New stabilising groups for lateral lithiation of ortho-cresol derivatives and a new route to 2-substituted chromans

Article abstract of DOI:10.1016/j.tet.2008.04.093

2-(2-Methoxyethoxy)-toluene and 2-(2-dimethylaminoethoxy)-toluene have been lithiated using sec-BuLi under a variety of conditions and the laterally lithiated species trapped with electrophiles, including but-1-ene oxide, leading to a new synthesis of 2-ethylchroman.

Full text of DOI:10.1016/j.tet.2008.04.093

Tetrahedron 64 (2008) 6329–6333
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New stabilising groups for lateral lithiation of ortho-cresol derivatives
and a new route to 2-substituted chromans
*
James A. Wilkinson , Eun-Ang Raiber, Sylvie Ducki
Centre for Molecular Drug Design, Biosciences Research Institute, Cockcroft Building, University of Salford, Salford M5 4WT, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
2-(2-Methoxyethoxy)-toluene and 2-(2-dimethylaminoethoxy)-toluene have been lithiated using sec-
BuLi under a variety of conditions and the laterally lithiated species trapped with electrophiles, including
but-1-ene oxide, leading to a new synthesis of 2-ethylchroman.
Received 30 January 2008
Received in revised form 4 April 2008
Accepted 24 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Available online 29 April 2008
Keywords:
Lateral lithiation
Alkylation
ortho-Cresol
Chromans
1. Introduction
2. Results and discussion
Lateral lithiation is an important methodology in organic syn-
thesis.1 Lateral lithiation of benzenoid aromatics requires a stabil-
ising group capable of either delocalising negative charge or
stabilising an organolithium by coordination.2 Oxygen-based sta-
bilising groups placed in the ortho-position have been used for
a number of lateral lithiations but are problematic in the case of
simple ortho-cresol derivatives. The methoxy group requires
superbase conditions to effect deprotonation and the methoxy-
methyl group gives exclusive ortho-lithiation (Scheme 1).3
In a previous work on diarylmethane derivatives we have used
the methoxyethoxy group in efficient lateral lithiations.4 This led us
to investigate the use of the same group as a potentially more
efficient stabiliser for lateral lithiation of ortho-cresol derivatives.
We have recently reported lateral lithiation reactions of ortho-
cresol derivatives using both the methoxyethoxy and dimethyl-
aminoethoxy stabilising groups.5 Here, we report in full the results
of these investigations.
Starting materials 2 and 3 were easily prepared by alkylation of
ortho-cresol 1 using sodium hydride in DMF (Scheme 2).
OH
OCH2CH2X
NaH, DMF
HalCH2CH2X
1
2 X=OMe, 98%
3 X=NMe2, 81%
Scheme 2.
The results of alkylations of 2 are shown in Table 1. Optimum
conditions for alkylation of 2 involved generating the lithio species
at ꢀ30 ꢁC for 2 h using 1.3 equiv of sec-BuLi before quenching
(entry 2). Generating the lithio species at ꢀ78 ꢁC for 2 h led to
isolation of starting material only, while stirring for a 4 h period
Li
OR
OR
Li
OR
R = Me
R = CH2OMe
Scheme 1.
before quenching or warming to ꢀ20 ꢁC led to lower conversions.
Our assumption was that the organolithium was slowly quenched
by solvent, which would explain the large amounts of starting
* Corresponding author. Tel.: þ44 161 295 4046; fax: þ44 161 295 5111.
E-mail address: j.a.wilkinson@salford.ac.uk (J.A. Wilkinson).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.093

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J.A. Wilkinson et al. / Tetrahedron 64 (2008) 6329–6333
Table 1
Reactions of 2
R
O
OH
OCH2CH2OMe
R
OCH2CH2OMe
OCH2CH2OMe
?
via
6
1
4
5
2
Entry
R–X
Solvent, concentration, additive
Product
4
5
1
2
1
2
3
4
5
6
7
8.
Me–I
Me–I
Me–I
Me–I
Allyl–Br
Allyl–Br
TMS–Cl
Diethyl ether, 0.06 M
Diethyl ether, 0.03 M
TBME
Diethyl ether, 0.03 M, TMEDA
Diethyl ether, 0.03 M
Diethyl ether, 0.03 M, Bu4NI
Diethyl ether, 0.03 M
Diethyl ether, 0.03 M
a
a
a
a
b
b
c
71
76
77
0
15
4
23
65
0
0
0
0
14
0
0
15
0
0
0
20
0
20
75
50
26
38
25
50 (47)
74 (70)
62 (59)
0
0
Benzophenone
d
Notes and conditions: Solution of 2 and sec-BuLi (1.3 equiv) in ether stirred at ꢀ30 ꢁC for 2 h followed by addition of electrophile (1.5 equiv) and warming to rt. Numbers in
brackets refer to isolated yields.
