv TMSCl

2 equiv HMPA

THF, –78 °C, 3 h

89%

96% E

Organomagnesium reagents undergo copper-catalyzed reaction

with alkyl, allyl, vinyl, and aryl halides or sulfonates, and with

A list of General Abbreviations appears on the front Endpapers

MAGNESIUM

3

epoxides.

57

For example (eq 14), n-butylmagnesium bromide un-

dergoes copper-catalyzed substitution of the propargyl methyl
ether to afford an allene.

61

The substitution proceeds in high chem-

ical yield and with good stereochemical control.

OMe

Bu

(14)

Bu

H

•

H

Bu

5 mol % CuBr–2Bu

3

P

THF, –78 to 5 °C

100%

BuMgBr

+

90% ee

A number of other transition metals catalyze interesting reac-

tions of organomagnesium reagents.

59,62

Of particular novelty is

the titanium-catalyzed hydromagnesiation of alkenes. For exam-
ple (eq 15), vinylcyclohexanol transmetalates with ethylmagne-
sium bromide in the presence of catalytic Cp

2

TiCl

2

to afford, after

capture by carbon dioxide, the γ-lactone shown in 58% yield.

63

–

65

(15)

1. EtMgBr
Cp

2

TiCl

2

O

O

HO

2. CO

2

Reductions with Magnesium.

Magnesium is a common

agent for reducing a variety of transition metal salts,

66

–

68

for ex-

ample the reduced titanium reagent (Titanium(IV) Chloride–Mg)
used widely in carbonyl coupling reactions.

69

Magnesium itself

effects the reductive dimerization (pinacol coupling) of ketones

70

and enones

71

(see also Magnesium Amalgam and TiCl

4

–Mg).

Magnesium effects the reductive dimerization of organotin
oxides

72

(eq 16) and dialkylantimony bromides (eq 17).

73

(16)

Mg, THF

82%

(i-Bu)

3

SnOSn(i-Bu)

3

(i-Bu)

3

SnSn(i-Bu)

3

(17)

Mg, THF

2 Bu

2

SbBr

Bu

2

SbSbBu

2

Magnesium has been used for the reduction of 1,1-dibromo-

alkanes,

74

although reductive dimerization has been found to com-

pete in some cases,

75,76

and in the formation of Ph

3

P=CCl

2

from

triphenylphosphine and carbon tetrachloride.

77

Magnesium has

been used as an alternative to n-Butyllithium or lithium amalgam
for the conversion of 1,1-dibromoalkenes to alkynes (eq 18).

78

RCHO

Ph

3

P

RCH=CBr

2

(18)

Mg, THF

RC

≡CH

CBr

4

65 °C

75–95%

Magnesium reacts with amines to form magnesium amides,

79

and with alcohols to form magnesium alkoxides. In the latter
context, magnesium has been used as a drying agent for alcohols,

80

but the combination of magnesium–methanol has also found
significant utility as a selective reducing agent for certain or-
ganic functional groups (e.g. conjugated ketones, esters, nitriles,
amides).

81

The combination of Cadmium Chloride–magnesium

in aqueous THF also shows interesting selective functional group
reductions, e.g. the selective 1,2-reduction of enones (eq 19) and
the selective reduction of an epoxide in the presence of an allylic
acetate (eq 20).

82,83

(19)

CdCl

2

, Mg

aq. THF

O

OH

25 °C, 15 min

95%

(20)

CdCl

2

, Mg

aq. THF

OH

O

OAc

OAc

25 °C, 15 min

82%

The combination of magnesium–Chlorotrimethylsilane has

been used for the reductive silylation of 1,1-dibromides,

84

conjugated trienes,

85

heterocycles,

86

and, as shown in eq 21,

certain chloro-substituted enynes.

87

Magnesium has been also

used as a reactive metal electrode in an electroreductive silyla-
tion of alkenes.

