Sequential ortho-lithiations; The sulfoxide group as a relay to enable meta-substitution

Article abstract of DOI:10.1039/b716954j

Sulfoxides are known to be powerful directing groups for ortho-lithiation, even in competition with other directors. This has been utilised to introduce substituents meta- to a methoxy-group by sequential lithiation, reaction with Me tert-butylsulfinate,

Full text of DOI:10.1039/b716954j

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Sequential ortho-lithiations; the sulfoxide group as a relay to enable
meta-substitution†
Jonathan P. Flemming,a,b Malcolm B. Berryb and John M. Brown*a
Received 1st November 2007, Accepted 17th February 2008
First published as an Advance Article on the web 25th February 2008
DOI: 10.1039/b716954j
Sulfoxides are known to be powerful directing groups for ortho-lithiation, even in competition with
other directors. This has been utilised to introduce substituents meta- to a methoxy-group by sequential
lithiation, reaction with Me tert-butylsulfinate, and a second lithiation. Electrophilic trapping of the
ensuing lithio-compound with a range of electrophiles followed by reductive removal of the sulfoxide
led to meta-substituted anisoles. Some interesting side-reactions were uncovered, including a short
synthesis of quinazolines arising from the use of PhCN in the second step.
Introduction
Directed metallation has become one of the most useful methods
for the regioselective introduction of substituents into an aromatic
ring.1,2 A clear majority of examples involve organolithium
reagents, and ortho-substitution is achieved by stabilisation of
the new organolithium species. In the majority of cases this
involves direct lithium ligation by the substituent, but simple in-
ductive carbanion-stabilising effects can also lead to regiospecific
metallation.3 The magnesium4 or zinc derivatives5 of hindered
secondary amines are also effective metallating agents towards
sp2-carbon. Similar results ensue in substituent-directed catalytic
CH-activations, leading to coupling reactions that occur ortho- to
the directing group.6 Cases where a substituent directs metallation
to more remote sites are infrequent, but lateral metallations
Fig. 1 Examples of meta-metallating procedures.
from the ortho-position of a biaryl to the ortho-position of the
remote ring are well established, however.7 In both ferrocene,8
and arenechromium tricarbonyl systems,9 metallation can occur
meta- to an existing substituent as outlined in Fig. 1. Comparable
examples in simple arenes have only recently been demonstrated.
Mulvey and co-workers have more recently shown that the metal-
lation of aromatics with mixed organozinc–organoalkali reagents
leads to the formation of a crystallographically characterised meta-
metallated species.10
Schlosser and co-workers have demonstrated that the buttress-
ing effect of a trialkylsilyl group can redirect the metallation of
1,3-dihalo-2-silylbenzenes to the remote CH-site, provided that
potassium or mixed potassium–lithium bases were used.11 The
iridium-catalysed borylation of aromatic rings is strongly influ-
enced by the steric consequences of existing substituents, leading
to intrinsic preference for para-substitution of monosubstituted
arenes, and for the substitution of more remote sites in polycyclic
systems.12
The motivation behind the present work was to develop a
protocol for the introduction of a meta-substituent into an
arene by two sequential directed ortho-metallations. This principle
has recently been established for ferrocenes by two indepen-
dent groups. Weissensteiner and co-workers demonstrated that
enantiomerically pure dimethylaminoethyl-ferrocene could be
lithiated and then brominated to give a single diastereomer of
the monobromo derivative. In turn, this could be ortho-lithiated
adjacent to –Br at low temperatures without LiBr elimination,
and the resulting lithio-compound then trapped by electrophiles.13
In the ferrocene series, elimination of ortho-halo lithium species
to form an aryne is far more difficult than for 6-ring arenes,
rendering this route possible. Reduction of C–Br led to the desired
meta-disubstituted product, Similarly acetal C–O ortho-direction
followed by sulfoxide trapping afforded a ferrocenyl sulfoxide that
could be further lithiated and the desired electrophile introduced at
the adjacent position. Removal of the “traceless” sulfoxide group
was achieved by direct reaction with tert-butyllithium.14
aChemical Research Laboratory, Mansfield Rd, Oxford, UK OX1 3TA.
E-mail: john.brown@chem.ox.ac.uk; Fax: 44 1865 285002; Tel: 44 1865
275642
bGlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts, UK SG1 2NY
† Electronic supplementary information (ESI) available: 13C Spectra for
compounds in Schemes 1, 2, 3; CIF files for 4b, 4d, 4f. See DOI:
10.1039/b716954j
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Results and discussion
Directed sulfoxide ortho-lithiations and trapping of the
intermediate
The dual characteristics of the sulfoxide group as a powerful
ortho-lithiation director, coupled with its ability to be “traceless”,
encouraged its use in the project.15 Methyl tert-butylsulfinate,
1, prepared from dimethyl sulfite following the method of
Mikolajczyk and Drabowicz in 94% yield,16 was reacted with 2-
lithioanisole, to afford 1-methoxy-2-tert-butylsulfinyl benzene, 2,
in 97% yield. Treatment of the substrate with 1.2 equivalents of
n-butyllithium at −78 ◦C in thf for 2 h, followed by D2O quench
gave only the desired 1,2,3-trisubstituted product 3 in 96% yield.
