COPPER(I) BROMIDE

1

Copper(I) Bromide

1

CuBr

[7787-70-4]

BrCu

(MW 143.45)

InChI = 1/BrH.Cu/h1H;/q;+1/p-1/fBr.Cu/h1h;/q-1;m
InChIKey = NKNDPYCGAZPOFS-ZFYMQJCYCJ
CuBr·SMe

2

[54678-23-8]

C

2

H

6

BrCuS

(MW 205.59)

InChI = 1/C2H6S.BrH.Cu/c1-3-2;;/h1-2H3;1H;/q;;+1/p-1/fC2H

6S.Br.Cu/h;1h;/q;-1;m

InChIKey = PMHQVHHXPFUNSP-GUDWEBAYCB

(precursor for organocopper(I) reagents and organocuprates;

1a

–

f

catalyst for diazo chemistry)

Alternate Name:

cuprous bromide.

Physical Data:

mp 504

◦

C; the complex with dimethyl sulfide

(DMS) decomposes at ca. 130

◦

C; d 4.720 g cm

−3

.

Solubility:

insoluble in H

2

O and most organic solvents; partially

soluble in dimethyl sulfide.

Form Supplied in:

light green or blue-tinged white solid. 99.999%

grade available. The DMS complex is a white solid.

Preparative Methods:

commercial copper bromide is often con-

taminated; the use of freshly prepared or purified copper bro-
mide is strongly advised. Copper bromide can be prepared by
reduction of CuBr

2

38

or CuSO

4

–NaBr.

39

Purity:

the colored impurities in the title reagent can be removed

from the commercial samples by dissolving an appropriate
quantity of CuBr in a saturated aqueous solution of KBr over
30 min. Subsequent cooling, treating with charcoal, filtering,
and diluting with water allows for the formation of the CuBr
precipitate.

40

Traces of iron salts can be removed via the sul-

fide complex.

41

Alternatively, copper bromide can be purified

by precipitation from 48% HBr. The precipitate is filtered and
washed sequentially with water, ethanol, and ether, then finally
dried under vacuum.

42

Handling, Storage, and Precautions:

maintenance of a dry N

2

or

Ar atmosphere is recommended. The DMS complex must be
tightly sealed to prevent loss of DMS. Storage of this complex
in a cold place is recommended.

Original Commentary

Steven H. Bertz & Edward H. Fairchild
LONZA, Annandale, NJ, USA

Precursor for Organocopper(I) Reagents and Organocup-

rates. Although Phenylcopper was prepared from Copper(I)
Iodide by Reich in 1923

2

and Gilman in 1936,

3

the material

used for the modern characterization of this archetypal arylcop-
per(I) is prepared from CuBr,

4

which continues to be a favored

precursor for new organocopper(I) compounds.

5

–

9

For example,

Bertz discovered that halide-free organocopper compounds can
be prepared from CuBr in Dimethyl Sulfide (DMS), owing to the
precipitation of LiBr from this solvent.

5

Thus it was possible to

prepare and structurally characterize the first bona fide ‘higher
order’ cuprate.

5a,6

Weiss recently reported the second example,

a higher order alkynyl cuprate,

9

prepared from CuBr·DMS. The

chemistry of organocopper reagents in DMS has now become a
flourishing subfield of organometallic chemistry.

5

–

9

For the first decade of the modern era of organocopper

reagents, CuI was used almost exclusively as the precursor to
organocopper(I) and organocuprate reagents.

1f

In 1975, House

introduced the DMS complex of CuBr, symbolized CuBr·SMe

2

or CuBr·DMS, as ‘a convenient precursor for the generation of
lithium organocuprates’.

10

Unlike the commercial CuBr, which

is invariably contaminated with traces of colored Cu

II

impurities,

CuBr·DMS is a microcrystalline white solid. This material should
be stored under a dry, inert atmosphere in a refrigerator in order to
minimize the loss of DMS, which is quite volatile (bp 38

◦

C). It is

not surprising that Lipshutz found that low quality material gave
poor results.

11

This author has found that for ultraprecision work,

where stoichiometry is of paramount importance, the ultrapure
(99.999%) grade of CuBr is preferable.

5

Nevertheless, in a side-by-side comparison of seven Cu

I

salts

(CuCN, CuI, CuBr, CuBr·DMS, CuCl, CuOTf, and CuSCN) as
precursors of a typical alkyl and a typical aryl cuprate (Lithium
Dibutylcuprate and Lithium Diphenylcuprate, respectively),
CuBr·DMS and Copper(I) Cyanide were found to give the
best results.

12

The comparison between ultrapure CuBr and

CuBr·DMS is especially interesting, as it demonstrates a dra-
matic effect for just 1 equiv of DMS in THF and especially in
ether. Another example of a significant difference between CuBr
and CuBr·DMS is provided by Davis’s study of 1,6 vs. 1,4 and
1,2-addition (eq 1).

13

O

O

O

R

HO

R

R

RMgCl

+

+

(1)

No Cu
CuBr
CuBr•DMS

4
4
3

1
1
1

3
15
30

CuBr•DMS

Some of the most fundamental studies in organocopper chem-

istry have been carried out using CuBr or CuBr·DMS as starting
materials. House showed that the chemoselectivity of Lithium
Dimethylcuprate–Lithium Bromide could be completely con-
trolled by the choice of solvent.

