Syntheses of extreme sterically hindered 4-methoxyboronic acids

Article abstract of DOI:10.1016/j.tet.2009.11.103

4-Iodoanisoles 3a,b, 3d and 4-bromoanisoles 4a-d were readily obtained. An extreme steric hindrance precluded obtaining 3c. Catalytic borylation of 3a,b, 3d followed by hydrolysis of boronic ester 26a,b, 26d easily provided the boronic acids 5a,b, 5d. Com

Full text of DOI:10.1016/j.tet.2009.11.103

Tetrahedron 66 (2010) 918–929
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Syntheses of extreme sterically hindered 4-methoxyboronic acids
a
a,
a
b
*
´ `
´
Vincent Diemer , Helene Chaumeil , Albert Defoin , Christiane Carre
a Laboratoire de Chimie Organique, Bioorganique et Macromole´culaire, CNRS FRE 3253, Ecole Nationale Supe´rieure de Chimie de Mulhouse, Universite´ de Haute Alsace, 3 rue Alfred
Werner, 68093 Mulhouse Cedex, France
b
´
ˆ
FOTON, CNRS UMR 6082, GET-ENST Bretagne, Departement Optique, Technopole Brest Iroise, CS 83818, 29238 Brest Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 April 2009
Received in revised form 23 November 2009
Accepted 24 November 2009
Available online 27 November 2009
4-Iodoanisoles 3a,b, 3d and 4-bromoanisoles 4a–d were readily obtained. An extreme steric hindrance
precluded obtaining 3c. Catalytic borylation of 3a,b, 3d followed by hydrolysis of boronic ester 26a,b, 26d
easily provided the boronic acids 5a,b, 5d. Compounds 5a and 5d were also synthesised, starting from 4a
and 4d, by halogen/metal exchange. Because of a too important steric hindrance, this last reaction failed
with 4c and 4b led to the unexpected but stable boronic ester 6. The final obtaining of 5b required
a strongly basic hydrolysis with heating.
Keywords:
Steric hindrance
Ó 2009 Elsevier Ltd. All rights reserved.
Halogenoanisoles
4-Methoxyphenylboronic esters
4-Methoxyphenylboronic acids
1. Introduction
semiempirical calculations, which indicate an enhancement of the
NLO properties of such molecules by increasing the interplanar
Our previous work highlighted the efficiency of pyridinium
phenolates as model compounds in non-linear optic (NLO) devices
(Fig. 1).1 Our purpose was to confirm experimentally the
angle existing between the two aromatic rings.2 The twist of the
pyridinium phenolates was obtained by introduction of alkyl groups
of increasing size at
a position of the intercyclic bond. Zwitterions
1a–g were unfortunately far too insoluble to allow the de-
termination of NLO properties by conventional EFISHG (Electronic
Field-Induced Second Harmonic Generation) measurements or HRS
(Hyper Rayleigh Scattering) method. On the other hand, the steric
hindrance induced in the neighbouring groups to the phenolate
functionality of compounds 2a–d limited the formation of aggre-
gates and enhanced the solubilities of these zwitterions.
Experimental measurements performed on compounds 2a–d in
agreement with semiempirical calculations indicated an increase of
the non-linear response of the chromophore with the raise of
dihedral angle existing between the two aromatic rings.1d Never-
theless, only moderate twisted conformations have been achieved.
Until now, the highest angle reached only a calculated value of 48ꢀ
with Zwitterion 2d. The zwitterion 2e was not yet studied. Our
purpose however still remains the synthesis of extremely twisted
R2 R1
H3C N
O
R3 R1
1a-g
1a 1b 1c 1d 1e 1f 1g
R1
R2
R3
H
H
H
H
H
H H Me Me
Me Me Et iPr
H
H
Me
Me
H
Me Et iPr
R4
H3C N
O
R5
2a-e
pyridinium phenolates, that is, tri or tetrasubstituted at a position of
2a 2b 2c 2d 2e
the intercyclic bond. The key step of their syntheses may be a Suzuki
cross-coupling reaction as Fachetti and co-workers have already
used it for the preparation of ortho-ortho0 tetrasubstituted twisted
R4
R5
H
H
H
Me Et iPr
Me Me Et iPr
p
-electron system biaryls.3 We take herein a special interest in the
Figure 1. Previously synthesised pyridinium phenolates.
syntheses of precursors of the phenolate moieties. According to
their future use in the Suzuki reaction, either as electrophile or
nucleophile, these precursors must be either 4-halogeno protected
phenols or 4-O-protected boronic acids. Two other constraints must
* Corresponding author. Tel.: þ33 389336864; fax: þ0033 389336875.
E-mail address: helene.chaumeil@uha.fr (H. Chaumeil).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.103

V. Diemer et al. / Tetrahedron 66 (2010) 918–929
919
be considered; first, the desired twist of the bicycle implies the
introduction of alkyl groups at meta positions of the future phe-
nolate functionality, secondly, as for 2a–e (vide supra), in order to
avoid a protonation of the phenolate functionality with traces of
water and/or a formation of aggregates, the introduction of bulky
groups, such as tert-butyl, in the neighbouring groups to the phe-
nolate group proved to be a necessity.1c We report therefore, herein,
the syntheses of both sterically hindered tri- and tetraalkylsub-
stituted 4-iodoanisoles 3a–c and 4-bromoanisoles 4a–c (Fig. 2). We
also disclose their various reactivity during the preparation of the
corresponding 4-methoxyboronic acids 5a–c. These acids were
synthesised either by catalytic borylation followed by hydrolysis of
the intermediate boronic esters or by halogen/metal exchange. The
synthesis of 2,3,5,6-tetramethyl-4-methoxyboronic acid 5d has
been undertaken, in order to understand better the influence of the
steric hindrance on the formation of the different boronic acids and
especially the unexpected obtaining of the boronic ester 6, by
halogen/metal exchange, from 4b.
2,6-di-tert-butyl-4-methoxy-benzene starting from 2-bromo-
1,3-bis(bromomethyl)-5-methoxybenzene.5 In order to apply this
method to the syntheses of 3a–c and 4a–c, the starting compounds
must obviously be 3,5-dialkyl-2,6-bis(bromomethyl) anisoles 7a–c
(Scheme 1).
2.1. Synthesis of 3,5-dialkyl-2,6-bis(bromomethyl)anisoles
7a–c
It turned out that anisoles 7a–c were readily synthesised in four
steps startingfromdimethyl-1,3-acetonedicarboxylate 9 (Scheme 1).
We have previously reported the syntheses of dimethyl phtha-
lates 10b,c (Scheme 1).1a It was a condensation of both pentane-
2,4-dione 8b and heptane-3,5-dione 8c with 9 under strongly basic
conditions. The monomethylated isophthalic acid dimethyl ester
10a was obtained according to lit.6 After reduction of intracyclic N-
oxide function of isoxazole 11, using Fe2(CO)9, the annelation of the
non-isolated b-enaminone 12 with ketone 9 afforded the desired
phenol 10a in a 39% yield. Phenol function of 10a–c was then
classically methylated in acetone.7 The corresponding anisoles 13a–
c were recovered in yields higher than 91%. In the next step, the
ester functions were reduced into alcohol functions, using LiAlH4 in
56–96% yields. The resulting diols 14a–c were finally brominated by
action of PBr3, in dioxane, at rt, according to Sharghi’s procedure.8
In these conditions, the desired bis(bromomethyl) derivatives 7a–c
were quasi-quantatively isolated (Scheme 1). It should be noted
that neither starting materials nor by-products were detected at
completion of each of these last three steps (protection, reduction
or substitution), limiting at each stage the number of purifications.
Therefore, compounds 7a–c were easily prepared in four steps
starting from dimethyl-1,3-acetone dicarboxylate 9 with global
yields ranging from 19% to 60%.
R1 R2
R4
R1 R3
O
O
O
B
O
6
a
b
c
d
3a-d, R4 = I
R1 t-Bu t-Bu t-Bu Me
R2
Me Et Me
R3 Me Me Et Me
4a-d, R4 = Br
5a-d, R4 = B(OH)2
H
Figure 2. Derivatives whose syntheses have been attempted and/or performed.
2. Results and discussion
At first, starting from symmetrically dialkylated phenols or from
bromophenols, a large variety of direct aromatic electrophile
substitutions has been tested in order to prepare 2,3,5,6-tetraal-
kylphenols or bromophenols (O-protected or not). None of these
many attempts has been successful.4 These failures were certainly
a consequence of the high desired steric hindrance in the final
products and/or electronic facts. To synthesise 4-iodoanisoles 3a–c
and 4-bromoanisoles 4a–c, we thus ended up by choosing a much
more laborious but successful synthetic pathway consisting in the
construction step by step of the tert-butyl substituents. Yoshifuji
and Coll. have described, in 2003, the synthesis of 1-bromo-
2.2. Synthesis of 2,6-di-tert-butylanisoles 21a–c and
tetramethylanisole 21d
The bis(bromomethyl) compounds 7a–c in hand, the construc-
tion of the tert-butyl groups were then considered (Scheme 2)
according to Yoshifuji and co-workers procedure.5 Cyano groups
were first introduced in benzylic positions by means of a nucleo-
philic substitution using KCN in the presence of nBu4NBr as phase
transfer catalyst, in
a biphasic solvent (CH2Cl2/water). The
O
MeOOC
COOMe
OH
9
9, AcOH, KF
Fe2(CO)9, H2O
benzene
MeOOC
R2
NaOH/MeOH, 88%
COOMe
R3
+
O
N
O
N
11
O
O
for 10b:
H H
benzene
10a-c
39% from 11
R2
R3
for 10c:
12
8b-c
Na/MeOH, 38%
K2CO3, MeI
acetone reflux
18h
a
b
c
PBr3, dioxane
rt, 18h
R2
H
Me Et
O
O
O
MeOOC
R2
COOMe
R3
R3 Me Me Et
HO
R2
OH
R3
Br
Br
R3
7a-c
R2
LiAlH4, Et2O
13a-c
rt, 18h
14a-c
Protection of Yield Reduction of Yield Substitution of Yield
phenol 10a-c
%
esters 13a-c
%
OH in 14a-c
%
13a
13b
13c
Quant.
91
92
14a
14b
14c
96
80
56
7a
7b
7c
Quant.
94
Quant.
Scheme 1. Preparation of 7a–c from 10a–c.