The 2H NMR shows a single peak at 7.7 ppm.
Fig. 2 X-Ray structure of 4d; ORTEP display. X-Ray structures of 4b
and 4f are also recorded in the ESI.†
diphenylquinazoline 5 was produced in 85% yield. The structure
This clearly demonstrates, as expected, that the sulfinyl group
is the predominant director of ortho-lithiation. This led us to
try a range of different electrophiles in conjunction with 2-
(tert-butylsulfinyl)-3-lithioanisole, with the outcome as reported
in Scheme 1. Thus a number of electrophiles were successfully
reacted with 2-tert-butylsulfinyl-3-lithioanisole, yielding 1,2,3-
trisubstituted benzenes, 4a–f. The dimethylamide 4a was prepared
in moderate yield from dimethylcarbamoyl chloride, whilst the
aldehyde, 4b, was prepared in 71% yield by reaction with ethyl
formate. In this case the electrophile had to be added to the
1
of this product was elucidated from its H NMR spectrum with
two distinguishing multiplets at 8.73–8.70 ppm (2H) and 7.91–
7.87 ppm (2H) associated with ortho protons on the phenyl
rings at the 2- and 4-positions, respectively. High-resolution mass
spectrometry gave m/z = 313.1346, corresponding to [M + H]+.
A possible pathway for the formation of compound 5 is shown in
Scheme 2. Following the initial ortho-lithiation of the sulfoxide,
nucleophilic attack on benzonitrile occurs. A further nucleophilic
attack by the substrate on a second equivalent of benzonitrile
takes place, followed by intramolecular SNAr displacement of the
sulfoxide moiety. Previous observations on the double addition
of benzonitrile to an aryllithium giving a quinazoline have been
conducted with either an −OR or Cl− as leaving group. In these
previously reported examples, the yields for the quinazoline were
low.17 Diverse reaction conditions were employed to try and
intercept the presumed intermediate 6. Using one equivalent of
benzonitrile gave 5 in 43% yield (50% maximum) suggesting that
addition to the second equivalent was faster than addition to
the first. Neither carrying out the reaction at −78 ◦C nor high
dilution proved successful. Use of 4-trifluoromethylbenzonitrile as
electrophile provided the quinazoline, 7, in 45% yield. Competition
between one equivalent of ortho-lithiated 3 and two equivalents of
benzonitrile and 4-trifluoromethylbenzonitrile gave 7 as the major
◦
reaction at −100 C to obtain this single trisubstituted product,
as a complex mixture of products resulted when the reaction took
place at −78 ◦C. Easy bromination of the aryllithium to 4c took
place in good yield using 1,1,2-tribromo-1,2,2-trifluoroethane.
Generation of the primary alcohol 4d proved successful using
1
paraformaldehyde giving the product in 52% isolated yield. H
NMR spectroscopy of the product showed diasterotopic benzylic
protons at 5.36 ppm and 4.24 ppm (J = 12.2 Hz). The X-ray crystal
structure indicated an intramolecular hydrogen bond between the
primary alcohol and the sulfoxide (Fig. 2). Generation of the
desired boronate occurred using B-isopropyl pinacolborate as the
electrophile. The use of one equivalent of the electrophile gave 4e
cleanly, which could then be used in subsequent steps without the
need for any purification, whereas the use of excess reactant led
to unidentified side-products. Finally, alkylation of the substrate
using iodomethane worked satisfactorily giving the product 4f
in high yield. When diisopropylcarbamoyl chloride, DMF or
acetyl chloride were employed however, the overall reaction was
unsuccessful.
Scheme 1 Trapping of the lithio reagent; 3 D2O −78 ◦C; 4a, Me2NCOCl,
−78 ◦C–ambient, then 16 h, 63%; 4b, EtOCHO, −100 ◦C, 1 h, 71%;
4c, CBrF2CFBr2, as 4a, 82%; 4d, (CH2O)n, as 4a, 52%; 4e, (i-PrB
(OCH2CH2O), as 4a, 89%; 4f, MeI, as 4a, 96%.
When benzonitrile was employed as the electrophile the
expected product was not formed. Instead, 8-methoxy-2,4-
Scheme 2 Route to quinazoline formation via double addition of PhCN.
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product, but analysis of the crude 1H NMR spectrum revealed ca.
4% of 5 (d 8.75 ppm) along with two other unidentified products
(d 8.89 ppm [4%] and d 8.69 ppm [6%]). There was no evidence for
crossover products in the GC-MS of the crude reaction product.