14

Thus a molecule with remote

bromoalkane and α-enone functional groups gave only conjugate
addition in ether–DMS and only displacement of the Br when
HMPA (Hexamethylphosphoric Triamide) was present (eq 2). In

t

-Bu

O

(CH

2

)

3

Br

t

-Bu

O

(CH

2

)

3

Br

t

-Bu

O

(CH

2

)

3

Me

(2)

ether–DMS

ether–DMS–HMPA

Me

2

CuLi·LiBr

Me

2

CuLi·LiBr

Avoid Skin Contact with All Reagents

2

COPPER(I) BROMIDE

a recent

13

C NMR study it was shown that phenylcuprates are

dimeric in nonpolar solvents and monomeric in polar solvents.

15

It was further conjectured that the dimer is responsible for the
conjugate addition reaction, and the monomer is responsible for
the (much slower) S

N

2-like displacement reaction.

The preparation of the first higher order cuprate, Ph

5

Cu

2

Li

3

=

[Ph

3

CuLi

3

][Ph

2

Cu] or Ph

3

CuLi

2

+ Ph

2

CuLi, from CuBr/DMS

was mentioned above.

5

House first proposed higher order

Ph

3

CuLi

2

in solutions prepared from 3 equiv of PhLi and CuBr in

ether to account for the higher reactivity observed for this mixture
in certain coupling reactions.

16

However,

13

C NMR and

6

Li NMR

studies did not detect any higher order phenylcuprate in ether or
THF, only in DMS.

5

While the presence of a small amount of

higher order cuprate acting as a catalytic intermediate cannot be
ruled out, a more plausible explanation involves the attack of PhLi
on a cuprate-complexed intermediate.

The first thermally stable phosphido- and amidocuprates were

prepared from CuBr·SMe

2

.

17

(It was also shown that LiBr has a

beneficial effect on the reactions of organocuprates with typical
substrates.

17c

) Chiral amidocuprates have been extensively stud-

ied because of their potential for asymmetric induction.

18

–

20

The

chiral auxiliary has also been put on the substrate, e.g. cuprates
have been added to chiral unsaturated imides.

21

A good recent

review provides many more examples.

1b

Whereas Grignard reagents and lithium reagents generally give

thiophilic addition to dithioesters, the corresponding organocop-
per reagents give carbophilic addition.

22

The best yields were

obtained with CuBr·DMS and Copper(I) Trifluoromethanesul-
fonate; good results were also obtained with CuCN and CuI.
This carbophilic addition has been applied to 1,3-thiazole-5(4H)-
thiones.

23

It is interesting to note that CuBr has also been used in

the preparation of the dithioesters (eq 3).

24

MeI

S

R

′

SMe

SH

R

R

′

R

R

′

MgX

(3)

CuBr (5–10%)

CS

2

R

2

CuLi·LiBr

Nakamura and Kuwajima have reported the CuBr·DMS

catalyzed acylation and conjugate addition reactions of the Zn
homoenolate from 1-alkoxy-1-siloxycyclopropanes and Zinc
Chloride.

25a

They have also reported the Chlorotrimethylsilane/

HMPA

accelerated

conjugate

addition

of

stoichiometric

organocopper reagents prepared from CuBr·DMS,

25b

and of

catalytic copper reagents,

25c

to α,β-unsaturated ketones and alde-

hydes. This procedure appears to be more general than that based
on putative cuprates of intermediate stoichiometry (see Copper(I)
Iodide). In a very significant observation, they report that
‘reagents derived from cuprous iodide consistently gave lower
yields’.

25b

Wipf has used CuBr·DMS to catalyze the addition of alkyl and

alkenylzirconocenes to acid chlorides to yield ketones,

26a

and

also the 1,4-addition of alkylzirconocenes to α-enones.

26b

The

hydrozirconation of alkynes followed by transmetalation to Cu

I

was devised by Schwartz et al.,

27

who used CuI and Copper(I)

Chloride. Transmetalation from Al, B, Pb, Mn, Hg, Sm, Sn, Te,
Ti, Zn, and Zr to Cu has been reviewed recently.

1h

Carbocupration of alkynes by organocopper reagents is a very

important area, as judged by the number of citations.

1a,i

An

interesting example involves the use of organocopper reagents
bearing protected α-hydroxy or α-thio functions.

28a

The prepara-

tion of γ-silylvinylcopper reagents via the addition of α-silylated
organocopper reagents to alkynes has also been described.

28b

The carbocupration of alkynes is the key step in the synthesis
of γ,γ-disubstituted allylboronates.

29

The stannylalumination of

1-alkynes is catalyzed by Cu

I

and involves stannylcupration by an

intermediate stannylcopper(I) reagent.

30

The use of Grignard reagents in conjunction with Cu

I

salts has

been thoroughly reviewed.

1a,d

A very edifying example of the

difference between organocopper reagents prepared from lithium
reagents vs. Grignard reagents has been provided by Curran
(eq 4).