material recovered when addition of the electrophile was delayed
longer. Methylation could be carried out cleanly with 76% conver-
sion to compound 4a. Separation of the desired product 4a from the
ortho-product 5a and 2 proved impossible by flash chromatography
or HPLC, hence the conversions are based on NMR spectra of the
crude products. There was an optimum concentration for this re-
action with formation of ortho-cresol (as well as 5a) accompanying
product formation above 0.05 M in 2. Use of tert-butyl methyl ether
as solvent (entry 3) led to increased methylation at the ortho-po-
sition. Use of TMEDA as an additive (entry 4), common in the
preparation of organolithium compounds, shifted the reaction from
lateral to ortho-lithiation products completely, again accompanied
by some of the deprotected compound 1. The vinyl ether 6 could be
identified in the crude product if a deuteration reaction was run in
THF, which led us to believe that the predominant pathway for
deprotection was via lithiation adjacent to the aryl oxygen followed
by elimination of methoxide and cleavage to 1 in the work-up. The
wide variations in product distribution with solvent, concentration
and electrophile suggested that the degree of aggregation of the
organolithium is crucial. The complete change of regioselectivity
when TMEDA was added would seem to support this.6
With optimal conditions established, other electrophiles were
investigated. Allylation (entry 5) gave a clean reaction at the lateral
position but with only 25% conversion to product 4c. This could be
improved to 50% by the addition of tetrabutylammonium iodide
(entry 6). Silylation with TMSCl (entry 7) was also clean and gave
somewhat better conversion to product as was the case with ben-
zophenone (entry 8). It is not clear why electrophiles other than
iodomethane did not give rise to deprotected ortho-cresol. Our
overall conclusion was that the methoxyethoxy group did stabilise
lateral lithiation in preference to ortho-, when TMEDA was not
added, but that the laterally lithiated species was problematic to
work with and underwent a number of side-reactions.
our basic ligands much more inconvenient but it was considered
here as a possible way to make the organolithium more stable. A
similar range of electrophiles was investigated with compound 3 as
had been used with 2 (Table 2). While optimum solvent, time and
temperature were similar to those required for reactions of 2, the
stoichiometry was different. In all cases, more than 2 equiv of sec-
BuLi were needed; no lithiation products were formed and no
colour change was observed at less than 2 equiv. A significant ex-
cess of electrophile was also required, at least 2.5 equiv suggesting
that the first equivalent of sec-BuLi was being coordinated by 3 in
such a way that rendered it less able to deprotonate the molecule,
rather than being quenched entirely. While methylation with
2.5 equiv of iodomethane (entry 1) produced only starting material,
10 equiv (entry 2) gave good conversion to the quaternized 10b. The
degree of quaternization was reduced in TBME (entry 3) but
methylated products were impossible to isolate pure due to the
presence of quaternised starting material 11 in the mixture. With
allyl bromide (entry 4) and TMSCl (entry 5), 2.5 equiv of electro-
phile was sufficient and reaction at nitrogen was not observed, al-
though TMSCl gave rise to
a
di-substituted product 12c.8
Benzophenone (entry 6) gave adequate conversion to product.
Generally, reactions of 3 gave cleaner conversion to lateral lithiation
products than those of 2. Neither deprotection to ortho-cresol nor
products of ortho-lithiation were observed in any of the reactions
though starting material was never completely absent from the
crude mixtures.
A method was developed for removal of the dimethylamino-
ethoxy group, which involved quaternisation of the nitrogen using
iodomethane, treatment with KOtBu in DMSO to eliminate tri-
methylammonium iodide and acidic work-up to cleave the vinyl
ether to the cresol derivative. This was used to prepare com-
pounds 7 and 8 from 3 in 64 and 62% overall yields, respectively
(Scheme 4).
Removal of the methoxyethyl group was carried out on com-
pounds 4a and 4b using aluminium triiodide in refluxing toluene
giving the known compounds 7 and 8 in 62 and 65% yields,
respectively (Scheme 3).7
Our work on inhibitors of HGF/SF activation of MET led us to
require an efficient synthesis of chroman derivatives substituted at
the 2-position.9 It was felt that the reaction of a laterally lithiated
species derived from 2 or 3 with an epoxide, followed by cyclisation
to form an ether would be a valuable approach. Laterally lithiated
species have only rarely been reacted with epoxides in the past but
there is some literature precedent.10 The reaction of the organo-
lithium derived from 2 with but-1-ene oxide 13 under our estab-
lished conditions led to a 38% yield of the desired product 14.
Attempts to transmetallate to a copper species, an approach used
with great success by other groups, failed to improve the conver-
sion.11 Lewis acids were able to promote the reaction, boron tri-
fluoride etherate and iron(III) chloride giving confusing mixtures of
products but diethylaluminium chloride gave a clean reaction and
a good recovery of 14 (Table 3).
OH
OCH2CH2OMe
AlI3
R
toluene reflux
R
7 R=Me
8 R=Allyl
Scheme 3. Conditions: AlI3, toluene, reflux, 12 h.
