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The copper catalysed reaction of sodium methoxide witharyl bromides : a mechanistic study leading to a facilesynthesis of anisole derivativesCitation for published version (APA):Aalten, H. L., Koten, van, G., Grove, D. M., Kuilman, T., Piekstra, O. G., Hulshof, L. A., & Sheldon, R. A. (1989).The copper catalysed reaction of sodium methoxide with aryl bromides : a mechanistic study leading to a facilesynthesis of anisole derivatives. Tetrahedron, 45(17), 5565-5578. https://doi.org/10.1016/S0040-4020(01)89502-8
DOI:10.1016/S0040-4020(01)89502-8
Document status and date:Published: 01/01/1989
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Terrahedron Vol. 45. No. 17. pp. 5565 to 5578, 1989
Printed in Great Britain. 004@4020/89 $3.00+ .OO
0 1989 Pergamon Press plc
THE COPPER CATALYSED REACTION OF SODIUM METHOXIDE WITH ARYL
BROMIDES. A MECHANISTIC STUDY LEADING TO A FACILE SYNTHESIS OF
ANISOLE DERIVATIVES
mk L. Aalten,a Gerard van ~oaen, *, fb b mid M. orove,c
Thijs KuilmanP Onno G. Piekstra,d Lumbertus A. Hulshof d and Koger A. Sheldond
a Anorganisch Chemisch Laboratotium. J.H. van ‘t Hoff Instituut, University of Amsterdam, Nieuwe
Achtergracht 166,1018 WV Amste&q TheNetherlands
b Present addmss; Labomnq for Organic Chemistry, Deptof Metal-Mediated Synthesis, University of Utmcht,
Padualaan 8,3584 CH Utrecht, ‘lhe Netherlands.
c See b.
d Andeno B.V., p.o. box 81.5900 AB Venlo.
(Received in UK 14 March 1989)
Abstract
The copper catalysed reaction of unactivated aryl bromides with sodium methoxide has been investigated by
studying a number of parameters (copper catalyst, cosolvent, concentration and relative ratio of the reactants,
additives and aryl bromide substituents) which influence this reaction. ‘Die ipso-substitution reaction was found
to proceed via an intimate electron transfer mechanism involving a cuprate-like intermediate, Na[Cu(OMe)2]. A
convenient synthesis of methyl aryl ethers from sryl bromides and concentrated sodium methoxide solutions in
dimethyl formami de and methanol is presented. Also an attempt to extend this reaction to the use of chlorine
derivatives was made.
INTRODUCTION
Previous investigations aimed at the synthesis of methyl aryl ethers from unactivated substrates (substrates
without strong electron withdrawing substituents) have had limited success. Methods for the introduction of
methoxy substituents onto aryl rings am important because several ethyl aryl ethers ate used as intermediates for
the synthesis of pharmace utical products. 1.3.5Trimethoxybenzene for instance is used in the synthesis of some
5565
5566 H. L. AALTEN et al.
msoactivc d~gc. Iblomxm methyl my1 ethers am possible interr&iater in alternative phenol syntheses since
dreir hydrolysis would yield phenol derivatives.1
The most suaightfawrrd inuoduction of a methoxide substituent is the ma&u of an aryl halide with methoxide
ion, q 1.
Arx + h&O- - ArOMe + x- (l)
This synthesis ofmthyl aryl ethers is successful with activated aryl substrates (aryl rings having strong electron
withdrawing substituents), when the ipso-substitution proaeds via an SRAr mechanism.2 Fu&ermom, methyl
aryl ethers am nccessible via the reaction of unactivated aryl chlorides. through substitution of the halide by
m&oxide ion in hexamethylpborpharic acid triatMe @IMPA).S This prouxke Hoover is not very convenient
(yield 50% of ankle in 18.5 h from chlombenzene; HMPA is a cancer suspect agent).
Methyl sryl ethers can also be synthesized from unactivated aryl bromides and iodides by a copper catslysed
ipsosubstitution reaction. The competition between the reduction and the substitution reaction of several aryl
bromides and iodides in methanol/collidine catalysed by CuI at 100-120 T was investigated by Bacon and
coworkers.‘t They found, firstly, that the amount of reduction increased when methoxy substituents wem present
ortho to the halogen atom and, secondly, that aryl iodides were mom responsive to reduction than the bromides.
Their best result was the total bromide substitution of I-bromonaphthalene by ethoxide ion in 6 hours (with
methoxide ion they reached %% substitution).4c
Litvak and Shein investigated the mechanism of the copper catalysed reaction of aryl bromides with sodium
methoxide in competition with the uncatalysed pmcess in rncthanol/pyrkW using low methoxide WlIcenuatiOns
(c 1.0 hQ.5 They found that the copper-catalysed ipso-substitution reaction was first order in aryl bromide and
catalya while the concentration of the sodium methanolate was irrelevant They made a Hammett correlation that
showed the infIuence of substituents in the copper catalysed reaction was relatively small @ = 0.48) compared to
their influence in the uncatalysed S@r substitution reaction (p = 5.0). They proposed a mechanism that
combined a radica_l reaction with a Ccenue substitution process (Scheme 1). Their study lacked the translation of
their mechanistic investigations into a useful synthetic procedure.
