Photochemically removable silyl protecting groups

Article abstract of DOI:10.1021/ja002370t

Several o-phenol-containing alkoxyvinylsilanes were prepared and their photochemistry was investigated. These materials were prepared via hydrosilylation of the corresponding o-acetoxy arylacetylenes. Two major classes of photochemical processes were identified in these reactants: trans→cis isomerization, leading to an intramolecular nucleophilic substitution process at silicon, and 1,5-silyl shift, leading to an unsymmetrical dialkoxysilane. The major outcome of this work is a novel class of photochemically removable protecting groups. Two alkyl substitutions on silicon, the dimethyl and diisopropyl, were examined. The latter is more stable and is preferred for protecting groups that must tolerate multiple steps or reagents. Protection of alcohols is generally performed starting with the arylethynyl acetate, which can be subjected to hydrosilylation, alcohol substitution, and acetate deprotection without isolation of intermediates. Two groups were studied in detail, the phenol and 2-naphthol vinyl silane derivatives. A variety of primary and secondary alcohols were protected with these reagents. These groups can be deprotected cleanly and in high yield by irradiation from 250 to 350 nm.

Full text of DOI:10.1021/ja002370t

3638
J. Am. Chem. Soc. 2001, 123, 3638-3643
Photochemically Removable Silyl Protecting Groups
Michael C. Pirrung,* Lara Fallon, Jin Zhu, and Yong Rok Lee‡
Contribution from the Department of Chemistry, LeVine Science Research Center, Box 90317, Duke
UniVersity, Durham, North Carolina 27708-0317
ReceiVed June 30, 2000
Abstract: Several o-phenol-containing alkoxyvinylsilanes were prepared and their photochemistry was
investigated. These materials were prepared via hydrosilylation of the corresponding o-acetoxy arylacetylenes.
Two major classes of photochemical processes were identified in these reactants: transfcis isomerization,
leading to an intramolecular nucleophilic substitution process at silicon, and 1,5-silyl shift, leading to an
unsymmetrical dialkoxysilane. The major outcome of this work is a novel class of photochemically removable
protecting groups. Two alkyl substitutions on silicon, the dimethyl and diisopropyl, were examined. The latter
is more stable and is preferred for protecting groups that must tolerate multiple steps or reagents. Protection
of alcohols is generally performed starting with the arylethynyl acetate, which can be subjected to hydrosilylation,
alcohol substitution, and acetate deprotection without isolation of intermediates. Two groups were studied in
detail, the phenol and 2-naphthol vinyl silane derivatives. A variety of primary and secondary alcohols were
protected with these reagents. These groups can be deprotected cleanly and in high yield by irradiation from
250 to 350 nm.
Introduction
over both the stability of groups to different reagents/reaction
conditions and the ability to selectively remove them in the
presence of other functionalities, including other silyl groups,
has enabled many advances in organic synthesis. Given the
general importance of photochemically removable protecting
groups, it is somewhat surprising that photochemically remov-
able silyl groups had not been developed. The first report of
such a group appeared in 1993,8 in a study that formed the basis
for the work reported here. Subsequently, Brook reported that
the tris(trimethylsilyl)silyl (sisyl) group is removed by short-
wavelength UV irradiation (eq 1).9 However, many of the
Photochemically removable protecting groups1 are an essential
part of several areas of science and technology. The ability to
control the unmasking of particular N-, O-, and S-containing
functionalities enables chemical reactivity to be “turned on” with
the time resolution of the duration of a light pulse and the rate
of deprotection. This ability has led to the widespread develop-
ment of “caged” compounds for the kinetic study of biological
processes.2 It can also be applied to the three-dimensional
mapping of biological processes, through spatially defined
control of deprotection chemistry based on the optical direction
of light. Spatial control of photochemistry is intrinsic to
photolithography, which allows for the fabrication of micro-
electronic3 and microfluidic4 devices, and is essential to light-
directed synthesis of polymer chains.5
biological molecules that would be targets for use in photo-
chemical protection would not be stable under these irradiation
conditions. Our original work also used short-wavelength
irradiation, though later studies showed that our initial groups
were also sensitive at longer wavelengths. However, the
continued development of this chemistry clearly called for a
group that was reactive with longer wavelengths.
One area of protecting group chemistry that has been heavily
developed in recent years is that of silyl groups.6 Important
applications for silyl protecting groups have been found in the
synthesis of nucleotides and nucleosides.7 Extremely fine control
‡ Current address: School of Chemical Engineering and Technology,
College of Engineering, Yeungnam University, Kyongsan 712-749, Korea.
(1) Pillai, V. N. R. Synthesis 1980, 1.
(2) Methods Enzymol. 1998, 291, 1-490.
Results
(3) Wallraff, G. M.; Hinsberg, W. D. Chem. ReV. 1999, 99, 1801-1821.