The dimethylaminoethoxy group had not been used in our re-
search on asymmetric alkylation since it would make removal of

J.A. Wilkinson et al. / Tetrahedron 64 (2008) 6329–6333
6331
Table 2
Reactions of 3
NMe3+I-
NMe3+I-
O
R
O
O
NMe2
O
NMe2
O
NMe2
R
R
3
9
10
11
12
Entry
R–X (equiv)
Solvent, additive
Product
9
10
3
11
12
1
2
3
4
5
6
Me–I (2.5)
Me–I (10.0)
Me–I (10.0)
Allyl–Br (2.5)
TMS–Cl (2.5)
Benzophenone
Diethyl ether
Diethyl ether
TBME
Diethyl ether
Diethyl ether
Diethyl ether
a
a
a
b
c
0
0
0
80
63
0
0
0
100
0
6
25
14
28
0
20
0
0
0
0
0
0
31
75a
0
0
86b
0
d
72c
0
Notes and conditions: solution of 3 and sec-BuLi (2.3 equiv) in ether stirred at ꢀ30 ꢁC for 2 h followed by addition of electrophile and warming to rt.
a
Isolated yield of 9b (59%).
Isolated yield of 12c (62%).
Isolated yield of 9d (48%).
b
c
NMe3+I-
OH
O
O
NMe2
c-d
a or b
7 R=Me 64%
8 R=allyl 62%
R
R
3
10
Scheme 4. Conditions: (a) (R¼Me) solution of 3 and sec-BuLi (2.5 equiv) in ether stirred at ꢀ30 ꢁC for 2 h followed by addition of MeI (10.0 equiv) and warming to rt; (b) (R¼allyl) (i)
solution of 3 and sec-BuLi (2.5 equiv) in ether stirred at ꢀ30 ꢁC for 2 h followed by addition of allyl bromide (2.5 equiv) and warming to rt; (ii) MeI (10.0 equiv), rt, 12 h; (c) KOtBu,
DMSO, rt, 2 h; (d) acidic work-up.
Table 3
This represents two short and fairly high-yielding syntheses of
2-ethylchroman from ortho-cresol.
Reactions of 2 with epoxide 13
OCH2CH2OMe
OH
OCH2CH2OMe
Overall we have demonstrated the utility of organolithium
species derived from 2 and 3 in reactions with a good range of
electrophiles.
cond.
O
13
14
2
Entry
Additive (equiv)
Conditions
Yield of 14 (%)
3. Experimental
3.1. General
1
2
3
4
FeCl3 (1.33)
BF3 (1.33)
CuCN$2LiCl (2.00)
Et2AlCl (1.33)
2 h, ꢀ30 ꢁC, warm up to rt
3 h, ꢀ78 ꢁC, warm up to rt
2 h, ꢀ30 ꢁC, warm up to rt
2 h, ꢀ30 ꢁC, warm up to rt
17
35
40
63
Melting points were determined on a Gallenkamp electrother-
mal apparatus. Infrared absorption spectra were recorded on
a Bruker VECTOR-200 instrument, as liquid films or solutions in
chloroform. NMR spectra (1H and 13C) were recorded on a Bruker
Conditions: 1.25 equiv sec-BuLi, 1.25 equiv but-1-ene oxide.
The product 14 was deprotected to 15 in acceptable yield
(Scheme 5) and Mitsonobu conditions effected efficient cyclisation
to the chroman 16 in an overall yield of 33% from 2.
1
AC-400 instrument, operating at 400 MHz for H and 100 MHz for
13C NMR. Chemical shifts are reported in parts per million relative
to tetramethylsilane as an internal standard. Mass spectra (MS)
were measured on a JEOL JMS-DX303 or JEOL JMN-SX-102A in-
struments, chemical ionisation with methane was used throughout.
Unless otherwise stated, all new compounds were determined to
be >95% pure by signal/noise ratio in the 13C NMR. Flash chroma-
tography was carried out with silica gel, Merck Type 60 (70–325
mesh ASTM) or Merck Type 60 (230–400 mesh ASTM).
O
OH
OCH2CH2OMe
b
a
15
16
OH
14
OH
Scheme 5. Conditions: (a) AlI3, toluene, reflux, 12 h, 56%; (b) Ph3P, DEAD, 93%.
The organolithium derived from 3 also reacted well with 13
under these conditions but the product was impossible to purify at
that stage, apparently due to the amino group coordinating to the
Lewis acid. For this reason, a direct synthesis of 15 from 3 was
developed (Scheme 6), with reaction with 13 followed by treatment
with excess iodomethane in situ, elimination with base and acid
work-up to give 15 in 38% yield from 3.
3.2. 2-(2-Methoxyethoxy)-toluene (2)12
To a well-stirred mixture of sodium hydride (60% dispersion)
(6.2 g, 0.15 mol) in anhydrous DMF (150 mL) was added ortho-
cresol 1 (5.4 g, 0.05 mol) in anhydrous DMF (50 mL). The reaction
mixture was stirred at rt for 1 h. 2-Methoxy-bromoethane (8.3 g,
0.06 mol) was added and after stirring overnight, the reaction was
quenched with satd ammonium chloride (150 mL). After extraction
into ethyl acetate (200 mL), the organic layer was washed with 2 M
sodium hydroxide (50 mL), water (5ꢂ200 mL), brine (200 mL),
dried over MgSO4 and purified by flash chromatography (cyclo-
hexane/ethyl acetate 9:1) to afford the 2-(2-methoxyethoxy)-
toluene 2 as a yellow oil (8.1 g, 98%). All data corresponded to
literature values.