Scheme 1
ArBr + C&OR&,,
I ArBr?ur(ORjLn_I
III I
-L - ( ArBrC&OR&,_1
+L ] = [ ArB&uu(OR)L,+l] =
I II
a ArOR + CurBrLu_,
Synthesis of anisole derivatives 5567
white&lea et al. showed that Cu(I) abxidcs, formed by the maction of methylcoppeso with alcohols, react at
mom temperatutu with aryl bromides atul lodides to give ethers.6Thir reaction ls synthetically incatvenknt but
the~tclearlyindicrterthtCuCI)~rreabletoorrnrferm~yOl’wpeomuylmboaue.CapperO
rllroxides~thaeforeliltelytobeimnmediruesinthtcoppa~~~~of~~mthoaidewitharyl
halides.
Our study concerns a thortnrgh investigation of vatious pamnHers thatinfluencethecoppercatalysedmactionof
aryl bromides with me&oxide. The aim of this study was, i. the dev&pment of a convenknt syntherls of methyl
atyl ethers from aryl bromi&s, ii. to elucidate the mechanism of this reaction and, fii, hopefully an extension of
this reaction to aryl chloride substrates. The use of the latter as starting material is economically and
environmentally favoumd since atyl chlorides are cheaper in the production process and sodium chloride instead
of sodium bromide is the waste product.
In the course of our investigation it has been found that the concentration of sodium mthoxide is very important
(contrary to the conclusion of Litvak and Shein) and that the teaction pmceeds via an intimate electron transfer
mechanism involving a cuprate-like intermedkte, NaKu(OMe)2].
RESULTS and DISCUSSION
The copper catalysed nuckophilic aromatic substitution reaction of aryl bromides with sodium methoxide was
studied by investigating the influence of several reaction parameters, namely i, the nature (oxidation state/ anion)
and concentration of the copper catalyst, ii, the cosolvents. iii, the concentration and number of equivalents of the
nucleophile, iv, the bmmidc concentration, and v, the aryl bromide substituent effects. The reactions that are
carried out, am summarized in Table I and theii course was followed by taking samples which were analysed by
GLC. The conversion percentages of bromobenzene to anisole after 6 h (unless stated otherwise) are listed in
Table L Other results of several mactions are summarized in Tables II and IIl and in Figutes 1 and 2.
The copper catalyst
The nature of the copper catalyst.
Although the valence of the reactive copper catalyst in copper catalysed nuckophilic substitution reactions is
generally considered to be +l (see ref. 7) several oopper catalysts with copper in diffemnt oxidation states were
investigated atKl the intluence of aging of various qpero catalysts studied.
A comparison of the first four entries clearly shows that the age of the C!u(l)Br is unimportant; tlte same mactivity
was found fa commercial (1, 3) as for freshly prepared copper(I) bromide (2, 4). This indicates that the
oxidation state (or purity) of .the copper catalyst used is not particularly televant since copper(I) bmmide is known
to disproportionate into copper bromide and copper metal or oxidize to copper bromide when it is St&
for long periods.
Tab
le L
Rea
ctio
n pa
ram
ems a
nd
colr
vers
ion
perc
enta
ges8
afth
ecop
paca
taly
sedr
wct
ion
sofs
odio
mm
etbo
Pdd
euit
hh
ambe
mm
e~aa
aiL
Rca
cnon
no.
C
&sB
r N
aOM
ein
McO
H
cata
lyst
0 A
ddit
iVC
S/~
SO
i~tS
m
mol
mL
+m
um
lM
mL
n
atu
re
mm
ol
naa
m
Tee
) %
Ram
r&
mm
01
UlL
bt
tml
rfta
6h
1 10
0 10
.3 1
00
1.67
60
C
dr.
10
R7i
52
.6
; 1:
5 6 7 ; 10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
100
10.3
100
1.
67
60
100
10.3
150
5.
4 27
.7
100
10.3
150
5.
4 27
.7
100
10.3
100
1.
67
60
100
10.3
150
5.
4 27
.7
100
10.3
150
5.
4 27
.7
100
10.3
10
0 5.
4 18
.5
100
10.3
-10
0 5.
4 18
.5
100
10.3
100
1.
67
60
100
10.3
100
1.
67
60
100
10.3
150
5.
4 27
.7
100
10.3
100
5.
4 18
.5
100
10.3
100
1.
67
60
100
10.3
100
5.
4 18
.5
100
10.3
150
5.
4 27
.7
100
10.3
150
5.
4 27
.7
100
10.3
150
5.
4 27
.7
100
10.3
150
5.
4 27
.7
100
10.3
150
5.
4 27
.7
30
3.1
300
5.4
54.4
30
3.
1 30
0 5.
4 54
.4
30
3.1
300
5.4
54.4
10
0 10
.3 1
50
5.4
27.7
10
0 10
.3 1
00
1.67
60
10
0 10
.3 1
00
1.67
60
10
0 10
.3 1
00
1.67
60
10
0 10
.3 1
00
1.67
60
CU
BP
8%
[cuo
Bz]
qd
vJ@
f4M
=
PP
=P
W~
cu
d C
uB
r C
lld
Cu
EIr
[C
u(O
Mej
2l
cuC
l2
cuC
l2
cuC
l2
Cu
BdC
uO
C
uB
rKu
Q2
Cu
BrK
uB
r
:s
Cu
Br
Cu
Br
CuB
r C
uB
r C
uB
r C
IlB
f C
uB
r C
uB
r
10
10
10
10
10
:: :x
:: :x
10
lO/l
om
lO/l
P
lO/l
P
:8 O&
3
3:
100
10
10
10
10
DM
F
iE
DM
F
DM
F
iE
MF
IlM
At
NF
P'
DM
It
52.z
i
:i 33:9
4.
