Development of trityl-based photolabile hydroxyl protecting groups

Article abstract of DOI:10.1021/jo200692c

A series of trityl-based photolabile hydroxyl protecting groups have been examined. These PPGs evolve from the traditional acid-labile trityl protecting group with proper electron-donating substituents. Structure-reactivity relationships have been explored. A m-dimethylamino group is crucial to achieve high photochemical deprotection efficiency. The o-hydroxyl group in 8 greatly improves the yield of the photochemical deprotection reaction, compared with the corresponding o-methoxyl-substituted counterpart 7. However, comparison between the photoreactions of 9 and 11 does not show similar structural relevance. The PPG in ether 1 (i.e., DMATr group) is structurally simple and easy to prepare and install. Its deprotection can be successfully carried out with irradiation of sunlight without requirement of photochemical devices.

Full text of DOI:10.1021/jo200692c

FEATURED ARTICLE
pubs.acs.org/joc
Development of Trityl-Based Photolabile Hydroxyl Protecting Groups
Lei Zhou, Haishen Yang, and Pengfei Wang*
Department of Chemistry, University of Alabama at Birmingham, 901 14th Street South, Birmingham, Alabama 35294, United States
S Supporting Information
b
ABSTRACT: A series of trityl-based photolabile hydroxyl
protecting groups have been examined. These PPGs evolve
from the traditional acid-labile trityl protecting group with
proper electron-donating substituents. Structureꢀreactivity
relationships have been explored. A m-dimethylamino group
is crucial to achieve high photochemical deprotection efficiency.
The o-hydroxyl group in 8 greatly improves the yield of the
photochemical deprotection reaction, compared with the cor-
responding o-methoxyl-substituted counterpart 7. However, comparison between the photoreactions of 9 and 11 does not show
similar structural relevance. The PPG in ether 1 (i.e., DMATr group) is structurally simple and easy to prepare and install. Its
deprotection can be successfully carried out with irradiation of sunlight without requirement of photochemical devices.
Scheme 1. Protection of Alcohol with DMATr
’ INTRODUCTION
Photolabile protecting groups (PPGs) are unique and useful
protecting groups not only in organic chemistry but also in
biochemistry, photolithography, and material science.1ꢀ3 Their
advantages stem from using light as a traceless reagent in the
removal process. Photochemical removal of protecting groups
often occurs under mild conditions and does not require chemical
reagents. In addition, light also provides precise temporal and
spatial control over the course of a reaction. New PPGs and
creative applications of PPGs have continued to emerge.4,5 Devel-
opment of more PPGs of different chemical and photochemical
properties will provide more options for different applications and
is highly desirable.
We have recently demonstrated that the traditional acid-
sensitive hydroxyl protecting group, the trityl (Tr) group, can
be converted to a robust photolabile hydroxyl protecting group
relatively insensitive toward acid treatments by introducing a
m-dimethylamino group to one of the three phenyl rings.6 As
shown in Scheme 1, an alcohol ROH can be protected as the
triarylmethyl ether 1 by using a new protection protocol recently
developed in our laboratory. Thus, heating the alcohol ROH
with the protecting group reagent 2 at 120 °C will lead to the
ether 1 in high yields without using any other chemical reagents.
Upon irradiation of 1 with UV light, the alcohol ROH can be
efficiently released in the presence of a hydrogen donor.6 For the
first time, both protection of an alcohol and removal of the
protecting group to release the alcohol can be carried out without
requiring any other chemical reagents. Moreover, owing to its
increased stability toward acid treatment, the new PPG (i.e.,
DMATr in 1) constitutes orthogonal protecting groups with the
traditional acid-sensitive trityl type of protecting group. Herein
we report our full account of developing new PPGs for hydroxyl
protection.
’ RESULTS AND DISCUSSION
Structural Effect. We have recently demonstrated that tradi-
tional acid-labile Tr and 4-methoxytrityl (MMTr) are also
responsive to UV irradiation of wavelength shorter than 280 nm
to release the protected alcohol.6 However, DMATr has a much
improved photochemical efficiency, which was attributed to the
excited-state meta effect introduced by the meta electron-donat-
ing group, i.e., the dimethylamino group.7 Interestingly, introdu-
cing additional m-dimethylamino group(s), whether to the same
or to a different phenyl ring of the triarylmethyl group, does not
necessarily further improve the photoreactivity of PPGs. On the
contrary, photochemical efficiency actually decreased when a
phenyl group in 1 was replaced with another 3-(dimethylamino)-
phenyl group. For example, irradiation of 3 and 4 under the same
reaction conditions in CD3OD led to release of 3-phenylpropanol
Received: April 1, 2011
Published: May 25, 2011
r
2011 American Chemical Society
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Table 1. Photochemical Cleavage of Trityl-Based Hydroxyl
Protecting Groups
in 84% yield from 3, but in 77% yield from 4 (Table 1, entries 1
and 2). Because of the solvent effects previously observed, we also
examined the photoreactions in MeCN/water (9:1).8 As expected,
yields obtained in MeCN/D2O (9:1) were inferior to those in
methanol and cleavage of the benzylic CꢀO was achieved in 76%
yield with the ether 3 while only in 48% yield with the ether 4
(Table 1, entries 1 and 2). In MeCN/water (9:1), photoreaction
products contained a small fraction of 3-phenylpropanal, pre-
sumably resulting from oxidization that occurred duringrelease of
3-phenylpropanol. Thus, the chemical yields of photochemically
breaking the benzylic CꢀO bond in MeCN/water (9:1) in
Table 1 were adjusted accordingly; i.e., the products included
both the alcohol and the aldehyde. The amount of the aldehyde
byproduct varied with different PPGs. In the case of 3, the ratio of
the aldehyde to the sum of the aldehyde and the alcohol was
typically around 20%, similar to the value obtained from 4. We
speculate that formation of the aldehyde could originate from
heterolysis of the benzylic CꢀO bond followed by hydride shift
between the geminate ion pair (i.e., alkoxide and the tritylium ion
in Scheme 1).9,10 Inspection of the crude reaction mixture by
NMR spectroscopy revealed that appearance of the aldehyde was
accompanied by the reduced PPG moiety, i.e., 1-(dimethylamino)-
phenyl-1,1-diphenylmethane. In control experiments, irradiation
of pure 3-phenyl-1-propanol or a 1:1 mixture of the alcohol and
the corresponding triarylmethyl alcohol in MeCN or in MeCN/
water (9:1) did not produce any detectable aldehyde, seemingly
in agreement with the speculated hydride transfer in the ion pair.