OH
OCH2CH2NMe2
a-d
15
OH
3
Scheme 6. Conditions: (a) solution of 3 and sec-BuLi (2.3 equiv) in ether stirred at
ꢀ30 ꢁC for 2 h followed by addition of Et2AlCl and but-1-ene oxide (2.4 equiv), stirring
for 2 h; (b) MeI (10.0 equiv) rt, 12 h; (c) KOtBu, DMSO, rt, 2 h; (d) acidic work-up.

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J.A. Wilkinson et al. / Tetrahedron 64 (2008) 6329–6333
3.3. 2-(2-Dimethylaminoethoxy)-toluene (3)
(MþNH4, 100), 239 (40), 90 (80). HRMS (ES): [MþNH4]þ
C13H26NO2Si requires 256.1727, found 256.1727.
To a well-stirred mixture of sodium hydride (60% dispersion)
(6.2 g, 0.15 mol) in anhydrous DMF (150 mL) was added ortho-
cresol 1 (5.4 g, 0.05 mol) in anhydrous DMF (50 mL). The reaction
mixture was stirred at rt for 1 h. 2-Dimethylaminoethylchloride
(6.5 g, 0.06 mol) was added and after stirring overnight, the
reaction was quenched with satd ammonium chloride (150 mL).
After extraction into ethyl acetate (200 mL), the organic layer was
washed with 2 M sodium hydroxide (50 mL), water (5ꢂ200 mL),
brine (200 mL), dried over MgSO4 and purified by flash chroma-
tography (ethyl acetate) to afford dimethylaminoethoxy-toluene as
a yellow oil (7.2 g, 81%). nmax (cmꢀ1) 3020, 2927, 2820, 1246, 1033.
3.4.4. 2-[2-(2-Methoxyethoxy)-phenyl]-1,1-diphenylethanol (4d)
2-[2-(2-Methoxyethoxy)-phenyl]-1,1-diphenylethanol was pre-
pared using benzophenone as electrophile according to general
procedure 1 as a yellow oil (62 mg, 59%). nmax (cmꢀ1) 3447, 3059,
2927, 1246. 1H NMR (400 MHz, CDCl3)
d 7.29–7.32 (4H, m, Ar–H),
7.19–7.28 (1H, m, Ar–H), 7.11–7.14 (4H, m, Ar–H), 7.03–7.09 (1H, m,
Ar–H), 7.00 (1H, dt, J¼7.5, 1.7 Hz, Ar–H), 6.71 (1H, dd, J¼8.2, 1.0 Hz,
Ar–H), 6.52 (1H, dt, J¼7.5, 1.2 Hz, Ar–H), 6.23 (1H, dd, J¼7.5, 1.7 Hz,
Ar–H), 4.18 (1H, s, OH), 4.01 (2H, t, J¼4.5 Hz, CH2OCar), 3.57 (2H, s,
CH2Car), 3.56–3.59 (2H, m, CH2O), 3.15 (3H, s, CH3O). 13C NMR
1H NMR (400 MHz, CDCl3)
d
7.12–7.14 (2H, m, Ar–H), 6.81–6.86 (2H,
(100 MHz, CDCl3) d 157.8, 148.0, 144.2, 132.6, 128.9, 128.6, 128.4,
m, Ar–H), 4.09 (2H, t, J¼5.7 Hz, CH2O), 2.78 (2H, t, J¼5.7 Hz, CH2N),
128.0, 127.9, 127.5, 127.0, 126.9, 126.8, 126.7, 126.3, 123.4, 121.0,
112.3, 71.3, 68.0, 59.3, 42.6. MS (EI) m/z 348 (Mþ, 40), 331 (100), 183
(40). HRMS (EI): [Mþ] C23H24O3 requires 348.1720, found 348.1715.
2.37 (6H, s, CH3N), 2.23 (3H, s, CH3). 1H NMR (100 MHz, CDCl3)
d
157.4, 131.0, 127.2, 127.1, 120.8, 111.4, 67.2, 58.8, 46.7, 16.7. MS (CI)
m/z 180 (Mþ1, 100). HRMS (ES): [MþH]þ C11H18NO required
180.1383, found 180.1381.
3.5. General procedure 2 for removal of the methoxyethoxy
group
3.4. General procedure 1 for lithiation reactions of 2 (Table 1)
Aluminium powder (19.0 mg, 0.7 mmol) and iodine (122 mg,
0.5 mmol) were heated at reflux in acetonitrile (1.0 mL) for 15 min.