#
7E
ii:!
iit:
63
.6
tz
ii:
93:1
az
82.0
10
0 10
0 49
.8
53.0
52
5 42
4 47
.4
29
i: 32
33
i:
;: 38
z 41
42
43
44
z 47
48
49
50
loo
10.3
10
3 5.
4 18
5 lo
o 10
.3
103
5.4
185
loo
10.3
10
3 5.
4 18
5 lo
o 10
.3
loo
1.67
60
lo
o 10
.3
loo
3.6
27.7
lo
o 10
.3
loo
5.4
18.5
lo
o 10
.3
loo
5.4
18.5
lo
o 10
.3
150
5.4
27.7
lo
o 10
.3 2
00
5.4
37.0
lo
o 10
.3 3
00
5.4
555
loo
10.3
10
3 5.
4 la
5 lo
o 10
.3
150
5.4
27.7
lo
o 10
.3
150
5.4
27.7
lo
o 10
.3
150
5.4
27.7
lo
o 10
.3
150
5.4
27.7
lo
o 10
.3
150
5.4
27.7
lo
o 10
.3
150
5.4
27.7
20
0 20
.6
300
10.8
g
loo
10.3
15
0 8.
1 g
200
20.6
30
0 10
.8 g
20
0 20
.6
300
10.8
g
200
20.6
30
0 10
.8 g
Cu
Br
Cu
Br
Cu
Br
Cu
Br
Cu
Br
Cu
Br
Cu
Br
Cu
Br
s Cu
Br
Cu
Br
Cu
Br
Cu
Br
Cu
Br
Cu
Br
Cu
Br
Cu
Br
Cu
Br
Cu
Br
Cu
Br
Cu
Br
10
10
10
10
10
:8
ii
10
10
:8
10
io”
;i 10
20
ii
EF
25
5’
,0
38
0.19
DM
F
091
DM
F
ii
4’
DA
@
:; 4
DM
F
4
DM
F/N
aBr
40f4
8.5
3l5g
Ii
Br
10
0.8
g C
OB
Q
10
2-2t
1,
3-D
NB
W
10
1.7
g cu
men
e 50
7.
0 g
DM
ZL
H
325
25
5Of3
0 bM
F
NM
WM
CO
H
5zo
DM
TlM
eoH
5o
m
-l-M
UV
MC
OH
5o
l30
EZ
iii
; E
t!
9272
iii:
92
72
110
110
110
110
110
110
110
110
110
110
110
110
55.5
18
.4
a.
b.
t 2 F:
1 . m
n.
0.
mkz
eeta
ges
wer
e ca
lcul
ated
fro
m G
LC
spe
ctra
usi
ng i
ntm
nai
Us-
3 sw
ud o
lhem
isc
anm
ncrc
iaIl
y ob
tain
ed (
i.e.
aged
) cop
per
salt
s w
ere
Ye
llow
-gre
w rt
acfio
n lnix
mm
. ~Y
pw4-
Jcop
pcrj
9~
Dar
k pur
ple-
bI* r
eedo
n m
ixtu
re.
Ed
reac
uOn m
umm
* *f
tsh~
%ie
D
ark b
lue n
zcti
on m
&c.
C
olou
rles
s mct
iq
mbq
nre c
onta
inin
g sol
id c
oppe
r
Afm
4h
!uic
dalli
me.
Aft
cr1h
reac
tiam
tim
c.
Aft
er30
m r
wai
anti
mc.
A
ffex
2Om
rex
tion
tim
e.
5570 H. L. AALTEN et al.
When copper(l) benxoate was used as a catalyst (5) the reaction proce&d more slowly than when catalysed by
cmppcrt9 bromide (1,2). When copper0 phthalocyanine (6) or copper powder (7) wets used as caudysts the
yield of anisolc is very pcor compamd 00 the identically executed copper@ bromide catalysed mactions (3.4).
The nactivity of copper(T) chloride and copper(T) bromide was comparable in both concentrated sodium
methoxide (used as a 5.4 M solution in methanol, mactions 8 and 9) and in diluted sodium methoxide (used as a
1.6 M solution in methanol, ltactions 10 and 11).
When copper salts wemud the substitution maction was highly dependent on the concentration of the
sodium methoxide in the reaction medium. If the concentration of sodium methoxide was high (5.4 M) then
copper methoxide (12) and copp&II) chloride (13) were effective catalysts (92.0 and 63.6% yields.
mspectively, after 6 h). However, if the concentration of sodium methoxidc was low (1.67 M) coppe@) chloride
(14) hardly camlysed the substitution maction (yield 3.6% after 6 h).
lhe temperatum (reflux) of the concentrated sodium methoxide reaction (13) was higher (T - 92 “C) than the
diluted sodium nuthoxide m&tion (14; T = 70 “C). The former reaction was also executed at 70 Y! to exclude an
unexpected extreme tempemtum effect. This reaction (15) gave a comparable amount of anisole as reaction 13
(66.7%. 6 h) and therefore it is clear that the efficacy of copper chloride as catalyst is determined by the
methoxide concentration and not by the reaction temperature. The difference between reaction 13 and 15 was that
reaction 13 was very fast in the beginning and after one hour already 50% bromobenxene had reacted while this
was only 16% in the low temperaturereaction (15).