1,3-disubstituted products 10a, 10b, 10c in good yield. In contrast,
compound 4b underwent reduction of both the carbon–sulfur
bond and the aldehyde, giving compound 10b.
When the aldehyde 4b was converted into the corresponding
dioxolane 11 prior to desulfurisation, an unusual reaction oc-
curred (Scheme 5), which can be rationalised thus. Conversion
of sulfanols into sulfinothioates with liberation of water is a
known process.20 Brodnitz et al. have also reported the thermal
decomposition of the sulfinothioate garlic extract, allicin, to its
corresponding disulfide.21 Under the acidic reaction conditions, we
propose that the aryl sulfoxide is protonated and then undergoes
elimination of tert-butyl cation to give the sulfanol, 12. This can
then be protonated once again, and the resulting cation undergoes
nucleophilic attack by a second molecule of 12, eliminating water
to produce the sulfanium cation, 13. A third molecule of 12 comes
into play, reducing 13 to the disulfide, 14 and forming the sulfinic
acid, 15 concomitantly. As a result the disulfide, 14 can only be
obtained in a maximum 67% yield.
Removal of the sulfoxide group
In initial attempts, direct nucleophilic displacement was explored.
Treatment of 2-t-butylsulfoxido-3-deuteroanisole 3 with two
equivalents of t-butyllithium in THF at −78 ◦C, however, did not
give the desired 1,3-disubstituted product 8 but instead yielded
the ligand coupled product 9 (Scheme 3). The structure of this
product was confirmed by NMR HMBC analysis, which showed
long range coupling between the protons of the tert-butyl group
and the carbon at the 2-position of the aromatic ring. The same
observation has been made by Clayden et al. but in their case a
SNAr mechanism was suggested, based on the demonstration from
13C-labelling that the t-butyl group of the sulfoxide is completely
lost in the coupled product.18 In our hands, however, the use of
n-BuLi leads only to ortho-lithiation. Our explanation of this is
that ligand coupling rather than SNAr is indeed the predominant
mechanism for the reaction. Attack of a nucleophile upon a
tetrahedral sulfoxide furnishes a pentacoordinate intermediate,
with the incoming nucleophile occupying an axial position. In the
case of t-BuLi attacking the aromatic sulfoxide 3, the tert-butyl
group from t-BuLi takes the axial position in the pentacoordinate
intermediate, which is disposed at 90◦ to the aromatic ring.
Reductive elimination of these two groups gives rise to the ligand-
coupled product 9. If this process is faster than pseudorotation, the
two tert-butyl groups remain distinct and only the one associated
with t-BuLi appears in the product.
Scheme 3 A ligand coupling mechanism for the formation of product 9.
Attempted reduction of 2-tert-butylsulfinyl-3-methoxy-N,N-
dimethylbenzamide, 4a, with methylmagnesium bromide gave no
reaction. Trying to increase the reactivity of the Grignard reagent
through addition of either lithium chloride or a lithium chloride–
15-crown-5 mixture also proved unsuccessful.19 Reduction of
4a was also attempted using lithium–naphthalene in THF at
Scheme 5 Indicated route to the disproportionation product 14.
Attempted reduction of pinacolboronate, 4e, was unsuccessful
and hence Suzuki coupling with iodobenzene was attempted first.
This gave a mixture of products, where the only one readily isolated
was 3-methoxy-2-phenylsulfanylbiphenyl, 16, in 14% yield. This
curious result demonstrates that the t-butylsulfinyl group is labile
under the conditions of Suzuki coupling, and the aryl sulfide so
formed can undergo heteroatom cross-coupling with PhI.22
◦
−78 C. Once again, no reaction was obtained, and the starting
material was recovered. In the light of these difficulties, reduction
of products 4a–f was attempted with Raney nickel (Scheme 4).
Compounds 4a, 4d, 4f were reduced cleanly to give the desired
Conclusions
The paper describes a method for the relay of lithiation from
the ortho- to the meta-position of an electron rich aromatic ring,
utilizing the superior ability of a sulfoxide in directed lithiation.
The principle is demonstrated and leads incidentally to a useful
synthesis of quinazolines. Its utility is diminished by the lack of
ease and generality in the final sulfoxide removal step. Future
publications will address this limitation.
Scheme 4 (a) Raney Ni, EtOH, reflux, 3 h, [MeOH for 4b].
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concentrated under reduced pressure yielding the title compound
(409 mg, 96%) as a colourless oil; mmax (KBr disc) 3064 (w, C–
H[aromatic]), 2964 [m, C–H[aliphatic], 2927 (m, C–H[aliphatic]),
Experimental
Techniques, materials and instrumentation
=
1581 (s, aromatic ring), 1034 (s, S O); dH (400 MHz; CDCl3;
All reactions were conducted in oven- or flame-dried glassware.