920
V. Diemer et al. / Tetrahedron 66 (2010) 918–929
KCN, H2O/CH2Cl2
NBu4Br
O
O
O
O
1) LDA, THF, -78°C
NC
CN
NC
R2
CN
NC
CN
NC
CN
R3
7a-c
R3
16a-c
R2
2) MeI, -78°C to rt
rt, 18h
17b
18b
15a-c
DIBALH,
toluene, O°C
O
O
O
NBu4HSO4
O
NH2NH2,H2O
O
HN
NH
a
b
c
R2
R3 Me Me Et
H Me Et
R2
R3
20a-c
R2
R3
R2
R3
KOH
CH2Cl2/H2O
rt, 18h
160 to 195°C
21a-c
19a-c
Introduction Yield Tetramethylation Yield Reduction
Yield Reduction of Yield
of nitriles in
7a-c
%
of 15a-c
%
of nitriles of
16a-c
20a
%
aldehydes of
20a-c
21a
%
15a
97
16a
52
99
58
15b
15c
96
89
16b
16c
95
82
20b
20c
81
83
21b
21c
64
61
Scheme 2. Preparation of 21a–c.
cyanomethyl derivatives 15a–c were isolated in excellent yields
(from 89% to 97%). The next stage of the synthesis of anisoles 21a–c
involved the introduction of two methyl groups at each benzylic
position. The proximity of both aromatic ring and cyano functions
enhanced the acidity of the benzylic protons. Yoshifuji and Coll.
removed them using NaH5a or KOH.5b,5c In the case of the dime-
thylated compound 15b, attempts using KOH,5b,5c NaOH,9 NaH,10
At the same time, 2,3,5,6-tetramethylanisole 21d had been
synthesised (Fig. 3). Two different pathways were tested. The first
one ended with the hydrogenolysis of diol 14b, on Pd/C. Un-
O
O
H2, Pd/C
55%
HO
OH
13b
10b
80%
91%
11
NaNH2 or t-BuOK12 mainly gave a monomethylation at each
21d
14b
benzylic position, leading to 18b. Better results were obtained using
lithium diisopropyl amide (LDA), in-situ synthesised by deproto-
nation of diisopropylamine with butyllithium.13 Using, for example,
five equivalents of LDA and methyliodide, an NMR analysis in-
dicated that 55% of tetramethylated anisole 16b was recovered
mixed with 32% of trimethylated derivative 17b and 13% of the
symmetrically dimethylated anisole 18b. The use of eight equiva-
lents of LDA and five equivalents of methyliodide induced an
increase in yield to 71%. The optimisation of the reaction conditions
indicated that an excess of 8 equiv of LDA and 12 equiv of methyl-
iodide afforded the completion of the tetramethylation of anisoles
in a 95% yield. Using these optimised conditions, the tetramethy-
lation of anisoles 15a and 15c was achieved in, respectively, 52%
and 82% yields (Scheme 2).
96%
LiAlH4,
Et2O, rt
18h
K2CO3, MeI
acetone reflux
18h, 90%
OH
OH
HO
OH
H2, Pd/C
92%
22
23
Figure 3. Preparation of 21d.
fortunately, the expected compound 21d was obtained in a disap-
pointing 55% yield. As a consequence, starting from isophthalate
10b, the total synthesis of 21d, in three steps (protection, reduction
of ester and hydrolysis), only reached a 40% yield. Subsequently,
still starting from 10b, another alternative was considered. As we
have it previously published,1a esters functions of 10b were first
reduced in a 96% yield. The two hydroxymethyl groups were then
hydrogenolysed in a 92% yield. The obtained tetramethylphenol
was finally O-methylated in a 90% yield. This time, starting from
10b, a global yield of 79% was achieved.
In order to reduce a,a, ,a
a0 0-tetramethylated anisole 16b, diiso-
butylaluminium hydride (DIBALH) was tested according to the lit.5
Surprisingly, as well an acidic as a basic hydrolysis of the reaction
mixture mainly led to diimine 19b. Only traces of the expected
dialdehyde 20b were detected by NMR analysis. The diimine 19b
was stable enough to be isolated. Its hydrolysis into dialdehyde 20
was achieved by treatment with tetrabutylammonium hydro-
genosulphate in a biphasic solvent (water/CH2Cl2). Dialdehyde 20b
was finally recovered in a 81% yield. This last synthetic sequence
(reduction with DIBALH following by treatment with tetrabuty-
lammonium hydrogenosulphate) was efficiently applied to the
conversion of 16a and 16c into the dialdehydes 20a and 20c in,
respectively, 99% and 83% isolated yields.
Aldehyde functions of 20a–c were then reduced in methyl groups
by the Huang–Minlon modification of the Wolff–Kishner reaction.14
Heating at 160–195 ꢀC, in the presence of hydrazine hydrate and
powdered KOH in diethylene glycol, involved the achievementof the
tert-butyl substituents. In these conditions, the three expected ani-
soles 21a–c were isolated in moderate yields (58–64%).
2.3. Halogenation of anisoles 21a–d
para-Iodination of anisoles 21a–d was performed by treatment
with iodine in dichloromethane in presence of silver tri-
fluoroacetate (Scheme 3). In the presence of tert-butyl substituents,
the experimental results underscored decreasing yields with the
steric hindrance of the alkyl groups (R2 and R3) anchored at meta
position of the methoxy function. Attempts of iodination of the
diethylanisole 21c only led to ipso-substitution of one of the tert-
butyl groups with iodine. The structure of the obtained compound
24c was unambiguously determined by 1H NMR Nuclear-Over-
hauser-effect (NOE) experiments. Irradiation of protons at
tion of the ethyl substituent at 2.85 ppm enhanced H-C(4) and
protons of a tert-butyl group, whereas, irradiation of protons at
a posi-

V. Diemer et al. / Tetrahedron 66 (2010) 918–929
921
O
O
O
I
R1
R3
AgCOOCF3,I2
CH2Cl2, rt
R1
R2
R1
R3
I
R1
R3
a
b
c
d
21a-d
+
+
R1 t-Bu t-Bu t-Bu Me
R2
Me Et Me
R3 Me Me Et Me
R2
R2
I
3a-d
I
H
24a-d
25a-d
Substrates
Product obtained (%)a
3a-d
(100)b
83 (71)b
-
24a-d
-
25a-d
21a
21b
21c
21d
-
3.5
-
13.5
100 (78)b
100 (61)b
-
-
ayields determined by NMR.
bisolated yields.
Scheme 3. Iodination of anisoles 21a–d.
a
position of the ethyl substituent at 2.71 ppm only enhanced
excellent yields. Contrary to iodination, no abstraction of tert-butyl
groups was observed during bromination of anisoles 21a–d.
H-C(4). In the case of 21b the reaction was not complete any longer.
The desired para-iodinated product (83%) was recovered mixed
with by-products resulting once more from the substitution of
a tert-butyl group (13.5%) followed by iodination of the free posi-
tion (3.5%). These results suggested that the substitution of a tert-
butyl group is dramatically furthered by the increase of the steric
hindrance induced in the neighbouring groups to the free para
position. On the other hand, iodinations of 21a and tetramethyla-
nisole 21d gave the only expected iodoanisoles 3a and 3d in,
respectively quantitative and 61% yields.
2.4. Synthesis of boronic esters 26 and acids 5
The next stage involved in the preparation of the boronic acids
starting from either para-iodoanisoles 3a–b, 3d or para-bromoa-
nisoles 4a–d. Two synthetic pathways were consequently
considered.
The first alternative consisted in the hydrolysis of the boronic
ester obtained through the Miyaura’s procedure from the foregoing
iodoanisole 3a–b, 3d.16 The borylation of iodoanisole 3b was first
run by using the accurate Miyaura’s experimental conditions. A
NMR analysis of the reaction mixture indicated the presence of
three compounds in almost equal proportions: the desired boronic
ester 26b, the starting iodoanisole 3b and the reduced anisole 21b
(Scheme 5, entry 1). The enhancement of the concentration of
bis(pinacolato)diboron limited dehalogenation. Unfortunately, the
amount of starting material still remained high (entry 2). On
the contrary, the enhancement of concentration of catalyst bettered
the borylation yield but still furthered the reduction of iodoanisole
3b (entry 3). Finally, the best result was achieved with 2.2 equiv of
bis(pinacolato)diboron in the presence of 10 mol % of catalyst
(entry 4). These optimised conditions were extended to the prep-
aration of the other boronic esters 26a and 26d (Scheme 6).
Many alternatives involving the hydrolysis of pinacol boronic
esters into boronic acids are reported in lit.17–20 To prepare boronic
acid 5b, we have tested three of them (Table 1).17c,19,20c No hydro-
lysis was detected using sodium periodate or diethanolamine
(entry 5 and 6). In the presence of 1.1 equiv of LiAlH4, an important
amount of unconsumed 27b was still recovered (entry 3). The best
Bromination of anisoles 21a–d at para position was performed
by using N-bromosuccinimide in acetonitrile at rt (Scheme 4).15
The desired bromoanisoles 4a–d were recovered in good to
a
b
c
d
O
R1
R2
R1
R3
R1 t-Bu t-Bu t-Bu Me
R2
Me Et Me
R3 Me Me Et Me
NBS
21a-d
H
acetonitrile, rt
Br
4a-d
Substrates Bromo Yields
anisoles
%
21a
21b
21c
21d
4a
4b
4c
4d
98
83
67
98
Scheme 4. Bromination of anisoles 21a–d.
O
B
O
O
O
O
O
O
B B
3b
+
+
O
KOAc, PdCl2dppf,
DMSO, 80 °C
O
I
H
3b
21b
26b
Relative quantity of reagents
Products detected in the
reaction mixture by
NMR (%)
Entry
Iodoanisole 3b Bis(pinacolato)diboron
PdCl2dppf
26b
3b
21b
(equiv.)
(equiv.)
1.2
2.2
1.2
mol%
3
3
10
10
1
2
3
4
1
1
1
1
35
51
53
89
34
30
15
-
31
19
32
11
2.2
Scheme 5. Optimisation of the syntheses of 26b.

922
V. Diemer et al. / Tetrahedron 66 (2010) 918–929
O
O
O
O
R1 R2
R1 R3
B B
R1 R2
R1 R3
1) LiAlH4, 2.2 equiv.
2) H2O
OH
OH
O
O
3a-b, 3d
O
B
O
B
KOAc, PdCl2dppf,
DMSO, 80 °C
26a-b, 26d
5a-b, 5d
a
b
d
R1 t-Bu t-Bu Me
R2
Me Me
R3 Me Me Me
H
Yield
Yield
Boronic esters
Boronic acids
%
72
89
72
%
67
63
68
26a
26b
26d
5a
5b
5d
Scheme 6. Syntheses of boronic esters 26a,b and 26d, boronic esters 5a,b and 5d, starting from bromoanisoles 3a,b and 3d.
Table 1
Hydrolysis of boronic esters 26b and 26e
Entry
Conditions of the reaction
ArHa
a
a
(1) LiAlH4 (2.2 equiv)20
(2) H2O
0%
21e
100%
5e
0%
26e
1
(1) LiAlH4 (2.2 equiv)
(2) H2O
(1) LiAlH4 (1.1 equiv)
(2) H2O
15%
21b
65% (63%)b
5b
20%
27b
2
3
14%
21b
52%
5b
34%
27b
4
9%
21b
0%
5b
91%
27b
(1) LiAlH4 (0.55 equiv)
(2) H2O
NaIO4, NH4OAc in acetone/H2O18c
5
6
0%
21b
0%
0%
5b
0%
5b
100%
27b
100%
27b
21c
(1) Diethanolamine in i-PrOH/Et2O
(2) HCl
21b
a
Yields determined by NMR.
Isolated yield.
b
results were obtained using 2.2 equiv of LiAlH4 as reducing agent.19
Only 63% of boronic ester 26b were converted into 5b (entry 2).
Besides, 15% of anisole 21b, resulting from protodeboronation, and
20% of starting material 26b were detected by NMR in the reaction
mixture. And yet, starting from boronic ester 26e, we had prepared
as a model, the expected boronic acid 5e was recovered quantita-
tively (entry 1). Nevertheless, this method was applied to the
preparation of the other boronic acids 5a and 5d (Scheme 6).
Bromoanisoles 4a–d were the starting point of a second alter-
native for the syntheses of boronic acids 5a–d. Bromoanisoles were
first treated with butyllithium in THF to lead to aryllithium
compounds via a metal/halogen exchange. Addition of triisopropyl
borate to the reaction mixture was supposed to give lithium aryl-
triisopropyl borates.21 An immediate hydrolysis afforded the
expected boronic acids.22 As for the reported borylations of
4-bromo-3,5-dimethylanisole23 and 4-bromo-2,6-ditertbutylani-
sole,24 such reactional sequences were observed during the
preparation of boronic acids 5a and 5d (Scheme 7).Unexpectedly,
the reaction involving 5b, gave the only aryldiisopropyl borate 6 in
a 66% yield. To the best of our knowledge, during a bromide/lithium
exchange, such a derivative is only obtained by acidification of
lithium aryltriisopropyl borate intermediates with anhydrous
1) BuLi, THF, -78°C
2) B(OiPr)3,
Li
R1 R2
R1 R2
5a, 5d
HCl
-78°C to rt
O
OH
OH
a
c
d
O
B O
O
O
B
R1 t-Bu t-Bu Me
R2
Et Me
R3 Me Et Me
R1 R2
R1 R3
4a-d
H
KOH, DMSO
96%
1) BuLi, THF, -78°C
2) B(OiPr)3,
-78°C to rt
OH
OH
O
O
O
B
O
B
66%
6
5b
Yield
Boronic acids
%
58
0
5a
5c
5d
55
Scheme 7. Syntheses of boronic acids 5a,b, 5d, starting from 4a,b, 4d.

