Aryl, alkyl bis-silyl ethers: Rapid access to monoprotected aryl alkyl and biaryl ethers

Article abstract of DOI:10.1055/s-2003-38744

A simple one-pot procedure has been developed for the selective etherification of aryl silyl ethers in aryl, alkyl bis-silyl ethers to generate alkyl tert-butyldimethylsilyl-protected aryl alkyl ethers and biaryl ethers in good to excellent yields.

Full text of DOI:10.1055/s-2003-38744

LETTER
825
Aryl, Alkyl bis-Silyl Ethers: Rapid Access to Monoprotected Aryl Alkyl and
Biaryl Ethers
Rapid
Access
u
to
M
onoprot
d
A
ryl
A
h
lkyl and Biar
a
yl Ethers V. Ankala, Gabriel Fenteany*
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607-7061, USA
Fax +1(312)9960431; E-mail: fenteany@uic.edu
Received 13 March 2003
OTBS
OTBS
Abstract: A simple one-pot procedure has been developed for the
selective etherification of aryl silyl ethers in aryl, alkyl bis-silyl
ethers to generate alkyl tert-butyldimethylsilyl-protected aryl alkyl
ethers and biaryl ethers in good to excellent yields.
LiOH, DMF,
TBSO
R2O
R2X, r.t.
R1
R1
Key words: protecting groups, phenols, LiOH/DMF, ethers, selec-
1
2
tive etherification
OTBS
LiOH, DMF,
O2N
O
As the complexity of synthetic targets has grown more de-
manding, discrimination between similar types of protect-
ing groups and direct transformation of one protecting
group into another have become essential for increasing
the efficiency of natural product synthesis. Among the
many protecting groups available for hydroxyl groups, si-
lyl and alkyl ethers are the most commonly used due to
their stability under various reaction conditions.1
NO2
F
R1
, r.t.
3
Scheme 1
of aryl silyl ethers in the presence of alcoholic silyl ethers
in a one-pot procedure. Several substituted phenols were
reacted with alkyl halides to form the corresponding aryl
alkyl ethers in good yields (Table 1). In addition, since
benzoate is a versatile protecting group for hydroxyl
groups,1 we wanted to examine this methodology in ben-
zoate formation. We found that this protocol allows for
the synthesis of aryl benzoates from the bis-silyl ethers in
good yields. The reaction was general both in terms of
phenol and alkyl halide and gave good to excellent yields,
irrespective of the substitution pattern on the aromatic
ring (Table 1).
While many procedures are available for the formation of
aryl alkyl ethers from phenols, no general method exists
for the direct conversion of aryl, alkyl bis-silyl ethers into
aryl alkyl ethers, keeping the alcoholic silyl group intact.
Cesium fluoride2a and tetrabutylammonium fluoride,2b
which are exploited as bases for the formation of aryl
alkyl ethers from aryl silyl ethers, are not suitable for this
particular transformation because of their ability to cleave
both alcoholic and phenolic tert-butyldimethylsilyl (TBS)
groups.3 Such a selective transformation is indeed of po-
tential use, as many natural products and amino acids are
endowed with both alcoholic and phenolic hydroxyl
groups.4 In addition, generation of aryl alkyl ethers from
phenols is an efficient way to produce a library of aryl
alkyl ethers,5 which are important constituents of many
pharmacologically important chemical templates.
With the intention of further expanding the scope of this
methodology, we explored the SNAr reaction of activated
aryl halide such as o-nitrofluorobenzene with various aryl,
alkyl bis-silyl ethers for the formation of monoprotected
biaryl ethers. Biaryl ethers are present in many biological-
ly interesting natural products, such as combretastatins
D-1 (4) and D-2 (5)8 (Figure 1), piperizenomycin,9
deoxybouvardin10 and many commercial polymers. Due
to the structural importance of biaryl ethers, there has
been considerable effort toward the development of gen-
eral methods for their construction. The most prominent
procedures for the synthesis of biaryl ethers include the
Ullmann reaction,11a oxidative phenolic coupling,11b met-
al-activated nucleophilic aromatic substitution,11c SNAr
reaction11d and boronic acid-driven biaryl ether synthe-
sis.11e Although the Ullmann reaction is a particularly im-
portant method for the synthesis of biaryl ethers, it has
several drawbacks, such as requirement for harsh reaction
conditions and long reaction times. Furthermore, it is suit-
able only for electron-rich phenols. Several bases have
been studied for inter- and intramolecular biaryl ether
We recently developed a novel methodology for the selec-
tive deprotection of either aryl or alkyl silyl ethers from
aryl, alkyl bis-silyl ethers.6 These efforts stemmed from
our need to synthesize certain analogs of a new inhibitor
of cell migration which we discovered, for use in struc-
ture-activity relationship studies.7 Our success with the
selective deprotection of aryl TBS ethers in the presence
of alkyl TBS ethers using LiOH/DMF6 prompted us to in-
vestigate the utility of this reagent system in the formation
of aryl alkyl ethers and biaryl ethers (Scheme 1). Using
this system, we accomplished the selective etherification
Synlett 2003, No. 6, Print: 05 05 2003.