Introduction to Microlithography; Thompson, L. F., Willson, C. G., Bowden,
M. J., Eds.; American Chemical Society: Washington, DC, 1994.
(4) Regnier, F. E.; He, B.; Lin, S.; Busse, J. Trends Biotechnol. 1999,
17, 101-106. Sundberg, S. A. Curr. Opin. Biotechnol. 2000, 11, 47-53.
(5) Lipshutz, R. J.; Fodor, S. P.; Gingeras, T. R.; Lockhart, D. J. Nat.
Genet. 1999, 21, 20-24.
Our strategy for removing a silyl group photochemically
draws on the previous results of Porter, concerning the depro-
tection of serines at protease active sites that have been acylated
with o-hydroxycinnamates.10 It employs a photochemical
transfcis isomerization that brings the ester into the proximity
of the phenol, which lactonizes, releasing the alcohol of the
(6) Pouzar, V. Chem. Listy 1988, 82, 715.
(7) Ogilvie, K. K. In Nucleosides, Nucleotides, Their Biol. Appl., Proc.
Int. Round Table, 5th ed.; Rideout, J. L., Henry, D. W., Beacham, L. M.,
III, Eds.; Academic: New York, 1983; pp 209-256. Ogilvie, K. K.;
Beaucage, S. L.; Entwistle, D. W.; Thompson, E. A.; Quilliam, M. A.;
Westmore, J. B. J. Carbohydr., Nucleosides, Nucleotides 1976, 3, 197-
227.
(8) Pirrung, M. C.; Lee, Y. R. J. Org. Chem. 1993, 58, 6961-6962.
(9) Brook, M. A.; Balduzzi, S.; Mohamed, M.; Gottardo, C. Tetrahedron
1999, 55, 10027-10040. Brook, M. A.; Gottardo, C.; Balduzzi, S.;
Mohamed, M. Tetrahedron Lett. 1997, 38, 6997-7000.
10.1021/ja002370t CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/28/2001

Photochemically RemoVable Silyl Protecting Groups
J. Am. Chem. Soc., Vol. 123, No. 16, 2001 3639
Table 1. Alcohols Protected with 2 and 3 and Their Deprotection
Reactions
ester (eq 2). The stability of the ester, both to dark hydrolysis
and to different wavelengths of light, can be tuned through
substituent effects.
A similar principle could be applied to silyl deprotection (eq
3). Access to vinyl silanes suitable for formation of ethers of
this type was unknown, as was their stability and photochem-
istry.
The known o-ethynylphenol11 was acetylated to form 1, which
was subjected to hydrosilation12 with either dimethylchlorosilane
or diisopropylchlorosilane catalyzed by chloroplatinic acid (eq
4). Product 2 was isolated and characterized, but both 2 and 3
a A THF solution of 2 or 3 (1.0 mmol) was treated with LiNMe2
(1.0 mmol), and the alcohol (1.2 mmol), dissolved in 5 mL THF, was
added. After stirring for 3 h at RT or 4 h at reflux (see below), thin-
layer chromatography showed that the reaction was complete. b A 0.01
M acetonitrile solution of the ether was irradiated in a quartz cell at
254 nm in a Rayonet reactor for 30 min. Thin-layer chromatography
showed that the reaction was complete, and the alcohol was isolated
by chromatography in the indicated yield. c 4 h, reflux. d R ) i-Pr.
were generally taken forward without extensive purification.
Simultaneous removal of the acetate and protection of the
alcohol was accomplished in situ by treatment with lithium
dimethylamide in THF (which also converts the chlorosilanes
into the aminosilane derivatives), followed by addition of the
alcohol to be protected (without any additional base).
butylcyclohexanol within 30 min (eq 5). In benzene, 6 is
The protection of primary and secondary alcohols with 2 and
3 is readily accomplished, but tertiary alcohols are unreactive.
The results are summarized in Table 1. The dimethylsilyl ethers
form within 3 h, while the diisopropylsilyl ethers require
overnight reaction, and in some cases warming. These com-
pounds generally show a strong short-wavelength absorption
band at 258 nm (log ꢀ 4.28) and a somewhat weaker, but still
significant, band at 309 nm (log ꢀ 3.94).
The photochemistry of these compounds is solvent dependent.
Irradiation of 6 (R ) Me, Rayonet reactor, 254 nm, quartz
reaction vessel) in acetonitrile produces 7 (84%) and the 4-tert-
converted to the interesting dimethylsilylidene derivative 9
(91%) within 20 min (eq 6). Parallel results were observed with
(10) Turner, A. D.; Pizzo, S. V.; Rozakis, G. W.; Porter, N. A. J. Am.