V. Diemer et al. / Tetrahedron 66 (2010) 918–929
923
Table 2
Global yields from 10a–c
Substrates
Iodoanisoles
Number of steps
Yields %
Boronic acids
Number of steps
Yields %
from 10a–c
from 10a–c
10a
10b
10c
10b
3a
3b
3c
3d
8
8
8
4
28
23
d
5a
5b
5c
5d
10
10
13
13
d
48
6
27
Substrates
Bromoanisoles
Number of steps
Yields %
Boronic acids
Number of steps
Yields %
from 10a-c
from 10a–c
10a
10b
10c
10b
4a
4b
4c
4d
8
8
8
4
27
27
13
78
5a
5b
5c
5d
9
10
16
17
d
5
43
hydrogen chloride.21 This unexpected acyclic boronic ester was
stable enough to be chromatographed and can be handled in air
without special precautions. Its easy obtaining was probably
a consequence of its stability attributable to the presence at the
same time, on the aromatic ring, of tert-butyl and methyl groups.
The leaving space between the two methyl groups was actually too
narrow for a bulky triisopropyl ester functionality. Moreover, ester
6 was stable as well in an acidic or a basic medium at rt. The ex-
treme steric hindrance considerably slowed hydrolysis of boronic
ester function. This hydrolysis was however performed by heating
at 60 ꢀC for two hours, using sodium hydroxide in a mixture of
DMSO/water, even though the hydrolysis of all acyclic boronic es-
ters is known to be very rapid.25 The expected boronic acid 5b was
thus recovered in a 96% yield. It must be pointed out that the hy-
drolysis of the pinacol ester 26b, in the above conditions of re-
action, did not succeed.
from sodium/benzophenone, DMSO and dioxane was dried over 3 Å
molecular sieves. All melting points were taken on a Kofler bench.
IR spectra (cmꢁ1) were recorded on a Nicolet 205 FTIR spectrom-
eter. 1H NMR (400 MHz) and 13C NMR (100.6 MHz) spectra were
measured on a Brucker Avance serie 400 at 295 K. Chemical shifts
are reported in ppm relative to SiMe4. HPLC analyses were
performed on an Agilent Technologies 1100 series system using
a Kromasil column (C18 4.6ꢂ250 mm, 100 Å, 5
mm) at an outflow of
1 mL/min, and a UV detection at 230 nm. Microanalyses were
performed by the analytical service of the Service de Microanalyse
du CNRS in Vernaison and high resolution MS was measured either
on a Waters Micromass Q-TOF Ultima API spectrometer in the firm
Basilea Pharmaceuticals in Basel (Switzerland) or by the analytical
service of the Service de Microanalyse du CNRS in Vernaison.
Previously reported procedures were used to prepare dimethyl
2-hydroxy-4-methylisophtalate 10a,6a dimethyl 2-hydroxy-4,6-
dimethylisophtalate 10b,1a dimethyl 4,6-diethyl-2-hydroxyisoph-
thalate 10c,1a 2,3,5,6-tetramethyphenol 231a and 4-bromo-3,5-di-
methyl anisole 4e.3a
Attempts to convert bomoanisole 4c into boronic acid 5c gave
a complete protodeboronation of the substrate leading to the only
recovery of 21c. The gap existing between the two ethyl groups was
certainly too narrow to allow a reaction with borate. This result was
however in accordance with the unsuccessful synthesis of iodoa-
nisole 3c.
4.2. General procedures
4.2.1. Procedure A, protection of phenol. To a solution of phenol
10a–c (1 equiv) in acetone (3 mL per mmol of 10a–c) were suc-
cessively added, under Ar, K2CO3 (1.2 equiv) and MeI (2 equiv). The
reaction mixture was heated at reflux overnight and was then
allowed to reach rt. Solids were filtered off and washed with ace-
tone. The filtrate was then evaporated under reduced pressure and
the crude dissolved in Et2O. This organic layer was successively
washed with aqueous 1 M Na2CO3 and water, dried over MgSO4 and
evaporated under reduced pressure to afford 13a–c. These crude
materials were used in the next step without further purification.
3. Conclusion
In conclusion, sterically hindered iodoanisoles 3a–b and 3d
were readily synthesised, as their corresponding boronic esters
26a–b, 26d and acids 5a–b, 5d. Global yields are tabulated in Table
2. A too large steric hindrance precluded the recovering of iodoa-
nisole 3c.
Sterically hindered bromoanisoles 4a–d and boronic acids 5a
and 5d were readily synthesised too (Table 2). However, after
a metal-lithium exchange, as the steric hindrance increased, the
reaction with triisopropyl borate became more and more difficult.
The bulky tert-butyl groups must lead to a bending of the molecule.
The two substituents at meta of the anisole function moving away
from tert-butyl groups, narrowed para position. The steric
hindrance in the vicinity of boron atom was extreme. As a conse-
quence, the reaction of dimethylbromoanisoles 4b afforded the
unexpected and stable aryldiisopropyl borate 6, and the reaction of
diethylbromoanisole 4c was totally unsuccessful, only proto-
deboronation occurred, leading to the only recovery of dehalo-
genated anisole 21c. The final obtaining of 5b from ester 6 required
a strong basic hydrolysis (DMSO/water) with heating.
4.2.2. Procedure B, reduction of the dimethyl ester. To a suspension
of LiAlH4 (2.5 equiv) in anhydrous THF (2.5 mL per mmol of 13a–c)
was added dropwise, under Ar, at 0 ꢀC, a solution of protected
dimethyl esters 13a–c (1 equiv) in anhydrous THF (2.5 mL per
mmol of 13a–c). The reaction mixture was stirred overnight at rt.
AcOEt was then carefully added at 0 ꢀC in order to neutralise LiAlH4
in excess. The reaction mixture was acidified with aqueous 1 M HCl
until total dissolution of the aluminium salts. The resulting aqueous
solution was extracted three times with AcOEt. The combined or-
ganic layers were dried over MgSO4 and evaporated under reduced
pressure to afford 14a–c, which were used in the next step without
further purification.
4. Experimental
4.2.3. Procedure C, substitution with Br. To a suspension of 14a–c in
dioxane (5 mL per mmol of 14a–c) was added dropwise, under Ar,
a solution of PBr3 in dioxane (1 mL per mmol of 14a–c). The
reaction mixture was stirred overnight at rt. The reaction mixture
was then poured over crushed ice and neutralised by addition of
4.1. General points
Reagents were purchased from commercial suppliers and used
without further purification. THF and toluene were freshly distilled

924
V. Diemer et al. / Tetrahedron 66 (2010) 918–929
solid K2CO3. The aqueous solution was extracted three times with
Et2O. The combined organic layers were dried over MgSO4 and
evaporated under reduced pressure to afford 7a–c, which were
used in the next step without further purification.
under Ar, first AgCO2CF3 (1.2 equiv) then a solution of I2 (1.2 equiv)
in chloroform (12 mL per mmol of 21a–d). On completion of the
reaction (about 15 min), the suspended silver salts were filtered off.
The filtrate was successively washed with aqueous saturated so-
lution of Na2S2O3 and water. The organic layer was dried over
MgSO4 and evaporated under reduced pressure. Purification by
column chromatography (cyclohexane) afforded the different
iodoanisoles.
4.2.4. Procedure D, substitution with CN. To an aqueous 0.25 M
NBu4Br solution (2 mL per mmol of 7a–c) were successively added
KCN (4 equiv) and a solution of 7a–c (1 equiv) in CH2Cl2 (2 mL per
mmol of 7a–c). The reaction mixture was vigorously stirred over-
night and then diluted with CH2Cl2. The organic layer was sepa-
rated and washed twice with water. CH2Cl2 was removed under
reduced pressure and the crude product dissolved in Et2O. This
organic layer was washed three times with water, dried over
MgSO4, and evaporated under reduced pressure to afford 15a–c.
The isolated products were used in the next step without further
purification.
4.2.9. Procedure I, bromination. To a solution of 21a–d (1 equiv) in
MeCN (8 mL per mmol of 21a–d) was added, under Ar, NBS
(1.4 equiv). The reaction mixture was stirred at rt overnight. The
solvent was evaporated under reduced pressure. Cyclohexane was
then added to the crude residue. Insoluble solids were filtered off
and rinsed with another portion of cyclohexane. The filtrate was
evaporated under reduced pressure. Purification by column
chromatography (cyclohexane) afforded the pure bromoanisoles
4a–d.
4.2.5. Procedure E, tetramethylation. To
a solution of NHiPr2
(8.2 equiv) in anhydrous THF (3.6 mL per mmol of 15a–c), at
ꢁ78 ꢀC, were successively added dropwise, under Ar, BuLi (1.6 M in
hexanes, 8.1 equiv) and 15a–c dissolved in anhydrous THF (5.6 mL
per mmol of 15a–c). The reaction mixture was stirred for 20 min at
ꢁ78 ꢀC. Methyliodide (12 equiv) was then added dropwise. After
two more hours, at ꢁ78 ꢀC, the reaction mixture was allowed to
reach rt. After a careful hydrolysis with water, this aqueous layer
was extracted with CH2Cl2. The organic layer was thoroughly
washed twice with aqueous 1 M HCl and once with water. The
combined organic layers were dried over MgSO4 and evaporated
under reduced pressure to afford 16a–c, which were used in the
next step without further purification.
4.2.10. Procedure J, preparation of the boronic esters. 4-Iodoanisoles
3a–b, 3d (1 equiv), PdCl2dppf, CH2Cl2 (0.1 equiv), K2CO3 (3 equiv),
bis(pinacolato)diboron (2.2 equiv) and DMSO (6 mL per mmol of
iodoanisole) were successively added in a flask under Ar. After
heating at 80 ꢀC overnight, the reaction mixture was allowed to
reach rt. Et2O was added and the organic layer was extracted three
times with water. The organic layer was dried over MgSO4 and
evaporated under reduced pressure. Purification by column chro-
matography afforded desired boronic esters 26a–b, 26d.
4.2.11. Procedure K, hydrolysis of boronic esters. To a suspension of
LiAlH4 (2.2 equiv) in anhydrous THF (2.5 mL per mmol of 26a–b,
26d) was added dropwise, under Ar, at 0 ꢀC, a solution of boronic
ester 26a–b, 26d (1 equiv) in anhydrous THF (2.5 mL per mmol of
26a–b, 26d). The reaction mixture was stirred for 2 h at 0 ꢀC and 1 h
more, at rt. Na2SO4$10H2O (4 equiv) was then added, to the reaction
mixture. The aluminium salts were dissolved by addition of aque-
ous 1 M H2SO4. The obtained aqueous solution was extracted three
times with Et2O. The combined organic layers were dried over
MgSO4 and evaporated under reduced pressure. Purification by
column chromatography (cyclohexane/ethyl acetate) afforded pure
5a–b, 5d.
4.2.6. Procedure F, reduction. To a solution of 16a–c (1 equiv) in
anhydrous toluene (2.5 mL per mmol of 16a–c) was added drop-
wise, under Ar, at 0 ꢀC, a solution of DIBALH (2.3 equiv) in anhy-
drous toluene. The reaction mixture was stirred at 0 ꢀC for 2 h and
then hydrolysed under stirring with water and made basic with
aqueous 1 M NaOH. 30 min later, the obtained solution was diluted
with aqueous 1 M NaOH and was extracted three times with Et2O.
The combined organic layers were then dried over MgSO4, and
evaporated under reduced pressure. The obtained residue was
dissolved in CH2Cl2 (5 mL per mmol of 16a–c). Water (5 mL per
mmol of 16a–c) and NBu4HSO4 (2.2 equiv) were successively added
and the reaction mixture was vigorously stirred at rt overnight. The
aqueous layer was separated and thoroughly extracted with CH2Cl2.
The organic layers were combined and evaporated under reduced
pressure. The crude product dissolved in Et2O was washed three
times with water. The organic layer was dried over MgSO4 and
evaporated under reduced pressure to afford 20a–c, which were
used in the next step without further purification.
4.2.12. Procedure L. To a solution of 4a–d (1 equiv) in anhydrous
THF (7 mL per mmol of 4a–d) under Ar, at ꢁ78 ꢀC, was added
dropwise BuLi (2.5 M in cyclohexane, 2.2 equiv). The reaction
mixture was stirred at ꢁ78 ꢀC for 1 h. The reaction mixture was
then transferred via cannula into a solution at ꢁ78 ꢀC of triiso-
propyl borate (5 equiv) in anhydrous THF (2.5 mL per mmol of
4a–d). The mixture was further stirred 1 h at ꢁ78 ꢀC and then
allowed to reach rt. Aqueous 1 M HCl (21.5 mL per mmol of 4a–d)
was added. The obtained aqueous phase was extracted three
times with Et2O. The combined organic layers were dried over
MgSO4 and evaporated under reduced pressure. Purification by
column chromatography (cyclohexane/ethyl acetate) afforded 5,
6, 5d, 21c.
4.2.7. Procedure G, Wolff–Kishner reaction. A Dean-Stark apparatus
was fitted on a flask under Ar, containing 20a–c (1 equiv),
NH2NH2$H2O (7 equiv) and powdered KOH (6.5 equiv) in dieth-
ylene glycol (4 mL per mmol of 20a–c). The reaction mixture was
heated by means of an oil bath at 160 ꢀC during 1.5 h and then at
200 ꢀC. The internal temperature of the reaction mixture raised
195 ꢀC and allowed the elimination of the excess of water and
hydrazine by an azeotropic distillation. The reaction mixture was
then allowed to reach rt. Water was then added. This aqueous
solution was extracted three times with cyclohexane. The com-
bined organic layers were washed with water, dried over MgSO4
and evaporated under reduced pressure. Purification by column
chromatography (cyclohexane) afforded the pure anisoles 21a–c.
4.3. Synthesis of derivatives
4.3.1. Dimethyl-2-methoxy-4-methylisophthalate (13a). Starting from
10a (2.39 g, 10.7 mmol), following procedure A, was obtained 13a
(2.54 g, quant.) as a colourless solid. Mp<40 ꢀC. 1H NMR (CDCl3)
d
¼2.33 (3H, s), 3.87 (3H, s), 3.91 (3H, s), 3.93 (3H, s), 7.01 (1H, d,
J¼8.1 Hz), 7.80 (1H, d, J¼8.1 Hz) ppm. 13C NMR (CDCl3, 100 MHz)
d¼19.6, 52.3, 52.5, 63.8, 121.9, 125.6, 130.7, 132.8, 141.7, 157.7, 165.8,
4.2.8. Procedure H, iodination. To a solution of anisoles 21a–
d (1 equiv) in chloroform (12 mL per mmol of 21a–d) were added,
168.1 ppm. IR (KBr) nmax: 799, 811,1002,1069,1115,1145,1153,1216,
1246, 1266, 1312, 1401, 1435, 1450, 1459, 1482, 1604, 1733,