To further elucidate the reactive oxidation state of the copper catalyst in the substitution reaction more copper
catalyst was added after a reaction tim of 2 hours. When ccpperpowder was added (16) the substitution reaction
was not influenced. Copper chloride (17) retarded the substitution reaction a little while copper(T) bromide
(18) accelerated the reaction in the first 30 mm after its addition (see Figure 1). These findings indicate that the
reactive copper catalyst is in the +1 oxidation state. Copper@) salts are nevertheless able to catalyse the
substitution reaction in concentrated sodium methoxide. This is only possible when reduction to copper(I) (by
concentrated sodium methoxide) occurs
The influence of concentrated sodium methoxide solutions on the oxidation state of the copper catalyst was further
investigated by postponed addition of bromobenxene to a mixtum of copper(Q bromide and concentrated sodium
methoxide (5.4 M in methanol) at 92 T. When after 16 hours (19) bromobenzent was added to this mixture, a
copper metal coloured suspension, formation of anisole was not found. When bromobenzcne was added after 2
hours (20), however, just a slightly lower conversion to anisole was found (82.7%. 6 h) compared to the normal
addition reaction (4.87.6%).
The formation of unreactive zerovalent copper metal in reaction 19 can be readily understood. In hard
coordinating solvents copper@ salts generally undergo valence disproportionation to zerovalent copper and
copper@). The copper@) salts formd can then be reduced by the concentrated sodium methoxide solution to
copper(I) (vi& supra ). The repetition of this reaction sequence (Scheme 2) finally results in only zerovalent
copper being pxsent. These findings indicate once more that concentrated sodium mthoxide soh~tions ax able to
nxluce copper(D) to copper(I) species which are then able to catalyse the reaction.
Synthesis of anisole derivatives 5571
Figure 1. The progma of the CuBr crtalywd reaction of phcnyl bromide with sodium mcthoxi& when variouscopjWcollminingspccicsateaddadafter2bours.
1oC
80
a
40
t
20 PbBr
P!Br (0.1 moly NaOhIc (0.15 mol, 5.4 B&/ CuBr (0.01 md)
0 1 2 3 4 5 6
llSCtiOIltime(h)
A&lllive
- CUQ - Cue/ none -CuBr
Scheme 2
i. solvent induced valence dispqxntionation
ii. reduction of Cukmcentrated NaOMe
The concentration qfthe copper catalyst.
The results of reactions 21-23 in which the amount of copper catalyst added to the reaction was varied showed
that the reactions proceeded faster with increasing catalyst concentration (see Table II). The increase in reaction
rate, however, appezued to be non-linear (a ten-fold increase in catalyst concentration increases the reaction rate
respectively, from 7.26 x 10-5 s-l (reaction 21) to 4.19 x 10-4 s-l (22) to 8.14 x 104 s-1 (23)).
The results of Feaction 24 disproves the suggestion that any increase in copper catalyst, with respect to sodium
methoxide and bromobenzne, should improve the substitution reaction (ratio NaOMe/PhBr/Cu(I)Br = 1 .5/ l/ 1).
The amount of substitution product in this reaction after 6 h was only 49.8% (100% after 2 h for reaction 23).
This behaviour indicates that copper(I) methoxide, presumably the effective catalyst, is formed by a methatbesis
reaction between Cu(I)Br and NaOMe (eq 2) and that it is not able to transfer its methoxkle ligand to the aryl
5512 H. L. AALTEN et al.
nucleus but tbat the 8ubstitution of the aromatic bromine atan mquires additional sodium tmtboxide. !kce we
have in reaction 24 only 0.5 equivalent of NaOMe left (with respect to bmnobcnzene) after the quantitative
formation of copper(I) methoxide, it is only possible to attain 50% (49.8% observed) product formation.
Cu(I)Br + NaOMe - Cu(I)OMe + NaBr (2)
Table II. The effect of the concentration of the catalyst.bb
Reaction no. [QW Conversion 96 after k x 10-4
(mol/L) 3Omi.n 6Omin (s-l)
cotr. co&.
21 0.0952 6.3 17.3 0.726 0.9950
22 0.052 54.3 81.5 4.19 0.9991
23 0.52 76.2 94.9 8.14 0.9999
a When the copper catalyst was added the reaction mixture became deeply colouted. Therefom,
it was difficult to determine if the reactions were homogeneous of not. Our data am treated as if
obtained from homogeneous mixtums.
b. First order kinetics assumed for bromobenzene.5
The cosolvent
Cosolvents in copper catalysed reactions am considered to i. act as ligands that increase the solubility of the
copper(I) catalyst and/or ii. stabiixe the reactive copper(I) oxidation state (thereby incmasiig the reactivity and/or
lifetime of the catalyst). Compared with the result of the standard substitution reaction 1 the only co-solvent found
to have a positive effect is DMF (11) while the other cosolvents either have no effect (methyl formiate (25).
NJ-dimethylacetamide (26)) or retard the substitution reaction (N-formylpiperidine (27).