88

(21)

Mg, TMSCl

HMPA, 25 °C

80%

H

•

Cl

H

H

H

H

TMS

H

H

1,3-Dienes form reactive complexes with magnesium.

89

In this

capacity, active magnesium has been used for the reductive silyla-
tion and dialkylation of certain conjugated 1,3-dienes. For exam-
ple (eq 22), treatment of 1,4-diphenyl-1,3-butadiene with Rieke
magnesium affords the magnesium–diene complex. Addition of
Dichlorodimethylsilane affords the cis-diphenylsilacyclopentene
in 66% yield.

90

Ph

Ph

SiMe

2

Ph

Ph

(22)

1. Mg*

66%

2. Me

2

SiCl

2

First Update

Jens Högermeier & Martin G. Banwell
The Australian National University, Canberra, Australian Capital
Territory, Australia

Introduction.

Since the original entry, many new applica-

tions and/or modified synthetic protocols involving magnesium
have emerged. This update is concerned with the use of mag-
nesium metal

91

for the preparation of organomagnesium com-

pounds and the application of these in synthesis. It includes dis-
cussions of activated forms of the metal such as Rieke

TM

-Mg

92,93

and Mg–anthracene. The use of Mg metal as a reducing agent,
particularly in pinacolic coupling reactions, is also covered. In
contrast, this article does not deal with those reactions involving a
magnesium source other than Mg metal. So, for example,
i

-PrMgBr, which is now used extensively in metal–halogen

exchange reactions for the synthesis of organomagnesium com-
pounds (see iso-propylmagnesium bromide in this series and
selected reviews),

94,95

is not dealt with here. Other related

Mg-based reagents and organomagnesium compounds that are

Avoid Skin Contact with All Reagents

4

MAGNESIUM

not included but that have been reviewed recently include
Mg/MeOH (see Mg/MeOH in this series and a review article

96

),

Mg/amalgam (see Mg/amalgam in this series), magnesium bis-
amides,

97

and heterocyclic organomagnesium compounds more

generally.

98

Formation and Reactions of Organomagnesium Com-

pounds. The reaction of Mg metal with organic halides has been
used routinely for about a century to form Grignard reagents. How-
ever, the mechanism of this transformation remains the subject of
study. By using a cell suitable for photomicrographic observations,
an assessment of the behavior of magnesium surfaces during the
formation of Grignard reagents was undertaken and it has thus
been confirmed that the addition of iodine or ferric chloride in-
creases the reactivity of Mg surfaces as much as scratching them
does.

99

The identification of efficient methods for the formation of

organomagnesium reagents continues. A comparison of several
means for metallating electron-rich aryl bromides has established
that heating Mg metal under reflux in THF for 24–48 h is ef-
fective while protocols involving i-PrMgCl are not. However,
the use of (s-Bu)

2

Mg·LiCl and (n-Bu)

2

Mg·LiCl proved supe-

rior, delivering the relevant organomagnesium species derived
from 4-bromoanisole in 8 h or under 5 min, respectively.

100

In-

vestigations into the formation of Grignard reagents containing
electron-withdrawing substituents such as those derived from 3-
or 4-iodobenzoates show that these can be formed smoothly at
low temperature. However, the decomposition of such species is
observed if they are allowed to stand at room temperature for
several hours.

101

An electrochemical alternative to the classical

method of using Mg turnings for the preparation of Grignard
reagents containing electron-withdrawing substituents has been
identified and involves using a Mg anode and a Pt cathode in a
solution of KClO

4

/DMSO. During electrolysis, the strong base

dimsyl

2

Mg is produced while potassium accumulates at the cath-

ode. The dimsyl

2

Mg derived from the sacrificial Mg anode can

deprotonate even weakly acidic substrates such as substituted fluo-
renes, thereby generating Grignard reagents that contain electron-
withdrawing substituents.