31

O

O

H

H

H

CO

2

H

R

H

CO

2

H

R

RLi

+

CuBr·DMS

(4)

+

Me

2

CuLi·LiBr, THF

Me

2

CuLi·LiBr, ether

MeCu·MgBr

2

MeCu·LiBr
MeCu·LiI
MeCu(CN)Li
Yields were 90–97%, except for the cuprate from CuCN: 60%

62
54
98
86
76
75

38
46
2
14
24
25

or

R

′MgBr

+

CuBr

·

DMS

In chemistry that is clearly related to that of organocop-

per reagents, aryl bromides and aryl iodides undergo a Gabriel
reaction with potassium phthalimide in the presence of CuBr (or
CuI).

32

They also undergo coupling reactions with the sodium

salts of active methylene compounds catalyzed by CuBr.

33

Copper-assisted nucleophilic substitution of aryl halogen has been
reviewed.

1g

In a potentially far-reaching development, thermally

stable, yet reactive formulations of organocuprates suitable for
commercialization have been patented.

34

Catalysts for Diazo Chemistry. CuBr has been used in other

reactions besides those involving organocuprates. It is a popular
catalyst for the activation of Diazomethane, e.g. tropylium per-
chlorate is isolated in 85% yield starting from benzene.

35

CuBr

has been used for the activation of diazoacetic esters,

1j

but not as

often as CuCN, and especially CuCl. CuBr is the preferred cata-
lyst for the Sandmeyer reaction of arenediazonium salts to afford
bromoarenes,

36

and for the Meerwein reaction, the arylation of

alkenes by diazonium salts.

37

Related Reagents. Copper(I) Bromide–Lithium Trimethoxy-

aluminum Hydride; Copper(I) Bromide–Sodium Bis(2-methoxy-
ethoxy)aluminum Hydride; Copper(I) Chloride; Copper(I)
Chloride–Oxygen;

Copper(I)

Chloride-tetrabutylammonium

Chloride Copper(I) Chloride–Sulfur Dioxide; Copper(I) Cyanide;
Copper(I) Iodide; Copper(I) Trifluoromethanesulfonate.

First Update

Irina Denissova & Louis Barriault
University of Ottawa, Ottawa, Ontario, Canada

A list of General Abbreviations appears on the front Endpapers

COPPER(I) BROMIDE

3

Allylic Substitution and Cross-coupling Reactions. Copper

bromide and its DMS complex are still widely used to prepare
organocopper reagents and organocuprates.

43,44

Reference 44

describes the preparative methods and the most common use of
organocopper reagents such as application in conjugated additions
and substitution reactions, including asymmetric versions. It pro-
vides updated information on the organocopper reactions reported
in the original chapter of Encyclopedia of Reagents.

In the past decade the allylic substitution reaction has received

increasing attention, especially its asymmetric catalytic version
allowing for the formation of branched chiral products. Several
methods employing copper(I) salts were developed. The copper-
mediated allylic substitution reaction can follow two routes, either
S

N

2

′

displacement of the leaving group (γ-substitution) or S

N

2

displacement (α-substitution) (eq 5).

R

Y

CuX
R

1

M

CuX
R

1

M

R

R

1

R

R

1

S

N

2

′ pathway

S

N

2 pathway

R

1

= alkyl, aryl, vinyl, allyl

Y = Br, Cl, SO

2

Ph, OR

2

, O(P)(OR

2

)

2

, OC(O)R

2

M = Li, MgX, ZnX, etc.

(5)

Interestingly, it is possible to control the regioselectivity of the

reaction by changing the stoichiometry of the copper reagent.
Calo and co-workers have studied the allylic substitution reaction
with allylic electrophiles containing heterocyclic leaving groups
and Grignard reagents in the presence of stoichiometric amounts
of CuBr.

45

The authors have found that the substitution with

RCuMgBr

2

cuprates, formed with an excess of CuBr, was en-

tirely S

N

2

′

selective, whereas R

2

CuMgBr cuprates gave S

N

2 prod-

ucts. The regioselectivity was also affected by the reaction solvent.
Thus, diethyl ether favored the S

N

2

′

route, while THF facilitated

the S

N

2 pathway. Breit and Demel reported the first catalytic

example of syn-selective allylic substitution using CuBr·DMS as a
catalyst and employing ortho-diphenylphosphanylbenzoyl group
as a reagent directed leaving group (eq 6).

46

Ph

O

Me

O

PPh

2

Ph

Me

Me

20 mol

% CuBr

regioselectivity 96:4
E

:Z = 95:5

ee > 99%

E

:Z >99:1

ee > 99%

(6)

1.1 equiv MeMgI, Et

2

O, rt

85%

There are only a few examples of copper-mediated catalytic

asymmetric allylic substitution reactions employing a chiral lig-
and on copper. Knochel and Dubner reported the substitution of
various unsymmetrical allyl chlorides with hindered diorganoz-
inc reagents in the presence of 1 mol % of CuBr·DMS and 10
mol % of chiral ferrocenyl amines.

47,48

The reaction was highly

regioselective (γ-selectivity) and resulted in products with enan-
tiomeric excess of up to 98%,

48

but the method was limited

to highly hindered dialkylzinc reagents. Later, Feringa and co-
workers used 1 mol % of CuBr·DMS and phosphoramidite ligand
to catalyze allyl alkylation with diethyl and dibutyl zinc and cin-
namyl bromide.