Starting material (0.3 mmol) in acetonitrile (0.2 mL) was added and
the reaction mixture was heated at reflux for a further 18 h. The
solvent was removed in vacuo and the crude product was dissolved
in ethyl acetate (5 mL). The organic layer was washed with water
(3ꢂ5 mL), brine (5 mL) and dried over magnesium sulfate. Purifi-
cation by column chromatography afforded 2-ethyl-phenol 7
(23 mg, 62%) or 2-but-3-enyl-phenol 8 (30 mg, 67%) as yellow oils.
Spectral data were in accordance with literature values.6
Under an argon atmosphere was added dropwise at ꢀ30 ꢁC sec-
BuLi (2.5 M in cyclohexane) (0.28 mL, 0.6 mmol) to a solution of 1-(2-
methoxyethoxy)-2-methyl-benzene 2 (0.05 g, 0.3 mmol) in diethyl
ether (5 mL). The reaction mixture was stirred at ꢀ30 ꢁC for 2 h fol-
lowed by addition of the electrophile (0.45 mmol). The reaction
mixturewasallowedtowarmtortover2 h.Dilutionwithether(5 mL)
was followed by washing with 2 M HCl (5 mL), water (3ꢂ5 mL) and
brine (5 mL). Drying over MgSO4, concentration in vacuo and purifi-
cation by column chromatography afforded the desired product.
3.6. General procedure 3 for lithiation reactions of 3 (Table 2)
3.4.1. 2-(2-Methoxyethoxy)-ethylbenzene (4a)
2-(2-Methoxyethoxy)-ethylbenzene was prepared using iodo-
methane as alkylating agent according to general procedure 1 as an
oil, contaminated with starting material 2. Discernible data: nmax
(cmꢀ1) 3023, 2966, 2930, 1244, 1127. 1H NMR (400 MHz, CDCl3)
Under an argon atmosphere was added dropwise at ꢀ30 ꢁC sec-
BuLi (2.5 M in cyclohexane) (0.23 mL, 0.5 mmol) to a solution of 2-
(2-dimethylaminoethoxy)-toluene (36 mg, 0.2 mmol) in diethyl
ether (5 mL). The reaction mixture was stirred at ꢀ30 ꢁC for 2 h.
This was followed by addition of the electrophile (0.5 mmol). The
reaction mixture was allowed to warm to rt over 2 h. The solvent
was removed in vacuo and purification by flash chromatography
afforded the desired product.
d
7.15–7.19 (2H, m, Ar–H), 6.92 (1H, dt, J¼7.5, 1.0 Hz, Ar–H), 6.85–
6.87 (1H, m, Ar–H), 4.15 (2H, t, J¼4.9 Hz, CH2OCar), 3.79 (2H, t,
J¼4.9 Hz, CH2O), 3.49 (3H, s, CH3O), 2.70 (2H, q, J¼7.5 Hz, CH2CH3),
1.24 (3H, t, J¼7.5 Hz, CH2CH3). 13C NMR (100 MHz, CDCl3)
d 157.0,
133.4,129.6,127.4,121.4,111.8, 71.7, 68.3, 59.6, 27.3,14.5. MS (CI) m/z
198 (Mþ18, 100), 181 (Mþ1, 60), 59 (20). HRMS (ES): [MþNH4]þ
C11H20NO2 requires 198.1489, found 198.1488.
3.6.1. 4-[2-(2-Dimethylaminoethoxy)-phenyl]-but-1-ene (9b)
4-[2-(-Dimethylaminoethoxy)-phenyl]-but-1-ene was prepared
using allyl bromide as electrophile according to general procedure 3
as a colourless oil (26 mg, 59%). nmax (cmꢀ1) 3024, 2940, 2826, 1242,
3.4.2. 2-(2-Methoxyethoxy)-but-3-enylbenzene (4b)
2-(2-Methoxyethoxy)-but-3-enylbenzene was prepared using
allyl bromide as alkylating agent according to general procedure 1 as
acolourlessoil(29 mg,47%).nmax (cmꢀ1) 3023, 2956, 2925,1288,1127.
1043.1H NMR (400 MHz, CDCl3)
d 7.11–7.18 (2H, m, Ar–H), 6.83–6.90
(2H, m, Ar–H), 5.83–5.93 (1H, m, CHvinylic), 5.05–5.00 (2H, m, CH2]),
4.09 (2H, t, J¼5.9 Hz, CH2O), 2.77 (2H, t, J¼5.7 Hz, CH2N), 2.73 (2H, t,
J¼7.5 Hz, CH2Car), 2.70 (2H, m, CH2CH]), 2.36 (6H, s, CH3). 13C NMR
1HNMR(400 MHz,CDCl3)
d7.12–7.18(2H, m, Ar–H), 6.81–6.91(2H,m,
Ar–H), 5.84–5.94 (1H, m, CHvinylic), 5.06–5.01 (2H, m, CH2]), 4.13 (2H,
t, J¼4.7 Hz, CarOCH2), 3.78 (2H, t, J¼4.7 Hz, CH2O), 3.47 (3H, s, CH3O),
2.96–2.95 (2H, m, CarCH2), 2.73–2.71 (2H, m, CH2CH]). 13C NMR
(100 MHz, CDCl3) d 157.1,139.1,130.8,130.2,127.4,120.8,116.7,114.8,
111.6, 67.4, 58.3, 46.6, 30.6. MS (CI) m/z 219 (Mþ,10), 56 (100). HRMS
(ES): [MþH]þ C14H22NO requires 220.1696, found 220.1697.