102

Another somewhat unusual way of

preparing Grignard reagents from Mg metal involves the use of mi-
crowave irradiation. While the irradiation of metals in a microwave
oven can be problematic, and even dangerous on occasion, heating
bromo- and chloro-aryls with Mg turnings under such conditions
has been shown to give the corresponding Grignard reagents that
can then be reacted with CO

2

to afford, after acidic workup, var-

ious aryl carboxylic acids in good yields. The Grignard reagents
prepared by this same method participate in transmetallation re-
actions with ZnCl

2

–TMEDA to give the corresponding aryl zinc

species that then engage in microwave-promoted Negishi cross-
coupling reactions.

103

Traditionally, the preparation of propargylic Grignard reagents

involved using Hg

II

salts as catalysts, but these can now be re-

placed by ZnBr

2

. The method requires only 2% of ZnBr

2

for the

smooth preparation of a range of different propargylic Grignard
reagents.

104

The preparation of bis-metallic derivatives of Mg has often

been challenging but now 1,4-bis(bromomagnesio)butadienes
can be readily generated, using Mg and dibromoethane, from
the corresponding 1,4-dibromobutadienes. The reaction of such
species with various ketones, aldehydes, and PhNO provides

highly substituted cyclopentadiene derivatives in a concise
manner (eq 23).

105

R

Br

R

R

′

R

′

Br

R

′

MgBr

R

R

R

′

MgBr

R

R

′

R

R

60

°C, 8 h

Mg, Br(CH

2

)

2

Br

R

′′COR′′′ 31–61%

R = Me, Pr, –(CH

2

)

4

–

R

′ = Me, Pr

R

′′ = Ph, Pr, –(CH

2

)

5

–, H

R

′′′ = R′′, Ar, het-Ar

(23)

R

′′′

R

′′

Similarly, reaction of 1,4-dibromobutane with Mg in THF

at 30

◦

C gives the corresponding bis-Grignard reagent that is

readily transformed into the analogous bis-heterocuprate, a
species that can react with axially-chiral bromoallenes to give
1,9-decadiynes.

106

Organomagnesium reagents are sometimes used as bases. For

example, a highly effective synthesis of 3-butyn-1-ol employs
EtMgBr, prepared from Mg and ethyl bromide, to deprotonate
acetylene. The resulting ethynyl Grignard then reacts with ethy-
lene oxide to give 3-butyn-1-ol.

107

This procedure is superior to

the equivalent employing lithium acetylide, which is less reactive
toward ethylene oxide.

One of the most common applications of organomagnesium

reagents involves their reaction with electrophiles. An interest-
ing group of electrophiles is the aryl bis-chalcogenides, parti-
cularly ArSe–SeAr and ArTe–TeAr. In the presence of Mg, these
undergo copper-catalyzed cleavage reactions of the chalcogene–
chalcogene single bond to give unsymmetrical diarylselenides
or tellurides (eq 24).

108

Another copper-catalyzed process in-

volves the reaction of alkyl Grignards with allyl chlorides, which
proceeds with high γ-selectivity.

109

Ar—I + 1/2 Ar

′X—XAr′

(24)

Mg, cat Cu

2

O-bpy

DMF, 110

°C

Ar—XAr

′

53–95%

Ar = o- and p-Ar
Ar

′ = p-Ar, naph, 2- and 3-pyr, 2-thiophene

X = Se or Te

A useful procedure for the carboethoxylation of organomag-

nesium compounds involves the reaction of such species with
diethyl dicarbonate and a Lewis acid under sonication conditions.
The best results are obtained using BF

3

·OEt

2

as the Lewis acid.

The method allows for the efficient mono- and di-carboxylation
of dibromoarenes of various types (eq 25).

110

S

Br

Br

S

EtO

2

C

CO

2

Et

(25)

Mg, Br(CH

2

)

2

Br

(EtO

2

C)

2

O, THF

sonication, BF

3

·OEt

2

63%

(+29% 2-bromo-5-ester)

also other ArBr where Ar = m-, p-Ar, Ph, pyr, indole

The replacement of both halogens in ring-fused gem-

dichlorocyclopropanes can be accomplished using TMSCl in the

A list of General Abbreviations appears on the front Endpapers

MAGNESIUM

5

presence of either lithium (containing 1% sodium) or with a mix-
ture of Mg, Zn, and CuCl. Generally, the former protocol is
superior (eq 26).