Reactions involving air- and water-sensitive reagents were per-
formed under a dry Ar atmosphere using a standard vacuum
line and Schlenk techniques. Solvents used in chromatography
were BDH AnalaR or GPR grade and were used without further
purification. Solvents used for reactions either were distilled prior
to use: CH2Cl2 (from CaH2); toluene, THF and Et2O (from
benzophenone and sodium) or dried via an alumina Grubb’s
column. All other solvents or reagents were used as commercially
supplied and were used without further purification except when
otherwise noted. Standard chromatographic and TLC procedures
were used. NMR spectra were recorded using a Bruker AV400
spectrometer, Bruker DPX400 or Bruker AMX500. FT IR spectra
were recorded as thin films on a KBr disc using a Perkin-Elmer
Paragon 1000 spectrometer. Mass spectra were recorded by the
author or Mr R. Proctor using either Micromass GCT (CI)
or V.G. Autospec spectrometers (EI and CI). Exact masses were
measured on a Waters 2790-Micromass LCT spectrometer or
a V.G. Autospec spectrometer using EI or CI.
CHCl3) 7.41 (1 H, dd, J 8.2 and 7.4, ArH), 7.11 (1 H, dd, J 7.4
and 1.1, ArH), 6.89 (1 H, dd, J 8.3 and 1.2, ArH), 3.81 (3 H, s,
OCH3), 1.17 (9 H, s, 3 × CH3); dC (100 MHz; CDCl3; CDCl3)
157.0, 132.2, 128.4, 127.3 (d), 120.8, 110.6, 57.3, 55.4, 22.8; dD
(500 MHz; CHCl3; CDCl3) 7.78 (1 D, br s, ArD); m/z (CI+)
213.0942 (M+, 100%, C11H15DO2S requires 213.0934).
N,N-Dimethyl-2-tert-butylsulfinyl-3-methoxybenzamide (4a).
To a solution of 1-methoxy-2-tert-butylsulfinyl-3-lithiobenzene at
−78 ◦C (2 mmol) was added dimethylcarbamyl chloride (0.55 ml,
6.0 mmol, 1.2 eq.) dropwise. The reaction was then warmed to
ambient temperature and stirred for 16 hours. The reaction was
quenched with sat. NH4Cl solution (10 ml) and the two layers
were separated. The aqueous layer was extracted with ethyl acetate
(3 × 10 ml). The combined organic phases were washed with
brine (3 × 10 ml) before being dried over anhydrous magnesium
sulfate, filtered and concentrated under reduced pressure. The
crude product was purified by flash column chromatography
(95 : 5 EtOAc–MeOH) yielding the title compound (898 mg,
63%): as a yellow solid; mp 110–112 ◦C; mmax (KBr disc) 3066
1-Methoxy-2-tert-butylsulfinylbenzene (2). Anisole (0.55 ml,
5.0 mmol, 1 eq.) was dissolved in anhydrous THF (5 ml) under
argon and treated with TMEDA (1.14 ml, 7.5 mmol, 1.5 eq.)
and 1.6M n-BuLi in hexanes (4.69 ml, 7.5 mmol, 1.5 eq.). The
reaction was stirred at ambient temperature for two hours before
being cooled to −78 ◦C and being treated with methyl tert-
butyl sulfinate17 (1.02 g, 15.0 mmol, 1.5◦eq.) in anhydrous THF
(5 ml). The reaction was stirred at −78 C for two hours before
being quenched with sat. NH4Cl solution (8 ml). The two layers
were separated and the aqueous layer was washed ethyl acetate
(2 × 20 ml). The combined organic phases were washed with
2 M HCl (3 × 20 ml) and brine (2 × 20 ml) before being
dried over anhydrous magnesium sulfate, filtered and concentrated
under reduced pressure. The product was purified by flash column
chromatography (3 : 2 pentane–ethyl acetate) yielding the title
compound (1.026 g, 97%) as a colourless oil; mmax (KBr disc) 3068
(m, C–H[aromatic]), 2977 (s, C–H[aliphatic]), 2867 (m, O–CH3),
=
(m, C–H[aromatic]), 2962 (m, C–H[aliphatic]), 1646 (s, C O),
=
1570 (m, aromatic ring), 1052 (s, S O); dH (400 MHz; CDCl3;
CHCl3) 7.28 (1 H, m, ArH), 6.77 (1 H, dd, J 8.3 and 1.0, ArH),
6.70 (1 H, dd, J 7.6 and 1.1, ArH), 3.67 (3 H, s, OCH3), 2.85
(3 H, s, NCH3), 2.47 (3 H, s, NCH3), 1.13 (9 H, s, 3 × CH3);
dC (100 MHz; CDCl3; CDCl3) 169.7, 156.6, 138.4, 131.8, 125.3,
120.9, 110.3, 59.9, 55.1, 38.5, 34.4, 24.2; m/z (CI+) 284.1310 (M
+ H+, C14H22NO3S requires 284.1320).