Chem. Soc. 1987, 109, 1274-1275. Turner, A. D.; Pizzo, S. V.; Rozakis,
G. W.; Porter, N. A. J. Am. Chem. Soc. 1988, 110, 244-250. Porter, N.
A.; Bruhnke, J. D. J. Am. Chem. Soc. 1989, 111, 7616-7618.
(11) Prey, V. Ber. Dtsch. Chem. Ges. 1943, 76, 156. Prey, V.; Pieh, G.
Monatsh. Chem. 1949, 80, 790-800.
(12) Brook, M. A.; Neuy, A. J. Org. Chem. 1990, 55, 3909-3916.

3640 J. Am. Chem. Soc., Vol. 123, No. 16, 2001
Pirrung et al.
the diisopropylsilyl derivatives. The observation of the silylidene
products 9 and 10 at this point presaged significant difficulties
later in the investigation. More detailed study of the mechanism
of this process,13 which can also be triggered thermally, showed
that it likely involves a 1,5-hydrogen shift followed by a 1,5-
silicon shift (eq 7).
Scheme 1a
a Conditions: (a) Ac2O/NaOH; (b) I2/TlOAc; (c) (Ph3P)4Pd/CuI/Et3N/
TMSCCH; (d) Et3N‚3HF/THF; and (e) ICl/AgOAc.
19, formally the product of HCl addition, was invariably
produced (eq 8). Because hydrochloric acid was postulated to
Preparative photochemical deprotection reactions of deriva-
tives 4 and 5 were conducted in acetonitrile at 10 mM with
254 nm irradiation over 30 min. The crude reaction mixtures
reflected essentially quantitative conversion to the free alcohols
and either 7 or 8. The isolated yields of alcohols after silica gel
chromatography are good to excellent, as reflected in Table 1.
The chemical stability of the protected alcohols was exam-
ined. Derivatives of 4 are comparable in stability to trimethylsilyl
ethers. They are deprotected on treatment with TBAF (5 equiv,
10 min, THF), 1 N NaOH (5 equiv, 30 min, THF), and 1 N
HCl (5 equiv, 10 min, THF). Derivatives of 5 are more stable,
as expected, and are comparable to triisopropylsilyl (TIPS)
ethers. They can withstand the following reaction conditions:
5 equiv tetrazole/THF; excess EtMgBr, 0 °C; excess NaBH4/
MeOH, and excess PDC/CH2Cl2. Consequently, further efforts
have focused on the more stable (hydroxystyryl)diisopropylsilyl
(HSDIS) protecting groups.
With this successful demonstration of photochemically re-
movable silyl protecting groups, we wished to improve their
long-wavelength absorption properties to enable them to be
removed in the near UV region. Lower energy radiation should
minimize concurrent absorption by biopolymers, such as pep-
tides and nucleic acids, when these silyl groups are used in their
synthesis. In principle, this would involve the addition of red-
shifting electron-donating groups to the chromophore. Two such
modified silyl derivatizing reagents, incorporating diethylamino
(11) and methylenedioxy (12) substituents, were initially
targeted.
be responsible for this reaction, a wide variety of precautions
were implemented (freshly distilled silane, inert atmosphere box,
and the addition of NaHCO3) without significant effect. Since
the source of HCl might also be the chloroplatinic acid, a variety
of rhodium hydrosilylation catalysts were investigated, also
without beneficial effect. Substitution of triethylsilane for the
chlorosilane led to a complex mixture of hydrosilylation and
reduction products. Encouraged that partial hydrosilylation
resulted with a silane other than the chlorosilane, an alternative,
two-step protecting strategy was considered on the basis on the
formation of a diisopropylsilyl ether followed by hydrosilylation.
A representative alcohol, 3′-acetylthymidine, was converted to
its diisopropylsilyl ether and examined in hydrosilylation of 15,
but both internal and terminal silyl addition were observed. The
aromatic nucleus 11 was therefore abandoned. Our unsuccessful
efforts to hydrosilylate 15 and investigation of relevant hy-
drosilylation literature revealed a significant gap in current
technology; very few acetylenes bearing functional groups have
been studied in this reaction.
Acetylene 18 was subjected to the following three-step
process without isolation of intermediates: hydrosilylation to
give silyl chloride 12, reaction with an alcohol (benzyl,
4-methylpentyl, and trans-4-tert-butylcyclohexyl), and removal
of the acetate group with a cyanide resin in methanol, giving
protected alcohol 20 (eq 9). However, long-wavelength irradia-
The synthetic approach to these compounds followed our
precedent via the hydrosilylation of the respective aryl acety-
lenes, which were prepared as shown Scheme 1. Iodination of
m-diethylaminophenyl acetate required use of a selective
iodination procedure reported by Cambie.14 The required
acetylenes, 15 and 18, were prepared in 36-37% overall yield
from m-diethylaminophenol and methylenedioxyphenol, respec-
tively.