111

Cl

Cl

SiMe

3

SiMe

3

Li (1% Na), TMSCl, THF

with Li
with Mg/Zn/Cu(I)

95%
47%

(26)

or

Mg, Zn (0.3 equiv), TMSCl

CuCl (0.03 equiv), THF

A nucleophilic addition–elimination reaction of a Grignard

compound to a suitably substituted naphthalene has been used
to synthesize axially chiral biaryl ligands required in the assem-
bly of metathesis catalysts. The requisite Grignard reagent, formed
by treating the precursor aryl bromide with Mg at 60

◦

C in THF, is

added to a 2-menthyl 1-menthyloxy-2-naphthoate thus giving the
desired product in 84% yield and with excellent diastereoselecti-
vity (19:1) (eq 27). Recrystallization of the crude reaction mixture
gives a single diastereoisomer.

112

MeO

Br

CF

3

O

CF

3

Me

MeO

O

i

-Pr

O

O

Me

O

i

-Pr

Me

i

-Pr

(27)

Mg, THF

C

6

H

6

, 60

°C

84% (19:1 ds)

+

Barbier-type processes, involving the reaction of Grignard

reagents with aldehydes or ketones, provide a remarkably
reliable means for C–C bond formation. Furthermore, while
Grignard reagents are generally considered moisture sensitive,
Barbier reactions have been carried out in aqueous media. Thus,
by using a combination of Mg and BiCl

3

in THF/water, allyl Grig-

nard reagents can be formed and then reacted in situ with various
aldehydes to give the expected secondary alcohols in up to 90%
yield. In contrast, with THF alone the same reagent combination
gave only 78% of the desired product.

113

Related studies have

shown that aqueous NH

4

Cl alone can serve as a medium for such

reactions, although under these conditions the products were ob-
tained in low to moderate yields (viz. 21–40%).

114,115

Barbier-

type reactions involving imines can also be effective processes,
thus providing a range of linear and branched amines.

116

–

118

Efficient C–C bond formation can be achieved through re-

ductive coupling of a Grignard reagent with an alkyl halide.
Thus, various ω-tetrahydropyranyloxyalkyl bromides have been
transformed under conventional conditions into the corresponding
Grignard reagents and these were then reacted with various long-
chain 1,ω-dihaloalkanes to produce bis-THP acetals (eq 28).

119

O

O–(CH

2

)

n

–Br

O

O–(CH

2

)

m

–O

O

Mg, THF, heat

I–(CH

2

)

8

–I or

Br–(CH

2

)

12

–Br

n

= 6, 12, 14

m

= 20, 32, 40

(28)

Among the many transition metal-catalyzed methods available

for C–C bond formation, the Pd

0

-catalyzed coupling reactions

are probably the most versatile, particularly the Kumada vari-
ant involving organomagnesium compounds and various elec-
trophiles. A few examples of Kumada cross-coupling reactions
are known where the requisite Grignard is synthesized directly
from Mg metal and not via exchange from a commercial Grig-
nard source (e.g., i-PrMgBr). For example, a diaryl bromide can
be converted into the corresponding bis-magnesio reagent by re-
fluxing it in THF with Mg metal and the bis-Grignard reagent
so-formed can, in turn, be coupled, under Pd

0

catalysis, with var-

ious dibromoarenes to generate a range of conjugated polymers
in good yields (eq 29).