Related preparations with lithiated 2 (4a–4f, 5, 7; 2 mmol scale)
follow:
2-tert-Butylsulfinyl-3-methoxybenzaldehyde (4b). With ethyl
formate (0.323 ml, 4.00 mmol, 2 eq.) at −100 ◦C; was stirred
for 50 minutes before being warmed to ambient temperature and
stirred for 1 h. Workup as above and recrystallisation from 60–80
petroleum spirit–ethyl acetate to give the title compound (343 mg,
71%) as a yellow solid; mp 110–113 ◦C (from petroleum spirit–
ethyl acetate); mmax (KBr disc) 3073 (m, C–H[aromatic]), 2978 (m,
=
1586 (s, aromatic ring), 1478 (s, aromatic ring), 1031 (s, S O), 759
(s, four adjacent aromatic C–H); dH (400 MHz; CDCl3; CHCl3)
7.73 (1 H, dd, J 1.8 and 7.7, ArH), 7.43–7.38 (1 H, m, ArH),
7.11 (1 H, m, ArH), 6.89 (1 H, dd, J 1.1 and 8.3, ArH), 3.81 (3
H, s, OCH3), 1.17 (9 H, s, 3 × CH3); dC (100 MHz; CDCl3; CDCl3)
157.0, 132.2, 128.5, 127.3, 120.9, 110.6, 57.3, 55.4, 22.8; m/z (CI+)
213.0954 (M + H+, C11H17O2S requires 213.0949). Spectroscopic
data is in agreement with the literature.17
=
C–H[aliphatic]), 1692 (s, C O), 1570 (s, aromatic ring), 1027 (s,
S O), 807 (m, 3 adjacent aromatic C–H); dH (400 MHz; CDCl3;
=
CHCl3) 11.26 (1 H, s, CHO), 7.57 (1 H, dd, J 7.7 and 1.3, ArH),
7.51 (1 H, m, ArH), 7.10 (1 H, dd, J 8.1 and 1.3, ArH), 3.85 (3
H, s, OCH3), 1.28 (9 H, s, 3 × CH3); dC (100 MHz; CDCl3; CDCl3)
191.9, 157.6, 141.5, 132.3, 129.7, 121.2, 115.1, 59.3, 56.1, 23.6; m/z
(CI+) 241.0898 (M + H+, C12H17O3S requires 241.0898).‡
ortho-Lithiation of 1-methoxy-2-tert-butylsulfinylbenzene. 1-
Methoxy-2-tert-butylsulfinylbenzene (424 mg, 2.00 mmol, 1 eq.)
was dissolved in anhydrous THF (20 ml) under argon and cooled
to −78 ◦C. 1.6 M n-BuLi in hexanes (1.5 ml, 2.4 mmol, 1.2 eq.) was
added to the reaction, which was stirred at −78 ◦C for two hours.
1-Methoxy-2-tert-butylsulfinyl-3-deuterobenzene (3). To this
solution was added D2O (2 ml) and the two layers were separated.
The aqueous layer was extracted with ethyl acetate (2 × 10 ml).
The combined organic phases were washed with brine (3 × 10 ml)
before being dried over anhydrous magnesium sulfate, filtered and
1-Bromo-2-tert-butylsulfinyl-3-methoxybenzene
(4c). With
1,1,2-tribromo-1,2,2-trifluoroethane (770 mg, 2.40 mmol, 1.2 eq)
◦
in anhydrous THF (10 ml) at −78 C, then warmed to ambient
temperature and stirred for 16 h. Workup as before and
purification by flash column chromatography (EtOAc) yielded◦the
title compound (476 mg, 82%) as a white solid; mp 104–107 C;
‡ CCDC reference numbers 665873, 672147 and 672148. For crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/b716954j
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mmax (KBr disc) 3071 (w, C–H[aromatic]), 2964 (m, C–H[aliphatic]),
2926 (m, C–H[aliphatic]), 2864 (w, O–CH3), 1575 (s, aromatic
16 h. Workup and recrystallisation from 60–80 petroleum spirit–
methanol giving the title compound (266 mg, 43%–maximum 50%
yield) as a white crystalline solid; mp 150–151 ◦C (60–80 petroleum
spirit–methanol); kmax (EtOH)/nm 298 (e/dm3 mol−1 cm−1 8333),
237 (e/dm3 mol−1 cm−1 3333), 222 (e/dm3 mol−1 cm−1 5100); mmax
(KBr disc) 3033 (w, C–H[aromatic]), 2983 (m, C–H[aliphatic]),
2904 (m, C–H[aliphatic]), 1611 (s, conjugated cyclic imine), 1537
(s, aromatic ring), 853 (s, three adjacent aromatic C–H), 779 (s,
five adjacent aromatic C–H); dH (400 MHz; CDCl3; CHCl3) 8.73–
8.70 (2 H, m, 2 × ArH), 7.91–7.87 (2 H, m, 2 × ArH), 7.72–7.68
(1 H, m, ArH), 7.61–7.58 (3 H, m, 3 × ArH), 7.55–7.44 (4 H,
m, 4 × ArH), 7.25–7.22 (1 H, m, ArH), 4.15 (3 H, s, OCH3);
dC (100 MHz; CDCl3; CDCl3) 168.1, 159.6, 155.3, 144.3, 138.2,
138.0, 130.4, 130.2, 129.8, 128.8, 128.4, 122.6, 118.5, 111.5, 56.4;
m/z (CI+) 313.1346 (M + H+, C21H17N2O requires 313.1341).