1,3-dimethylimidaxolidone (28)).
The positive effect of DMF as a cosolvent was further investigated in reactions using 10 equivalents of sodium
methoxide (reactions 29-31; compare with 22). It was found that increasing the DMF : copper(I) bromide ratio
from 0.25 (29) to 0.5 (30) to 1.2 (31). the conversion after 15 minutes increased from 10% to 16% to 21%,
respectively. After prolonged reaction times, however, the conversions hecame similar.
The nucleophile
The concentration of sodium methoxide.
Since the sodium methoxide concentration is found to have a large influence on the copper chloride catalysed
reactions we have also investigated its influence on the copper(I) bromide catalysed reactions (reactions 32-34).
These reactions were ail canied out at 72 “C to exclude temperatum effects though the temperatme of ma&on 34
(using 5.4 M NaOMe in methanov proved difficult to control since the ma&on was very exothermic.
Synthesis of anisole derivatives 5513
Thenactionwithl.sMlodiummcthoxiderdutioninmethrnol(32)~~letsMisolethurthereacti~swith
3.6 M or 5.4 M sodium methoxide (33 and 34) that reached comparable conversions after 6 hours. Reaction 34.
however, proceeded faster in the beginning than ruction 33 (e.g. after 15 min the conversions m 34% and 25%
tespectively).
The explanation for these results is that the (@formation of the active catalyst is only very effective in
concentrated sodium m&oxide reaclion mixtums. This conclusion was already reached from the results of the
influence of the sodium mthoxidc cona5ntration on rhe copper(n) chloride catalyscd reactions (vkfe supra ). It is
noteworthy that the substitution reactions in concentrated sodium m&oxide solutions (5.4 M) all proceed very
quickly in the beginning (i.e. it takes ca. 30 min until a conversion of about 5096 is reached) and then slow down
considerably. The explanation for this is that as the sodium methoxide reacts. its concentration drops until it is
eventually below a critical level where the refmn of the active copper catalyst becomes vezy slow.
Our conclusions contradict with those of Litvak and Sheins who stated that the substitution reaction was
independent of the concentration of sodium mrhoxide. It must be noted however that they generally used low
(c 1 .O M) sodium methoxide concentrations.
The number of equivulents of sodium methoxide.
In reactions 35-39 using 100 mmol of bromobenxene (and 10 mm01 of copper(I) bromide) it was found that
increasing the relative number of quivalents of sodium methoxide with respect to bromobenzene f?om 1: 1 to 10: 1
had a positive influence on the progress of the reaction when the mixture was kept at constant nflux. In the fit
15 min of these reactions there is not a great difference conversion percentages; they range from 32.7 to 40.0%.
However, over more prolonged reaction times the substitution reaction proceeds better when the amount of
sodium methoxide present is higher.
The conversions in these experiments depend on two factors, namely the reflux temperam and the methoxide
concenaation; both of which change as the reaction proceeds. In particular at low NaOMe to bromobenzene ratios
the reflux temperature decreases rapidly (from 92 to 75 ‘C in the initial 30 min). This is primarily due to the
release of “solvent cage bonded” methanol from sodium methoxide. When the NaOMe to PhBr ratio is initially
10: 1 the reflux temperature drops only 2 “C! in two hours. Regarding the NaOMe concentration we have already
shown that when this drops below a critical value the nformation of the active copper(I) catalyst slows down and
consequently the reaction pmceeds more slowly (vi& suprcl ).
The bromide concentration
One of the products of the copper catalysed substitution reaction of sodium methoxide with bmmobenzene was
sodium bromide (besides unidentified copper salts, anisole and traces of benzene (< 1%. only found in reactions
24. 37 and 40. see Table I); biphenyl was never found). The possible reversibility of the copper catalysed
aromatic substitution reaction of aryl bromides with sodium methoxide was investigated by adding bromide
containing salts to the reaction mixtu~ (reactions 40-42). Addition of sodium bromide had little effect on the
reaction but this is probably due to the limited solubiity of this salt under the conditions employed. When either
lithium bromide (41) or cobalt(U) bromide (42) was added, the reaction was significantly retarded. This result is
5.574 H. L. hLTEN et aI.
ambiguous ud could be explained by either 1, a mvcrsible reaction or U, form&on of mixed metal species which life prwutnably less active catalysts for the substitution reaction.
Substituent effects
Substituent effects in the copper catalyscd ipso-substitution reaction of sodium methoxide with aiyl bromides
were investigated by malting a Hammett correlation based on competition reactions between bmmobenxene and
various aryl bmmides. The aryl ring substituents used were p-OMe. m-OMe, p-Me, m-Me, p-Cl and m-Cl. The
results of the competition reactions with m-methylbromobenxene were not included in the final Hammett
conelation since they showed too large a discrepancy with each other and with the other measurements. Ortho
substituted aryl bromide derivatives were excluded because of their possible steric and chelating consequences.
Strong electron accepting groups were also not used because then the uncatalysed reaction would begin to play an
impoltant role.5
Ihe Hammett correlation was measured by competition experiments using lOequivalents, with respect to the total
amount of aryl halogen& present, of sodium n&oxide (see experimental). These pseudo first order reactions
gave a p value of 0.49 (can: coef. = 0.9032) see Table III, Figun 2). This value indicates that the slow reaction
step, in the product forming reaction sequence, has a minor nucleophilic nature (p values found for the SNAr
reactions are always > 2). The p value we found is in good agreement with the value found by Litvak and Shein
for the cqper cataIysed reaction in diluted sodium methoxide solution in methanol/pyridine @ = 0.48).