120

BrMg

OC

8

H

17

MgBr

OC

8

H

17

Br

Br

S

Br

Br

Br

Br

Br–Ar–Br:

Br

Br

Br–Ar–Br

conjugated

polymers

PdCl

2

(ddpf)

THF, reflux

58%

40%

73%

51%

(29)

+

A related and very useful process involves the Fe

III

-catalyzed

homo- or cross-coupling Grignard reagents. For example, such
reagents, when generated from the corresponding bromide using
metal Mg in THF at room temperature, homocouple very effi-
ciently in the presence of Fe(acac)

3

or Fe(DBM)

3

(eq 30).

121

R–Br

R–R

2% Fe(acac)

3

or Fe(DBM)

3

Mg, THF

41–92%

DBM = dibenzoyl methane
R = o-, m- or p-aryl, alkyl, cycloalkyl

(30)

Highly activated forms of magnesium have been studied

extensively in recent years. For example, Rieke

TM

-Mg has been

successfully employed in the generation of organomagnesium
compounds that can react with electrophiles as varied as Weinreb
amides,

122

aldehydes,

123

furanoses,

124

and CO

2

.

125

In a study

of the addition of organometallics to an acylpyridinium salt,
Rieke

TM

-Mg proved to be a good choice as metal source for

generation of the required organomagnesium compound since
higher yields of product were obtained with this species than
when the corresponding lithiates or cuprates were employed.

126

Thienylmagnesium compounds derived from the direct reaction of
Rieke

TM

-Mg with thienyl iodides can be successfully employed

Avoid Skin Contact with All Reagents

6

MAGNESIUM

in Pd

0

- or Ni

II

-catalyzed cross-coupling reactions with a range of

electrophiles (eq 31).

127,128

S

I

S

MgI

S

E

Mg*

THF, rt

electrophile

Pd

0

or Ni

II

THF

33–87%

(31)

E = PhCO

, RCH(OH)

, C

6

H

13

S

Applications of activated Mg in total syntheses continue to be

disclosed. Thus, Rieke

TM

-Mg has been employed for the forma-

tion of an aryl bromide-derived Grignard reagent that reacts in the
expected manner with oxirane so as to install the β-hydroxyethyl
side chain of the cytotoxic and antibacterial sesquiterpenes
pterosines B and C.

129

During studies directed toward the

total synthesis of the phomoidride CP-255,917, the C9 side chain
of the molecule was introduced by reacting the relevant alkyl
bromide with Rieke

TM

-Mg at −78

◦

C in the presence of TMEDA.

Subsequent addition of the resulting long-chain alkyl Grignard to
two different aldehydes then gave the desired products in 94 and
92% yield, respectively.

130

The synthesis of Mg metallacycles using Rieke

TM

-Mg has been

reported.

131

Thus, the treatment of 1,3-dienes with Rieke

TM

-Mg

leads to a diene Mg complex that reacted with epoxides to deliver
another Grignard reagent that can itself undergo a second reaction
with other electrophiles such as CO

2

. By such means, the rapid

and efficient assembly of δ-lactones is achieved (eq 32). In an anal-
ogous fashion, and by using imines as primary electrophiles and
CO

2

as the secondary one, a range of γ-lactams can be formed.

132

R

R

CO

2

OMg

R

Mg

O

R

R

R

CO

2

Mg

R

R

O

R

R

O

O

THF, –78

°C

0

°C to rt

1. H

+

2. 40

°C

39–84%

(32)

Mg*

THF, rt

Mg–anthracene complexes represent another synthetically

useful source of activated Mg. The preparation and properties of
such complexes have been explored extensively,

133,134

and it has

been shown that Mg–anthracene is especially effective in the gen-
eration of Grignard reagents.

135

Solid-supported Mg–anthracene

complexes have been reported and are available on silica

136

as well

as on organic polymers.

137

Both such supported reagents display

good reactivity in the formation and reaction of benzylic Grig-
nards and the support itself can be reloaded with Mg by treating
it with fresh Mg–anthracene.