The hydrosilylation of 15 was investigated under a variety
of conditions.15 With diisopropylchlorosilane, the vinyl chloride
(13) Pirrung, M. C.; Lee, Y. R. Tetrahedron Lett. 1993, 34, 8217.
(14) Cambie, R. C.; Rutledge, P. S.; Smith-Palmer, T.; Woodgate, P.
D. J. Chem. Soc., Perkin Trans. 1 1976, 1161-1164.
tion of these compounds afforded only the silylidene products
21, and unlike the case of 6, the outcome is solvent independent.
(15) Brook, M. A.; Neuy, A. J. Org. Chem. 1990, 55, 3609-3616.

Photochemically RemoVable Silyl Protecting Groups
J. Am. Chem. Soc., Vol. 123, No. 16, 2001 3641
We hypothesized that the difficulties with these two reactants
lay in their polar substituents, which in one case disrupted
hydrosilylation and in the other favored the polar reaction
pathway previously invoked8 to explain silylidene formation.
An alternative strategy was therefore pursued for red-shifting
the absorption maximum by extending the conjugation length
using a naphthyl system. Two target molecules, the 1-naphthyl
and 2-naphthyl systems 22 and 23, were considered. The former
was pursued initially because of the availability of starting
materials.
The preparation of 22 followed previous routes (eq 10).
Figure 1. UV/vis spectrum of compound 27f at 2.527 × 10-4 M in
CH3CN; A346 0.697.
Hydrosilylation was successful and delivered the protected
alcohol 25. However, this compound converted to the silylidene
derivative even upon brief storage. The instability of this
material is rationalized by the double migration pathway in
which the putative quinone methide intermediate 26 is stabilized
by benzo substitution (eq 11). If this is the case, it should be
of a tertiary amine base to provide the silyl ethers. Removal of
the acetate, as shown before, gives the protected ether 27.
possible to eliminate silylidene formation by using the 2-naph-
thyl derivative, where the initial 1,5-H shift would be energeti-
cally disfavored because it disrupts the aromaticity of the full
naphthalene ring system (eq 12). This was the rationale behind
The absorption spectrum of the geranyl ether of 27 is shown
in Figure 1. The absorption maximum at 346 nm has an
extinction coefficient of nearly 3 000. Initial investigation of
the photolysis of the benzyl ether of 27 in acetonitrile was
somewhat disappointing. While the cyclic siloxane 32 was the
major product, the silylidene derivative 33 was concurrently
formed. Investigation of solvent effects on this process showed
that the use of methanol completely suppressed the formation
of 33 (eq 15). The UV spectrum of 32 has its major absorption
the targeting of 27.
A new synthetic route was required to prepare the 2-naphthyl
vinylsilane derivatives because of limited availability of starting
materials. Selective protection of naphthalene-2,3-diol with
TBDMSCl, which can be accomplished in 96% yield (eq 13),
differentiates the alcohols. The remaining alcohol, after conver-
sion to the triflate, is used to introduce the alkyne through
Sonogashira coupling. This step is amenable to scale-up and
has been used to prepare >10 g quantities of the trimethylsilyl
acetylene. This material was usually converted to 23 in smaller
batches. Hydrosilylation of 23 gives the intermediate chlorosi-
lane 31, which is directly treated with alcohols in the presence
maximum at λ < 310 nm and, therefore, does not interfere with
longer-wavelength irradiation/deprotection.

3642 J. Am. Chem. Soc., Vol. 123, No. 16, 2001
Pirrung et al.
Table 2. Alcohols Protected with 31 and Their Deprotection
Reactions
2,2-Diisopropyl-2H-benzo[e][1,2]oxasiline (8). 1H NMR (CDCl3):
δ 1.02 (d, J ) 4.2, 6H), 1.04 (d, J ) 3.3, 6H), 1.06 (m, 2H), 5.84 (d,
J ) 14.4, 1H), 6.85-7.11 (m, 4H), 7.35 (d, J ) 14.4, 1H). IR (neat,
cm-1): 2943, 2865, 1598, 1480, 1272, 1262, 1100, 920, 777, 751. MS
(m/z, CI): 233 (M++ 1). HRMS (EI): calcd for C14H20OSi, 232.1283;
found, 232.1290.
(4-tert-Butyl-cyclohexyloxy)-dimethyl-(2-vinyl-phenoxy)-silane (9).
1H NMR (600 MHz, CDCl3): δ 0.24 (s, 6H), 0.81 (s, 9H), 0.93-1.93
(m, 9H), 3.72 (m, 1H), 5.21 (dd, J ) 11.4 and 1.2 Hz, 1H), 5.69 (dd,
J ) 17.4 and 1.2 Hz, 1H), 6.92 (m, 2H), 6.99 (dd, J ) 17.4 and 11.4
Hz, 1H), 7.11 (ddd, J ) 8.1, 7.5, and 1.8 Hz, 1H), 7.46 (dd, J ) 7.5
and 1.8 Hz, 1H). IR (neat, cm-1): 2946, 2867, 1598, 1552, 1484, 1452,
1255, 1088, 927, 801, 754. MS (m/z, CI): 333 (M++ 1). HRMS (EI):
calcd for C20H32O2Si, 332.2171; found, 332.2168.