(100 MHz, CDCl3) d 157.1, 139.2, 138.9, 130.1, 127.5, 121.2, 114.8, 111.6,
71.7, 68.8, 68.0, 64.4, 30.5. MS (EI) m/z 206 (Mþ,10),133 (60), 39 (100).
HRMS (ES) [MþNH4]þ C13H22NO2 requires 224.1645, found 224.1643.
3.6.2. 2-[2-(2-Dimethylaminoethoxy)-phenyl]-1,1-diphenyl-
ethanol (9d)
3.4.3. 2-(2-Methoxyethoxy)-benzyltrimethylsilane (4c)
2-[2-(2-Dimethylaminoethoxy)-phenyl]-1,1-diphenylethanol was
prepared using benzophenone as electrophile according to general
procedure 3 as ayellowoil (48 mg, 67%). nmax (cmꢀ1) 3020, 2947, 2826,
2-(2-Methoxyethoxy)-benzyltrimethylsilane was prepared us-
ing trimethylsilyl chloride as electrophile according to general
procedure 1 as a colourless oil (50 mg, 70%). nmax (cmꢀ1) 3021,
1248,1057.1H NMR (400 MHz, CDCl3)
d 7.72–7.74 (4H, m, Ar–H), 7.54–
2934, 2893, 1244, 1130. 1H NMR (400 MHz, CDCl3)
d
7.14–7.19 (2H,
7.56 (4H, m, Ar–H), 7.39–7.48 (3H, m, Ar–H), 7.13 (1H, dd, J¼8.2,1.0 Hz,
Ar–H), 6.91 (1H, dt, J¼7.5, 1.2 Hz, Ar–H), 6.54 (1H, dd, J¼7.5, 1.7 Hz, Ar–
H), 4.35 (2H, t, J¼5.5 Hz, CH2O), 3.96 (2H, s, CH2), 2.92 (2H, t, J¼5.5 Hz,
m, Ar–H), 6.80–6.82 (2H, m, Ar–H), 4.08 (2H, t, J¼3.8 Hz, CH2OCar),
3.75 (2H, t, J¼3.8 Hz, CH2O), 3.43 (3H, s, CH3O), 2.12 (2H, s, CH2Si),
0.0 (9H, s, Si(CH3)3). 13C NMR (100 MHz, CDCl3)
d
155.9, 133.6, 129.3,
CH2N), 2.38 (6H, s, CH3N). 13C NMR (100 MHz, CDCl3)
d 158.4, 148.9,
125.3, 120.8, 111.2, 72.2, 67.2, 60.0, 27.3, 0.0. MS (CI) m/z 256
132.1, 128.3, 128.1, 127.9, 127.7, 127.3, 126.8, 126.6, 126.5, 120.6, 112.2,

J.A. Wilkinson et al. / Tetrahedron 64 (2008) 6329–6333
6333
64.4, 59.1, 45.9, 42.3. MS (CI) m/z 362 (Mþ1, 45), 344 (40), 56 (100).
3.9.2. Method B
HRMS (ES): [MþH]þ C24H28NO2 requires 362.2115, found 362.2116.
Under an argon atmosphere was added dropwise at ꢀ30 ꢁC sec-
BuLi (2.5 M in cyclohexane) (1.00 mL, 2.5 mmol) to a solution of 2-
dimethylaminoethoxy-toluene 3 (0.21 g, 1.2 mmol) in diethyl ether
(20 mL). The reaction mixture was stirred at ꢀ30 ꢁC for 2 h. This
was followed by addition of diethylaluminium chloride (0.28 mL,
2.5 mmol). After stirring for 1 min, but-1-ene oxide 13 (0.21 mL,
2.5 mmol) was added. The reaction mixture was allowed to warm
to rt over 2 h. Dilution with ether (10 mL) was followed by washing
with satd ammonium chloride (10 mL), water (3ꢂ20 mL) and brine
(20 mL). Drying over MgSO4 and concentration in vacuo was
followed by dissolving the crude product in boiling acetonitrile
(10 mL) and hot filtration to remove aluminium salts. Concentra-
tion afforded a crude product, which was subjected to general
procedure 4 to give 1-[2-(2-methoxyethoxy)-phenyl]-pentan-3-ol
15 as a colourless oil (52 mg, 38%).
