Synthesis of multiply ortho-substituted diaryl ethers via lithiation and oxidation of a dibenzosiloxane (phenoxasilin)

Article abstract of DOI:10.1055/s-2006-933111

Lithiation of dibenzosiloxanes (phenoxasilins or 9-silaxanthenes), followed by oxidation of the C-Si bonds, provides a versatile method for the synthesis of 2,6,2′,6′-tetrasubstituted diaryl (biaryl) ethers. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-933111

LETTER
745
Synthesis of Multiply ortho-Substituted Diaryl Ethers via Lithiation and
Oxidation of a Dibenzosiloxane (Phenoxasilin)
S
M
ynthesis of Multiply
o
a
rtho-Subst
r
itute
d
D
k
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
Fax +44(161)2754939; E-mail: clayden@man.ac.uk
Received 8 November 2005
Tricyclic diaryl ethers are cleanly doubly lithiated,5,6 so
we turned to the dibenzosiloxane (phenoxasilin) 3 in the
hope that (a) its lithiation would be straightforward and
(b) subsequent oxidation (ipso electrophilic aromatic sub-
Abstract: Lithiation of dibenzosiloxanes (phenoxasilins or 9-sila-
xanthenes), followed by oxidation of the C–Si bonds, provides a
versatile method for the synthesis of 2,6,2¢,6¢-tetrasubstituted diaryl
(
biaryl) ethers.
7
stitution) of the C–Si bonds would allow the formation of
Key words: diaryl ether, synthesis, lithiation, ipso electrophilic ar-
omatic substitution
functionalized acyclic ethers. Taking di-p-tolyl ether 2 in
diethyl ether, we added s-BuLi (3 equiv) in TMEDA.
Quench with dichlorodimethylsilane yielded the dibenzo-
8
9
siloxane 3 in 40% yield on a multigram scale.
Diaryl ethers 1 are key structural features of important
biologically active compounds such as thyroxine, the
1
2
3
bastadins, vancomycin and its analogues and have gen-
erally been made by metal-promoted coupling or nucleo-
(i)
(ii)
Li
Li
Li
3
philic aromatic substitution. As part of an investigation
O
O
of the stereochemistry of diaryl ether compounds, we
needed a versatile way of introducing up to four substitu-
ents ortho to the diaryl ether C–O bond. An OAr group is
a moderately effective director of lithiation,4,5 so we
attempted directed metallation reactions of 2. Ether 2 was
treated with 2.5 equivalents n-BuLi in neat TMEDA (0–
Si
Me Me
Si
Me Me
6
10
(iii)
O
(iii)
O
E
2
0 °C, 24 h) and acetone was added. A mixture of single
Si
Me Me
Si
Me Me
and double addition products 4 and 5 were formed, along
with remaining 2 (Scheme 1). Even after protection as
their methyl or trimethylsilyl ether derivatives, these com-
pounds were highly resistant towards further lithiation.
7
a (E = Me) 76%
7b (E = C(Me)HOH) 20%
c (E = CMe2OH) 27%
11 (E = Me) 47%
7
(iv)
(iv)
R1
R3
O
O
O
X
Y
I
I
I
I
R R4
2
8 58%
v), (vi)
OH
12 64%
(v), (vi)
OH
1
(
O
O
(
i), (ii)
HO
HO
Si
2
Me Me 3 40%
O
O
(i), (iii)
HO
OH HO
O
9
52%
13 57%
O
+
Scheme 2 Diaryl ethers from dibenzosiloxane 3. Reagents and con-
ditions: (i) s-BuLi (2 equiv), TMEDA, Et O, 0 °C, 2 h; (ii) s-BuLi (3.5
2
4
45%
5 23%
equiv), TMEDA, Et O, 0 °C, 2 h; (iii) MeI or MeCHO or acetone; (iv)
2
ICl, CH Cl ; (v) n-BuLi, THF; (vi) acetone.
2
2
Scheme 1 Lithiation of di-p-tolyl ether. Reagents and conditions:
i) n-BuLi, TMEDA, 20 °C; (ii) Me SiCl ; (iii) acetone.
(
2
2
5
Further lithiation was easy. Treating 3 with 2 equivalents
s-BuLi in TMEDA–Et O at 0 °C led to immediate colora-
2
tion, and quenching this yellow organolithium (presum-
ably 6) with methyl iodide,10 acetaldehyde or acetone
yielded 7. Similarly, after lithiation with 3.5 equivalents s-
BuLi, methylation of the dianion 10 returned the doubly
alkylated siloxane 11 (Scheme 2).
SYNLETT 2006, No. 5, pp 0745–0746
Advanced online publication: 09.03.2006
DOI: 10.1055/s-2006-933111; Art ID: D33705ST
1
7.
0
3.