2-O-(tert-Butyldimethyl)silyl-3-hydroxynaphthalene. To a solution
of 2,3-dihydroxynaphthalene (5.00 g, 31.2 mmol) in 50 mL of
acetonitrile was added triethylamine (6.50 mL, 46.7 mmol). At -20
°C, tert-butyldimethylsilyl chloride (4.70 g, 31.2 mmol) in 50 mL
acetonitrile was added dropwise to the solution over 3 h. The reaction
mixture was poured into 200 mL ethyl acetate and washed with brine.
The organic phase was dried over MgSO4, and the solvent was removed
in vacuo. The residue was purified by flash chromatography on silica
gel using ethyl acetate and hexane (6:1) as eluent. A colorless oil (8.21
1
g, 96%) was obtained. H NMR (CDCl3): δ 7.69 (2H, m), 7.36 (2H,
m), 7.35 (1H, s), 7.22 (1H, s), 5.91 (1H, s), 1.11 (9H, s), 0.40 (6H, s).
13C NMR (CDCl3): δ 146.97, 143.09, 130.00, 128.66, 126.21, 126.08,
124.22, 123.47, 112.91, 109.31, 25.74, 18.28, -4.30. IR (CH2Cl2, cm-1):
3529, 2928, 1474. Anal. Calcd for C16H22O2Si: C, 70.03; H, 8.08.
Found: C, 69.98; H, 8.00.
a The yield of the cyclization product 32 is reported due to the
2-O-(tert-Butyldimethyl)silyl-3-O-(trifluoromethanesulfonyloxy)-
naphthalene (29). 2-O-(tert-butyldimethyl)silyl-3-hydroxynaphthalene
(0.95 g, 3.46 mmol) was taken up in 80 mL of triethylamine, and the
solution was cooled to 0 °C. Triflic anhydride (0.79 mL, 4.67 mmol)
was added to the solution, and the mixture was allowed to stir for 2 h.
The mixture was poured into 100 mL ethyl acetate and washed with
brine. The organic phase was dried over MgSO4, and the solvent was
removed in vacuo. The residue was purified by flash chromatography
on silica gel using ethyl acetate and hexane (9:1) as eluent. A light
yellow oil (1.24 g, 89%) was obtained. 1H NMR (CDCl3): δ 7.79 (2H,
m), 7.73 (1H, s), 7.48 (2H, m), 7.35 (1H, s), 1.11 (9H, s), 0.39 (6H, s).
13C NMR (CDCl3): δ 145.69, 141.03, 133.05, 127.95, 127.47, 127.09,
126.35, 124.97, 120.76, 120.32, 116.51, 116.15, 25.63, 18.40, -4.33.
IR (CH2Cl2, cm-1): 2962, 2939, 1600, 1468. Anal. Calcd for
C17H21F3O4SSi: C, 50.23; H, 5.21. Found: C, 50.34; H, 5.20.
2-O-(Trifluoromethanesulfonyloxy)-3-hydroxynaphthalene. To a
solution of compound 29 (10.0 g, 24.6 mmol) in 150 mL of
dichloromethane at 0 °C was added 1.0 M tetrabutylammonium fluoride
(32 mL, 32.0 mmol). The mixture was allowed to stir for 1 h, was
poured into 100 mL ethyl acetate, and was washed with brine. The
organic phase was dried over MgSO4, and the solvent was removed in
vacuo. The residue was purified by flash chromatography on silica gel
using ethyl acetate and hexane (5:1) as eluent. A light yellow oil (6.10
g, 83%) was obtained. 1H NMR (CDCl3): δ 7.74 (1H, d, J ) 8.2 Hz),
volatility of the alcohol.
With this protecting group design verified, the protection of
several alcohols with 31 and the photodeprotection of the
resulting ((2-hydroxy-3-naphthyl)vinyl)diisopropylsilyl (HNVDS)
groups 27 was investigated, as summarized in Table 2. The high
isolated, purified yields on the relatively small scale and very
clean crude reaction mixtures (1H NMR) strongly suggest that
deprotection is quantitative. This outcome strongly recommends
this group for a variety of applications in photochemical
deprotection.16
Summary
A new class of photochemically removable silyl protecting
groups has been developed. The (hydroxystyryl)diisopropylsilyl
(HSDIS) group can be formed by hydrosilylation of o-
ethynylphenyl acetate with chlorodiisopropylsilane followed by
conversion to the dimethylsilylamine and direct reaction with
an alcohol to be protected. The ((2-hydroxy-3-naphthyl)vinyl)-
diisopropylsilyl (HNVDS) group can be formed by a one-pot
hydrosilylation of 3-ethynyl-2-naphthyl acetate, alcohol protec-
tion in the presence of a tertiary amine base, and acetate removal
with cyanide in methanol. The HSDIS group is removed with
254 nm irradiation, while the HNVDS group is removed with
350 nm irradiation.