V. Diemer et al. / Tetrahedron 66 (2010) 918–929
925
2952 cmꢁ1. HRMS (ESI-Q-Tof) m/z calcd for C12H14O5 [MþLi]ꢃþ
compound 7b (608 mg, 94%) as a colourless solid. An analytically
245.1001, found 245.0990.
pure sample was obtained by sublimation (100 ꢀC, 1 Torr). Mp
124 ꢀC. 1H NMR (CDCl3)
d
¼2.38 (6H, s), 4.04 (3H, s), 4.61 (4H, s),
4.3.2. Dimethyl-2-methoxy-4,6-dimethylisophthalate (13b). Starting
from 10b (10 g, 42 mmol), following procedure A, was obtained 13b
6.85 (1H, s) ppm. 13C NMR (CDCl3)
d
¼18.9, 26.3, 62.3, 127.6, 129.1,
140.2, 157.5 ppm. IR (KBr) nmax: 459, 539, 556, 566, 582, 816, 871,
(9.66 g, 91%) as a colourless solid. Mp 64 ꢀC. 1H NMR (CDCl3)
d
¼2.27
933, 996, 1028, 1057, 1142, 1187, 1198, 1208, 1243, 1299, 1401, 1426,
(6H, s), 3.80 (3H, s), 3.90 (6H, s), 6.82 (1H, s) ppm. 13C NMR (CDCl3)
1439, 1458, 1561, 1564, 1608, 2956 cmꢁ1
. Anal. Calcd for
d
¼19.6, 52.4, 63.6, 126.0, 127.6, 138.5, 155.1, 168.1 ppm. IR (KBr)
C11H14Br2O (322.04): C, 41.03; H, 4.38. Found: C, 40.86; H, 4.25.
HRMS (ESI-Q-Tof) m/z calcd for C11H14Br2O [MþNa]ꢃþ 342.9309,
found 342.9319.
nmax: 864, 890, 933, 954, 1004, 1026, 1043, 1084, 1120, 1194, 1207,
1264, 1284, 1308, 1386, 1399, 1443, 1481, 1610, 1687, 1720, 1728,
2950, 2994 cmꢁ1. HRMS (ESI-Q-Tof) m/z calcd for C13H16O5 [MþLi]ꢃþ
259.1158, found 259.1130.
4.3.9. 2,6-Bis(bromomethyl)-3,5-diethylanisole (7c). Starting from
14c (2.76 g, 12.3 mmol), following procedure C, was obtained
compound 7c (4.41 g, quant.) as a colourless solid. An analytically
pure sample was obtained by sublimation (90 ꢀC, 0.1 mmHg). Mp
4.3.3. Dimethyl-4,6-diethyl-2-methoxyisophthalate (13c). Starting
from 10c (6.4 g, 24.1 mmol), following procedure A, was obtained 13c
(6.20 g, 92%) as a colourless oil. 1H NMR (CDCl3)
d
¼1.20 (6H, t,
J¼7.6 Hz), 2.59 (4H, q, J¼7.6 Hz), 3.81 (3H, s), 3.90 (6H, s), 6.88 (1H, s)
ppm. 13C NMR (CDCl3)
90 ꢀC. 1H NMR (CDCl3)
d
¼1.29 (6H, t, J¼7.6 Hz), 2.76 (4H, q,
J¼7.6 Hz), 4.06 (3H, s), 4.64 (4H, s), 6.91 (1H, s) ppm. 13C NMR
d¼15.5, 26.8, 52.4, 63.6, 124.6, 125.8, 144.7,
(CDCl3)
d
¼14.9, 25.2, 25.7, 62.3, 125.2, 127.0, 146.1, 157.7 ppm. IR
154.7, 168.3 ppm. IR (film) nmax: 913, 975, 987, 1038, 1072, 1095, 1113,
1180,1202,1233,1263,1303,1330,1403,1434,1455,1463,1469,1559,
1564, 1605, 1732, 1737, 2877, 2904, 2950, 2971 cmꢁ1. HRMS (ESI-Q-
Tof) m/z calcd for C15H20O5 [MþH]ꢃþ 281.1389, found 281.1367.
(KBr) nmax: 469, 501, 577, 665, 884, 920, 967, 983, 1028, 1052,
1068, 1143, 1209, 1228, 1236, 1259, 1280, 1405, 1426, 1446, 1450,
1561, 1597, 2834, 2873, 2965, 2994 cmꢁ1
. Anal. Calcd for
C13H18Br2O (350.09): C, 44.60; H, 5.18. Found: C, 44.53; H, 5.18.
HRMS (ESI-Q-Tof) m/z calcd for C13H18Br2O [MþNa]ꢃþ 370.9622,
found 370.9631.
4.3.4. 2,6-Bis(hydroxymethyl)-3-methylanisole(14a). Starting from
13a (2.88 g, 12.1 mmol), following procedure B, was obtained, after
purification by column chromatography (AcOEt/cyclohexane 3:7),
14a (2.11 g, 96%) as a colourless solid. Mp was in agreement with the
4.3.10. 2,6-Bis-(cyanomethyl)-3-methylanisole (15a). Starting from
7a (2.55 g, 8.3 mmol), following procedure D, was obtained com-
pound 15a (1.61 g, 97%) as a colourless solid. An analytically pure
sample was obtained by sublimation (120 ꢀC, 1 Torr). Mp 75–80 ꢀC.
lit.26 1H NMR (CDCl3)
d
¼2.00 (2H, br s), 2.41 (3H, s), 3.87 (3H, s), 4.70
(2H, s), 4.76 (2H, s), 6.98 (1H, d, J¼7.8 Hz), 7.22 (1H, d, J¼7.8 Hz) ppm.
1H NMR (CDCl3)
d
¼2.42 (3H, s), 3.72 (2H, s), 3.73 (2H, s), 3.86 (3H, s),
4.3.5. 2,6-Bis(hydroxymethyl)-3,5-dimethylanisole (14b). Starting
from 13b (5 g, 19.8 mmol), following procedure B was obtained 14b
(3.09 g, 80%) as a colourless solid. Mp was in agreement with the lit.
7.06 (1H, d, J¼7.8 Hz), 7.32 (1H, d, J¼7.8 Hz) ppm. 13C NMR (CDCl3)
d¼15.1, 18.5, 19.6, 62.1, 117.4, 117.8, 121.9, 123.5, 127.2, 129.7, 139.4,
156.1 ppm. IR (KBr) nmax: 817, 950, 1004, 1065, 1197, 1220, 1260,
1276, 1300, 1417, 1451, 1459, 1488, 1579, 2251, 2931, 2944,
2968 cmꢁ1. Anal. Calcd for C12H12N2O (200.24): C, 71.98; H, 6.04; N,
13.9. Found: C, 72.06; H, 6.20; N, 13.61.
27 1H NMR (CDCl3)
d
¼1.84 (2H, t, J¼5.3 Hz), 2.37 (6H, s), 3.88 (3H, s),
4.73 (4H, d, J¼5.3 Hz), 6.86 (1H, s) ppm.
4.3.6. 3,5-Diethyl-2,6-bis(hydroxymethyl)anisole (14c). Starting from
13c (6.3 g, 22.5 mmol), following procedure B, was obtained, after
purification by column chromatography (AcOEt/cyclohexane 5:5),
14c (2.84 g, 56%) as a colourless solid. An analytically pure sample
was obtained by sublimation (120 ꢀC, 1 Torr). Mp 112 ꢀC. 1H NMR
4.3.11. 2,6-Bis-(cyanomethyl)-3,5-dimethylanisole (15b). Starting from
7b (3.8 g, 11.8 mmol), following procedure D, was obtained com-
pound 15b (2.42 g, 96%) as a colourless solid. An analytically pure
sample was obtained by sublimation (110 ꢀC, 1 Torr). Mp 138 ꢀC. 1H
(CDCl3)
J¼7.6 Hz), 3.90 (3H, s), 4.74 (4H, d, J¼5.6 Hz), 6.90 (1H, br s) ppm.
13C NMR (CDCl3)
¼16.1, 26.0, 57.1, 63.4, 125.7, 129.2, 144.9,
158.3 ppm. IR (KBr) nmax: 876, 979, 998,1018,1026,1044,1077,1092,
1336, 1408, 1425, 1453, 1459, 1481, 1605, 2905, 2965, 3310 cmꢁ1
Anal. Calcd for C13H20O3 (224.30): C, 69.61; H, 8.99, found: C, 69.35;
H, 8.97. HRMS (ESI-Q-Tof) m/z calcd for C13H20O3 [MþNa]ꢃþ
247.1310, found 247.1315.
d
¼1.23 (6H, t, J¼7.6 Hz), 1.98 (2H, t, J¼5.6 Hz), 2.73 (4H, q,
NMR (CDCl3)
d
¼2.38 (6H, s), 3.69(4H, s), 3.87 (3H, s), 6.92(1H, s)ppm.
13C NMR (CDCl3)
d
¼15.1, 19.5, 62.6, 117.6, 120.8, 129.0, 138.7,
d
156.5 ppm. IR (KBr) nmax: 628, 880, 954, 998, 1036, 1078, 1216, 1305,
1384,1407,1424,1449,1463,1482,1567,1615, 2248, 2935, 2969, 2978,
3010 cmꢁ1. Anal. Calcd for C13H14N2O (214.26): C, 72.87; H, 6.59; N,
13.07. Found: C, 72.88; H, 6.59; N, 13.00.
.
4.3.12. 2,6-Bis-(cyanomethyl)-3,5-diethylanisole (15c). Starting from
7c (3.95 g, 11.3 mmol), following procedure D, was obtained com-
pound 15c (2.43 g, 89%) as a colourless solid. An analytically pure
sample was obtained by sublimation (110 ꢀC, 1 Torr). Mp 93 ꢀC. 1H
4.3.7. 2,6-Bis(bromomethyl)-3-methylanisole (7a). Starting from
14a (1.82 g, 10 mmol), following procedure C, was obtained
compound 7a (3.08 g, quant.) as a colourless solid. An analyti-
cally pure sample was obtained by sublimation (100 ꢀC, 1 Torr).
NMR (CDCl3)
d
¼1.29 (6H, t, J¼7.6 Hz), 2.72 (4H, q, J¼7.6 Hz), 3.71
(4H, s), 3.90 (3H, s), 6.96 (1H, s) ppm. 13C NMR (CDCl3)
d
¼14.6, 14.7,
Mp 95 ꢀC. 1H NMR (CDCl3)
d
¼2.41 (3H, s), 4.03 (3H, s), 4.55 (2H,
s), 4.62 (2H, s), 6.97 (1H, d, J¼7.8 Hz), 7.28 (1H, d, J¼7.8 Hz) ppm.
13C NMR (CDCl3)
26.1, 62.5, 118.1, 120.3, 125.3, 144.6, 156.7 ppm. IR (KBr) nmax: 881,
936, 972, 986, 1034, 1077, 1086, 1207, 1284, 1328, 1414, 1451, 1459,
1469, 1569, 1608, 2249, 2873, 2936, 2969 cmꢁ1. Anal. Calcd for
C15H18N2O (242.32): C, 74.35; H, 7.49; N, 11.56. Found: C, 74.52; H,
7.39; N, 11.23.
d
¼19.0, 25.7, 28.1, 62.4, 127.1, 129.3, 130.3,
131.9, 140.7, 157.1 ppm. IR (KBr) nmax: 584, 743, 788, 826, 925,
971, 997, 1051, 1123, 1132, 1198, 1208, 1239, 1260, 1406, 1427,
1443, 1459, 1487, 1576, 1602, 2941 cmꢁ1
. Anal. Calcd for
C10H12Br2O (308.01): C, 38.99; H, 3.93. Found: C, 39.28; H, 4.01.
HRMS (ESI-Q-Tof) m/z calcd for C10H12Br2O [MþNa]ꢃþ 328.9153,
found 328.9164.
4.3.13. 2,6-Bis[2-(2-cyanopropyl)]-3-methylanisole (16a). Starting
from 15a (1.51 g, 7.55 mmol), following procedure E, was obtained
compound 16a (1.0 g, 52%) as a colourless solid. An analytically pure
sample was obtained by sublimation (120 ꢀC, 1 Torr). Mp 145 ꢀC. 1H
4.3.8. 2,6-Bis(bromomethyl)-3,5-dimethylanisole (7b). Starting from
14b (392 mg, 2 mmol), following procedure C, was obtained
NMR (CDCl3)
d
¼1.76 (6H, s), 2.01 (6H, s), 2.61 (3H, s), 3.87 (3H, s),
6.96 (1H, d, J¼8.1 Hz), 7.14 (1H, d, J¼8.1 Hz) ppm. 13C NMR (CDCl3)