Art Id.1437-2096,E;2003,0,06,0825,0828,ftx,en;S01303ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

826
S. V. Ankala, G. Fenteany
LETTER
Table 1 Synthesis of Various Aryl Alkyl Ethers from Aryl Alkyl bis-Silyl Ethers
No
bis-TBS ether
RX
Time (h)a
Product (Yield%)b
OTBS
1a
BnBr
5
4.5
5
5
5.5
2a (92)
2b (95)
2b (94)
2c (95)
2d (79)
Allyl iodide
Allyl bromide
Propargyl bromide
PhCOCl
OTBS
1b
1c
PhCOCl
Allyl iodide
3
2
2e (70)
2f (80)
O2N
OTBS
OTBS
BnBr
BnBr
6
4
2g (92)
2h (94)
TBSO
NHBoc
NHCbz
TBSO
1d
1e
TBSO
TBSO
TBSO
BnBr
Allyl iodide
MeI
9
8
8.5
2i (90)
2j (85)
2k (91)
TBSO
TBSO
1f
Allyl iodide
PhCOCl
BnBrc
15
15.5
16
2l (89)
2m (76)
2n (91)
2o (95)
OMe
OTBS
OTBS
MeI
16
1g
1h
Allyl iodide
BnBr
5
5.5
2p (92)
2q (89)
TBSO
Br
MeI
4
4.5
4.5
2r (89)
2s (91)
2t (75)
BnBrc
PhCOCl
OTBS
OTBS
OTBS
1i
Allyl iodide
BnBr
MeI
17
17
18
2u (92)
2v (92)
2w (89)
OTBS
a Use of less than 3.0 equiv of LiOH also gave products, but the reaction times were increased.
b Isolated yields.
c These reactions, when performed with CsF as a base, led to a mixture of compounds.
formation from phenols.12 However, there has been less
OH
OH
attention paid to the selective conversion of aryl silyl
ethers to biaryl ethers starting from aryl, alkyl bis-silyl
ethers. Therefore, we sought a general method to generate
TBS-protected biaryl ethers from aryl, alkyl bis-silyl
O
O
O
O
ethers that is also applicable to electron-deficient phenols.
O
O
O
Several aryl, alkyl bis-silyl ethers were reacted with o-ni-
trofluorobenzene in the presence of LiOH/DMF in a one-
Combretastatin D-2 (5)
Combretastatin D-1 (4)
step protocol to form biaryl ether products of high purity
and in good yields (Scheme 2).
Figure 1
also suitable for electron-deficient phenols, unlike the
Ullmann ether synthesis.
The results summarized in Table 2 clearly show the scope
of the method with respect to various substituted aryl,
alkyl bis-silyl ethers, including tyrosine-derived bis-silyl
ether. These results demonstrate that the present method is
Finally, we wished to show that this methodology could
be applied to the synthesis of more complex molecules.
Synlett 2003, No. 6, 825–828 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
Rapid Access to Monoprotected Aryl Alkyl and Biaryl Ethers
827
OTBS
erational simplicity of the present methodology was dem-
onstrated by synthesizing a potential key intermediate for
the synthesis of 4 and 5. The methodology presented here
could also be exploited for the parallel synthesis of com-
pound libraries.
OTBS
NO2
F
LiOH, DMF,
r.t.