=
ring), 1059 (s, S O), 776 (s, three adjacent aromatic C–H), 730
(s, C–Br); dH (400 MHz; CDCl3; CHCl3) 7.24–7.17 (2 H, m, 2 ×
ArH), 6.91 (1 H, dd, J 7.8 and 1.3, ArH), 3.84 (3 H, s, OCH3),
1.36 (9 H, s, 3 × CH3); dC (100 MHz; CDCl3; CDCl3) 160.7, 132.9,
129.9, 126.6, 125.3, 111.8, 60.3, 55.9, 24.9; m/z (CI+) Found:
291.0058 (M + H+, C11H16BrO2S requires 291.0054).
2-tert-Butylsulfinyl-3-methoxyphenylmethanol
(4d). With
paraformaldehyde (120 mg, 4.00 mmol, 2 eq.), in anhydrous
THF (20 ml) at −78 ◦C; the reaction mixture was warmed to
ambient temperature and stirred for 16 h, workup as before.
Recrystallisation from diethyl ether–methanol yielded the title
compound (121 mg, 25%) as a white solid. The supernatant liquid
was concentrated under reduced pressure and the remaining
crude product was purified by flash column chromatography
(ethyl acetate) yielding the title compound (130 mg, 27%) as a
8-Methoxy-2,4-bis(4-(trifluoromethyl)phenyl) quinazoline (7).
With 4-trifluoromethylbenzonitrile (171 mg, 1 mmol, 2 eq.) as
for the preparation of 5. The product was purified by flash
column chromatography (9 : 1 pentane–ethyl acetate) giving
the title compound (100 mg, 45%) as a white solid; mp 174–
178 ◦C; kmax (EtOH)/nm 300 (e/dm3 mol−1 cm−1 8500), 220
(e/dm3 mol−1 cm−1 6000); mmax (KBr disc) 2956 (w, C–H[aliphatic]),
1608 (m, conjugated cyclic imine), 1539 (m, aromatic ring), 1120
(s, C–F), 855 (s, two adjacent aromatic C–H), 766 (s, three adjacent
aromatic C–H), 752 (m, C–F); dH (400 MHz; CDCl3; CHCl3) 8.80
(2 H, d, J 8.1, 2 × ArH), 7.99 (2 H, d, J 8.0, 2 × ArH), 7.87 (2 H, d,
J 8.1, 2 × ArH), 7.77 (2 H, d, J 8.3, 2 × ArH), 7.62 (1 H, dd, J 8.4
and 1.1, ArH), 7.54 (1 H, t, J 7.8, ArH), 7.29 (1 H, dd, J 7.8 and 1.0,
ArH) 4.17 (3 H, s, OCH3); dC (100 MHz; CDCl3; CDCl3) 167.0,
158.2, 155.5, 144.2, 141.2, 130.5, 129.0, 128.1, 125.6–125.4 (m),
122.6, 117.8, 112.0, 56.5; m/z (CI+) 448.1015 (M+, C23H14F6N2O
requires 448.1010).
◦
white solid (251 mg, 52% total); mp 123–126 C; mmax (KBr disc)
3383 (br s, OH), 2962 (s, C–H[aliphatic]), 2935 (s, C–H[aliphatic]),
=
1574 (s, aromatic ring), 1026 (s, S O), 760 (m, three adjacent
aromatic C–H); dH (400 MHz; CDCl3; CHCl3) 7.37 (1 H dd, J
8.4 and 7.5, ArH), 7.00 (1 H, dd, J 7.6 and 1.3, ArH), 6.87 (1 H,
dd, J 8.4 and 1.2, ArH), 5.36 (1 H, d, J 12.2, CHHOH), 4.24 (1
H, d, J 12.2, CHHOH), 3.78 (3 H, s, OCH), 1.31 (9 H, s, 3 ×
CH3); dC (100 MHz; CDCl3; CDCl3) 158.3, 144.6, 132.5, 125.8,
125.4, 111.1, 64.5, 60.1, 55.7, 24.1; m/z (CI+) 243.1057 (M + H+,
C12H19O3S requires 243.1055).