926
V. Diemer et al. / Tetrahedron 66 (2010) 918–929
d
¼22.5, 28.9 (2C), 28.9 (2C), 33.5, 36.1, 65.2, 125.5, 125.6, 125.8,
1710, 1724, 2718, 2816, 2940, 2979 cmꢁ1. HRMS (ESI-Q-Tof): m/z
calcd for C16H22O3 [MþH]ꢃþ 263.1647, found 263.1633.
128.5, 133.0, 133.6, 139.0, 158.0 ppm. IR (KBr) nmax: 815, 997, 1018,
1039, 1167, 1206, 1227, 1251, 1376, 1388, 1446, 1459, 1467, 2231,
2948, 2989 cmꢁ1. HRMS (ESI-Q-Tof) m/z calcd for C16H20N2O
[MþH]ꢃþ 257.1654, found 257.1664.
4.3.19. 3,5-Dimethyl-2,6-bis[2-(2-formylpropyl)]anisole
(20b). Starting from 16b (9.5 g, 35.2 mmol), following procedure F,
was obtained compound 20b (7.9 g, 81%) as a colourless solid. An
analytically pure sample was obtained by recrystallisation from i-
4.3.14. 2,6-Bis[2-(2-cyanopropyl)]-3,5-dimethylanisole
(16b). Starting from 15b (1.07 g, 5 mmol), following procedure E,
was obtained compound 16b (1.28 g, 95%) as a colourless solid. An
analytically pure sample was obtained by sublimation (120 ꢀC,
PrOH. Mp 173–174 ꢀC. 1H NMR (CDCl3)
d
¼1.44 (12H, s), 2.44 (6H, s),
3.14 (3H, s), 6.83 (1H, s), 9.35 (2H, s) ppm. 13C NMR (CDCl3)
d
¼20.4,
22.1, 24.1, 48.8, 60.9, 134.6, 134.7, 137.0, 154.3, 195.5 ppm. IR (KBr)
nmax: 712, 832, 892, 913, 989, 1004, 1039, 1061, 1100, 1184, 1209,
1246, 1279, 1363, 1389, 1444, 1465, 1596, 1719, 2708, 2806, 2940,
1 Torr). Mp 120 ꢀC. 1H NMR (CDCl3)
d
¼1.91 and 1.98 (12H, br s, 2
rotamers), 2.53 (6H, s), 3.67 (3H, s), 6.80 (1H, s) ppm. 13C NMR
(CDCl3)
d¼22.3 (2CH3aryl), 29.0 and 29.7 (br s, 4CH3propyl, 2
2984, 3418 cmꢁ1
. HRMS (ESI-Q-Tof): m/z calcd for C17H24O3
rotamers), 35.6 (2Cpropyl, 2 rotamers), 65.1 (OCH3), 125.9 (2CN),
130.8 (C(2), C(6)), 133.1 (C(4)), 136.9 (C(3), C(5)), 158.0 (C(1)) ppm. IR
(KBr) nmax: 847, 996, 1023, 1034, 1065, 1106, 1124, 1177, 1188, 1232,
1286, 1376, 1388, 1438, 1485, 1471, 2229, 2943, 2985 cmꢁ1. HRMS
(ESI-Q-Tof) m/z calcd for C17H22N2O [MþNH4]ꢃþ 288.2076, found
288.2072.
[MþH]$þ 277.1804, found 277.1805.
4.3.20. 3,5-Diethyl-2,6-bis[2-(2-formylpropyl)]anisole (20c). Starting
from 16c (2.12 g, 7.11 mmol), following procedure F, was obtained
compound 20c (1.79 g, 83%) as a colourless solid. Mp 153 ꢀC. 1H
NMR (CDCl3)
(2H, dq, J¼14.5, J¼7.1 Hz), 2.86 (2H, dq, J¼14.5, J¼7.1 Hz), 3.12 (3H,
s), 6.97 (1H, s), 9.36 (2H, s) ppm. 13C NMR (CDCl3)
d¼1.30 (6H, t, J¼7.1 Hz), 1.46 (6H, s), 1.48 (6H, s), 2.71
4.3.15. 2-(1-Cyanoethyl)-6-[2-(2-cyanopropyl)]-3,5-dimethylanisole
(17) and 2,6-bis-(1-cyanoethyl)-3,5-dimethylanisole (18). Compounds
17 and 18 were separated from 16b by HPLC (Acetonitrile/Water
60:40) and were only characterised by NMR.
¼1.62 (3H, d, J¼8 Hz),1.91 (3H, s),
1.94 (3H, s), 2.49 (3H, s), 2.54 (3H, s), 3.75 (3H, s), 4.51 (1H, q, J¼8 Hz),
6.84(1H, s) ppm.13C NMR (CDCl3)
22.4 (Cethyl), 22.7 (C(5)-CH3aryl), 29.6 (CH3propyl), 29.7 (CH3propyl), 35.6
(Cpropyl), 63.9(OCH3),121.5 (CNethyl),126.0 (CNpropyl),129.6 (C(6)),132.5
(C(4)), 137.3 (C(3)), 137.5 (C(5)), 156.1 (C(1)) ppm.
d¼16.4, 21.5,
24.8, 26.5, 48.6, 60.9, 131.1, 133.9, 143.5, 153.6, 195.2 ppm. IR (KBr)
nmax: 710, 834, 885, 902, 968, 1005, 1021, 1056, 1077, 1100, 1268,
1335, 1366, 1391, 1438, 1444, 1453, 1457, 1467, 1474, 1476, 1542,
1594, 1648, 2813, 2817, 2885, 2940, 2965, 2980, 2993 cmꢁ1. Anal.
Calcd for C19H28O3 (304.42): C, 74.96; H, 9.27. Found: C, 74.62; H,
9.29.
Compound 17: 1H NMR (CDCl3)
d
d¼18.4 (CH3ethyl),19.3 (C(3)-CH3aryl),
4.3.21. 2,6-Di-tert-butyl-3-methylanisole (21a). Starting from 20a
(627 mg, 2.39 mmol), following procedure G, was obtained com-
pound 21a (324 mg, 58%) as a colourless solid. An analytically pure
sample was obtained by sublimation (70 ꢀC, 1 Torr). Mp 32 ꢀC. 1H
Compound 18: 1H NMR (CDCl3)
d¼1.615 (6H, d, J¼8 Hz, 2 di-
astereomers), 1.625 (6H, d, J¼8 Hz, 1 diastereomer), 2.47 (6H, s, 2
diastereomers), 2.48 (6H, s, 2 diastereomers), 3.82 (3H, s), 4.41 (2H, q,
J¼8 Hz, 2 diastereomers), 4.42 (2H, q, J¼8 Hz, 2 diastereomers), 6.86
NMR (CDCl3)
d
¼1.38 (9H, s), 1.53 (9H, s), 2.51 (3H, s), 3.57 (3H, s),
6.79 (1H, d, J¼8.1 Hz), 7.04 (1H, d, J¼8.1 Hz) ppm. 13C NMR (CDCl3)
(1H, s) ppm. 13C NMR (CDCl3)
d¼18.4 (2CH3ethyl, 1 diastereomer), 18.5
d¼24.0, 31.7 (3C), 32.6 (3C), 35.4, 37.1, 64.5, 124.5, 127.5, 137.0, 141.4,
(2CH3ethy, 1 diastereomer), 19.5 (2CH3aryl, 2 diastereomers), 22.7
(2Cethyl, 2 diastereomers), 63.3 (OCH3, 2 diastereomers), 121.4 (2CN,
br, 2 diastereomers), 126.7 (C(2), C(6), br, 2 diastereomers), 130.9 (C(4)
1 diastereomer), 131.0 (C(4), 1 diastereomer), 137.6 (C(3), C(5), br, 2
diastereomers), 155.3 (C(1), 1 diastereomer), 155.4 (C(1), 1 di-
astereomer) ppm.
141.8, 160.7 ppm. IR (KBr) nmax: 650, 794, 815, 873, 930, 996, 1018,
1046, 1109, 1166, 1190, 1210, 1233, 1363, 1369, 1380, 1440, 1455,
,
1465, 1478, 1616, 2872, 2914, 2931, 2964, 2987, 3027, 3440 cmꢁ1
.
HRMS (ESI-Q-Tof): m/z calcd for C16H26O [MþH]ꢃþ 235.3850, found
235.2065.
4.3.22. 2,6-Di-tert-butyl-3,5-dimethylanisole (21b). Starting from
20b (7.05 g, 25.5 mmol), general procedure G, afforded compound
21b (4.06 g, 64%) as a colourless solid. An analytically pure sample
was obtained by sublimation (70 ꢀC, 1 Torr). Mp 93 ꢀC. 1H NMR
4.3.16. 2,6-Bis[2-(2-cyanopropyl)]-3,5-diethylanisole (16c). Starting
from 15c (250 mg, 1.03 mmol), following procedure E, was obtained
compound 16c (252 mg, 82%) as a colourless oil. 1H NMR (CDCl3)
d
¼1.31 (6H, t, J¼7.3 Hz), 1.89 (6H, br s), 2.00 (6H, br s), 2.85 (2H, m),
(CDCl3)
d
¼1.49 (18H, s), 2.45 (6H, s), 3.46 (3H, s), 6.61 (1H, s) ppm.
2.92 (2H, m), 3.63 (3H, s), 6.94 (1H, s) ppm. 13C NMR (CDCl3)
d¼16.4,
13C NMR (CDCl3)
d
¼24.2, 32.9 (6C), 37.3, 64.4, 132.8, 134.9, 139.7,
26.7, 30.0 (br), 30.6 (br), 35.7, 65.3, 126.6, 129.7, 130.1, 143.8,
157.5 ppm. IR (film) nmax: 978, 1033, 1059, 1079, 1104, 1124, 1188,
1231, 1276, 1372, 1387, 1463, 1534, 1598, 2229, 2877, 2940,
2979 cmꢁ1. HRMS (ESI-Q-Tof) m/z calcd for C19H26N2O [MþNa]ꢃþ
321.1943, found 321.1907.
161.7 ppm. IR (KBr) nmax: 861, 931, 996, 1024, 1065, 1106, 1203, 1245,
1267, 1357, 1361, 1379, 1442, 1458, 1471, 1589, 2833, 2874, 2927,
2956, 3012 cmꢁ1. Anal. Calcd for C17H28O (248.40): C, 82.20; H,
11.36. Found: C, 82.15; H, 11.54.
4.3.23. 2,6-Di-tert-butyl-3,5-diethylanisole (21c). Starting from 20c
(1.61 g, 5.3 mmol), following procedure G, was obtained compound
21c (896 mg, 61%) as a colourless solid. An analytically pure sample
was obtained by sublimation (70 ꢀC, 1 Torr). Mp 63 ꢀC. 1H NMR
4.3.17. 2,6-Bis[2-(2-iminomethylpropyl)]-3,5-dimethylanisole
(19b). 1H NMR (CDCl3)
d¼1.49–1.54 (12H, m), 2.44 (6H, s), 3.19 (3H,
s), 6.77 (1H, s), circa 8 (2H, br s), 8.22 (2H, s) ppm.
The other unstable diimines 19a and 19c were not isolated.
(CDCl3)
d
¼1.25 (6H, t, J¼7.6 Hz), 1.48 (18H, s), 2.79 (4H, q, J¼7.6 Hz),
3.41 (3H, s), 6.73 (1H, s) ppm. 13C NMR (CDCl3)
d
¼17.6, 28.2, 33.9
4.3.18. 3-Methyl-2,6-bis[2-(2-formylpropyl)]anisole (20a). Starting
from 16a (1.81 g, 7.07 mmol), following procedure F, was obtained
compound 20a (1.83 mg, 99%) as a colourless solid. Mp 108 ꢀC. 1H
(6C), 37.4, 64.7, 129.8, 138.6, 142.1, 160.8 ppm. IR (KBr) nmax: 720,
847, 881, 907, 1024, 1035, 1058, 1079, 1108, 1191, 1202, 1242, 1264,
1319, 1364, 1378, 1396, 1455, 1478, 1523, 1591, 2878, 2968,
3010 cmꢁ1. Anal. Calcd for C19H32O (276.47): C, 82.55; H, 11.67.
Found: C, 82.55; H, 11.87.
NMR (CDCl3)
7.04 (1H, d, J¼8.1 Hz), 7.17 (1H, d, J¼8.1 Hz), 9.36 (1H, s), 9.51 (1H, s)
ppm. 13C NMR (CDCl3)
d¼1.36 (6H, s), 1.48 (6H, s), 2.50 (3H, s), 3.22 (3H, s),
d
¼22.6, 24.5 (4C), 48.8, 49.1, 61.8, 126.7,
130.5, 136.5, 137.3, 138.2, 154.4, 195.8, 199.6 ppm. IR (KBr) nmax: 728,
4.3.24. 2,4,5,6-Tetramethylanisole (21d). (a) Compound 14b (389 mg,
833, 901, 994, 1002, 1042, 1235, 1362, 1384, 1391, 1447, 1459, 1465,
1.98 mmol), was hydrogenolysed over 5% Pd/C (90 mg) in MeOH