Table III. The reactivity of sevual substituted aryl bromides
nkaive to jhenyl bromide in the coppa catalyscd reaction of aryt
bmmides with sodium methoxide.
substitllult 0 LxFH(sW logWH
PoMe -0.28 05636 (0.1572) - 0.242490
m-OMe 0.10 1.1890 (0.1425) 0.0752
PMe - 0.14 0.9091 (O.OtW) - 0.0414
PC1 0.24 1.1302 (O.os75) 0.0531
m-Cl 0.37 1.3264 (0.1430) 0.1227
The reaction mechanism
Figure 2. The dependence of log kx/log kH on (he (I wostants of the substituenls
y = 0.49 x + c (CUT. coef. = 0.9032)
From our study of the paramters influencing the copper catalysed nucleophilic aromatic substitution reaction of
sodium methoxide with unactivated aryl bromides it was concluded that i, the reactive catalyst is copper(I)
methoxide which was, however, not able to transfer its methoxide ligand to the aryl moiety (it needed at least
another equivalent of sodium methoxide to substitute the bromine atom on the aryl ring), ii, the reaction order in
copper catalyst under our conditions is smaller than 1, iii, the conversion of the reaction increased with increased
ratio of sodium methoxide to aryl bromide and iv, the p value found (0.49) indicates that the slow reaction step,
in the prcduct forming reaction sequence, has a minor nucleophilic nature.
Synthesis of anisole derivatives 5575
Bkwdonthese~lurionrrheporriblemechraitnu~thir~canberesaictedtotwo,I.c.eitheranS~l
or an intimate electron transfer me&a&m. Tbe mechanism was further investigated by the addition of radical
scavengers to discover whether it hrd a fxec radical chmactcr or not. When 1,3dinitmbenzcne (1,3-DNB) was
&ed (1 equivalent with nspect to the copper catalyst) five minutes after tbe substitution xeaction was started, the
tea&on was inbibited completely (43). This effect can either be due to 1,3-DNB scavenging tbe radical reaction
aritsbindingtothe~crulynmakingitunrerctive.Incontratttheadditionofcumne had no effect on the
faction and no tq-mtbylstyrene was t?mned (44). This indicates that the copper catdyscd substitution reaction
procecdsrath~viaenintimoae~aansftr~hrurismthanviaafreeradicalmchanism.
We propose that cuprate-lie intermediates e.g. Na+[Cu(OMe)2]‘, are tbe reactive catalysts in the copper
catalyscd substitution IW&XIS of sryl bromides using concentrated sodium metboxide (see Scheme 3). After the
formation of the reactive cuprate catalyst the next step in the reaction sequence must be the formation of an
aggregate between tbe copper-centre and the aryl moiety. This aggregate can be formed by the coordination of the
aryl moiety to the copper atom via its Ir-electrons or via the n-electron of the halogen atom. The possibility of the
n-electron coordination mode is illustrated by several known complexes of aryl rings towards copper(I)
salts.9~10 The next step in the reaction will be the transfer of electron density (s 1 electron) from the copper(I)
atom to the aryl moiety. Thii electron density initiates the weakening of the carbon-bromine bond when it is
situated in the o*-orbitaLl The complete bond breakage between the bromine and the carbon atom can then
proceed via two reaction routes; A, via consecutive oxidative addition-reductive elimination reactions or B. via a
concerted process. Tk oxidative addition-reductive elimination reaction path seems unlikely since then trivalent
copper intermediates would have to be formed This is not likely to happen in a reaction medium where even
copper (II) is reduced to copper(l).
The release of an aryl bromide radical anion from intermediate IV must be responsible for the formation of
benzene that is found as the only minor side-product in our reactions. From this radical anion the bromide anion
dissociates and the aryl radical than forms benzene by interaction with the solvent.
The order in Cu(I)Br found for these reactions (< 1) is explained by a monomer-dimer equilibrium for
Na+[Cu(OMe)2]-_ The monomer would then be the reactive catalytic species while the dimer is unreactive (eq 3).
2 [Na+[Cu(OMe)a-] _ Kactive
INa+FXOM21-12 llllleactive
(3)
Synthetic considerations
The knowledge obtained about the mechanism of tbe copper catalysed nucleophilic aromatic substitution reaction
of sodium methoxide with bromobenxene has been used to develop a convenient synthesis of anisole (or its
derivatives). The reaction kinetics indicate that the concentration of the sodium methoxide in methanol must be as
high as possible for a fast reaction. Since DMF appeared to be a useful cosolvent this was used as such.