The nature of the electron-donating group(s) and the substitu-
tion pattern affects the photochemical efficiency. Compared with
the dimethylamino group, a methoxyl group is less effective in
causing a bathochromic shift of PPG's UV absorption and in
improving its photochemical efficiency. For instance, the quantum
yield of 3 was 0.2 in methanol, while the quantum yields of 5ꢀ7
were only 0.04, 0.03, and 0.04, respectively (Table 1, entries 1
and 3ꢀ5).11,12 In MeCN/water (9:1), the quantum yield of 3 is
also higher than that of 5.6 Chemical yields of the photoreactions
of 6 and 7 were measured after irradiation for 10 min in methanol
or 12 min in MeCN/water (9:1), and they were all considerably
lower than that of 3after 7 min of irradiation. Irradiation was carried
out with a medium pressure mercury lamp equipped with a Pyrex
filter sleeve. There was only a trace amount of 3-phenylpropanal
observed in the reactions of 6 and 7 in MeCN/water (9:1).
However, compound 8 showed significantly improved photo-
chemical yields compared with 6 and 7 in both methanol and
MeCN/water (9:1) solutions (Table 1, entry 6). In methanol,
irradiation of 8 for 10 min led to 82% yield of the CꢀO bond
cleavage versus only 13% yield from 7; in MeCN/water (9:1),
irradiation of 8 for 12 min resulted in 94% yield of the bond
cleavage versus only 8% yield from 7 under the same conditions.
The compounds 7 and 8 have similar structures except that there
is the o-hydroxyl group in 8 rather than a methoxyl group as in 7.
We attribute the increased reaction efficiency of 8 to the increased
acidity of the phenolic hydrogen in its S1 state. It can facilitate the
cleavage of the benzylic CꢀO via intramolecular catalysis. It has
been suggested that the high reactivity of generating quinone
methides from o-hydroxybenzyl alcohols lies in the proximity of
the phenolic hydroxyl with respect to the departing benzylic
group.13 This observed influence of the o-hydroxyl group on
cleavage of the benzylic CꢀO (Table 1, entry 6) is in agreement
with the literature results.13,4k,14 In a control experiment, thermal
decomposition of 8 was not detected when the solution of 8 was
heated at 60 °C in the dark within the same time frame of irradiation.
a Measured in MeCN. b Measured in 5 mM CD3OD solution. c Values in
parentheses were measured in 5 mM CD3CN/D2O (9:1) solution
irradiated in an NMR tube. d Monochromatic light centered at 312 nm
by filtering through a 2 mM K2CrO4 in a 5% K2CO3 aqueous solution.
e Monochromatic light centered at 286 nm by filtering through 2 M
NiSO4 in 5% H2SO4, 0.8 M CoSO4 in 5% H2SO4 and 0.246 mM BiCl3 in
concd HCl/H2O (2:3)3. f Monochromatic light centered at 317 nm by
filtering through a solution of 2.5 M NiSO4 and 0.1 M CoSO4.
g Irradiated with Pyrex-filtered light for 7 min in CD3OD and yields
determined by 1H NMR analysis. h Yields in parentheses were obtained
from reactions in CD3CN/D2O (9:1) under the same irradiation
conditions and determined by 1H NMR analysis.
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Figure 2. Photocleavable ethers 13ꢀ15.
MeCN/water (9:1) solutions where the photoreaction of 11 did
not yield any detectable amount of 3-phenylpropanal.
Figure 1. UV spectra of ethers 3 and 9ꢀ11.
In addition to studying the effect of an additional electron-
donating substitution at the (dimethylamino)phenyl ring of
DMATr, we also screened photochemical efficiencies of the
ethers 13ꢀ15 (Figure 2). In 13, two 4-methoxyphenyl groups
replaced the two phenyl groups in 3. It is known that the
4-methoxyphenyl groups do not absorb Pyrex-filtered UV light.6
However, we anticipated that they would stabilize the triaryl-
methyl cation better than two phenyl groups upon heterolysis of
the benzylic CꢀO bond, which would facilitate the bond
cleavage. However, irradiation of 13 (5 mM in CD3CN/D2O
9:1) for 7 min with a Pyrex-filtered mercury lamp led to cleavage
of the benzylic CꢀO bond in 67% yield, slightly lower than the
yield of 3 (i.e., 76%, Table 1, entry 1) under the same reaction
conditions. The ether 14 has two 4-fluorophenyl groups, and its
photochemical efficiency of breaking the benzylic CꢀO bond
was 63%, only slightly lower than that of 13. Similarly, compar-
ison between 4 (48%) and 15 (50%) showed very similar
efficiency, and both are lower than that of 3, 13, and 14 under
the same irradiation conditions. These results revealed that
additional substitution as shown in 13ꢀ15 would not yield new
PPGs better than DMATr. Therefore, we focused on studying
DMATr and expanding its scope.
Synthesis. The ethers 4 and 13ꢀ15 were readily prepared
(Scheme 2). Thus, treatment of the substituted methyl benzoates
16ꢀ18 with the Grignard reagents 19 or 20 led to the triaryl
alcohols 22ꢀ24. Alternatively, the triarylmethanol can be prepared
from the corresponding substituted benzophenone and Grignard
reagent. For example, reaction of 4,40-difluorobenzophenone 21
and the Grignard reagent 19 led to the triarylmethanol 25. The
ethers 4, 13, and 15 were obtained by reacting 3-phenylpropanol
with the corresponding triaryl alcohols 22, 23, and 24, respectively,
in the presence of a catalytic amount of TFA. Alternatively, the
triarylmethanol 25 was converted to its acetate which was used in
the neutral protection protocol to afford the ether 14.