V. Diemer et al. / Tetrahedron 66 (2010) 918–929
927
(7 mL) at rt for 8 h. The catalyst was removed by filtration through
Celite using CH2Cl2 as eluent. After evaporation under reduced
pressure, the crude product was purified by column chromatogra-
phy (cyclohexane/CH2Cl2, 3:1). Anisole 21d was obtained as a col-
ourless solid (180 mg, 55%)
1172, 1212, 1295, 1374, 1387, 1420, 1433, 1438, 2923, 2934, 2950,
2997 cmꢁ1
.
4.3.29. 4-Bromo-2,6-di-tert-butyl-3-methylanisole (4a). Starting from
21a (236 mg, 1.01 mmol), following procedure I, was obtained
compound 4a (309 mg, 98%) as a colourless solid after purification
by column chromatography (cyclohexane). Mp 30.5 ꢀC. 1H NMR
(b) Starting
from
2,3,5,6-tetramethylphenol
23
(2.77 g,
18.47 mmol), following procedure A, was obtained compound
21d (2.72 g, 90%) as a colourless solid after purification by
column chromatography.
(CDCl3)
d
¼1.35 (9H, s), 1.52 (9H, s), 2.51 (3H, s), 3.57 (3H, s), 7.35
(1H, s) ppm. 13C NMR (CDCl3)
d
¼24.7, 31.3 (3C), 32.7 (3C), 35.5, 37.8,
64.6, 122.6, 128.9, 136.2, 142.9, 144.1, 160.1 ppm. IR (film) nmax: 871,
996, 1022, 1050, 1112, 1208, 1228, 1237, 1353, 1380, 1392, 1401, 1411,
1446, 1471, 2873, 2929, 2961, 3015 cmꢁ1. Anal. Calcd for C16H25BrO
(313.27): C, 61.34; H, 8.04; Br, 25.51. Found: C, 61.19; H, 8.15; Br,
25.67.
Spectroscopic data were in agreement with lit.28
4.3.25. 2,6-Di-tert-butyl-4-iodo-3-methylanisole (3a). Starting from
21a (90 mg, 0.38 mmol), following procedure H, was obtained
compound 3a (138 mg, quant.) as a colourless oil after purification
by column chromatography (cyclohexane). 1H NMR (CDCl3)
d
¼1.35
(9H, s), 1.51 (9H, s), 2.57 (3H, s), 3.58 (3H, s), 7.64 (1H, s) ppm. 13C
NMR (CDCl3)
4.3.30. 4-Bromo-2,6-di-tert-butyl-3,5-dimethylanisole (4b). Starting
from 21b (222 mg, 0.89 mmol), general procedure I afforded com-
pound 4b (242 mg, 83%) as a colourless solid. An analytically pure
sample was obtained by recrystallisation from CH3CN. Mp 97 ꢀC. 1H
d¼30.9, 31.3 (3C), 32.7 (3C), 35.3, 37.9, 64.6, 100.1,
135.7, 139.3, 143.3, 143.9, 161.2 ppm. IR (film) nmax: 873, 1021, 1049,
1107, 1207, 1228, 1234, 1243, 1348, 1364, 1401, 1409, 1446, 1471,
1479, 2873, 2960, 3015 cmꢁ1. HRMS (ESI-Q-Tof): m/z calcd for
C16H25IO [M]ꢃþ 360.2736, found 360.0965.
NMR (CDCl3)
(CDCl3)
d
¼1.50 (18H, s), 2.57 (6H, s), 3.43 (3H, s) ppm. 13C NMR
d
¼25.9, 33.3 (6C), 37.9, 64.6, 129.4, 135.6, 141.2, 160.3 ppm.
IR (KBr) nmax: 680, 991, 1064, 1210, 1236, 1272, 1353, 1362, 1380,
1444, 1448, 1459, 2927, 2944, 2959 cmꢁ1. Anal. Calcd for C17H27BrO
(327.30): C, 62.38; H, 8.31; Br, 24.41, found: C, 62.60; H, 8.36; Br,
24.28.
4.3.26. 2,6-Di-tert-butyl-4-iodo-3,5-dimethylanisole (3b), 2-tert-bu-
tyl-6-iodo-3,5-dimethyl anisole (24b) and 2-tert-butyl-4,6-diiodo-
3,5-dimethylanisole (25b). Starting from 21b (30 mg, 0.12 mmol),
following procedure H, was obtained compound 3b (32 mg, 71%) as
a colourless solid after purification and separation from 24b and
25b by column chromatography (cyclohexane). Compound 24b and
25b were only characterised by 1H NMR, and 24b from the crude
mixture.
4.3.31. 4-Bromo-2,6-di-tert-butyl-3,5-diethylanisole (4c). Starting
from 21c (500 mg, 1.81 mmol), following procedure I, was obtained
compound 4c (431 mg, 67%) as a colourless oil after purification by
column chromatography (cyclohexane). 1H NMR (CDCl3, T¼338 K)
d
¼1.26 (6H, t, J¼7.3 Hz), 1.52 (18H, s), 3.14 (4H, q, J¼7.3 Hz), 3.40
Compound 3a: mp 132 ꢀC. 1H NMR (CDCl3)
d
¼1.50 (18H, s), 2.66
(3H, s) ppm. 13C NMR (CDCl3, T¼338 K)
¼15.6, 29.0, 34.0 (6C), 38.3,
d
(6H, s), 3.43 (3H, s) ppm. 13C NMR (CDCl3)
d¼33.0, 33.3 (6C), 38.1,
64.4, 127.9, 140.7, 142.3, 161.3 ppm. IR (film) nmax: 668, 780, 827,
1025,1035,1053,1080,1192, 1211,1229,1262,1357,1367,1399,1451,
1482, 2833, 2936, 2968 cmꢁ1. HRMS (ESI-Q-Tof): m/z calcd for
C19H31BrO [M]ꢃþ 354.1558, found 354.1553.
64.6, 113.7, 138.6, 140.8, 161.6 ppm. IR (KBr) nmax: 661, 882, 917, 936,
988, 1025, 1065, 1099, 1191, 1211, 1232, 1270, 1348, 1361, 1378, 1398,
1425, 1446, 2834, 2925, 2955, 3018 cmꢁ1. Anal. Calcd for C17H27IO
(374.30): C, 54.55; H, 7.27; I, 33.90, found: C, 54.53; H, 7.31; I, 33.77.
Compound 24b: 1H NMR (CDCl3)
(3H, s), 3.66 (3H, s), 6.82 (1H, s) ppm.
Compound 25b: mp 78 ꢀC. 1H NMR (CDCl3)
(3H, s), 2.92 (3H, s), 3.62 (3H, s) ppm. 13C NMR (CDCl3)
d
¼1.51 (9H, s), 2.37 (3H, s), 2.48
4.3.32. 4-Bromo-2,3,5,6-tetramethylanisole (4d). Starting from 21d
(2.103 mg, 12.81 mmol), following procedure I, was obtained
compound 4d (3.04 g, 98%) as a colourless oil after purification by
column chromatography (cyclohexane/AcOEt 7:3). Spectroscopic
data were in conformity with the lit.26
d
¼1.52 (9H, s), 2.68
d¼29.8, 33.0
(3C), 33.3, 38.2, 62.4, 98.6, 107.2, 140.3, 142.3, 143.3, 158.8 ppm. IR
(KBr) nmax: 633, 919, 933, 969, 989, 1070, 1218, 1283, 1336, 1375,
1448, 2927, 2955 cmꢁ1
.
4.3.33. 2-(3,5-Di-tert-butyl-4-methoxy-2-methylphenyl)-4,4,5,5-tet-
ramethyl-[1,3,2]dioxaborolane (26a). Starting from 3a (215 mg,
0.59 mmol), following procedure J, was obtained compound 26a
(155 mg, 72%), after column chromatography (cyclohexane/AcOEt
4.3.27. 2-tert-Butyl-3,5-diethyl-6-iodoanisole (24c). Starting from
21c (296 mg, 1.07 mmol), following procedure H, was obtained
compound 24a (289 mg, 78%) as a colourless solid after purification
by column chromatography (cyclohexane). Mp 45 ꢀC. 1H NMR
98:2) as a colourless solid. Mp 130 ꢀC. 1H NMR (CDCl3)
d
¼1.33 (12H,
s),1.37 (9H, s),1.52 (9H, s), 2.65 (3H, s), 3.56 (3H, s), 7.49 (1H, s) ppm.
13C NMR (CDCl3)
(CDCl3)
2.71 (2H, q, J¼7.6 Hz), 2.85 (2H, q, J¼7.6 Hz), 3.64 (3H, s), 6.87 (1H, s)
ppm. 13C NMR (100 MHz)
d
¼1.20 (3H, t, J¼7.6 Hz), 1.25 (3H, t, J¼7.6 Hz), 1.51 (9H, s),
d
¼23.1, 24.8 (4C), 31.4 (3C), 32.7 (3C), 35.10, 36.9,
64.1, 83.1 (2C), 125.5, 131.7, 139.7, 141.4, 143.9, 163.0 ppm. IR (KBr)
nmax: 883, 970, 1047, 1119, 1145, 1229, 1294, 1326, 1344, 1362, 1380,
1390, 1400, 1450, 1468, 2934, 2961 cmꢁ1. HRMS (ESI-Q-Tof): m/z
calcd for C22H37BO3 [MþNa]ꢃþ 383.2733, found 283.2725.
d
¼14.6, 17.4, 28.2, 33.4 (3C), 34.4, 37.2,
62.5, 98.7, 127.7, 138.6, 145.9, 146.1, 158.2 ppm. IR (KBr) nmax: 690,
875, 914, 976, 1010, 1024, 1036, 1062, 1076, 1085, 1204, 1226, 1274,
1365, 1380, 1450, 1455, 1459, 1480, 2873, 2894, 2932, 2948,
2968 cmꢁ1. HRMS (ESI-Q-Tof): m/z calcd for C15H23IO [MþH]$þ
347.0872, found 347.0861.
4.3.34. 2-(3,5-Di-tert-butyl-4-methoxy-2,6-dimethylphenyl)-4,4,5,5-
tetramethyl-[1,3,2]dioxaborolane (26b). Starting from 3b (598 mg,
1.6 mmol), following procedure J, was obtained compound 26b
(536 mg, 89%), after column chromatography (cyclohexane/AcOEt
4.3.28. 4-Iodo-2,3,5,6-tetramethylanisole (3d). Starting from 21d
(180 mg, 1.10 mmol), following procedure H, was obtained com-
pound 3d (195 mg, 61%) as a colourless solid, after purification by
column chromatography (cyclohexane/AcOEt 95:5). 1H NMR spec-
95:5) as a colourless solid. Mp 188 ꢀC. 1H NMR (CDCl3)
d
¼1.40
(12H, s), 1.46 (18H, s), 2.48 (6H, s), 3.36 (3H, s) ppm. 13C NMR
(CDCl3)
d
¼23.5, 25.3 (4C), 33.1 (6C), 37.1, 64.2, 83.8, C-B was in-
troscopic data were in agreement with lit.29 1H NMR (CDCl3)
d
¼2.29
¼14.4, 27.1,
60.1, 105.5, 127.5, 135.5, 156.7 ppm. IR (KBr) nmax: 903, 1002, 1093,
visible, 137.7, 138.9, 162.4 ppm. IR (KBr) nmax: 860, 1058, 1120, 1142,
1212, 1237, 1262, 1302, 1320, 1363, 1372, 1380, 1381, 1399, 1447,
1537, 2872, 2881, 2932, 2961, 2979, 3009 cmꢁ1. Anal. Calcd for
(6H, s), 2.48 (6H, s), 3.64 (3H, s) ppm. 13C NMR (CDCl3)
d