2-[2-tert-Butylsulfinyl-3- methoxyphenyl]-4,4,5,5-tetramethyl-[1,
3,2]dioxaborolane (4e; 1 mmol scale). With 2-isopropoxy-4,4,5,5-
tetramethyl-1,3,2-dioxoborane (0.21 ml, 1.0 mmol, 1 eq.), stirred
at −78 ◦C for 16 h. Standard workup yielded the title compound
(302 mg, 89%) as a yellow oil; mmax (KBr disc) 3071 (w, C–
H[aromatic]), 2964 (m, C–H[aliphatic]), 2926 (m, C–H[aliphatic]),
2839 (w, O–CH3), 1566 (s, aromatic ring), 1467 (s, aromatic ring),
Competition reaction between two equivalents of benzonitrile and
two equivalents of 4-trifluoromethylbenzonitrile for one equivalent
of 1-methoxy-2-tert-butylsulfinyl-3-lithiobenzene. To a s◦olution
of 1-methoxy-2-tert-butylsulfinyl-3-lithiobenzene at −78 C pre-
pared on a 0.5 mmol scale was added 4-trifluoromethylbenzonitrile
(171 mg, 1 mmol, 2 eq.) and benzonitrile (103 ll, 1 mmol, 2 eq.)
at the same time followed by warming to ambient temperature
and stirring for 16 hours. The reaction was quenched with 2 M
aqueous NaOH solution (2 ml) and the two layers were separated.
The aqueous layer was extracted with ethyl acetate (2 × 10 ml).
The combined organic phases were washed with brine (3 ×
10 ml) before being dried over anhydrous magnesium sulfate,
filtered and concentrated under reduced pressure. Analysis of
the crude product by 1H NMR showed that 8-methoxy-2,4-bis(4-
(trifluoromethyl)phenyl) quinazoline was achieved as the major
product with agreement to previously recorded spectra.
=
1371 (s, B–O), 1032 (s, S O), 942 (s, B–C), 782 (s, three adjacent
aromatic C–H); dH (400 MHz; CDCl3; CHCl3) 7.37 (1 H, dd, J
7.8 and 7.4, ArH), 7.23 (1 H, dd, J 7.2 and 0.7, ArH), 6.74 (1 H,
dd, J 8.0 and 0.6, ArH), 3.73 (3 H, s, OCH3), 1.26 (6 H, s, 2 ×
CH3), 1.22 (9 H, s, 3 × CH3), 1.20 (6 H, s, 2 × CH3); dC (100 MHz;
CDCl3; CDCl3) 154.9, 133.3, 124.9, 124.1, 109.7, 80.3, 60.4, 55.0,
25.7, 24.5, 23.9; m/z (CI+) 361.1616 (M + Na+, C17H27BNaO4S
requires 361.1615).
2-tert-Butylsulfinyl-3-methoxytoluene (4f). With iodomethane
(0.17 ml, 2.7 mmol, 1.33 eq.) at −78 ◦C then warmed to
ambient temperature and stirred for 16 h. Workup yielded the
◦
title compound (432 mg, 96%) as a white solid; mp 112–114 C;
mmax (KBr disc) 3074 (w, C–H[aromatic]), 2961 (m, C–H[aliphatic]),
=
2952 (m, C–H[aliphatic]), 1573 (s, aromatic ring), 1048 (s, S O),
787 (s, 3 adjacent aromatic C–H); dH (400 MHz; CDCl3; CHCl3)
7.25 (1 H, dd, J 8.3 and 8.0, ArH), 6.77 (1 H, dd, J 7.7 and 0.5,
ArH), 6.74 (1 H, dd, J 8.3 and 0.5, ArH), 3.78 (3 H, s, OCH3),
2.64 (3 H, s, ArCH3), 1.29 (9 H, s, 3 × CH3); dC (100 MHz;
CDCl3; CDCl3) 158.8, 142.4, 131.5, 125.6, 125.1, 109.0, 59.4, 55.5,
24.2, 19.4; m/z (CI+) 227.1114 (M + H+, C12H19O2S requires
227.1106).‡
2-tert-Butyl-3-deuteroanisole
(9). 1-Methoxy-2-tert-butyl-
sulfinyl-3-deutero benzene (322 mg, 1.55 mmol, 1 eq.) was
dissolved in anhydrous THF (5 ml) under argon and cooled to
−78 ◦C. 1.5 M t-BuLi in pentane (2.6 ml, 3.90 mmol, 2.5 eq.)
was added and the reaction stirred at −78 ◦C for 5 minutes.