49

The use of bimetallic catalyst systems in order to improve

existing and to explore new transformations is popular in mod-
ern transition-metal-catalyzed organic synthesis. Copper(I) salts
are known to accelerate reactions catalyzed by PdL

4

. Their use as

co-catalysts in combination with a palladium catalyst in the Stille
reaction has been widely reported, particularly for cross-coupling
of sterically hindered reactants. For example, Saa showed that
either CuBr or CuI can be employed in 2–4 fold excess rela-
tive to the palladium catalyst for synthesis of highly hindered
2,2

′

,6-trisubstituted and even 2,2

′

,6,6

′

-tetrasubstituted biaryls as

well as terphenyls.

50

The groups of Farina,

51

Liebeskind,

51

–

53

and

Espinet

54

studied the nature of the ‘copper effect.’ They demon-

strated that copper(I) participates in the scavenging of a free lig-
and L, released during the oxidation of PdL

4

in the catalytic cycle,

thus promoting formation of the species responsible for the trans-
metalation step. Also, Liebeskind suggested that in some cases
Cu(I) can transmetalate Sn, resulting in a more reactive organocop-
per species.

52

The majority of the articles related to the copper-

assisted Stille coupling employed copper iodide.

51,52,54

–

57

How-

ever, in some cases copper bromide,

50,58,59

copper chloride,

60,61

copper cyanide,

62

and copper oxide

63,57

were superior to CuI.

Clearly, the choice of a copper salt is strongly dependent on
the reaction substrate. Guillaumet and co-workers have recently
described a Stille type reaction between various aryl and vinyl
stannanes and electron-poor heteroaromatic derivatives bearing a
thiomethyl ether function as a leaving group.

64

The authors re-

port that a stoichiometric amount of copper(I) salt and palladium
[Pd(PPh

3

)

4

] catalyst were essential for the reaction to proceed.

The performances of copper bromide, copper bromide·DMS, cop-
per iodide, and copper(I) methylsalicylate in the cross-coupling
between 3-methylthiotriazine with 2-tributylstannylfuran were
compared (eq 3). CuBr·DMS complex resulted in the highest yield
(90%), whereas CuI, CuBr, and copper(I) methylsalicylate gave
only 50% and 60% yields.

Another example of the accelerating effect of copper salts is

the cross-coupling reaction of (Z)-1,2-difluoroethenylzinc iodide
and various aryl iodides in the presence of tetra-kispalladium and
copper(I) bromide reported by Burton.

65

In the absence of copper

bromide, the reaction would not go to completion.

Copper bromide can also be successfully applied as a

co-catalyst with various palladium species in Sonogashira
coupling,

66,67

though copper iodide is most commonly used.

68

Copper bromide is commonly used as a catalyst in cross-coup-

ling reactions of vinyl zinc compounds. For instance, Shibuya
described the cross-coupling reaction of [(diethoxyphospho-
ryl)difluoromethyl]zinc bromide with β-iodo alkenoates catalyzed
by copper bromide.

69

Burton utilized copper bromide for a

Avoid Skin Contact with All Reagents

4

COPPER(I) BROMIDE

self-coupling of α-halovinyl zinc compounds in order to gener-
ate fluorinated cumulated butatrienes in high yields (eq 7).

70

•

R

1

R

2

•

R

1

R

2

R

1

Br

Zn

R

2

cat CuBr

R

1

= Ph, C

6

F

5

R

2

= CF

3

, C

2

F

5

, C

3

F

7

(7)

DMF

65

−72%

Copper Bromide as a Lewis Acid. Recently, Knochel has re-

ported an enantioselective synthesis of propargylamines by copper
bromide/Quinap-catalyzed addition of alkynes to enamines with
enantioselectivities ranging from 50 to 90% (eq 8).

71

R

1

+

N

R

2

R

3

R

4

N

PPh

2

R

4

R

1

N

R

2

R

3

5 mol

% CuBr, 5.5 mol

% Quinap

Quinap

50

−99% yields

55

−90% ee’s

(8)

toluene, rt, 24

−96

h

This is a first example of metal-catalyzed enantioselective ad-

dition of alkynes to enamines. A number of alkynes bearing
different functionalities were successfully used. Among the vari-
ous metal salts tested, including Sc(OTf)

3

, Zn(OTf)

2

, Yb(OTf)

3

,

and Cu

I

and Cu

II

salts, copper(I) and copper(II) demonstrated

the best results. Dax has previously reported that copper chloride
(not catalytic) promoted a reaction of resin-bound propargylamine
and various imines formed in situ from the corresponding sec-
ondary amine and paraformaldehyde.

72

Carreira has shown that

the [IrCl(COD)

2

] complex can catalyze the addition reaction of

trimethylsilylacetylene to imines as well.

73

Reductive Properties of Copper Bromide.

ATRP—Atom Transfer Radical Polymerization. ATRP was

developed independently by the groups of Matyjaszewski

74

and

Sawamoto

75

in 1995, and it became one of the most success-

ful methods for controlled/living radical polymerization systems.
In this type of polymerization, a reversible metal-catalyzed atom
transfer is used to generate the propagating radicals as opposed
to thermally or photochemically promoted homolytic cleavage.
ATRP allows for the preparation of a vast range of polymeric

materials with controlled molecular weight and well-defined
chain architectures. Although many transition metal complexes
catalyze ATRP, according to a comprehensive review by
Matyjaszewski and Xia: ‘copper catalysts are superior in ATRP
in terms of versatility and cost

.’