The ethers 6ꢀ12 were prepared from the reactions of salicyl
alcohols and 3-phenylpropanol. Thus, treating salicyl alcohols
26, 27, and 28 with acetyl chloride and triethylamine in
methylene chloride for 2ꢀ3 h followed by addition of 3-phenyl-
propanol led to the ethers 29, 8, and 11, respectively (Scheme 3).
Presumably, treatment of the salicyl alcohols with acetyl chloride
and triethylamine led to the intermediate 30 via acetylation of the
phenolic hydroxyl group followed by intramolecular acetyl
transfer. Direct acetylation of a triarylmethyl alcohol proved to
be difficult.15 Elimination of acetic acid from 30 would lead to the
o-quinone methide intermediate 31. Subsequent conjugate addi-
tion with the alcohol led to the ethers 29, 8, and 11, respectively.
Methylation of these intermediates provided the ethers 6, 7, and
9. The ethers 10 and 12 were obtained by reacting 11 under
In MeCN/water (9:1), there was no oxidized 3-phenylpropanol
observed in the photoreactions of 8.
We were attracted to the PPG in 1 (i.e., DMATr) owing to its
simple structure and associated advantageous properties in spite
of the high photochemical efficiency of the PPG in 8. We then
attempted structuralmodifications of DMATr for property improve-
ments. Thus, ethers 9ꢀ12 were synthesized (Table 1, entries 7ꢀ10).
Structural modification of DMATr by introducing an additional
electron-donating group to the (dimethylamino)phenyl ring of
DMATr resulted in new trityl derivatives which are all photo-
reactive and can serve as PPGs for hydroxyl protection. Among
them, the ethers 9ꢀ11 showed comparable photochemical yields
of deprotection in both methanol and MeCN/water as the ether
3 equipped with DMATr. They all absorb UV of longer wave-
lengths (λ = 322ꢀ325 nm) than 3 (λ = 309 nm). For example,
addition of a methoxyl group to DMATr at the position para to
the dimethylamino group led to the new PPG in the ether 9, with
the UV absorption shifting to 322 nm from 309 nm of DMATr
(Figure 1). The quantum yields of releasing the alcohol from 9
did not improve, i.e., 0.2 of 3 versus 0.19 of 9 in methanol
(Table 1, entries 1 and 7). The chemical yields obtained upon
irradiation with Pyrex-filtered mercury lamp were similar in
methanol (i.e., 84% of 3 versus 85% of 9) but slightly improved
in MeCN/water (9:1) (i.e., 76% of 3 versus 85% of 9). In the
photoreaction of 9 in MeCN/water (9:1), the ratio of the
generated aldehyde to the sum of the aldehyde and the alcohol
dropped to ca. 10% (versus ca. 20% in the case of 3).
There was no significant spectral shifting or change of ε values
with other groups replacing the o-methoxyl group (Table 1,
entries 8ꢀ10, and Figure 1). The photochemical efficiencies
remained similar, except that the AcO-substituted PPG (as in 12,
Table 1, entry 10) showed declining reactivity. Under the same
reaction conditions, the compound 12 released the alcohol in
51% yield, lower than the typical yields (84ꢀ89%) of other
ethers bearing the m-dimethylamino group. In parallel, photo-
reactivity of 12 also declined in MeCN/water (9:1), i.e., 50%
yield of benzylic CꢀO bond cleavage of 12 versus 76ꢀ90%
yields of others.
While the comparison of photochemical reactivity between 7
and 8 revealed an obvious case of ortho phenolic hydrogen-
facilitated benzylic CꢀO cleavage, the expected improved re-
activity of the ether 11 (having an o-hydroxyl group) compared
with that of 9 (having an o-methoxyl group) was not observed.
Instead, the ethers 11 and 9 have similar photochemical effi-
ciency. Under the same photoreaction conditions, the ether 9
released the alcohol in 85% yield, only slightly lower than the
88% yield obtained from 11. Similar results were also obtained in
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Scheme 2. Protection of Alcohol with New PPGs
Scheme 3. Protection of Alcohol with New PPGs
Scheme 4. Removal of DMATr with Sunlight
standard silylation and acetylation conditions with tert-butyldi-
methylsilyl chloride or acetyl chloride, respectively.
Deprotection with Sunlight. Among different PPGs, the
appealing overall quality of DMATr as a PPG for hydroxyl
protection warranted further investigation. We then examined
its deprotection with sunlight to expand the scope in that efficient
deprotection with sunlight is an economical green chemistry
method which would not only avoid the use of any photoche-
mical equipments but also be suitable for large-scale reactions
and various applications.
Alternatively, it could be readily prepared from the acetylated
mannoside 35 via the intermediate 36 by using a routine procedure.
The DMATr-protected mannoside 34 showed increased solubility
in highly polar solvent systems.
To demonstrate photochemical deprotection with sunlight,
we synthesized monosaccharides 32aꢀd and protected them
with DMATr by using the simple protection protocol recently
reported by us (Scheme 4).6 The corresponding ethers 33aꢀd
were obtained in 89%, 91%, 91%, and 83% yields, respectively.
These compounds were stable under indoor lighting and did not
require special precautions to prepare and handle. A solution
(MeOH/MeCN 14:1) of 33 in a Pyrex test tube was kept in a
water bath and placed outdoors under sunlight in clear weather.
Acetonitrile was used as the cosolvent because of the poor
solubility of 33 in methanol. The reaction temperature varied
between 20 and 30 °C during the reaction course. The photo-
reactions typically completed in 4.5 h. It appeared that the reaction
time could be affected by the shape of the reaction vessel, and a
larger exposure area of the reaction solution should accelerate the
reaction. The monosaccharides 32aꢀd were isolated in 84%, 84%,
82%, and 83% yields, respectively.