Mg–anthracene has been used for the conversion of certain

perfluoroalkanes and perfluoroarenes into the corresponding
arylfluoro-Grignard reagents. Thus, reaction of either perfluo-
robenzene (C

6

F

6

) or perfluorocyclohexane (C

6

F

12

) with the rele-

vant quantities of Mg–anthracene affords C

6

F

5

MgF, which when

treated with CO

2

gives perfluorobenzoic acid in 6–34% yield. It

should also be noted that fluoro-Grignards (R–MgF) can sponta-
neously decompose.

138

An interesting and sometimes efficient two-fold C-acylation

reaction of anthracene or benzyl acrylates with acid chlorides was
discovered when these compounds were treated with acyl chlo-
rides and Mg metal in DMF. The acylation of anthracene is readily
achieved to give the product 9,10-diacyl-9,10-dihydroanthracene
in good yield. The two-fold C-acylation of benzyl acrylates with
various acid chlorides can be effected in a similar fashion and
1,4-diketones are thus obtained.

139

Magnesation of allyl sulfides can be achieved by treating such

substrates with Mg, anthracene and dibromoethane and then
subjecting the resulting mixture to sonication.

140

In suitably

constituted substrates, the resulting allylmagnesium compounds
undergo an ene-type cyclization with a pendant alkene and the
product of this process can then be trapped with various elec-
trophiles, including PhSe–SePh. Such a reaction cascade has been
employed in the total synthesis of the monoterpene metatabiether
(eq 33).

OH

SePh

OH

PhS

MgSPh

OH

1. MeMgBr, THF, –20

°C

2. Mg, Br(CH

2

)

2

Br

anthracene, sonication
23

°C, 8–10 h, THF

3. THF, reflux, 5 h
4. PhSe–SePh

78%

(33)

Reductions with Magnesium. Because of its ability to act as

a one-electron donor, Mg metal (reduction potential –2.37 eV) is
often employed as a reducing agent. For example, the metal can
effect the reductive desulfonylation of difluoromethyl sulfonates
(–CF

2

SO

2

Ph) to difluoromethyl groups (–CF

2

H). Such conver-

sions can be carried out using Mg/HOAc/AcONa in DMF/H

2

O

(5:1 v/v) at room temperature.

141

Efficient defluorinative alkyla-

tions and silylations of trifluoromethylated aromatics,

142,143

ke-

tones, and imines

144,145

have been reported using Mg and such

conversions have been reviewed.

146

By using Mg metal in a flash

vacuum pyrolysis (FVP) apparatus, various o-disubstituted bis-
halomethyl arenes can be converted, by dehalogenation, into the
corresponding benzocyclobutenes (eq 34).

147

X

X

R

R

R

+

FVP, Mg

X = Cl, Br
R = H, CH

3

, F, Cl, Br, I

73–80%

8–15%

(34)

Freshly prepared Grignard reagents have been shown to readily

and efficiently reduce 9,10-diformylanthracene to the corres-
ponding 9,10-dialkyldienyl- or 9,10-diaryldienyl-9,10-dihydro-
anthracenes. Activated Mg that was obtained by the reaction of
Li–naphthalene with MgCl

2

gives similar results.

148

Some very

efficient reducing agents are obtained by combining Mg metal
with different metal halides. Thus, Mg–ZnCl

2

in an aqueous

A list of General Abbreviations appears on the front Endpapers

MAGNESIUM

7

medium is an effective reagent for the selective reduction of α,β-
unsaturated carbonyl compounds to the corresponding ketones.

149

Mg–SnCl

2

can be used for the reduction of aldehydes to primary

alcohols while ketones are unaffected by this reagent. However, it
does transform ketones into ethylene ketals when used in the pres-
ence of glycol. The reagent also dehalogenates benzyl halides.

150

Similarly, a combination of SnCl

2

·2H

2

O and Mg metal in aque-

ous media allows for the conversion of nitroalkenes into carbonyl
compounds.

151

Various active metals can be formed when the corresponding

metal salt is reduced with Mg. Thus, activated Mn

0

can be gen-

erated (for use in radical cyclization reactions) from Li

2

MnCl

4

and Mg.