The successful high yield synthesis of anisole is carried out by adding 150 mm01 of sodium methoxide (27.7 mL
of a 5.4 M solution in methanol), bromobenxene (10.3 mL, 1OCi mmol) and DMF (25 mLJ to a reaction vessel,
heating the mixture to a mflux temperature of 110 T, with methanol being allowed to distil out of the reaction
vessel, followed by the addition of copper(I) bromide (1.44 g; reaction 45). Quantitative formation of anisole
5516 H. L. AALTEN et al.
NaOMe + CuBr - CuOMe + NaBr NaoMew Na [Cu’ (OMe)d I II 1 electron
shift ArBr =
Me0 OMe_
Ill
Na+ I\
Me0 1 OMe Na+
IV
A
-
B
oxidative addition t
Br
Me6
+ Na[Cu’(OMe)Br]
1 _
reductive elimination
OMe
1 Na+ +
Na[Cu’(OMe)Br]
Scheme 3. Proposed mechanism of the copper catalysed reactiori of aryl bromides with sodium methoxide.
Synthesis of anisoie derivatives 5511
was finished within 30 min. An alternative faster method using solid sodium mthoxide was aim developed
(maction 46, me q&mental)
When no methanol was added to the DMF reaction mixture (47) the fosmation of anisole was poor, presumably
some methanol is necessary to enable the reaction because of its ability to dissolve sodium mthoxide (not all
methanol is distilled ok in mazion 451).
With the aim to further improve the substitution reaction (to enable the use of chlorobenxene instead of
bromobensene) the use of other cosolvents with an amide function was also investigated in the reaction with
bromobenane using solid sodium methoxide. When N-methylpyriIidinone (48) or 1,3-dlmethylimidaxolidone
(49) were used instead of DMF the reaction proceeded even faster. These mactions have the disadvantage that
they am exothermic and themfom difkult to conuol. Conmquently these solvents cannot be mccmmended for the
synthetic pmcedum with btomobenxene. The maction canied out with tetramethylumum (TMU. tea&on 50) was
somewhat slower than the DMF maction (46).
Since in the competition reactions no severe difference in mactivity between bromobenzcne and the aryl bromides
used @-OMe-. m-Oh%?-, p-Me-, m-Me-, p-Cl- and m-Cl-bromobenxene ) was found we assume that this
synthetic procedure is of general nature when aryl bromides are used without strong electron withdrawing
substituents.
Possible chloride substitution
The copper catalysed nucleophilic aromatic substitution reaction of sodium methoxide with chlorobenxene was
attempted using the optimal conditions far the bmmobenzene substitution react& with N-methylpyrilidinone as a
solvent. After 1 hour this reaction yielded only 4 % of anisole and thereafter this amount did not increase.
However a considerable amount of benzene (16 %) was formed in this reaction mixture after 6 hours. This result
indicates that the carbon-chlorine bond is activated but that instead of the substitution reaction mduction is taking
place.
It has been found with aryl halides that chlorine substitution is far more difficult in copper catalysed reactions.
This is most readily explained by the more diffuse n-electrons of bromine and iodine derivatives compared to
those of the chlorine derivatives. The more diffuse n-electrons of the bromine and iodine derivatives are able to
improve the complexation step (leading to intermediate III, Scheme 3) and/or the intimate electron transfer step
(leading to intermediate IV). It can therefore be understood that either of these two steps are impossible (or
proceed very slow) in the copper catalysed nucleophilic aromatic substitution reaction of sodium m&oxide with
chlorobenzene. The low conversion of chlorobenxene is thus in good agreement with our proposed reaction
mechanism.
EXPERIMENTAL
General
Reactions were carried out under dry oxygen-free nitrogen wing standad Schlatk techniques. Suhtts wen ratefully dried and distilled prior to use. AryI branides (Meek) were dktilkd and stored undez nitrogm. Metal salts wcn genaally used ILF canmQcially available (CuBr. Cut32 from AMrich; copper powder, LiBr. NaBr. NaOAc f&n Mack; copper pl&taloc~anine from Flulra; C~BQ from Ventron). CIICI,~~ CIIB~,*~ (inciitly used ftcdtly prqated) coppa btmzate14 and m nsth~xide~~ wuc synthesked accordingtolitgatltreproccduressndstoredundslnitrogenIntbc~The5AMN~Mein~lsoluti~rvereobtainedfrom BASF or Dynamit Nobel. The sodium methoxide solutions used in the cunpetition teactiuns was synthesized [ram Dolid sodium mcthoxide and methanol. Solid NaOMe was obtained from BASF awl hated prior 10 use (content always > 99.9 9b).
5578 H. L. hLTEN et al.
General remthn procedurea ’ ThereageatcombinuionsusuiPeibtedinRMeI.Torth+n&d rMctiontidQsOmL)equippulwithacooler(wilhrJliuogea in/out-iet) and a thamometcr wae d&d the uyi bromide. mdium methoxide md the aha soivems & add&iv& at ambient tunpmhIherercliantlraLm~tothehction mmpemmmauitilecappeXamiyuwnaddai*rhenrlta Ihethhllwckwas equipp&withrrPlrmup.
Competition reactions
To I tiuce-necked reretion flask (250 mL) equipped with a cooiu (with a nitrogm in/out-i@ &,a tbennometu were added bromobenzne (7.85 g. SO mmoi. 5.16 mL). the aryi bromide (SO mmoi). the intand reference mesityienc (1.2 g, 10 mmoi, 1.39 mL) and xodium methoxi6e (1 moi. 185 mL of a 5.4 M dutiom in methanol). ‘Ihe readon mixture was lroagbt to the reflux lanperPaue~OC)wharRarthecoppsr~(io~,lA40)wuddcdmdmethird~sp~withrmumcep.