For comparison, the ether 34 was first irradiated under the
same conditions as 33aꢀd (i.e., 5 mM in MeOH/MeCN 14:1
irradiated with sunlight for ca. 4.5 h), and a similar product
distribution was observed. The released mannoside 37 was
obtained in 84% yield. Some other identified products included
38 (39%), 39 (5%), 40 (11%) and a trace amount of 41ꢀ43 and
benzophenone (Scheme 5). The structures of 41ꢀ43 were
1
elucidated on the basis of H NMR analysis and confirmed by
converting 41ꢀ43 to the corresponding dimethylamino coun-
terparts 38ꢀ40 via methylation with methyl iodide. Formation
of 40 could stem from either hydride abstraction of the trityl
cationic intermediate in its ground-state singlet or hydrogen
abstraction in its ground-state triplet.9,10 However, the pathways
leading to formation of 41ꢀ43 were unclear. Change of the
solvent system from MeOH/MeCN (14:1) to pure MeOH only
slightly affected the reaction outcome. The mannoside 37 was
produced in 87% yield, while 38ꢀ40 were obtained in 43%, 5%,
and 11%, respectively. However, the photoreaction of 34 in
MeOH/H2O (1:1) became cleaner and led to 37 in 97% yield
after irradiation with sunlight under the same reaction condi-
tions. The products 38 and 39 changed to 41% and 27% yields,
It appeared that the reactions preferred polar solvents.6,8 In
order to increase solubility of 33 in a solvent more polar than
MeOH/MeCN (14:1), we chose to prepare compound 34
(Scheme 5). It can be obtained by removing the four benzyl groups
in 33c with a standard hydrogenolysis procedure using Pd/C.
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Scheme 5. Solvent Effect on Removal of DMATr with
Sunlight
studies showed that one m-dimethylamino group is crucial for
high photochemical deprotection efficiency. The efficiency of
DMATr was compared with a variety of differently substituted
Tr, and it seemed to be more suitable for various applications not
only because of its photochemical reactivity but also its simple
structure, ease of preparation and installation, and its dark
stability. The sunlight deprotection proved to be highly efficient,
which could potentially expand its application, for example, in
large-scale deprotection reactions without the requirement of
special photochemical devices. We also observed the expected
acceleration of benzylic CꢀO bond cleavage by an o-hydroxyl
group in 8 when compared with the corresponding o-methoxyl-
substituted counterpart 7. Interestingly, the similar acceleration
anticipated for 11 relative to its counterpart 9 was not observed.
’ EXPERIMENTAL SECTION
General Procedure for Preparation of PPG Reagents
22ꢀ25. To the Grignard reagents 19 (prepared from 3-bromo-N,N0-
dimethylaniline) or 20 (prepared from 4-bromoanisole) was added
methyl benzoate 16, methyl 3-(dimethylamino)benzoate 18, 4,40-difluoro-
benzophenone 21, or methyl 4-methoxybenzoate 17. The reaction mixture
was stirred at room temperature under argon overnight. Workup followed
by flash chromatography afforded the corresponding PPG reagents 22ꢀ25.
General Procedure for Preparation of 4, 13, and 15. A PPG
reagent (i.e., 22, 23, or 25), 3-phenyl-1-propanol, and p-TsOH were
stirred in toluene at room temperature under argon overnight. Upon
completion, the reaction mixture was purified by flash column chromato-
graphy to afford the corresponding ether.
Scheme 6. Preparation of Water-Soluble Substrate
3,30-(Phenyl(3-phenylpropoxy)methylene)bis(N,N-dimethyl-
aniline) (4). Prepared from 22 (145 mg, 0.42 mmol), 3-phenyl-1-propanol
(85 μL, 0.63 mmol), and p-TsOH (40 mg, 0.21 mmol) in toluene (0.5 mL)
by using the general procedure. The reaction mixture was directly purified
with column chromatography (petroleum ether/ethyl acetate = 9/1) to
provide 4 (45.9 mg, 24%): Rf 0.3 (petroleum ether/ethyl acetate = 9/1); 1H
NMR (300 MHz, CDCl3) δ 7.50 (m, 2 H), 7.31ꢀ7.10 (m, 10 H), 6.97 (s, 2
H), 6.81 (d, J = 7.9 Hz, 2 H), 6.62 (dd, J = 2.4, 8.1 Hz,
2 H), 3.17 (t, J = 6.3 Hz, 2 H), 2.88 (s, 12 H), 1.92 (m, 2 H), 2.74 (m, 2
H); 13C NMR (75 MHz, CDCl3) δ 150.0, 145.2, 145.1, 142.4, 128.8, 128.4,
128.2, 128.1, 127.4, 126.6, 125.6, 118.1, 113.7, 111.2, 86.9, 62.9, 40.8, 32.8,
32.2; IR (neat) 2925, 1560, 1597, 1496, 1435, 1351, 1217, 978, 746, 704;
HRMS (ESI) m/e calcd for C32H37N2O 465.2906, found 465.2911.
3-(Bis(4-methoxyphenyl)(3-phenylpropoxy)methyl)-N,N-
dimethylaniline (13). Preparedfrom23 (15 mg, 0.05 mmol), 3-phenyl-
1-propanol (20 μL, 0.15 mmol), and p-TsOH (1.9 mg, 0.01 mmol) in
toluene (0.05 mL) by using the general procedure. The reaction mixture
was directly purified with column chromatography (petroleum ether/ethyl
acetate = 5/1) to provide 13 (14.4 mg, 72%): Rf 0.5 (petroleum ether/
respectively, while 40 decreased to 4% and benzophenone did
not appear. In both pure methanol and MeOH/water (1:1), there
were similar amounts of compounds 41ꢀ43 as observed in the
reaction conductedinMeOH/MeCN (14:1). These experimental
results confirmed that the removal of DMATr could accomplish
high yields and a cleaner reaction mixture would be obtained in
more polar solvents in the presence of water.