7.72 (1H, s), 7.64 (1H, d, J ) 8.2 Hz), 7.44 (2H, m), 7.30 (1H, s). 13
C
NMR (CDCl3): δ 145.44, 138.31, 133.50, 128.39, 128.02, 127.85,
126.57, 125.44, 121.14, 120.98, 116.90, 113.34. IR (CH2Cl2, cm-1):
3529, 1634, 1594, 1531, 1417. LRMS 292.0 (M+). HRMS: calcd for
C11H7F3O4S, 292.0017; found, 292.0013 (M+).
2-O-(Trifluoromethanesulfonyloxy)-3-acetoxynaphthalene (30).
To a solution of 2-O-(trifluoromethanesulfonyloxy)-3-hydroxynaph-
thalene (6.50 g, 22.6 mmol) in 50 mL of dichloromethane was added
acetic anhydride (2.80 mL, 29.7 mmol) followed by the addition of
triethylamine (4.35 mL, 31.3 mmol) at room temperature. The mixture
was allowed to stir for 4 h. The mixture was poured into 100 mL ethyl
acetate and washed with brine. The organic phase was dried over
MgSO4, and the solvent was removed in vacuo. The residue was purified
by flash chromatography on silica gel using ethyl acetate and hexane
(9:1) as eluent. A white solid (6.78 g, 91%) identified as compound
30 was obtained. Mp 126 °C. 1H NMR (CDCl3): δ 7.84 (2H, m), 7.80
(1H, s), 7.77 (1H, s), 7.57 (2H, m), 2.43 (3H, s). 13C NMR (CDCl3):
δ 168.51, 140.13, 139.84, 132.65, 131.20, 128.09, 128.00, 127.89,
Experimental Section
Compounds described in Table 1 were previously reported in the
Supporting Material for ref 8.
2,2-Dimethyl-2H-benzo[e][1,2]oxasiline (7). 1H NMR (CDCl3): δ
0.33 (s, 6H), 5.89 (d, J ) 14.4, 1H), 6.87-7.13 (m, 4H), 7.23 (d, J )
14.4, 1H). IR (neat, cm-1): 3061, 2995, 2974, 1599, 1552, 1480, 1449,
1273, 1263, 1101, 1030, 923, 795, 752. MS (m/z, CI): 177 (M++ 1).
HRMS (CI): calcd for C10H13OSi, 177.0736; found, 177.0726.
(16) Pirrung, M. C.; Bradley, J.-C. J. Org. Chem. 1995, 60, 6270. McGall,
G. H.; Barone, A. D.; Diggelmann, M.; Fodor, S. P. A.; Gentalen, E.; Ngo,
N. J. Am. Chem. Soc. 1997, 119, 5081-5090. Pirrung, M. C.; Fallon, L.;
McGall, G. H. J. Org. Chem. 1998, 63, 241-246.

Photochemically RemoVable Silyl Protecting Groups
J. Am. Chem. Soc., Vol. 123, No. 16, 2001 3643
127.46, 122.37, 121.08, 116.79, 21.07. IR (CH2Cl2, cm-1): 1772, 1468,
1428. Anal. Calcd for C13H9F3O5S: C, 46.71; H, 2.71. Found: C, 46.75;
H, 2.73.
and treated with an excess of cyanide on Amberlyst (3 mmol/g). The
solvent was poured off the beads and removed in vacuo. The resulting
oil was purified using flash chromatography on silica gel eluting with
5:95 EtOAc:hexane to give 37 mg (78%) of the desired compound as
2-(Trimethylsilylethynyl)-3-acetoxynaphthalene. To a solution of
compound 30 (4.70 g, 14.0 mmol) in 100 mL DMF was added
dichlorobis(triphenylphosphine)palladium(II) (196 mg, 0.28 mmol)
followed by triethylamine (3.90 mL, 28.0 mmol). After stirring for 5
min, trimethylsilylacetylene (2.97 mL, 21.0 mmol) was added to the
mixture. The mixture was stirred for 30 min, and the temperature was
brought to 90 °C. After stirring for 10 h, the solvent was removed in
vacuo. The residue was redissolved in diethyl ether and washed with
30 mL 1 N HCl and brine. The organic phase was dried over MgSO4,
and the solvent was removed in vacuo. The residue was purified by
flash chromatography on silica gel using ethyl acetate and hexane (9:
1) as eluent. A white solid (3.32 g, 84%) was obtained. Mp 123 °C.