The reaction was quenched with sat. NH4Cl solution (5 ml) and
the two layers were separated. The aqueous layer was extracted
with ethyl acetate (2 × 10 ml). The combined organic phases
were washed with brine (3 × 10 ml) before being dried over
8-Methoxy-2,4-diphenylquinazoline (5). With benzonitrile
(0.205 ml, 2.00 mmol, 1 eq.) at −78 ◦C then ambient for
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anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure giving 325 mg of product. A 260 mg sample of
the product was purified by flash column chromatography (4 : 1
pentane–ethyl acetate) yielding the title compound (70 mg, 34%)
as a colourless oil; mmax (KBr disc) 3063 (w, C–H[aromatic]), 2960
(s, C–H[aliphatic]), 2836 (m, O–CH3), 1592 (s, aromatic ring),
1574 (s, aromatic ring); dH (400 MHz; CDCl3; CHCl3) 7.23 (1 H,
m, ArH), 6.93 (2 H, m, 2 × ArH), 3.88 (3 H, s, OCH3), 1.43 (9
H, s, 3 × CH3); dC (100 MHz; CDCl3; CDCl3) 158.5, 138.1, 127.0,
126.3 (t), 120.1, 111.5, 60.3, 54.9, 29.7; m/z (CI+) 165.1238 (M+,
C11H15DO requires 165.1264).
3-Methoxy-2-phenylsulfanylbiphenyl (16). 2-[2-tert-Butylsul-
finyl-3-methoxyphenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
(408 mg, 1.2 mmol, 1 eq.) was dissolved in THF (5 ml)
and treated with iodobenzene (0.40 ml, 3.6 mmol, 3 eq.),
tetrakis(triphenylphosphine) palladium (0) (69 mg, 0.06 mmol, 5
mol%) and 2 M aqueous potassium carbonate solution (5.7 ml,
11.4 mmol, 9.5 eq.). The reaction was heated at reflux for 22 hours
before being cooled and the two layers were separated. The
aqueous phase was extracted with ethyl acetate (2 × 10 ml)
and the combined organic phases were washed with brine (2 ×
10 ml), before being dried over anhydrous MgSO4, filtered and
concentrated under reduced pressure. The residue was purified by
flash column chromatography yielding the title compound (40 mg,
14%) as a yellow oil; mmax (KBr disc) 3064 (m, C–H[aromatic]),
2953 (s, C–H[aliphatic]), 2890 (s, O–CH3), 1598 (s, aromatic ring),
779 (s, three adjacent aromatic C–H); dH (400 MHz; CDCl3;
CHCl3) 7.47 (1 H, t, J 7.8, ArH), 7.35–7.30 (5 H, m, 5 × ArH),
7.20–6.95 (7 H, m, 7 × ArH), 3.75 (3 H, s, OCH3); dC (100 MHz;
CDCl3; CDCl3) 159.2, 141.3, 137.6, 136.9, 131.0, 129.1, 128.9,
127.1, 126.8, 125.2, 123.7, 121.7, 111.7, 54.9; m/z (CI+) 293.0990
(M + H+, C19H17OS requires 293.0995).
N,N-Dimethyl-3-methoxybenzamide (10a)23. N,N-Dimethyl-
2-tert-butylsulfinyl-3-methoxy benzamide (400 mg, 1.40 mmol,
1 eq.) was dissolved in ethanol (30 ml) and treated with Raney
nickel. The reaction was heated at reflux for 3 h. The reaction was
cooled and filtered through celite before being concentrated under
reduced pressure yielding the title compound (180 mg, 72%) as a
colourless oil; dH (400 MHz; CDCl3; CHCl3) 7.29–7.25 (1 H, m,
ArH), 6.95–6.89 (3 H, m, 3 × ArH), 3.78 (3 H, s, OCH3), 3.07 (3
H, s, NCH3), 2.94 (3 H, s, NCH3); dC (100 MHz; CDCl3; CDCl3)
171.2, 159.4, 137.5, 129.3, 119.0, 115.2, 112.2, 55.2, 39.4, 35.2; m/z
(CI+) 180.1 (M + H+, 100%).
Acknowledgements
JPF thanks EPSRC and GSK for a CASE award, and University
College, Oxford for a Scholarship.
3-Methoxybenzyl alcohol (10b)24. 2-tert-Butylsulfinyl-3-me-
thoxyphenylmethanol (66 mg, 0.27 mmol, 1 eq.) as 10a gave 10b
(35 mg, 94%) as a colourless oil; dH (400 MHz; CDCl3; CHCl3)
7.25 (1 H, t, J 8.1, ArH), 6.93–6.91 (2 H, m, 2 × ArH), 6.83–6.80
(1 H, m, ArH), 4.63 (2 H, s, CH2OH), 3.79 (3 H, s, OCH3); dC
(100 MHz; CDCl3; CDCl3) 159.7, 142.5, 129.5, 119.0, 113.1, 112.1,
65.0, 55.1; m/z (CI+) 138.1 (M+, 100%).
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