3.6.3. 2-(2-Dimethylaminoethoxy)-phenyl-bis-trimethyl-
silylmethane (12c)
2-(2-Dimethylaminoethoxy)-phenyl-bis-trimethylsilylmethane
was prepared using trimethylsilyl chloride as electrophile accord-
ing to general procedure 3 as a colourless oil (40 mg, 62%). nmax
(cmꢀ1) 3046, 2952, 2820, 1247, 1047. 1H NMR (400 MHz, CDCl3)
d
6.95–7.01 (2H, m, Ar–H), 6.78–6.85 (2H, m, Ar–H), 4.04 (2H, t,
J¼6.1 Hz, CH2O), 2.76 (2H, t, J¼6.1 Hz, CH2N), 2.36 (6H, s, CH3N), 0.3
(1H, s, CH), 0.0 (18H, s, CH3Si). 13C NMR (100 MHz, CDCl3)
155.9,
d
133.6, 132.3, 139.4, 120.5, 111.5, 66.6, 58.1, 45.9, 18.0, 0.0. MS (CI) m/z
324 (Mþ1, 5), 70 (100), 56 (58). HRMS (ES): [MþH]þ C17H34NOSi
requires 324.2173, found 324.2172.
3.7. General procedure 4 for removal of
dimethylaminoethoxy group
All spectral data were identical to those above for method A.
3.10. 2-Ethylchroman13 (16)
Starting material (0.4 mmol) was dissolved in iodomethane
(4 mmol) and the reaction mixture was stirred at rt for 12 h. The
remaining iodomethane was removed in vacuo and the crude
product was dissolved in anhydrous DMSO (1 mL). Potassium tert-
butoxide (68 mg, 0.6 mmol) was added and the reaction mixture
was stirred at rt for 1 h. Ethyl acetate (5 mL) was added and the
organic layer was washed with water (5ꢂ10 mL), brine (5 mL) and
dried over magnesium sulfate. Concentration in vacuo and purifi-
cation by column chromatography afforded the desired compounds
7 (33 mg, 68%) or 8 (37 mg, 62%).
2-(3-Hydroxypentyl)-phenol 15 (62 mg, 0.34 mmol) and tri-
phenylphosphine (0.18 g, 0.7 mmol) were dissolved in freshly
distilled THF (1 mL). Diethyl azodicarboxylate (40% in toluene)
(0.22 mL, 0.7 mmol) was added dropwise and the mixture was
stirred for 3 h at rt. After removing the solvent in vacuo, the crude
product was purified by flash chromatography (cyclohexane/ethyl
acetate 9:1) to afford 2-ethylchroman 16 as a yellow oil (51 mg,
93%). All data accorded with literature values.
3.8. 1-[2-(2-Methoxyethoxy)-phenyl]-pentan-3-ol (14)
Acknowledgements
Under an argon atmosphere was added dropwise at ꢀ30 ꢁC sec-
We thank the EPSRC for mass spectrometry services.
BuLi (2.5 M in cyclohexane) (1.12 mL, 1.5 mmol) to a solution of 2-
methoxyethoxy-toluene
2 (0.20 g, 1.2 mmol) in diethyl ether
(20 mL). The reaction mixture was stirred at ꢀ30 ꢁC for 2 h. This
was followed by addition of diethylaluminium chloride (0.19 mL,
1.6 mmol). After stirring for 1 min, but-1-ene oxide 13 (0.13 mL,
1.5 mmol) was added. The reaction mixture was allowed to warm to
rt over 2 h. Dilution with ether (10 mL) was followed by washing
with satd ammonium chloride (10 mL), water (3ꢂ20 mL) and brine
(20 mL). Drying over MgSO4, concentration in vacuo and purifica-
tion by flash chromatography (cyclohexane/ethyl acetate 8:2)
afforded the 1-[2-(2-methoxyethoxy)-phenyl]-pentan-3-ol 14 as
a colourless oil (180 mg, 63%). nmax (cmꢀ1) 3420, 2926, 1243, 1126.
References and notes
1. Some recent synthetic applications of lateral lithiation include: Uchida, K.;
Fukuda, T.; Iwao, M. Tetrahedron 2007, 63, 7178–7186 and references cited
therein. Sae-Lao, P.; Kittakoop, P.; Rajivroongit, S. Tetrahedron Lett. 2006, 47,
345–348; Burkhart, D. J.; Zhou, P.; Blumenfeld, A.; Twamley, B.; Natale, N. R.
Tetrahedron 2001, 57, 8039–8046; Kowalczyk, B. A. Synthesis 2000, 1113–1116;
Wang, C.-C.; Li, J. J.; Huang, H.-C.; Lee, L. F.; Reitz, D. B. J. Org. Chem. 2000, 65,
2711–2715; Allen, D. A. Synth. Commun. 1999, 447–451.
2. Clayden, J. Organolithiums: Selectivity for Synthesis; Pergamon: Oxford, 2002;
Chapter 2.
3. (a) Bates, R. B.; Siahaan, T. J.; Suvannachut, K. J. Org. Chem. 1990, 55, 1328–1334;
(b) Winkle, M. R.; Ronald, R. C. J. Org. Chem. 1982, 47, 2101–2108. The MOM
group supports lateral lithiation if ortho-lithiation is impossible, e.g., Yang, D.;
Ye, X.-Y.; Xu, M. J. Org. Chem. 2000, 65, 2208–2217. The dianion derived directly
from ortho-cresol has also been alkylated, see: Andringa, H.; Verkruijsse, H. D.;
Brandsma, L.; Lochmann, L. J. Organomet. Chem. 1990, 393, 307–314; Bates, R. B.;
Siahaan, T. J. J. Org. Chem. 1986, 51, 1432–1434. Clayden’s group have used
a carbamate to stabilise both lateral and ortho-lithiated species, see: Clayden, J.;
Pink, J. H.; Westlund, N.; Wilson, F. X. Tetrahedron Lett. 1998, 39, 8377–8380.