O2N
O
TBSO
+
R1
R1
1
3
6
Scheme 2
General Experimental Procedure for the Synthesis of Alkyl
TBS-Protected Aryl Alkyl Ethers (2)
Table 2 Synthesis of Various Biaryl Ethers from Aryl, Alkyl bis-
LiOH (0.90 mmol) was added to a stirred solution of bis-TBS ether
(0.30 mmol) in anhyd DMF (1 mL) and the reaction mixture was
stirred at r.t. After consumption of the starting material, alkyl halide
(0.60 mmol) was added and stirring was continued until completion
of the reaction as indicated by thin-layer chromatography (TLC).
The reaction mixture was then diluted with EtOAc, washed with
H2O and brine, dried (Na2SO4) and concentrated under reduced
pressure. The residue was purified by flash chromatography over
silica gel column using EtOAc/hexanes as eluent.
Silyl Ethers
bis-TBS ether
Time (h)a
Product (Yield%)b
3a (95)
1a
1b
1c
1e
1f
5.5
18
6
3b (92)
3c (93)
10
12
8
3e (88)
General Experimental Procedure for the Synthesis of Alkyl
TBS-Protected Biaryl Ethers (3)
3f (90)
To a stirred solution of bis-TBS ether (0.25 mmol) in anhyd DMF
(1 mL), LiOH (1.25 mmol) and o-nitrofluorobenzene (0.30 mmol)
were added successively at r.t. under argon atmosphere. The reac-
tion mixture was stirred at r.t. until completion, as indicated by
TLC. Then the reaction mixture was partitioned between water and
EtOAc. The organic layer was washed with brine, dried (Na2SO4)
and evaporated under reduced pressure. The resultant biaryl ether
was purified by column chromatography over silica gel column us-
ing EtOAc/hexanes as eluent.
1g
1h
3g (93)
10
3h (91)
a Typical reaction conditions for the desired transformation include
the use of 5.0 equiv of LiOH and 1.2 equiv of o-nitrofluorobenzene.
Decreasing the amount of LiOH used to 3.0 equiv resulted in consid-
erably increased reaction times.
b Isolated yields.
Spectroscopic Data for Selected New Compounds
Compound 2r: IR (film): 2929, 2370, 2345, 1254, 1093, 837 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.12 (s, 6 H), 0.96 (s, 9 H), 3.79
(s, 3 H), 4.70 (s, 2 H), 6.68 (d, 1 H, J = 8.6 Hz), 7.30 (dd, 1 H,
J = 8.6, 2.3 Hz), 7.56 (d, 1 H, J = 2.4 Hz). 13C NMR (100 MHz,
CDCl3): d = 18.4, 25.9, 55.2, 59.6, 111.0, 112.9, 129.4, 129.9,
132.1, 154.8. HRMS: Calcd for C14H23O2SiBrNa [M + Na]+:
353.0548. Found: 353.0548.
Compound 2v: IR (film): 2927, 1459, 1251, 1077, 834, 774 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.16 (s, 3 H), 0.17 (s, 3 H), 0.94
(s, 9 H), 1.71–1.80 (m, 2 H), 1.98–2.73 (m, 2 H), 2.73–2.78 (m, 2
H), 4.77–4.80 (m, 1 H), 5.06 (s, 2 H), 6.77 (d, 1 H, J = 7.9 Hz), 7.04
(d, 1 H, J = 7.7 Hz), 7.15 (t, 1 H, J = 7.9 Hz), 7.31–7.45 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 14.0, 18.9, 22.6, 25.8, 31.5, 69.3,
69.6, 109.3, 120.2, 125.8, 126.9, 127.6, 128.4, 137.5, 141.3, 155.9.
HRMS: Calcd for C23H32O2SiNa [M + Na]+: 391.2069. Found:
391.2069.
Compound 3h: IR (film): 2928, 2360, 1530, 1252, 838, 777 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.07 (s, 6 H), 0.90 (s, 9 H), 4.73
(s, 2 H), 6.70 (d, 1 H, J = 9.0 Hz), 6.94 (d, 1 H, J = 8.3 Hz), 7.19–
7.26 (m, 1 H), 7.34 (d, 1 H, J = 8.3 Hz), 7.50 (t, 1 H, J = 7.9 Hz),
7.72 (s, 1 H), 7.96 (d, 1 H, J = 8.1 Hz). 13C NMR (100 MHz,
CDCl3): d = 18.2, 25.8, 59.4, 117.8, 119.6, 119.8, 123.3, 125.8,
130.9, 131.1, 134.2, 135.1, 150.4, 152.3. HRMS: Calcd for
C19H24BrNO4SiNa [M + Na]+: 460.0556. Found: 460.0554.