928
V. Diemer et al. / Tetrahedron 66 (2010) 918–929
C23H39BO3 (374.36): C, 73.79; H, 10.50; B, 2.89. Found: C, 73.67; H,
10.44; B, 2.84.
3254, 3261 cmꢁ1. HRMS (ESI-Q-Tof): m/z calcd for C17H29BO3
[MH]ꢃþ 293.2288, found 293.2275.
4.3.35. 2-(4-Methoxy-2,3,5,6-tetramethylphenyl)-4,4,5,5-tetra-
methyl-[1,3,2]dioxaborolane (26d). Starting from 3d (100 mg,
0.34 mmol), following procedure J, was obtained compound 26d
(72 mg, 72%), after column chromatography (cyclohexane/AcOEt
4.3.39. (4-Methoxy-2,3,5,6-tetramethyl)-phenyl
boronic
acid
(5d). Starting from 26d (35 mg, 0.12 mmol), following procedure K,
was obtained compound 5d (17 mg, 68%), after column chroma-
tography (cyclohexane/AcOEt 7:3) as a colourless solid.
Starting from 4d (400 mg, 1.6 mmol), following procedure L
was obtained compound 5d (188 mg, 55%), after column
chromatography.
98:2) asa colourless solid. Mp117 ꢀC.1H NMR (CDCl3)
d
¼1.40 (12H, s),
2.16 (6H, s), 2.28 (6H, s), 3.62 (3H, s) ppm. 13C NMR (CDCl3)
d
¼12.3,
19.6, 35.17 (4C), 60.0, 83.8, circa 120 (C-B),126.3,138.3, 157.6 ppm. IR
(KBr) nmax: 707, 698, 857, 957,1006,1020,1098,1144,1166,1209,1295,
1348,1352,1363,1371,1379,1420,1448,1572, 2935, 2978 cmꢁ1. Anal.
Calcd for C17H27BO3 (290.21): C, 70.36; H, 9.38; B, 3.73. Found: C,
70.66; H, 9.09; B, 3.47.
Mp 160 ꢀC. 1H NMR (CD3OD)
d
¼2.14 (6H, s), 2.23 (6H, s), 3.60
(3H, s) ppm. 13C NMR (CD3OD)
d
¼12.4, 20.3, 60.4, C-B was invisible,
126.5, 137.0, 157.7 ppm. IR (KBr) nmax: 998, 1087, 1215, 1232, 1385,
1354, 1383, 1408, 1422, 1448, 1571, 1575, 2490, 2940, 2952, 3363,
3665 cmꢁ1. HRMS (ESI-Q-Tof): m/z calcd for C11H17BO3 [MþNa]ꢃþ
231.1168, found 231.1167.
4.3.36. 2-(4-Methoxy-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-
[1,3,2]dioxaborolane (26e). NEt3 (557
0.05 mmol) and pinacolborane (435
m
L, 4 mmol), Pd(OAc)2 (11 mg,
mL, 3 mmol.) were successively
4.3.40. Diisopropyl (3,5-di-tert-butyl-4-methoxy-2,6-dimethyl)-phenyl
boronate (6). Starting from 4b (607 mg, 1.86 mmol), following
procedure L was obtained compound 6 (464 mg, 66%) after column
chromatography (cyclohexane/CH2Cl2 85:15) as a colourless solid.
added, under Ar, to a solution of 4-bromo-3,5-dimethyl anisole 4e
(215 mg, 1 mmol) in anhydrous dioxane (2.4 mL per mmol of 4e).
The reaction mixture was heated, overnight, at 80 ꢀC and then
allowed to reach rt. Aqueous saturated solution of NH4Cl was
added. The obtained aqueous layer was extracted three times with
Et2O. The combined organic layers were dried over MgSO4, filtrated
and evaporated under reduced pressure. Purification by column
chromatography (cyclohexane/CH2Cl2 5:5) afforded pure 26e
(199 mg, 76%) as a colourless solid. An analytically pure sample was
obtained by sublimation (120 ꢀC, 1 mmHg). Mp 62 ꢀC. 1H NMR
Mp 79 ꢀC. 1H NMR (CD3OD)
d
¼1.18 (12H, d, J¼6.3 Hz), 1.47 (18H, s),
2.40 (6H, s), 3.39 (3H, s), 4.23–4.31 (2H, m) ppm. 13C NMR (CDCl3)
d
¼23.8, 24.5, 24.7, 33.1, 37.1, 64.2, 65.9, 66.6, C-B was invisible, 136.1,
138.9, 161.7 ppm. IR (KBr) nmax: 1065, 1113, 1122, 1235, 1262, 1304,
1370, 1380, 1397, 1445, 1457, 1465, 2930, 2973, 3012 cmꢁ1. HRMS
(ESI-Q-Tof): m/z calcd for C23H41BO3 [M]ꢃþ 376.3149, found
376.3115.
(CDCl3)
d
¼1.37 (12H, s), 2.40 (6H, s), 3.76 (3H, s), 6.51 (2H, s) ppm.
13C NMR (CDCl3)
d
¼22.7, 25.1 (4C), 55.0, 83.5, 112.5,144.6,160.5, C-B
Acknowledgements
was invisible ppm. IR (KBr) nmax: 832, 857, 1049, 1141, 1160, 1191,
1274, 1297, 1311, 1337, 1363, 1370, 1378, 1603, 2839, 2921, 2939,
2978, 2987, 2991 cmꢁ1. Anal. Calcd for C15H23BO3: C, 68.72; H, 8.84;
B, 4.12. Found: C, 68.62; H, 9.02; B, 4.05. HRMS (ESI-Q-Tof): m/z
calcd for C15H23BO3 [MþH]ꢃþ 263.1819, found 263.1815.
´
The Region Alsace, the program Interreg III A Rhenaphotonics
and Dr. D. Le Noue¨n are gratefully acknowledged for their financial
supports.
We gratefully acknowledge Dr. Mathias Wind for some of the
´
mass determinations and Dr. Cecile Joyeux for HPLC separations.
4.3.37. (3,5-di-tert-Butyl-4-methoxy-2-methyl)-phenyl-1-boronic
acid (5a). Starting from 26a (102 mg, 0.28 mmol), following pro-
cedure K, was obtained compound 5a (53 mg, 67%), after column
chromatography (cyclohexane/AcOEt 7:3) as a colourless solid.
Starting from 4a (243 mg, 0.78 mmol), following procedure L was
obtained compound 5a (125 mg, 58%), after column chromatography.
The authors thank also the undergraduate students Fabien
Dorilleau, Vincent Duplan and Remi Rigault for their dedicated help
in the syntheses.
References and notes
Mp 239 ꢀC. 1H NMR (CD3OD)
(3H, s), 3.55 (3H, s), 6.97 (1H, s) ppm. 13C NMR (CD3OD)
d
¼1.36 (9H, s), 1.53 (9H, s), 2.45
1. (a) Diemer, V.; Chaumeil, H.; Defoin, A.; Fort, A.; Boeglin, A.; Carre´, C. Eur. J. Org.
Chem. 2006, 2727–2738; (b) Diemer, V.; Chaumeil, H.; Defoin, A.; Fort, A.;
Boeglin, A.; Carre´. Eur. J. Org. Chem. 2008, 1767–1776; (c) Diemer, V.; Chaumeil,
H.; Defoin, A.; Boeglin, A.; Barsella, A.; Fort, A.; Carre´, C. Proc. Spie- Org. Opto-
electron. Photonics II 2006, 6192, 559–565; (d) Boeglin, A.; Barsella, A.; Fort, A.;
Mançois, F.; Rodriguez, V.; Diemer, V.; Chaumeil, H.; Defoin, A.; Jacques, P.;
d
¼23.8, 32.0
(3C), 33.2 (3C), 35.8, 37.8, 64.9, C-B was invisible, 127.9, 139.8, 142.5,
162.3 ppm. IR (KBr) nmax: 1050, 1209, 1227, 1250, 1318, 1376, 1392,
1413, 2937, 2962, 3399 cmꢁ1. HRMS (ESI-Q-Tof): m/z calcd for
C16H27BO3 [MþNa]ꢃþ 301.1951, found 301.1940.
´
Carre, C. Chem. Phys. Lett. 2007, 442, 289–301.
2. (a) Keinan, S.; Zojer, E.; Bre´das, J.-L.; Ratner, M. A.; Marks, T. J. Theochem. 2003,
227–235; (b) Kang, H.; Frachetti, A.; Zu, P.; Jiang, H.; Yang, Y.; Cariati, E.;
Righetto, S.; Ugo, R.; Zuccaccia, C.; Macchioni, A.; Stern, C.; Liu, Z.; Ho, S.-T.;
Marks, T. J. Angew. Chem., Int. Ed. 2005, 44, 7922–7925.
3. (a) Kang, H.; Fachetti, A.; Stern, C. L.; Rheingold, A. L.; Kassel, W. S.; Marks, T. J.
Org. Lett. 2005, 7, 3721–3724; (b) Marks, T.J.; Kang, H. U.S. Patent
WO2,006,102,620(A2), 2006.
4. See for example (a) Bandgar, B. P.; Upalla, L. S.; Sadavarte, V. S. J. Chem. Res.,
Synop. 2000, 282–583; (b) Schleusener, E.; Eugster, C. H. Helv. Chim. Acta 1972,
55, 986–1002; (c) Burmistrov, S.I.; Martsinkevich, S. L. E. S.U. Patent 168,303
19,650,218, CA 1965, 62, 16128d. (d) Sasaki, S.-I.; Mizuno, M.; Koichiro, K.; Tobe,
Y. J. Org. Chem. 2000, 65, 275–283; (e) Nagel, N.; Hansen, H.-J. Helv. Chim. Acta
2000, 83, 1022–1048; (f) Houben-Weyl Methoden der Organischen Chemie, 4th
ed.; Georg Thiem Ed.: Stuttgart, 1976; Vol. VI-1c; 926–1137; (g) Rajakumar, P.;
Murati, V. Tetrahedron Lett. 2002, 43, 7695–7698; (h) Gagne´, R. R.; Spiro, C. L.;
Smith, T. J.; Hamann, C. A.; Thies, W. R.; Shiemke, A. K. J. Am. Chem. Soc. 1981,
103, 4073–4081; (i) Thoer, A.; denis, G.; Delmas, M.; Gaset, A. Synth. Commun.
1988, 16–18, 2095–2102; (j) Casiraghi, G.; Casnati, G.; Puglia, G.; Sarton, G.;
Terenghi, G. J. Chem. Soc., Perkin Trans. 1 1980, 1862–1865.
4.3.38. (3,5-di-tert-Butyl-4-methoxy-2,6-dimethyl)-phenyl boronic
acid (5b). Starting from 26b (45 mg, 0.12 mmol), following pro-
cedure K, was obtained compound 5b (23 mg, 63%), after column
chromatography (cyclohexane/AcOEt 7:3) as a colourless solid.
Under Ar, 10 M aqueous KOH (0.73 mL, 10 equiv) was added to
a suspension of boronic ester 6 (273 mg, 0.73 mmol) in DMSO
(3.6 mL). The reaction mixture was heated at 60 ꢀC for 2 h, and then
allowed to reach rt. Aqueous 1 M HCl (40 mL) was added. The
obtained aqueous layer was extracted three times with Et2O. The
combined organic layers were dried over MgSO4, filtrated and
evaporated under reduced pressure. Purification by column chro-
matography (cyclohexane/AcOEt 7:3) afforded pure 5b (203 mg,
96%) as a colourless solid.
Mp 200 ꢀC. 1H NMR (DMSO-d6)
d
¼1.44 (18H, s), 2.29 (6H, s), 3.36
(3H, s), 8.03 (2H, s) ppm. 13C NMR (DMSO-d6)
d
¼23.4, 33.0 (6C),
5. (a) Yoshifuji, M.; Nakazawa, M.; Sato, T.; Toyota, K. Tetrahedron 2000, 56, 43–55;
(b) Toyota, K.; Kawasaki, S.; Nakamura, A.; Yoshifuji, M. Chem. Lett. 2003, 32,
430–431; (c) Toyota, K.; Kawasaki, S.; Yoshifuji, M. J. Org. Chem. 2004, 69,
5065–5070.
36.6, 64.2, circa 120 (C-B),135.4,137.7,160.3 ppm. IR (KBr) nmax: 991,
1071,1184,1239,1267,1301,1357,1401,1438,1449,1457, 2956, 3247,