1H NMR (CDCl3): δ 8.05 (1H, s), 7.78 (2H, m), 7.53 (1H, s), 7.48
(2H, m), 2.39 (3H, s), 0.29 (9H, s). 13C NMR (CDCl3): δ 160.80,
148.07, 133.57, 133.13, 130.85, 127.42, 127.25, 127.20, 126.11, 119.19,
116.14, 99.87, 99.21, 20.84, -0.06. IR (CH2Cl2, cm-1): 2962, 2355,
2161, 1766. Anal. Calcd for C17H18O2Si: C, 72.30; H, 6.42. Found:
C, 72.21; H, 6.47.
1
a clear oil. H NMR (CDCl3): δ 1.12 (12H, m), 1.20 (2H, m), 4.89
(2H, s), 5.07 (1H, s), 6.51 (1H, d, J ) 20 Hz), 7.23-7.39 (8H, m),
7.44 (1H, d, J ) 20 Hz), 7.59 (1H, d, J ) 8.4 Hz), 7.23 (1H, d, J )
8.4 Hz), 7.85 (1H, s). 13C NMR (CDCl3): δ 12.63 (CH), 17.64 (CH3),
65.39 (CH2), 110.05 (CH), 123.89 (CH), 125.28 (CH), 125.86 (CH),
126.11 (CH), 126.57 (CH), 126.97 (CH), 127.77 (C), 127.99 (CH),
128.28 (CH), 128.98 (C), 134.27 (C), 141.36 (C), 141.53 (CH), 151.35
(C). HRMS (FAB, MH+) calcd for C25H31O2Si, 391.2093; found,
391.2090.
Photolysis of 27g. 2,2-Diisopropyl-2H-1-oxa-2-sila-anthracene
(32). Compound 27g (0.07 g, 0.19 mmol) was dissolved in 14 mL
(0.013 M) of methanol and irradiated for 45 min in a Rayonet
photochemical reactor (350 nm phosphor lamps). The solvent was
removed in vacuo, and the photoproduct was isolated using flash
chromatography on silica gel eluting with 2:98 EtOAc:hexanes to give
1
35.0 mg (66%) of a clear oil. H NMR (CDCl3): δ 1.01 (14H, m),
1.12 (2H, m), 6.00 (1H, d, J ) 14.4 Hz), 7.23 (1H, s), 7.25 (1H, m),
7.34 (1H, m), 7.52 (1H, s), 7.55 (1H, d, J ) 14.4 Hz), 7.61 (1H, d, J
) 8.0 Hz), 7.68 (1H, d, J ) 8.0 Hz). 13C NMR (CDCl3): δ 13.42
(CH), 16.65 (CH3), 113.78 (CH), 121.26 (CH), 123.66 (CH), 126.20
(CH), 126.50 (CH), 127.76 (CH), 128.81 (C), 130.29 (CH), 134.61
(C), 147.44 (CH), 152.48 (C). HRMS (FAB, MH+): calcd for C18H23-
OSi, 283.1518; found, 283.1510.
2-Ethynyl-3-acetoxynaphthalene (23). To a solution of 2-(tri-
methylsilylethynyl)-3-acetoxynaphthalene (300 mg, 1.06 mmol) in 50
mL of dichloromethane was added tetrabutylammonium fluoride (1.25
mmol fluoride/g on silica gel) (4.42 g, 5.30 mmol). The mixture was
allowed to stir at room temperature for 2 h and was poured into 50 mL
of saturated aqueous ammonium chloride. The mixture was extracted
with ethyl acetate. The organic phase was dried over MgSO4, and the
solvent was removed in vacuo. The residue was purified by flash
chromatography on silica gel using ethyl acetate and hexane (9:1) as
eluent. A white solid (192 mg, 86%) identified as compound 23 was
General Procedure for the Protection of Alcohols. The alkyne
23 (108 mg, 0.51 mmol) was azeotroped from toluene and taken up in
5.0 mL diethyl ether. An aliquot (30 µL) of a prepared solution (0.10
M in 2-propanol) of hydrogen hexachloroplatinate(IV) hydrate was
added to 1.0 mL of diethyl ether, and to this solution was added chloro-
diisopropylsilane (0.20 mL, 1.17 mmol). This solution was stirred for
5 min followed by the addition of the alkyne solution. The reaction
was stirred for 10 h at room temperature, and the solvent was removed
in vacuo. The flask was refilled with nitrogen. The resulting oil was
taken up in 5 mL of tetrahydrofuran, and the solution was cooled to 0
°C. Diisopropylethylamine (0.18 mL, 1.03 mmol) and alcohol (0.46
mmol) were added to the reaction mixture. The mixture was allowed
to stir overnight. The solution was poured into ethyl acetate, washed
with brine, and dried over MgSO4. The solvent was removed in vacuo.