2
0
0
6
©
Georg Thieme Verlag Stuttgart · New York

7
46
M. S. Betson, J. Clayden
LETTER
Conversion of the alkylated dibenzosiloxanes to acyclic
d = 158.0, 134.1, 132.2, 131.7, 119.0, 118.0, 21.0, –0.0. MS
(
EI): m/z (%) = 254 (50) [M], 239 (100) [M – CH ]. HRMS:
diaryl ethers was achieved with ICl. Double ipso electro-
3
1
1
m/z calcd for C H OSi: 254.1121; found: 254.1129.
16 18
philic aromatic substitution of the silyl group yielded the
(
9) (a) Gilman, H.; Oita, K. J. Am. Chem. Soc. 1957, 79, 339.
1
2
versatile diiodo derivatives 8 and 12. Further manipula-
tion of the iodo substituents is evidently possible in a va-
riety of ways: we chose to treat 8 and 12 with n-BuLi and
acetone to yield the tri-ortho-substituted and tetra-ortho-
substituted diaryl ethers 9 and 13.
(
(
b) Gilman, H.; Miles, D. J. Org. Chem. 1958, 23, 1363.
c) Hitchcock, C. H. S.; Mann, F. G.; Vanterpool, A.
J. Chem. Soc. 1957, 4537. (d) Corey, J. Y.; Chang, V. H. T.
J. Organomet. Chem. 1980, 190, 217.
(10) 3,6,8,10,10-Pentamethyl-9-silaxanthene (7a)
The dibenzosiloxane 3 (500 mg, 1.965 mmol) was dissolved
Details of our stereochemical investigations of 9, 13 and
in dry Et O (10 mL) and dry TMEDA (0.44 mL, 2.95 mmol)
2
other heavily substituted diaryl ethers will be reported
and cooled to –78 °C under a nitrogen atmosphere. s-BuLi
(1.1 M solution in cyclohexane, 2.68 mL, 2.95 mmol) was
added and after 10 min the dry ice bath was replaced with an
ice bath. The orange solution was stirred for 2 h and MeI
1
3
shortly.
Acknowledgment
(
0.18 mL, 2.95 mmol) was added. The mixture was stirred
for 14 h with gradual warming to r.t. Then, sat. aq NH Cl
solution (5 mL) was added and the layers separated. The
4
We are grateful to the Leverhulme Trust for support.
aqueous layer was washed with Et O (3 × 5 mL) and the
2
combined organic fractions were washed with H O (2 × 5
References and Notes
2
mL), brine (5 mL), dried (MgSO ) and solvents removed
4
(
(
(
1) Couladouros, E. A.; Pitsinos, E. N.; Moutsos, V. I.;
Sarakinos, G. Chem. Eur. J. 2005, 11, 406.
2) Nicolaou, K. C.; Boddy, C. N. C.; Bräse, S.; Winssinger, N.
Angew. Chem. Int. Ed. 1999, 38, 2096.
under reduced pressure. The residue was purified by flash
chromatography (silica, PE) to give the dibenzosiloxane 7a
as a colorless oil (400 mg, 1.49 mmol, 76%); R = 0.67 (PE).
f
IR (film): nmax = 2951 (CH), 2920 (CH), 1604 (aromatic),
–
1 1
3) (a) Theil, F. Angew. Chem. Int. Ed. 1999, 38, 2345.
1586 (aromatic) cm . H NMR (300 MHz; CDCl ): d = 7.39
3
(
b) Sawyer, J. S. Tetrahedron 2000, 56, 5045. (c) Liu, Z.;
(2 H, s, ArH), 7.32–7.14 (4 H, m, 4 × ArH), 2.50 (3 H, s,
ArMe ), 2.45 (3 H, s, ArMe ), 2.42 (3 H, s, ArMe ), 0.54
(6 H, s, SiMe2). C NMR (75 MHz, CDCl ): d = 158.2,
Larock, R. C. Org. Lett. 2004, 6, 99. (d) Evans, D. A.; Katz,
J. L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937.
A
B
C
1
3
3
(
e) Chan, D. M. T.; Monaco, K. L.; Wang, R.; Winters, M.
156.2 (O–C), 134.0, 133.6, 132.1, 131.7, 131.5, 126.9,
126.7, 119.2, 118.6, 118.0 (aromatics), 21.0, 20.9, 17.2
P. Tetrahedron Lett. 1998, 39, 2933.
+
(
(
(
4) (a) Oita, K.; Gilman, H. J. Org. Chem. 1956, 21, 1009.
(ArMe), –0.06 (SiMe ). MS (EI): m/z (%) = 268 (50) [M ],
2
(b) Gschwend, H. W.; Rodriguez, H. R. Org. React. 1979,
253 (100) [M – Me]. HRMS: m/z calcd for C H OSi:
1
7
20
26, 1.
286.1622; found: 286.1622.
5) Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.;
van Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J.
Organometallics 1995, 14, 3081.
(11) Similar ortholithiation–silylation–electrophilic substitution
sequences have been employed for ortho halogenation, see:
(a) Clayden, J.; Lund, A.; Youssef, L. H. Org. Lett. 2001, 3,
4133. (b) Zhao, Z.; Snieckus, V. Org. Lett. 2005, 7, 2523.