152

Another good reagent combination for reductions

is Mg/hydrazine hydrate. This has been used to convert azoxy-
arenes into hydrazoarenes.

153

The same system effects the reduc-

tive removal of common peptide protecting groups such as the N-
benzyloxycarbonyl, N-2-chlorobenzyloxycarbonyl, benzyl ester,
and o-benzyl ether moieties.

154

Similarly, the Mg/AcOH system

has been explored in peptide synthesis for the selective deprotec-
tion of phenacyl esters in the presence of Boc, Fmoc, and/or Cbz
groups.

155

The reduction of carbonyl compounds to alcohols with Mg in

the presence of trimethylsilyl chloride or bis(chlorodimethylsilyl)
compounds gives rise to α-trimethylsilylalkyl trimethylsilyl ethers
and cyclic siloxanes. Since such reactions are carried out in the
absence of a proton source, a pair of TMS residues is incorpo-
rated into the product, allowing for further useful transformations
(eq 35).

156

R

O

R

′

R

R

′

TMSO

TMS

(35)

Mg, TMSCl

DMF, 20 h, rt

14–82%

R = alkyl, alkenyl, aryl
R

′ = H, alkyl

The powerful reducing properties of Mg metal also allow it to

be used in ketyl–olefin couplings, offering an interesting means
for forming new C–C bonds under radical conditions. For exam-
ple, the cyclizations of phenylthiovinyl-tethered ketones were con-
ducted using Mg/THF–EtOH in the presence of catalytic amounts
of HgCl

2

to obtain various highly substituted cyclopentanes in

excellent yields and with good diastereoselectivity (eq 36).

157

Presumably, the role of the Hg

II

in this process is simply to

provide amalgamated magnesium.

EtO

2

C

O

SPh

EtO

2

C

OH

SPh

EtO

2

C

OH

SPh

+

Mg

cat HgCl

2

93% (17:1 ds)

(36)

Related intermolecular variants of such processes involving the

coupling of stilbene derivatives with carbonyl compounds have
been achieved using Mg/TMSCl in DMF.

158

Frequently, pinacolic couplings of ketones or aldehydes are

best effected using Mg metal and, nowadays, such reactions are
often promoted by ultrasonication.

159,160

Thus, the cross-coupling

of aromatic ketones with aliphatic carbonyl compounds can be
carried out using Mg/TMSCl.

161

The reductive couplings of α,β-

unsaturated ketones and 1,3-diketones to produce bis-silyl enol

ethers and bis-conjugated enones can be achieved by using Mg
metal in the presence of TMSCl (eq 37).

162

R

′

R

′

R

R

R

′′

OTMS
OTMS

R

′′

(37)

Mg, TMSCl, DMF

48–72%

R = H, Me, –(CH

2

)

n

–R

′

R

′ = H, Me, –(CH

2

)

n

–R, or –(CH

2

)

n

–R

′′

R

′′ = H, –(CH

2

)

n

–R

′

= –(CH

2

)

n

, n = 2,3,4

R

′′

R

O

R

′

The Mg metal-mediated reduction of 1,3-cyclohexanedione has

been reported to give the desired pinacolic coupling product ex-
clusively while the analogous SmI

2

-mediated reaction furnished

the hydrodimerization product.

163

A wide variety of mixtures of Mg metal and metal salts can be

used to effect various pinacolic coupling reactions. Thus, activated
Ni

0

, obtained by treating NiCl

2

with stoichiometric amounts of

Mg and TMSCl, is a useful reagent for this purpose.

164

Other suc-

cessfully applied systems include a mixture of Mg/TMSCl with
catalytic amounts of InCl

3

,

165

catalytic amounts of zirconocene

dichloride with Mg,

166

and low-valent samarium obtained by

reduction of SmCl

3

with Mg.