76

Among copper catalysts,

copper bromide and copper chloride are most commonly used.
Matyjaszewski first reported in 1995 that copper bromide and
copper chloride complexed by three molecules of bipyridine in
the presence of commercially available alkyl halides served as
efficient initiators for the controlled polymerization of styrene,
MA, and MMA.

74,77

Polymers with molecular weights up to

100 000 and quite narrow polydispersities were synthesized with
good control. Ligands can considerably increase the rate of poly-
merization either by making the catalyst more soluble or by
changing the redox potential of the catalyst system. Polydentate
ligands such as phenatroline, its derivatives, substituted 2,2

′

:6

′

,2

′′

-

terpyridine, pyridineimines, and multidentate branched and linear
aliphatic amines are often used in ATRP.

ATRC–Atom Transfer Radical Cyclization.

Another area

where reductive properties of copper(I) bromide are exploited is
in the atom transfer radical cyclization of a C–X bond across
a carbon-carbon multiple bond. Organostannane reagents are
known to catalyze this type of reaction;

78

however their toxicity,

high cost, and difficulties related to purification impose a
certain limitation on their use. Like ATRP, a number of transition-
metal catalysts can be employed. For example, RuCl

2

(PPh

3

)

3

,

FeCl

2

[P(OEt)

3

]

3

,

79

and Ni

80

metal have been reported to

catalyze atom transfer with 2,2,2-trichlorinated carbonyl com-
pounds. However, copper(I) halide complexes (mostly copper
chloride and copper bromide) are by far the most applicable
because of their low cost, simple work-up procedure (many
times only flashing through a silica column is required), and the
catalytic nature of the process. Clark has investigated 5-exo

81,82

and 5-endo

83

cyclizations of various substituted bromo

acetamides catalyzed by copper bromide (eq 9).

N

N

C

5

H

11

30 mol

%

O

N

Br

Ts

O

N

Br

Bn

N

NMe

2

NMe

2

Me

2

N

O

N

Bn

N

Me

Me

Br

O

Ts

30

mol

% CuBr

CH

2

Cl

2

, rt, 48

h

97%

30 mol

% CuBr

30 mol

% ligand

ligand =

(9)

CH

2

Cl

2

, rt, 20 min

99%

A list of General Abbreviations appears on the front Endpapers

COPPER(I) BROMIDE

5

He has also studied 4-exo cyclization of terminally substituted

enamides, which allowed for the synthesis of β-lactams in very
high yields (eq 10).

84

O

N

Br

Bn

N

N

N

N

N

O

Br

Bn

O

N

Br

Bn

N

O

Bn

30 mol

% CuBr, 30 mol

% ligand

ligand =

(10)

30 mol

% CuBr

30 mol

% ligand

2.8:1 mixture of diastereomers

CH

2

Cl

2

, rt, 20 min

97%

toluene, reflux

82%

Interestingly, no product resulting from the 5-endo attack was

detected even at 110

◦

C in toluene. The 5-exo atom transfer radi-

cal cyclization of 1-halo-N-propargylacetamides catalyzed by the
tripyridylamine–copper bromide complex has been reported.

85

A

recent review summarizes the majority of the examples related to
copper-mediated ATRC.

86

Reductive Homocoupling. Ghelfi used copper(I) bromide to

promote a reductive homocoupling of α-bromo-α-chlorocarboxy-
lates to dimethyl α,α

′

-dichloro-succinate derivatives in the pres-

ence of CuBr/LiOCH

3

in methanol.

87

Lithium methoxide was

necessary for the reaction to occur. It was speculated that the
reductive power of copper(I) increases in the presence of the
methoxy ligands. The same coupling can be also performed using
a CuBr/Fe

0

couple.

88

In this case, the authors proposed that orig-

inally Fe

0

was oxidized to Fe

II

by copper(I) bromide, thus giving

rise to FeBr

2

which would then initiate a homocoupling. When

copper bromide was replaced by copper chloride, less satisfactory
results were obtained.

Miscellaneous. Gevorgyan

has

recently

reported

a

copper-assisted double pyrrolization of pyrimidine derivatives
into the bis-pyrrolopyrimidines allowing for construction of a
5-6-5 tricyclic heteroaromatic skeleton (eq 11).

89

N

N

R

1

R

2

N

N

R

1

R

2

CuBr, Et

3

N

−DMA

(11)

R

1

= H, R

2

= Me

R

1

= Me, R

2

= H

R

1

= C

2

H

5

, R

2

= H

150

°C, 10

h

48

−52%

In the presence of 1 equiv of copper bromide in TEA/DMA at

150

◦

C, bis-propynylpyrimidines were converted into the desired

bis-pyrrolopyrimidines in 48–52% yield.

Cohen discovered that copper bromide–dimethyl sulfide

complex can be an alternative to copper(I) triflate or
tetrakis(acetonitrile) copper(I) in removing the thiophenoxide
group.

90

CuBr·DMS showed comparable results with little or no

yield loss, though more vigorous conditions were required. How-
ever, the much lower cost compared to that of copper(I) triflate or
tetrakis(acetonitrile) copper(I) as well as its easy and safe handling
make CuBr·DMS an attractive substitute.