(12) 2,2¢-Diiodo-4,4¢,6-Trimethylbiphenyl Ether (8)
The dibenzosiloxane 7a (890 mg, 3.317 mmol) was
6) (a) Schwartz, E. B.; Knobler, C. B.; Cram, D. J. J. Am. Chem.
Soc. 1992, 114, 10775. (b) Hillebrand, S.; Bruckmann, J.;
Krüger, C.; Haenel, M. W. Tetrahedron Lett. 1995, 36, 75.
(
c) Clayden, J.; Lund, A.; Vallverdú, L.; Helliwell, M.
dissolved in dry CH Cl (20 mL) under a nitrogen
2
2
Nature (London) 2004, 431, 966.
atmosphere and cooled to 0 °C. Iodine monochloride (1.0 M
in CH Cl , 6.97 mL, 6.97 mmol) was added and the mixture
(
(
7) Eaborn, C. J. Organomet. Chem. 1975, 100, 43.
8) 3,6,10,10-Tetramethyl-9-silaxanthene (3)
p-Tolyl ether (5.0 g, 25.2 mmol) was dissolved in dry
TMEDA (50 mL) and cooled to 0 °C under a nitrogen
atmosphere. n-BuLi (2.5 M solution in hexane, 30.3 mL,
2
2
stirred for 30 min after which time the ice bath was removed.
And stirred for a further 12 h. Then, sat. aq Na S O solution
2
2
3
(25 mL) was added and the layers separated. The aqueous
layer was washed with CH Cl (3 × 25 mL) and the
2
2
7
0
5.7 mmol) was added and the mixture stirred for 20 min at
°C. The ice bath was removed and the mixture was stirred
combined organic fractions were washed with H O (2 × 25
2
mL), brine (25 mL), dried (MgSO ) and solvents removed.
4
for 12 h, after which time the solution had turned dark
orange. The mixture was cooled to 0 °C and dimethyl-
dichlorosilane (4.60 mL, 37.9 mmol) added dropwise which
resulted in an exothermic reaction. The mixture was stirred
The residue was purified by flash chromatography (silica,
PE) to give the ether 8 (859 mg, 1.85 mmol, 55%) as a
crystalline solid (plates), mp 122.5–124.2 °C (hexane–
EtOAc). R = 0.55 (PE). IR (film): n = 3019 (CH), 2919
f
max
–
1 1
for a further 2 h at 0 °C and sat. aq NH Cl solution (50 mL)
(CH), 1602 (aromatic), 1481 (aromatic) cm . H NMR (300
4
added, followed by EtOAc (50 mL). The layers were
separated and the aqueous layer washed with EtOAc (3 × 30
mL) and the combined organic fractions were washed with
MHz, CDCl ): d = 7.74 [1 H, d, J = 2.0 Hz, (ICCH) ], 7.58
3
A
(1 H, s, (ICCH) ], 7.08 (1 H, s, MeCCHCMe), 6.98 (1 H, dd,
B
J = 8.5, 2.0 Hz, OCCHCH), 6.20 (1 H, d, J = 8.5 Hz, OCCH),
aq HCl (3 M, 30 mL), H O (30 mL), brine (30 mL), dried
2.36 (3 H, s, ArMe ), 2.31 (3 H, s, ArMe ), 2.16 (3 H, s,
2
A
B
1
3
(
MgSO ) and solvents removed. The residue was purified by
ArMeC). C NMR (75 MHz, CDCl ): d = 153.8, 151.1,
140.5, 138.3, 138.0, 137.3, 133.4, 132.7, 133.4, 132.7,
4
3
flash chromatography (silica, PE) to give the dibenzo-
siloxane 3 as a viscous colorless oil (2.47 g, 9.71 mmol,
132.6, 130.1, 113.1, 92.0 (C–I), 85.4 (C–I), 20.7, 20.4, 17.6.
+
40%) which crystallized on standing (plates, mp 47–
MS (EI): m/z (%) = 464 (15) [MH ], 210 (100) [M – I ].
2
4
9.5 °C); R = 0.50 (PE). IR (film): n = 2952 (CH), 2919
HRMS: m/z calcd for C H OI : 463.9129; found:
f
max
15 14
2
–
1 1
(
CH), 1458 (aromatic) cm . H NMR (300 MHz, CDCl ):
463.9127.
3
d = 7.40–7.36 (2 H, m, SiCCH), 7.32–7.26 (2 H, m,
(13) Betson, M. S.; Clayden, J.; Worrall, C. P.; Peace, S.,
MeCCH), 7.16 (2 H, d, J = 8.4 Hz, OCCH), 2.46 (6 H, s,
manuscript in preparation.
1
3
PhMe), 0.54 (6 H, s, SiMe2). C NMR (75 MHz, CDCl ):
3
Synlett 2006, No. 5, 745–746 © Thieme Stuttgart · New York