To examine photoreactions in water, the mannoside 34 was
converted to the more water-soluble derivative 44 by treatment
with succinicanhydride and triethylamine (Scheme 6). Irradiation
of 44 in water with sunlight was stopped after 4.5 h, and the R
groups were then removed under basic conditions. The product
ratio of 37:39:40:42:43 was about 52:27:12:7:7. The conversion
of 44 (ca. 60%) was relatively lower than that of 34 in methanol-
containing solvent systems. We attribute the low photoefficiency
to low light absorption of 44 in the opaque reaction mixture
caused by production of hydrophobic compounds (e.g., 39 and 40)
from the PPG part of 44. Therefore, to fully study photochemical
behavior of the new PPG in an aqueous environment, it is necessary
to modify the PPG and convert it into a hydrophilic segment.
Research along this direction is currently being undertaken in our
laboratory.
ethyl acetate =5/1); 1H NMR (300 MHz, CDCl3)
δ 7.36
(m, 4 H), 7.28ꢀ7.09 (m, 6 H), 6.95 (s, 1 H), 6.79 (m, 5 H), 6.61
(d, J = 7.6 Hz, 1 H), 3.79 (s, 6 H), 3.12 (t, J = 6.3 Hz, 2 H), 2.89 (s, 6 H),
2.73 (m, 2 H), 1.91 (m, 2 H); 13C NMR (75MHz, CDCl3) δ 158.2, 150.1,
145.9, 142.3, 137.0, 130.1, 129.2, 128.4, 128.2, 125.6, 117.4, 113.0, 112.8,
110.9, 85.9, 62.7, 55.2, 40.7, 32.7, 32.0; IR (neat) 3023, 2935, 2842, 2793,
1597, 1495, 1446, 1335, 1247, 975, 800, 746; HRMS (ESI) m/e calcd for
C32H36NO3 482.2695, found 482.2692.
3,30-((4-Methoxyphenyl)(3-phenylpropoxy)methylene)-
bis(N,N-dimethylaniline) (15). Prepared from 24 (38 mg, 0.10
mmol), 3-phenyl-1-propanol (40 μL, 0.30 mmol), and p-TsOH (1 mg,
0.005 mmol) in toluene (0.1 mL) by using the general procedure. The
reaction mixture was directly purified with column chromatography
(petroleum ether/ethyl acetate = 5/1) to provide 15 (23.7 mg, 48%):
In summary, we demonstrated that electron-donating group-
substituted trityl groups can be photochemically active and be
useful photolabile hydroxyl-protecting groups. Structureꢀreactivity
1
Rf 0.3 (petroleum ether/ethyl acetate = 5/1); H NMR (300 MHz,
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CDCl3) δ 7.31 (m, 2 H), 7.21ꢀ7.00 (m, 7 H), 6.91 (s, 2 H), 6.73
(m, 4 H), 6.53 (dd, J = 2.3, 7.9 Hz, 2 H), 3.71 (s, 3 H), 3.08 (t, J = 6.3 Hz,
2 H), 2.81 (s, 12 H), 2.67 (m, 2 H), 1.84 (m, 2 H); 13C NMR (75 MHz,
CDCl3) δ 158.2, 150.1, 145.7, 142.5, 136.9, 130.4, 128.4, 128.2, 128.1,
125.6, 117.8, 113.4, 112.7, 111.0, 86.5, 62.8, 55.2, 40.8, 32.8, 32.2; IR
(neat) 3431, 2930, 1602, 1495, 1458, 1438, 1352, 1250, 1185, 838, 732;
HRMS (ESI) m/e calcd for C33H39N2O2 495.3012, found 495.3016.
Preparation of 3-(Bis(4-fluorophenyl)(3-phenylpropoxy)-
methyl)-N,N-dimethylaniline (14). The PPG reagent 25 (34 mg,
0.10 mmol) wasdissolvedindistilledtoluene(0.1mL), followedbyaddition
of molybdenum(VI) dichloride dioxide (0.2 mg, 0.001 mmol), acetic
anhydride (14 μL, 0.15 mmol), and triethylamine (14 μL, 0.10 mmol).
The reaction mixture was heated at 120 °C under argon for 2 h. Then the
solvent was removed, and the residue was washed with petroleum ether.
The combined petroleum ether solutions were concentrated to afford
(3-(dimethylamino)phenyl)bis(4-fluorophenyl)methyl acetate (34 mg,
89%) as a light yellow oil. It was used without further purification.
(3-(Dimethylamino)phenyl)bis(4-fluorophenyl)methylacetate(19 mg,
0.05 mmol) and 3-phenyl-1-propanol (10 μL, 0.075 mmol) in distilled
toluene (0.05 mL) were heated at 120 °C under argon for 6 h. The
reaction mixture was directly purified with column chromatography
(petroleum ether/ethyl acetate = 25/1) to provide 14 (12 mg, 52%):
153.6, 150.6, 142.5, 142.1, 134.9, 128.7, 128.3, 128.13, 127.08, 126.5,
125.5, 114.2, 113.4, 112.4, 84.6, 62.5, 55.5, 55.4, 32.5, 31.8; IR (neat)
3030, 2941, 2249, 1465, 1418, 1275, 1224, 1181, 1021, 982, 881, 802,
731; HRMS (ESI) m/e calcd for C30H30O3Na 461.2093, found
461.2092.