A combination of CuBr–Ag

2

CO

3

or CuBr–H

2

O was used to

catalyze the addition of various Grignard reagents to vinyltri-
phenylphosphonium bromide followed by an addition of alkyl
or aryl aldehyde to yield alkenes.

91

In the absence of either sil-

ver carbonate or water, the desired product was obtained in only
25% yield. Copper chloride could also be employed in the re-
action, giving similar results. The reaction of lithium cuprates
with vinyltriphenylphosphonium bromide followed by the reac-
tion with an aldehyde has been previously demonstrated.

92

The

addition of phenyllithium cuprate to vinyltriphenylphosphonium
bromide and consequent reaction of the resulting phosphorane
with para-N,N-dimethylaminobenzaldehyde gave a 45:55 mixture
of E- and Z-isomers. Alternatively, the reaction of phenylmagne-
sium bromide in the presence of CuBr–Ag

2

CO

3

resulted in higher

yields and gave 100% E-selectivity.

CuBr is also used to catalyze the Crabbe reaction, in which

various alk-1-ynes react with an excess of formaldehyde and
di-isopropylamine in the presence of catalytic copper bromide
in refluxing dioxane to give the corresponding allene homologs
(eq 12).

93

•

R

H

R

CH

2

O, iPr

2

NH, CuBr

(12)

1.5

−30 h

40

−62 %

The reaction does not proceed in the absence of copper bromide,

though its role is not precisely known. Copper in oxidation states
(0), (I), and (II) has been detected in the course of the reaction.

1.

(a) Lipshutz, B. H.; Sengupta, S., Org. React. 1992, 41, 135. (b) Rossiter,
B. E.; Swingle, N. M., Chem. Rev. 1992, 92, 771. (c) Chapdelaine,
M. J.; Hulce, M., Org. React. 1990, 38, 225. (d) Erdik, E., Tetrahedron
1984, 40, 641. (e) Posner, G. H., An Introduction to Synthesis Using
Organocopper Reagents

; Wiley: New York, 1980. (f) Posner, G. H., Org.

React. 1975

, 22, 253; also see: Posner, G. H., Org. React. 1972, 19, 1.

(g) Lindley, J., Tetrahedron 1984, 40, 1433. (h) Wipf, P., Synthesis 1993,
537. (i) Normant, J. F.; Alexakis, A., Synthesis 1981, 841. (j) Dave, V.;
Warnhoff, E. W., Org. React. 1970, 18, 217.

2.

Reich, M. R., C. R. Hebd. Seances Acad. Sci., Ser. C 1923, 177, 322.

3.

Gilman, H.; Straley, J. M., Recl. Trav. Chim. Pays-Bas 1936, 55, 821.

4.

Costa, G.; Camus, A.; Gatti, L.; Marsich, N., J. Organomet. Chem. 1966,
5

, 568.

5.

(a) Bertz, S. H.; Dabbagh, G., J. Am. Chem. Soc. 1988, 110, 3668.
(b) Bertz, S. H.; Dabbagh, G., Tetrahedron 1989, 45, 425.

6.

Olmstead, M. M.; Power, P. P., J. Am. Chem. Soc. 1990, 112, 8008.

7.

Lenders, B.; Grove, D. M.; Smeets, W. J. J.; van der Sluis, P.; Spek,
A. L.; van Koten, G., J. Organomet. Chem. 1991, 10, 786.

Avoid Skin Contact with All Reagents

6

COPPER(I) BROMIDE

8.

Kapteijn, G. M.; Wehman-Ooyevaar, I. C. M.; Grove, D. M.; Smeets, W.
J. J.; Spek, A. L.; van Koten, G., Angew. Chem., Int. Ed. Engl. 1993, 32,
72.

9.

Olbrich, F.; Kopf, J.; Weiss, E., Angew. Chem., Int. Ed. Engl. 1993, 32,
1077.

10.

House, H. O.; Chu, C.-Y.; Wilkins, J. M.; Umen, M. J., J. Org. Chem.
1975, 40, 1460.

11.

Lipshutz, B. H.; Whitney, S.; Kozlowski, J. A.; Breneman, C. M.,
Tetrahedron Lett. 1986

, 27, 4273.

12.

Bertz, S. H.; Gibson, C. P.; Dabbagh, G., Tetrahedron Lett. 1987, 28,
4251.

13.

Davis, B. R.; Johnson, S. J., J. Chem. Soc., Perkin Trans. 1 1979, 2840.

14.

House, H. O.; Lee, T. V., J. Org. Chem. 1978, 43, 4369.

15.

Bertz, S. H.; Dabbagh, G.; He, X.; Power, P. P., J. Am. Chem. Soc. 1993,
115

, 11640.

16.

House, H. O.; Koepsell, D. G.; Campbell, W. J., J. Org. Chem. 1972, 37,
1003.

17.

(a) Bertz, S. H.; Dabbagh, G.; Villacorta, G. M., J. Am. Chem. Soc. 1982,
104

, 5824. (b) Bertz, S. H.; Dabbagh, G., J. Chem. SOc., Chem. Commun.

1982, 1030. (c) Bertz, S. H.; Dabbagh, G., J. Org. Chem. 1984, 49, 1119.

18.

Bertz, S. H.; Dabbagh, G.; Sundararajan, G., J. Org. Chem. 1986, 51,
4953.

19.