We chose to prepare an advanced intermediate for the
synthesis of 4 and 5,8 compounds that stabilize microtu-
bules.13 We first prepared the hitherto unknown tris-silyl
ether 8 starting from commercially available 4-fluoro-3-
nitrobenzaldehyde.14 Treatment of the readily available
phenols 78f with LiOH and the tris-silyl ether 8 in DMF
gave the anticipated coupled product 9 in excellent yield
(Scheme 3).15
OBn
NO2
OBn
O
OR
F
OTBS
LiOH, DMF
OTBS
NO2
OTBS
OTBS
OTBS
8
CO2Et
CO2Et
OTBS
7a R=H
(r.t., 24h, 92% yield from 7a)
(r.t., 30h, 90% yield from 7b)
9
7b R=TBS
Scheme 3
In summary, we have developed a mild, efficient and gen-
eral method for the conversion of aryl, alkyl bis-silyl
ethers to alkyl TBS-protected aryl alkyl ethers and aryl
benzoates. A number of aryl, alkyl bis-silyl ethers were
smoothly converted to the corresponding biaryl ether
frameworks in good yields. The nitro group present in the
biaryl ether can be used as a handle to introduce various
functionalities on the aromatic ring. The mildness and op-
Compound 3c: IR (film): 2929, 1711, 1504, 1249, 1166, 837 cm–1.
[a]D20 –19.4 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3): d = 0.05
(s, 6 H), 0.92 (s, 9 H), 1.42 (s, 9 H), 2.82 (d, 2 H, J = 6.8 Hz), 3.49–
3.57 (m, 2 H), 3.70–3.85 (m, 1 H), 4.76 (s, 1 H), 6.96–6.99 (m, 3 H),
7.14–7.26 (m, 3 H), 7.46 (t, 1 H, J = 7.6 Hz), 7.93 (dd, 1 H, J = 1.2,
7.6 Hz). 13C NMR (100 MHz, CDCl3): d = 18.2, 25.8, 28.3, 36.7,
52.9, 63.0, 79.2, 119.3, 119.9, 122.7, 125.6, 130.9, 133.9, 134.9,
155.3. HRMS: Calcd for C26H38N2O6SiNa [M + Na]+: 525.2397.
Found: 525.2397.
Synlett 2003, No. 6, 825–828 ISSN 1234-567-89 © Thieme Stuttgart · New York

828
S. V. Ankala, G. Fenteany
LETTER
20
Compound 8: IR (film): 2929, 1541, 1255, 1093, 835 cm–1. [a]D
(4) (a) Evans, D. A.; Dinsmore, C. J.; Ratz, A. M.; Evrard, D. A.;
Barrow, J. C. J. Am. Chem. Soc. 1997, 119, 3417.
(b) Boger, D. L.; Kim, S. H.; Mori, Y.; Weng, J.-H.; Rogel,
O.; Castle, S. L.; McAtee, J. J. J. Am. Chem. Soc. 2001, 123,
1862. (c) Angle, S. R.; Wada, T. Tetrahedron Lett. 1997, 38,
7955. (d) Wagner, I.; Musso, H. Angew. Chem., Int. Ed.
Engl. 1983, 22, 816.
–24.0 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3): d = –0.20 (s, 3
H), –0.10 (s, 3 H), –0.02 (s, 3 H), 0.02 (s, 6 H), 0.09 (s, 3 H), 0.84
(s, 9 H), 0.86 (s, 9 H), 0.88 (s, 9 H), 3.13–3.18 (m, 1 H), 3.62–3.75
(m, 2 H), 4.80 (d, 1 H, J = 2.8 Hz), 7.16–7.21 (m, 1 H), 7.59–7.67
(m, 1 H), 8.08 (dd, 1 H, J = 2.0, 7.3 Hz). 13C NMR (100 MHz,
CDCl3): d = 17.9, 18.0, 18.2, 25.6, 25.8, 63.5, 72.9, 77.2, 117.0,
117.5, 124.3, 133.4, 133.6, 139.3. HRMS: Calcd for
C27H52NO5Si3FNa [M + Na]+: 596.3035. Found: 596.3052.
(5) Xu, W.; Mohan, R.; Morissey, M. M. Tetrahedron Lett.
1997, 42, 7337.