2-(Hydroxydiphenylmethyl)-4,6-dimethoxyphenol (8). To
a stirred solution of 2-(hydroxydiphenylmethyl)-4,6-dimethoxy-
phenol (168 mg, 0.50 mmol) in dichloromethane (0.5 mL) was added
triethylamine (77 μL, 0.55 mmol). Then acetyl chloride (36 μL,
0.50 mmol) was slowly added dropwise. The reaction mixture was
stirred at room temperature under argon for 3 h. Then 3-phenyl-1-
propanol (267 μL, 2.00 mmol) was added, and the reaction mixture was
stirred at room temperature under argon overnight. The solvent was
removed, and the residue was purified with flash column chromatogra-
phy (petroleum ether/ethyl acetate = 5/1) to provide 8 (138 mg, 61%)
as a colorless oil: Rf 0.4 (petroleum ether/ethyl acetate = 5/1); 1H NMR
(300 MHz, CDCl3) δ 8.50 (s, 1 H), 7.49ꢀ7.00 (m, 15 H), 6.42 (d, J =
2.8 Hz, 1 H), 6.21 (d, J = 2.8 Hz, 1 H), 3.79 (s, 3 H), 3.57 (s, 3 H), 3.26 (t,
J = 6.3 Hz, 2 H), 2.67 (m, 2 H), 1.94 (m, 2 H); 13C NMR (75 MHz,
CDCl3) δ 151.7, 148.7, 141.2, 140.8, 139.5, 128.9, 128.5, 128.2, 128.1,
127.6, 127.5, 125.6, 105.5, 98.8, 89.6, 63.5, 55.8, 55.4, 32.1, 31.3; IR
(neat) 3517, 3331, 3059, 2940, 1602, 1485, 1468, 1208, 1166, 1153,
1054, 1035, 957, 835, 732, 699; HRMS (ESI) m/e calcd for
C30H30O4Na 477.2042, found 477.2042.
4-(Dimethylamino)-2-(diphenyl(3-phenylpropoxy)methyl)-
phenol (11). To a solution of 5-amino-2-hydroxybenzoic acid (3.094
g, 20 mmol) in methanol (40 mL) was added sulfuric acid (4.5 mL). The
reaction mixture was refluxed at 85 °C for 19 h. The solvent was then
removed, and the reaction mixture was neutralized with saturated
sodium bicarbonate until pH = 7 and washed with brine. The product
was extracted with dichloromethane, and the organic layers were
combined, dried over anhydrous Na2SO4 and concentrated to
provide methyl 5-amino-2-hydroxybenzoate (3.276 g, 98%) as a pale
yellow solid.
Toasolutionof methyl5-amino-2-hydroxybenzoate(1.672 g, 10 mmol)
in aceticacid(30mL) were added paraformaldehyde (3.161g, 100 mmol)
and sodium cyanoborohydride (1.885 g, 30 mmol) at room temperature.
The reaction mixture was stirred for 17 h. The solvent was then removed,
and the reaction mixture was neutralized with saturated sodium bicarbo-
nate until pH = 7 and washed with brine. The product was extracted with
ethyl acetate, and the organic layers were combined, dried over anhy-
drous Na2SO4, and concentrated to provide methyl 5-(dimethylamino)-
2-hydroxybenzoate (1.952 g, 99%) as a yellow oil.
To a solution of methyl 5-(dimethylamino)-2-hydroxybenzoate (1.952 g,
10 mmol) in freshly distilled tetrahydrofuran (10 mL) was slowly added
phenyllithium (20 mL, 40 mmol, 2.0 M solution in dibutylether) at
ꢀ78 °C under argon protection. The reaction temperature was raised to
room temperature over 8 h. The reaction was then quenched with
saturated ammonium chloride until pH = 7. The aqueous layer was
extracted with dichloromethane, and the organic layers were combined,
washed with brine, and concentrated. The residue was purified by recrys-
tallization to provide 4-(dimethylamino)-2-(hydroxydiphenylmethyl)phenol
(2.565 g, 80%) as a pale white solid.
1
Rf 0.3 (petroleum ether/ethyl acetate = 25/1); H NMR (300 MHz,
CDCl3) δ 7.40 (m, 4 H), 7.30ꢀ7.09 (m, 6 H), 6.96 (m, 4 H), 6.84
(s, 1 H), 6.70 (d, J = 7.6 Hz, 1 H), 6.62 (dd, J = 2.4, 8.1 Hz, 1 H), 3.11
(t, J = 6.3 Hz, 2 H), 2.89 (s, 6 H), 2.72 (m, 2 H), 1.92 (m, 2 H); 13C NMR
(75 MHz, CDCl3) δ 163.3, 160.0, 150.2, 144.5, 142.0, 140.4, 140.4,
130.4, 130.3, 128.4, 128.4, 128.3, 125.7, 117.3, 114.6, 114.3, 112.9, 111.3,
85.9, 62.8, 40.6, 32.6, 31.8, 29.7; IR (neat) 2925, 2862, 2259, 2244, 2195,
1597, 1510, 1228, 839; HRMS (ESI) m/e calcd for C30H30NOF2
458.2295, found 458.2298.
((3-Phenylpropoxy)(2,3,5-trimethoxyphenyl)methylene)-
dibenzene (7). To a stirred solution of 2-(hydroxydiphenylmethyl)-
4,6-dimethoxyphenol1 (135 mg, 0.40 mmol) in dichloromethane
(0.4 mL) was added triethylamine (62 μL, 0.44 mmol). Then acetyl
chloride (29 μL, 0.40 mmol) was slowly added dropwisely. The reaction
mixture was stirred at room temperature under argon for 3 h. 3-Phenyl-
1-propanol (214 μL, 1.60 mmol) was then added, and the reaction
mixture was stirred at room temperature under argon overnight. The
solvent was removed, and the reaction mixture was dissolved in THF
(0.4 mL). Sodium hydride (19.2 mg, 0.48 mmol) was added at 0 °C, and
the resulting mixture was stirred at room temperature for 3.5 h before
iodomethane (252 μL, 4.00 mmol) was added. The reaction mixture was
stirred for another 5 h. The solvent was removed, and the residue was
purified with flash column chromatography (petroleum ether/ethyl
acetate = 20/1) to provide 7 (153 mg, 82%) as a white solid: Rf 0.3
(petroleum ether/ethyl acetate = 20/1); 1H NMR (300 MHz, CDCl3)
δ 7.46 (m, 4 H), 7.24ꢀ6.97 (m, 12 H), 6.34 (d, J = 3.0 Hz, 1 H), 3.70
(s, 3 H), 3.62 (s, 3 H), 2.96 (s, 3 H), 2.92 (t, J = 6.4 Hz, 2 H), 2.59
(m, 2 H), 1.81 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ 154.9, 153.6,
142.6, 142.1, 140.2, 139.6, 128.7, 128.3, 128.2, 127.4, 126.6, 125.6, 103.4,
99.2, 84.7, 62.5, 59.1, 55.5, 55.4, 32.5, 31.8; IR (neat) 3023, 2940, 2878,
2250, 1594, 1469, 1423, 1325, 1275, 1238, 993, 981, 734; HRMS (ESI)
m/e calcd for C31H32O4Na 491.2198, found 491.2196.