V. Diemer et al. / Tetrahedron 66 (2010) 918–929
929
6. (a) Takeuchi, N.; Okazaki, K.; Ohki, J.; Tobinaga, S. Heterocycles 1984, 21, 615–
616; (b) Takeuchi, N.; Goto, K.; Sasaki, Y.; Fujita, T.; Okazaki, K.; Kamata, K.;
Tobinaga, S. Heterocycles 1992, 33, 357–374.
7. (a) Bethell, R. J.; Maitland, P. J. Chem. Soc. 1962, 3751–3758; (b) Farhni, C. J.;
Pfalz, A. Helv. Chim. Acta 1998, 81, 491–506.
8. Shargi, H.; Nasseri, M. A.; Niknam, K. J. Org. Chem. 2001, 7287–7293.
9. Axton, C. A.; Billingham, M. E. J.; Bishop, P. M.; Gallagher, P. T.; Hicks, T. A.;
Kitchen, E. A.; Mullier, G. W.; Owton, W. M.; Parry, M. G.; Scott, S.; Steggles, D. J.
J. Chem. Soc., Perkin Trans. 1 1992, 2203–2209.
10. Ackerley, N.; Brewster, A. G.; Brown, G. R.; Clarke, D. S.; Foubister, A. J.; Griffin,
S. J.; Hudson, J. A.; Smithers, M. J.; Whittamore, P. R. O. J. Med. Chem. 1995, 38,
1608–1628.
H.; Liu, K.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125,
9032–9034.
18. Pennington, T. E.; Kardimann, C.; Hutton, C. A. Tetrahedron Lett. 2004, 45,
6657–6660.
19. Yang, W.; He, H.; Drueckhammer, D. G. Angew. Chem., Int. Ed. 2001, 40,1714–1718.
20. (a) Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1999, 64, 2976–2977; (b) Ma, D.; Wu,
Q. Tetrahedron Lett. 2001, 5279–5281; (c) Zaidlewicz, M.; Wolan, A. J. Organo-
met. Chem. 2002, 657, 129–135.
21. Bouillon, A.; Lancelot, J.-C.; Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron 2002, 58,
3323–3328.
22. Matteson, D. S. J. Organomet. Chem. 1999, 581, 51–65.
23. Kang, H.; Facchetti, A.; Stern, C. L.; Rheingold, A. L.; Kassel, W. S.; Marks, T. J.
Org. Lett. 2005, 3721–3724.
24. Liao, Y.; Xie, C.; Lahti, P. M.; Weber, R. T.; Jiang, J. J.; Barr, D. P. J. Org. Chem. 1999,
64, 5176–5182.
11. Turro, N. J.; Mattay, J. J. Am. Chem. Soc. 1981, 103, 4200–4204.
12. Prasad, G.; Hanna, P. E.; Noland, W. E.; Venkatraman, S. J. Org. Chem. 1991, 56,
7188–7190.
´
13. Pascal, C.; Dubois, J.; Guenard, D.; Gueritte, F. J. Org. Chem. 1998, 63, 6414–6420.
25. Hall, D. G. Boronic Acids; Wiley-VCH: Weinheim, 2005.
26. Reese, J. Chem. Ber. 1953, 86, 979–985.
14. Huang-Minlon. J. Am. Chem. Soc. 1946, 68, 2487–2488.
15. Carren˜o, M. C.; Garcia Ruano, J. L.; Sanz, G.; Toledo, M. A.; Urbano, A. J. Org.
Chem. 1995, 60, 5328–5331.
16. Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508–7510.
17. (a) Falck, J. R.; Bondlela, M.; Venkaraman, S. K. J. Org. Chem. 2001, 66, 7148–7150;
(b) Yu, S.; Saenz, J.; Srirangam, J. K. J. Org. Chem. 2002, 67, 1699–1702; (c) Deng, J.-
27. Roberts, J. C. J. Chem. Soc. 1955, 2989–2991.
28. Gruter, G.-J. M.; Akkerman, O. S.; Bickelhaupt, F. J. Org. Chem. 1994, 59,
4473–4481.
29. Cornforth, J.; Sierakowski, A. F.; Wallace, T. W. J. Chem. Soc., Perkin Trans. 1 1982,
2299–2316.