(6) Ankala, S. V.; Fenteany, G. Tetrahedron Lett. 2002, 43,
4729.
(7) Mc Henry, K. T.; Ankala, S. V.; Ghosh, A. K.; Fenteany, G.
ChemBioChem 2002, 11, 1105.
Compound 9: IR (film): 2929, 1736, 1532, 1256, 1091, 777 cm–1.
20
1
[a]D –46.0 (c 1.00, CHCl3). H NMR (400 MHz, CDCl3): d =
–0.19 (s, 3 H), –0.12 (s, 3 H), –0.02 (s, 3 H), 0.00 (s, 6 H), 0.06 (s,
3 H), 0.85 (s, 9 H), 0.88 (s, 9 H), 0.90 (s, 9 H), 1.22 (t, 3 H, J = 7.2
Hz), 2.57 (t, 2 H, J = 7.6 Hz), 2.87 (t, 2 H, J = 7.6 Hz), 3.13–3.17
(m, 1 H), 3.63–3.72 (m, 2 H), 4.07–4.13 (q, 2 H, J = 7.2 Hz), 4.78
(d, 1 H, J = 3.1 Hz), 5.03 (s, 2 H), 6.76 (d, 1 H, J = 8.7 Hz), 6.92–
6.98 (m, 3 H), 7.28–7.40 (m, 5 H), 7.42 (dd, 1 H, J = 2.1, 8.7 Hz),
7.96 (d, 1 H, J = 2.0 Hz). 13C NMR (100 MHz, CDCl3): d = 14.1,
17.9, 18.1, 18.2, 25.7, 25.9, 30.1, 35.8, 60.4, 63.6, 70.9, 73.0, 77.5,
115.6, 117.1, 121.8, 123.9, 125.6, 126.8, 127.7, 128.4, 128.5, 132.1,
134.4, 136.5, 136.6, 139.1, 143.9, 148.5, 150.5, 172.6. HRMS: Cal-
cd for C45H71NO9Si3Na [M + Na]+: 876.4334. Found: 876.4312.
(8) (a) Boger, D. L.; Sakya, S. M.; Yohannes, D. J. Org. Chem.
1991, 56, 4204. (b) Deshpande, V. H.; Gokhale, N. J.
Tetrahedron Lett. 1992, 33, 4213. (c) Couladouros, E. A.;
Soufli, I. C. Tetrahedron Lett. 1994, 35, 4409.
(d) Rychnovsky, S. D.; Hwang, K. Tetrahedron Lett. 1994,
35, 8297. (e) Rychnovsky, S. D.; Hwang, K. J. Org. Chem.
1994, 59, 5414. (f) Couladouros, E. A.; Soufli, I. C.
Tetrahedron Lett. 1995, 36, 9369. (g) Couladouros, E. A.;
Soufli, I. C.; Moutsos, V. I.; Chadha, K. R. Chem.–Eur. J.
1998, 4, 33.
(9) Tamai, S.; Kaneda, M.; Nakamura, S. J. J. Antibiot. 1982,
35, 1130.
Acknowledgment
(10) Itokawa, H.; Takeya, K. Heterocycles 1993, 35, 1467.
(11) (a) Lindley, J. Tetrahedron 1984, 40, 1433. (b) Noda, H.;
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(c) Pearson, A. J.; Lee, K. J. Org. Chem. 1994, 59, 2304.
(d) Zhu, J. Synlett 1997, 133; and the references cited
therein. (e) Evans, D. A.; Katz, J. L.; West, T. R.
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Monaco, K. L.; Wang, R. P.; Winters, M. P. Tetrahedron
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(12) (a) Marcoux, J. F.; Doye, S.; Buchwald, S. L. J. Am. Chem.
Soc. 1997, 119, 10539. (b)Palomo, C.; Oiarbide, M.; Lopez,
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(c) Schmittling, E. A.; Sawyer, J. S. J. Org. Chem. 1993, 58,
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(14) Preparation of 8 will be reported elsewhere.
(15) It is noteworthy that the ester groups in both 7a and 7b
remained intact after exposure to 3.0 equiv of LiOH/DMF at
r.t. and the coupled product 9 could be obtained in excellent
yields.
This work was supported by the National Cancer Institute of the
National Institutes of Health (CA095177 to G. F.).
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Synlett 2003, No. 6, 825–828 ISSN 1234-567-89 © Thieme Stuttgart · New York