((2,5-Dimethoxyphenyl)(3-phenylpropoxy)methylene)-
dibenzene (6). Synthesis of 6, starting with 2-(diphenyl(3-pheny-
lpropoxy)methyl)-4-methoxyphenol (123 mg, 0.40 mmol), was similar
to that of 7. The crude product was purified with flash column
chromatography (petroleum ether/ethyl acetate = 20/1) to provide
6 (120 mg, 68%) as a white solid: Rf 0.3 (petroleum ether/ethyl
acetate = 20/1); 1H NMR (300 MHz, CDCl3) δ 7.45 (d, J = 3.0 Hz, 1
H), 7.38 (m, 4 H), 7.19ꢀ6.96 (m, 11 H), 6.64 (dd, J = 3.0, 8.8 Hz, 1
H), 6.57 (d, J = 8.8 Hz, 1 H), 3.65 (s, 3 H), 3.19 (s, 3 H), 2.94 (t, J = 6.3
Hz, 2 H), 2.58 (m, 2 H), 1.80 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ
To a stirred solution of 4-(dimethylamino)-2-(hydroxydiphenylmethyl)-
phenol (160 mg, 0.50 mmol) in dichloromethane (0.5 mL) was
added triethylamine (77 μL, 0.55 mmol). Then acetyl chloride
(36 μL, 0.50 mmol) was slowly added dropwisely. The reaction mixture
was stirred at room temperature under argon for 3 h. Then 3-phenyl-
1-propanol (267 μL, 2.00 mmol) was added, and the reaction mixture
was stirred at room temperature under argon overnight. The solvent was
removed, andtheresidue waspurifiedwithflashcolumnchromatography
(petroleum ether/ethyl acetate = 4/1) to provide 11 (151 mg, 69%) as a
colorless or light pink oil: Rf 0.5 (petroleum ether/ethyl acetate = 4/1);
1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1 H), 7.36ꢀ6.98 (m, 15 H), 6.71
5878
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FEATURED ARTICLE
(d, J = 8.8 Hz, 1 H), 6.62 (dd, J = 2.9, 8.8 Hz, 1 H), 6.33 (d, J = 2.9 Hz,
1 H), 3.24 (t, J = 6.4 Hz, 2 H), 2.62ꢀ2.57 (m, 8H), 1.84ꢀ1.94 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 148.7, 143.9, 141.3, 141.2, 129.0, 128.3,
128.2, 128.1, 127.8, 127.6, 125.8, 117.7, 116.7, 115.2, 90.2, 63.8, 41.9,
32.2, 31.5; IR (neat) 3348, 3032, 2936, 2875, 2798, 1673, 1497, 1449,
1236, 1210, 1121, 1022, 982, 883, 748, 701, 612; HRMS (ESI) m/e calcd
for C30H32NO2 438.2433, found 438.2433.
1.2 mmol). Following the addition, the solution was stirred at room
temperature for 1.5 h. Ethanol (0.4 mL) was then added followed by
0.18 mL of 3 N sodium hydroxide. After the mixture was cooled to
0ꢀ5 °C, hydrogen peroxide (35%, 0.2 mL) was added dropwise and the
reaction mixture was stirred overnight. After being heated at 80 °C for 1 h,
the cooled solution was extracted with ether (10 mL ꢁ 4). The combined
extracts were washed with water and brine, dried over Na2SO4, and
concentrated. Flash column chromatography on silica gel, eluted with
petroleum ether/ethyl acetate = 3/1, afforded 32a (0.557 g, 88%) as a
3-(Diphenyl(3-phenylpropoxy)methyl)-4-methoxy-N,N-
dimethylaniline (9). Toa stirredsolution of11 (138 mg, 0.315 mmol)
in THF (0.5 mL) was added sodium hydride (19 mg, 0.473 mmol). The
reaction mixture was stirred at room temperature for 1 h. Then
iodomethane (159 μL, 2.523 mmol) was added, and the reaction mixture
wasstirredfor5 h. The solvent wasremoved, andthe reaction mixture was
dissolved in DMF (1.0 mL). Sodium thiosulfate (157 mg, 0.631 mmol)
was added, and the reaction mixture was stirred at 100 °C under argon.
The crude product was washed with water and extracted with dichlor-
omethane. The organic layer was combined, dried over anhydrous sodium
sulfate, and concentrated. The residue was purified with flash column
chromatography (petroleum ether/ethyl acetate = 7/1) to provide 9 (98
mg, 73%) as a pale yellow solid: Rf 0.4 (petroleum ether/ethyl acetate = 7/
1); 1H NMR (300 MHz, CDCl3) δ 7.47 (m, 5 H), 7.32ꢀ7.08 (m, 11 H),
6.74 (d, J = 8.7 Hz, 1 H), 6.68 (dd, J = 2.9, 8.7 Hz, 1 H), 3.32 (s, 3 H),
3.05 (t, J = 6.3 Hz, 2 H), 2.90 (s, 6 H), 2.70 (m, 2 H), 1.91 (m, 2 H); 13C
NMR (75 MHz, CDCl3) δ 142.5, 136.9, 130.4, 128.4, 128.2, 128.1,
125.6, 117.8, 113.4, 112.7, 111.0, 86.5, 62.8, 55.2, 40.8, 32.8, 32.2;
IR(neat) 2941, 2845, 1605, 1502, 1452, 1249, 1181, 977, 802, 748, 732,
699; HRMS (ESI) m/e calcd for C31H34NO2 452.2590, found
452.2586.