Rossiter, B. E.; Eguchi, M.; Miao, G.; Swingle, N. M.; Hernández, A. E.;
Vickers, D.; Fluckiger, E.; Patterson, R. G.; Reddy, K. V., Tetrahedron
1993, 49, 965.

20.

Dieter, R. K.; Lagu, B.; Deo, N.; Dieter, J. W., Tetrahedron Lett. 1990,
31

, 4105.

21.

Melnyk, O.; Stephan, E.; Pourcelot, G.; Cresson, P., Tetrahedron 1992,
48

, 841.

22.

Bertz, S. H.; Dabbagh, G.; Williams, L. M., J. Org. Chem. 1985, 50,
4414.

23.

Jenny, C.; Wipf, P.; Heimgartner, H., Helv. Chim. Acta 1986, 69, 1837.

24.

Westmijze, H.; Kleijn, H.; Meijer, J.; Vermeer, P., Synthesis 1979, 432.

25.

(a) Nakamura, E.; Kuwajima, I., J. Am. Chem. Soc. 1984, 106, 3368.
(b) Nakamura, E.; Matsuzawa, S.; Horiguchi, Y.; Kuwajima, I.,
Tetrahedron Lett. 1986

, 27, 4029. (c) Horiguchi, Y.; Matsuzawa, S.;

Nakamura, E.; Kuwajima, I., Tetrahedron Lett. 1986, 27, 4025.

26.

(a) Wipf, P.; Xu, W., Synlett 1992, 718. (b) Wipf, P.; Smitrovich, J. H.,
J. Org. Chem. 1991

, 56, 6494.

27.

Yoshifuji, M.; Loots, M. J.; Schwartz, J., Tetrahedron Lett. 1977, 18,
1303.

28.

(a) Gardette, M.; Alexakis, A.; Normant, J. F., Tetrahedron 1985, 41,
5887. (b) Foulon, J. P.; Bourgain-Commerçon, M.; Normant, J. F.,
Tetrahedron 1986

, 42, 1389.

29.

Hoffmann, R. W.; Schlapbach, A., Liebigs Ann. Chem. 1990, 1243.

30.

Sharma, S.; Oehlschlager, A. C., J. Org. Chem. 1989, 54, 5064.

31.

Curran, D. P.; Chen, M.-H.; Leszczweski, D.; Elliott, R. L.; Rakiewicz,
D. M., J. Org. Chem. 1986, 51, 1612.

32.

Bacon, R. G. R.; Karim, A., J. Chem. Soc., Chem. Commun. 1969,
578.

33.

Setsune, J.-i.; Matsukawa, K.; Kitao, T., Tetrahedron Lett. 1982, 23, 663.

34.

Hatch, H. B.; Wedinger, R. S. WO Patent Appl. 91 11 494, 1991 (Chem.
Abstr. 1991

, 115, 232 514s).

35.

Müller, E.; Fricke, H., Justus Liebigs Ann. Chem. 1963, 661, 38.

36.

Buck, J. S.; Ide, W. S., Org. Synth., Coll. Vol. 1943, 2, 130.

37.

Cleland, G. H., J. Org. Chem. 1961, 26, 3362.

38.

Keller, R. N.; Wycoff, H. D., Inorg. Synth. 1946, 2, 1.

39.

(a) Hartwell, J. L., Org. Synth. Coll. 1955, 3, 185. (b) Vogel’s Textbook
of Practical Organic Chemistry

; Furniss, B. S.; Hannaford, A. J.; Smith,

P. W. G.; Tatchell, A. R., Eds.; 5th ed.; Longmans: London, 1989, p 428.

40.

Kauffman, G. B.; Teter, L. A., Inorg. Synth. 1963, 7, 9.

41.

House, H. O.; Umen, M. J., J. Org. Chem. 1973, 38, 3893.

42.

Dieter, R. K.; Silks, L. A., III; Fishpaugh, J. R.; Kastner, M. E., J. Am.
Chem. Soc. 1985

, 107, 4679.

43.

Organocopper Reagents. A Practical Approach

; Taylor, R. J. K., Ed.;

Oxford University Press: New York, 1994.

44.

Modern Organocopper Chemistry

; Krause, N., Ed.; Wiley: Federal

Republic of Germany, 2002.

45.

Calo, V.; Nacci, A.; Fiandanese, V., Tetrahedron 1996, 52, 10799, and
references therein.

46.

Breit, B.; Demel, P., Adv. Synth. Catal. 2001, 343, 429.

47.

Knochel, P.; Dubner, F., Angew. Chem., Int. Ed. 1999, 38, 379.

48.

Knochel, P.; Dubner, F., Tetrahedron Lett. 2000, 41, 9233.

49.

Malda, H.; van Zijl, A. W.; Arnold, L. A.; Feringa, B. L., Org. Lett. 2001,
3

, 1169.

50.

Saa, J. M.; Martorell, G., J. Org. Chem. 1993, 58, 1963.

51.

Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L., J. Org.
Chem. 1994

, 59, 5905.

52.

Liebeskind, L. S.; Fengl, R. W., J. Org. Chem. 1990, 55, 5359.

53.

Allred, G. D.; Liebeskind, L. S., J. Am. Chem. Soc. 1996, 118, 2748.

54.

Casado, A. L.; Espinet, P., Organometallics 2003, 22, 1305, and
references therein.

55.