4. (a) Wilkinson, J. A.; Rossington, S. B.; Leonard, J.; Hussain, N. Tetrahedron Lett.
2004, 45, 5481–5484; (b) Wilkinson, J. A.; Rossington, S. B.; Ducki, S.; Leonard,
J.; Hussain, N. Tetrahedron 2006, 62, 1833–1844.
1H NMR (400 MHz, CDCl3)
d 7.15–7.17 (2H, m, Ar–H), 6.82–6.80 (2H,
m, Ar–H), 4.09 (2H, t, J¼3.8 Hz, CH2OCar), 3.74 (2H, t, J¼3.8 Hz,
CH2O), 3.51–3.46 (1H, m, CHOH), 3.44 (3H, s, CH3O), 2.94–2.86 (2H,
m, CarCH2), 2.70–2.64 (2H, m, CarCH2CH2), 1.79–1.75 (2H, m,
CH2CH3), 1.19 (3H, t, J¼7.5 Hz, CH2CH3). 13C NMR (100 MHz, CDCl3)
d
156.1, 134.6, 129.3, 126.3, 126.0, 120.6, 73.2, 72.2, 67.0, 60.8, 37.4,
30.8, 27.3, 10.5. MS (CI) m/z 239 (Mþ1, 40), 221 (100), 59 (30). HRMS
(ES): [MþNH4]þ C14H26NO3 requires 256.1907, found 256.1904.
5. Wilkinson, J. A.; Raiber, E.-A.; Ducki, S. Tetrahedron Lett. 2007, 48, 6434–6436.
6. For
a review of structural aspects of lateral and ortho-lithiated benzene
3.9. 2-(3-Hydroxypentyl)-phenol (15)
derivatives, see: Wheatley, A. Eur. J. Inorg. Chem. 2003, 3291–3303.
7. Yates, P.; Macas, T. Can. J. Chem. 1988, 66, 1–10.
8. Eisch, J. J.; Tsai, M. R. J. Organomet. Chem. 1982, 225, 5–24.
9. Raiber, E.-A.; Wilkinson, J. A.; Manetti, F.; Botta, M.; Deakin, J.; Gallagher, J.;
Lyon, M.; Ducki, S. Bioorg. Med. Chem. Lett. 2007, 17, 6321–6325.
3.9.1. Method A
2-(3-Hydroxypentyl)-phenol (15) was prepared from 14
according to general procedure 2 as a pale yellow oil (71 mg, 56%).
10. Additions of organolithium species to epoxides: Chemla, F.; Vrancken, E. The
Chemistry of Organolithium Reagents; Rapoport, Z., Marek, I., Eds.; Wileyand Sons:
New York, NY, 2004; pp 1165–1242. Reactions involving laterally lithiated benz-
enoid aromatics: Clayden, J.; Stimson, C. C.; Helliwell, M.; Keenan, M. Synlett
2006, 873–876; Schlosser, M.; Gorecki, J.; Castagnetti, E. Eur. J. Org. Chem. 2003,
3, 452–462; Reich, S. H.; Melnick, M.; Pino, M. J.; Fuhry, M.-A. M.; Trippe, A. J.;
Appelt, K.; Davies, J. F.; Wu, B.-W.; Musick, L. J. Med. Chem. 1996, 39, 2781–2794.
11. For example: Ortiz, R.; Yus, M. Tetrahedron 2005, 61, 1699–1707.
12. Wada, A.; Kanamoto, S.; Nagai, S. Chem. Pharm. Bull. 1985, 33, 1016–1022.
13. Schweizer, E. E.; Minami, T.; Anderson, S. E. J. Org. Chem. 1974, 39, 3038–3042.
nmax (cmꢀ1) 3435, 2984, 2929. 1H NMR (400 MHz, CDCl3)
d 7.18–7.15
(2H, m, Ar–H), 6.90–6.82 (2H, m, Ar–H), 3.52–3.48 (1H, m, CHOH),
2.98–2.95 (2H, m, CarCH2), 2.72–2.68 (2H, m, CarCH2CH2), 1.80–1.78
(2H, m, CH2CH3), 1.19 (3H, t, J¼7.4 Hz, CH2CH3). 13C NMR (100 MHz,
CDCl3)
d 155.1, 136.8, 130.9, 127.9, 121.0, 116.8, 72.2, 37.3, 31.4, 26.5,
10.2. MS (EI) m/z 180 (Mþ, 10), 163 (55), 107 (100). HRMS (ES):
[MþNH4]þ C11H20NO2 requires 198.1489, found 198.1487.