The residue was purified by flash chromatography on silica gel using
ethyl acetate and hexane (9:1) as eluent. This intermediate acetate (0.35
mmol) was dissolved in 4 mL of methanol and treated with an excess
of cyanide (1.40 mmol) on Amberlyst (3 mmol cyanide/g). The solvent
was poured off the beads and removed in vacuo. The residue was
purified by flash chromatography on silica gel using ethyl acetate
and hexane (7:1) as eluent. Evaporation of solvent afforded com-
pounds 27.
1
obtained. Mp 115 °C. H NMR (CDCl3): δ 8.08 (1H, s), 7.79 (2H,
m), 7.55 (1H, s), 7.48 (2H, m), 3.29 (1H, s), 2.40 (3H, s). 13C NMR
(CDCl3): δ 169.00, 148.00, 134.12, 133.29, 130.77, 127.39, 127.27,
126.21, 119.36, 115.10, 81.45, 78.87, 20.87. IR (CH2Cl2, cm-1): 3248,
2355, 1760, 1537. Anal. Calcd for C14H10O2: C, 79.98; H, 4.79.
Found: C, 79.80; H, 4.91.
Hydrosilylation of 23. 2-Acetoxy-3-[trans-diisopropyl(benzyloxy)-
silyl)vinyl] Naphthalene. The alkyne 23 (0.35 g, 1.66 mmol) was
azeotroped from acetonitrile and taken up in 6.0 mL of diethyl ether.
An aliquot (50 µL) of a prepared solution (0.10 M in 2-propanol) of
hydrogen hexachloroplatinate(IV) hydrate was added to 1.0 mL of
diethyl ether, and to this solution was added chlorodiisopropylsilane
(0.65 mL, 3.81 mmol). This solution was stirred for 5 min followed
by the addition of the alkyne solution. The reaction was stirred for 3
h at room temperature, and the solvent was removed in vacuo. The
flask was refilled with argon, the resulting oil was taken up in 5 mL of
tetrahydrofuran, and the solution was cooled in an ice bath. Diisopro-
pylethylamine (1.66 mL, 9.50 mmol) and benzyl alcohol (1.97 mL,
19.04 mmol) were added to the reaction mixture that was allowed to
stir overnight. The solution was poured into EtOAc, washed with water,
and dried over NaSO4. The desired compound was obtained following
flash chromatography on silica gel eluting with 5:95 EtOAc:hexane to
give 0.04 g of a clear oil that was slightly impure. The oil was further
purified on silica gel eluting with a gradient of 0:100 to 2:98 diethyl
General Procedure for the Deprotection of Silyl Ethers 27. The
protected alcohol (0.20 mmol) 27 was dissolved in 10 mL of methanol
and irradiated for 45 min in a Rayonet photochemical reactor (350 nm
phosphor lamps). The solvent was removed in vacuo, and the residue
was purified by flash chromatography on silica gel using ethyl acetate
and hexane (15:1) as eluent.
1
ether:pentane to give 0.40 g (58%) of a clear oil. H NMR (CDCl3):
Acknowledgment. Financial support provided by NIH GM-
46720. The assistance of L. LaBean in administrative support
of this work is greatly appreciated.
δ 1.22-1.27 (14H, m), 2.32 (3H, s), 5.01 (2H, s), 6.65 (1H, d, J )
19.5 Hz), 7.32-7.62 (9H, m), 7.87 (1H, m), 7.95 (1H, m), 8.15 (1H,
s). 13C NMR (CDCl3): δ 12.59 (CH), 17.52 (CH3), 17.46 (CH3), 20.64
(CH3), 65.23 (CH2), 119.58 (CH), 125.77 (CH), 125.92 (CH), 125.99
(CH), 126.12 (CH), 126.59 (CH), 126.92 (CH), 127.27 (CH), 127.99
(CH), 128.25 (CH), 130.48 (C), 131.66 (C), 133.40 (C), 140.65 (CH),
141.27 (C), 146.27 (C), 169.37 (C). HRMS (FAB, MH+): calcd for
C27H33O3Si, 433.2200; found, 433.2204.
Supporting Information Available: Experimental descrip-
tions and/or spectral data for 14, 15, 17-19, 20a-c, 21, 22,
24, 25, 27a-f; UV/vis spectrum of 32; 1H and 13C NMR spectra
of compound 27b-f (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
2-Hydroxy-3-[trans-diisopropyl (benzyloxy)silyl)vinyl]naphtha-
lene (27g). 2-Acetoxy-3-[trans-diisopropyl (benzyloxy)silyl)vinyl]-
naphthalene (0.04 g, 0.10 mmol) was dissolved in 4 mL of methanol
JA002370T