Liebeskind, L. S.; Riesinger, S. W., J. Org. Chem. 1993, 58, 408, and
references therein.

56.

Hudgens, T.; Turnbull, K. D., Tetrahedron Lett. 1999, 40, 2719.

57.

Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M., Chem.
Rev. 2002

, 102, 1359.

58.

Gomez-Bengoa, E.; Echavarren, A., J. Org. Chem. 1991, 56, 3497.

59.

Plisson, G.; Chenault, J., Heterocycles 1999, 51, 2627.

60.

Han, X.; Stoltz, B. M.; Corey, E. J., J. Am. Chem. Soc. 1999, 121, 7600.

61.

Sugiyama, H.; Yokokawa, F.; Shioiri, T., Org. Lett. 2000, 2, 2149.

62.

Ye, J.; Bhatt, R. K.; Falck, J. R., J. Am. Chem. Soc. 1994, 116, 1.

63.

Sakurai, S.; Goto, H.; Yashima, E., Org. Lett. 2001, 3, 2379.

64.

Alphonse, F. A.; Suzenet, F.; Keromnes, A.; Lebret, B.; Guillaumet, G.,
Org. Lett. 2003

, 5, 803.

65.

Liu, Q.; Burton, D. J., Tetrahedron Lett. 2000, 41, 8045.

66.

Singh, R.; Just, G., J. Org. Chem. 1989, 54, 4453.

67.

Akhtaruzzaman, M.; Tomura, M.; Zaman, M. B.; Nishida, J.; Yamashita,
Y., J. Org. Chem. 2002, 67, 7813.

68.

Campbell, I. B., In Organocopper Reagents. A Practical Approach;
Taylor, R. J. K., Ed.; Oxford University Press: New York, 1994, 217.

69.

Yokomatsu, T.; Abe, H.; Yamagishi, T.; Suemune, K.; Shibuya, S.,
J. Org. Chem. 1999

, 64, 8413 and references therein.

70.

Morken, P. A.; Bachand, P. C.; Swenson, D. C.; Burton, D. J., J. Am.
Chem. Soc. 1993

, 115, 5430.

71.

Koradin, C.; Polborn, K.; Knochel, P., Angew. Chem., Int. Ed. 2002, 41,
2535.

72.

Youngman, M. A.; Dax, S. L., Tetrahedron Lett. 1997, 38, 6347.

73.

Fischer, C.; Carreira, E. M., Org. Lett. 2001, 3, 4319.

74.

Wang, J.-S.; Matyjaszewski, K., J. Am. Chem. Soc. 1995, 117, 5614.

75.

Kato,

M.;

Kamigaito,

M.;

Sawamoto,

M.;

Higashimura,

T.,

Macromolecules 1995

, 28, 1721.

76.

Matyjaszewski, K.; Xia, J., Chem. Rev. 2001, 101, 2921.

77.

Wang, J. S.; Matyjaszewski, K., Macromolecules 1995, 28, 7901.

78.

Curran, D. P.; Chen, M. H.; Kim, D., J. Am. Chem. Soc. 1989, 111, 6265.

79.

Iqbal, J.; Bhatia, B.; Nayyar, N. K., Chem. Rev. 1994, 94, 519.

80.

Boivin, J.; Yousfi, M.; Zard, S. Z., Tetrahedron Lett. 1994, 35, 5629.

81.

Clark, A. J.; Duncalf, D. J.; Filik, R. P.; Haddleton, D. M.; Thomas,
G. H.; Wongtap, H., Tetrahedron Lett. 1999, 40, 3807.

82.

Clark, A. J.; Filik, R. P.; Thomas, G. H., Tetrahedron Lett. 1999, 40,
4885.

83.

Clark, A. J.; Dell, C. P.; Ellard, J. M.; Hunt, N. A.; McDonagh, J. P.,
Tetrahedron Lett. 1999

, 40, 8619.

A list of General Abbreviations appears on the front Endpapers

COPPER(I) BROMIDE

7

84.

Clark, A. J.; Battle, G. M.; Bridge, A., Tetrahedron Lett. 2001, 42, 4409.

85.

Clark, A. J.; Battle, G. M.; Bridge, A., Tetrahedron Lett. 2001, 42, 1999.

86.

Clark, A. J., Chem. Soc. Rev. 2002, 31, 1.

87.

Boni, M.; Ghelfi, F.; Pagnoni, U. M.; Zucchi, C., Tetrahedron Lett. 1994,
35

, 7263.

88.

Benincasa, M.; Forti, L.; Ghelfi, F.; Pagnoni, U. M., Tetrahedron Lett.
1995, 36, 1103.

89.

Kim, J. T.; Gevorgyan, V., Org. Lett. 2002, 4, 4697.

90.

Cohen, T.; Shook, C.; Thiruvazhi, M., Tetrahedron Lett. 1994, 35,
6041.

91.

Shen, Y.; Yao, J., J. Org. Chem. 1996, 61, 8659.

92.

Just, G.; O’Connor, B., Tetrahedron Lett. 1985, 26, 1799.

93.

Searles, S.; Li, Y.; Nassim, B.; Robert Lopes, M. T.; Tran, P. T.; Grabbe,
P., J. Chem. Soc., Perkin Trans. 1 1984, 747.

Avoid Skin Contact with All Reagents