167

A popular reagent is obtained by treating titanium halides with

Mg to generate a low-valent titanium species and this is capa-
ble of effecting various reductions. The reagents so-formed have
been employed in the synthesis of imidazolines,

168

the synthesis

of α,α-disubstituted acids,

169

as well as for effecting McMurry-

type reactions,

170

and in pinacolic couplings that are promoted by

ultrasound.

171

Miscellaneous Reactions. Mg metal turnings, when used in

combination with TMSCl in DMF, provide a mild and efficient
method for the conversion of aliphatic tertiary alcohols into the
corresponding silyl ethers.

172

Similarly formed triflates can be

converted into ethers. Thus, the alcoholate is formed by reac-
tion, under reflux, of the corresponding alcohol with Mg and I

2

.

After the addition of 0.5 molar equiv of Tf

2

O, the resulting ethers

can be isolated in moderate to excellent yields.

173

Unsymmetri-

cal ethers can be formed by reacting the Mg alcoholate with the
trifluoromethanesulfonyl ester of a different alcohol (eq 38).

ROH

(RO)

2

Mg

Tf

2

O

R–O–R

Mg, I

2

reflux

R

′OTf

R–O–R

′

R, R

′ = alkyl, phenyl, benzyl

25–90%

40–94%

(38)

Novel magnesium enolates can be prepared from α-

chloroglycidic esters by treating them with MgI

2

and then Mg

metal. The product enolates are versatile building blocks that can
be used in a variety of ways, particularly for the purpose of prepar-
ing α-alkoxy-α,β-unsaturated esters (eq 39).

174

Avoid Skin Contact with All Reagents

8

MAGNESIUM

R

CO

2

i-

Pr

O

Cl

R

O

Oi-Pr

O

R

′

R

O

Oi-Pr

O

I

R

O

Oi-Pr

OMgI

MgI

2

Mg

R

′X

20%-quant.

(39)

Protocols involving either a cobalt reagent or Mg in

THF have been used to obtain β-ketophosphonates from α-
halophosphonates and a variety of carboxylic acid esters.

175

The

preferred choice of metal is determined by the structure of the
ester used and the cobalt-based method is generally the superior
one.

The utility of the Mg/TiCl

4

/THF reagent combination in gener-

ating useful carbenoids from a range of chloromethanes has been
highlighted recently. If reacted with dichloromethane, this com-
bination forms a carbene complex similar to that associated with
the Tebbe reaction, and one which is useful for the methylenation
of sterically hindered ketones and aldehydes. For example, it can
be applied to the methylenation of camphor and fenchone as well
as related substrates (eq 40).

176

The methylenation of esters is

also possible

177

and enamines can be cyclopropanated using this

reagent.

178

CH

2

Cl

2

Ti

Cl

Mg

Cl

THF

R

R

′

R

R

′

O

THF

TiCl

4

, Mg

61–95%

R = alkyl

(40)

OR,

R

′ = alkyl,

(CH)

n

CO

2

R,

(CH)

n

NHAc,

(CH)nAryl

Replacing dichloromethane with chloroform in the above-

mentioned processes leads to the efficient chloromethylenation of
ketones.

179

When carbon tetrachloride is used, then the resulting

Ti–Mg complexes allow for the gem-dichlorocyclopropanation
of cis- and trans-alkenes as well as for carbonyl olefination
(eq 41).

180

Ti

Cl

Mg

Cl

2

C

Cl

THF

R

R

′

CCl

2

R

R

′

O

R

′′

R

′′′

CCl

2

R

′′

R

′′′

84–94%

62–92%

TiCl

4

/Mg/THF

CCl

4

(41)

A further variation of this interesting new methodology is its

application to the synthesis of polysubstituted chlorocyclo-
propanes, which can be achieved using variously substituted
chloroform derivatives, for example, PhCCl

3

or Cl

3

CCO

2

Me,

as the carbene source.

181

Related

Reagents.

Tetrachloro(η

5

-cyclopentadienyl)nio-

bium–Magnesium.

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A list of General Abbreviations appears on the front Endpapers