Anaipt of products
ReoclionswercfallowedbytlllciapcunplesdthereCcrionmixMe~~tbtrennncrpwitbtyriaOetechaiquesmdthw suspcndii the samplea $l dtchiommdale Afier~donofthecopparrltrtbeproduculatbedichlommethaele~wen quaotitativciy melysed by gas-liquid cbrbmsloenphy (GU!) on PtrLin Elmer PI7 gas w usingr9%Apiamnand1% carbowax column (1 m x i/8 inch; flow IO mL N2/min). Analysis d the organic products afta tbe comperition =tions ~8s carried out by combii GC-MS and GLC aoafysis. The GC-MS lBldySiS~-Oll8KnltCSMSSUCOlllbidgasehromrtogreph-lMSS q~ummcm (BP 1 column @.0&h 25 m x 0.33 mm x0.5Ir;flow2m~;split~).~mrrssrptctnmrelacadsdU~~voiragcof40eV. Tlleconversi~ paccntageswaecelarlatedfimnpealcPeasusingintanalwandard~iqutsandhadsnaccllracydf2rti.%.
Synthesis of anisolc
Using solid sodium m&oxide.
At ambient temw solid sodium me&oxide (16.2 g. 300 mmoi) was added to a solution of komobenzen e (31.4 g, 200 mmoi, 21 .O mL) in dimethyi fofmamifle (50 mL) and methanol (20 mL) in a -necked reaction flask (250 mL) equipped as for the general Raction~d,~~~~dthcreectionfleslrwaPrPisedto110OCandcoppaObromide(2.9g,#).mmoi) was~dc&AfvrUminthereaaioawasstDppadbycoolingthenaction~tDnxwn Pwnpaature.Thercactioomixturewasthen poundintoUK)mLdarPtessndtbe~extnctsdbywPrhinewithd.The~Ch~wradriedwitbmaenesium
sulphaleandaflerwocenr&onollarotary e~poraur the anisoie was scperatcd by distiUion (hp 15&158 Oc; yieid 95%).
Using 5.4 M so&m mctkxidt s&lion in m&a&.
At ambient tempera- was added a 55.5 mL of a 5.4 M soiutioo of sodium methoxide in methanol (55.5 mL. 5.4 M, 300 mmol) to a soiution of bromobenzene (220 mmd. 21.0 mL) in &methyl famamide (50 a&.) in a thK!c-oecked rtrction fiask (250 mL) quipped wilhaDeanandStarLapperatus.ThetanperatllreoftherractionflaslrwasraisedilOOCwhilemahanolwssalbwedtadistiloff sndwascollectedinthcDcanmdStPlitapperatus.CoppaO~~(2.9g,20~oi)~~sddedto~nactionmixaut.During the reaction (at 110 “C) methanol was cuotiouousiy distilled off. Reaction time, w&-up and ix&ion of anisoie wue identical to the synthesis using soiid me&oxide (vi& sypm).
References
1) 2a)
W
W
z z 9 10) 11) 12) 13) 14) 15)
L. Testaferri. M. Tiecco, hi. Tingoii, D. CXaneU, M. Montaoucci, Synrksis. 751(1983). Meisenheimer. Justus Liebigs Ann. Ckm.. 323.205 (1902); b) RX. Norris. in “The Ckmistry of Fr~n~lionnl Groups”, S. F’atai and 2. w cd., J. Wiley and Sons, N.Y.. 1983. Suppi. D, ch. 16, p. 681. J.E. Shaw. D.C. Kunerth, S.B. Swanson, J. Org. Chem..41.732 (1976); b) L. Tcstaferri. Id. Tiecco. M. Tingoii, D. Chianeiii, M. Montanucci. Tetruhedron. 39,193, (1983). R.GR. Bacon. OJ. Stewart. 1. Ckm. Sot.(C). 301 (1969); b) RGR. Bawn. S.C. Rennison, J. Ckm. &c.(C). 308 (1%9); c) R.G.R. Bacon. S.C. Rennison, J. Ckm. Sot.(C), 313 (1969); a) R.GR. Bacon, J.R. Wright, J. Ckm. Sot.(C), 308
ww. V.V. Lih&, S.M. Shein. U. Org. Khim.. 10,236O. Eng. ed. p. 2373. (1974). G.M. White&&s, J.S. Sadowski. J. Lilti, 1. Am. Ckm. Sec.. 96.2829 (1974). J. Liodky, Tefrahedron, 60.1433 (1984) and refatmces cited therein. WJ. Mooie. Physical Chemistry. ed. LayFan, London. 1978, Ch. 9. R.W. Turner, EL. Arnmq J. Am. Ckm. Sot., 85.4046 (1963). P.F. Rhodesiler. EL. Amma, 1. Ckm. Sot.. Ckm. Commun.. 599 (1974). C. Amatore, MA. Otumn. J. Pinson. J.M. Saveant, A Thi6bauit. 1. Am. Ckm. Sot.. 107.3451 (1978). G. Brauer, Han&uch der Prdpradven Anorganisckn Ckmie. cd., Enke. Stuttgart, 1981, p. 972. ibid., p. 973. D.A. Edwards, R. Richards, J. Chem. Sot, Dalton Trans., 2463 (1973). C.H. B~hkt~. J. Inorg. Nuci. Ckm., 27,59 (i%S).