4-((tert-Butyldimethylsilyl)oxy)-3-(diphenyl(3-phenylpro-
poxy)methyl)-N,N-dimethylaniline (10). To a stirred solution of
11 (44 mg, 0.10 mmol) in dichloromethane (0.1 mL) were added tert-
butylchlorodimethylsilane (30 mg, 0.20 mmol) and imidazole (20 mg,
0.30 mmol). The reaction mixture was stirred at room temperature
overnight. The solvent was removed, and the residue was purified with
flash column chromatography (petroleum ether/ethyl acetate = 12/1) to
provide 10 (51 mg, 93%) as a colorless oil: Rf 0.3 (petroleum ether/ethyl
acetate = 12/1); 1H NMR (300 MHz, CDCl3) δ 7.46ꢀ7.50 (m, 4 H),
7.33 (d, J = 2.5 Hz, 1 H), 7.12ꢀ7.27 (m, 11 H), 6.66 (dd, J = 0.5, 8.6 Hz,
1 H), 6.62 (dd, J = 2.7, 8.8 Hz, 1 H), 3.07 (t, J = 6.5 Hz, 2 H), 2.86
(s, 6 H), 2.68ꢀ2.73 (m, 2 H), 1.88ꢀ1.98 (m, 2 H), 0.72 (s, 9 H), ꢀ0.13
(s, 6 H); 13C NMR (75 MHz, CDCl3) δ 145.2, 144.8, 143.4, 142.3,
133.5, 128.5, 128.3, 128.2, 127.3, 126.3, 125.6, 119.1, 115.7, 113.3, 85.2,
62.8, 41.7, 32.7, 32.0, 26.1, 18.6, ꢀ4.5; IR (neat) 3030, 2937, 2864, 2797,
1605, 1496, 1473, 1450, 1254, 979, 836, 739; HRMS (ESI) m/e calcd for
C36H46NO2Si 552.3298, found 552.3303.
1
colorless oil: Rf 0.3 (petroleum ether/ethyl acetate = 3/1); H NMR
(300 MHz, CDCl3) δ 7.41ꢀ7.20 (m, 14 H), 4.93 (d, J = 10.8 Hz, 1 H),
4.69 (m, 6 H), 3.71 (m, 8 H), 3.43 (td, J = 6.0, 9.8 Hz, 1 H), 2.19 (s, 1 H),
1.74 (p, J = 6.0 Hz, 2 H), 1.33 (d, J = 5.8 Hz, 3 H); 13C NMR (75 MHz,
CDCl3) δ 138.4, 138.3, 138.2, 128.2, 127.9, 127.7, 127.5, 127.4, 97.9,
80.3, 79.9, 75.2, 74.9, 72.7, 72.1, 67.9, 64.9, 60.2, 31.9, 17.9; IR (neat)
3426, 3036, 2920, 1724, 1456, 1383, 1281, 1145, 980, 843, 732; HRMS
(ESI) m/e calcd for C30H36O6Na 515.2410, found 515.2414.
3-(((2S,3R,4S,5R)-3,4,5-Tris(benzyloxy)tetrahydro-2H-py-
ran-2-yl)oxy)propan-1-ol (32b). BH3 Me2S (350 mg, 4.34 mmol)
3
was added dropwise at 0 °C under argon to a solution of 2-allyloxy-3,4,5-
tris(benzyloxy)tetrahydropyran (1.0 g, 2.17 mmol) in THF (8 mL), and
the resultant solution was stirred at room temperature for 13 h. Then
hydrogen peroxide (35%, 2.0 mL) and sodium hydroxide (3 N, 20 mL)
were added subsequently at room temperature, and the reaction mixture
was stirred for a further 6 h. Workup as usual followed by flash column
chromatography afforded 32b (0.845 g, 81%) as a colorless oil: Rf 0.3
1
(petroleum ether/ethyl acetate = 3/1); H NMR (300 MHz, CDCl3)
δ 7.42ꢀ7.22 (m, 13 H), 4.87 (m, 2 H), 4.75 (dd, J = 11.9, 13.4 Hz, 2 H),
4.61 (m, 3 H), 3.81 (m, 5 H), 3.50 (m, 6 H), 1.83 (m, 2 H); 13C NMR
(75 MHz, CDCl3) δ 138.7, 138.1, 138.0, 128.32, 128.31, 128.2, 127.9,
127.8, 127.7, 127.6, 127.4, 97.2, 81.3, 79.3, 77.8, 75.6, 73.4, 73.3, 67.1,
61.3, 59.9, 31.5; IR (neat) 3464, 3034, 2929, 2884, 1723, 1455, 1366,
1274, 1207, 1156, 975, 726; HRMS (ESI) m/e calcd for C29H34O6Na
501.2253, found 501.2252.
3-(((2S,3S,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-((benzyloxy)-
methyl)tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol (32c).
BH3 Me2S (0.35 mL, 1.7 mmol) was added dropwise at 0 °C under
3
argon to a solution of2-allyloxy-3,4,5-tris(benzyloxy)-6-benzyloxymethyl-
tetrahydropyran (1.0 g, 1.7 mmol) in THF (8 mL), and the resultant
solution was stirred at room temperature for 15 h. Then hydrogen
peroxide (35%, 2.0 mL) and sodium hydroxide (3 N, 20 mL) were added
subsequently at room temperature, and the reaction mixture was stirred
for further 6 h. Workup as usual followed by flash column chromato-
graphy afforded 32c (0.829 g, 80%) as a colorless oil: Rf 0.3 (petroleum
ether/ethyl acetate = 3/1); 1H NMR (300 MHz, CDCl3) δ 7.42ꢀ7.10
(m, 20 H), 4.93ꢀ4.49 (m, 9 H), 4.00ꢀ3.58 (m, 9 H), 3.48 (td, J = 5.7,
9.8 Hz, 1 H), 2.13 (s, 1H), 1.75 (m, 2 H); 13C NMR (75 MHz, CDCl3)
δ 138.3, 138.27, 138.26, 138.1, 128.28, 128.23, 127.9, 127.7, 127.58,
127.55, 127.5, 127.4, 97.9, 80.1, 75.0, 74.9, 74.8, 73.3, 72.6, 72.1, 71.9,
69.2, 64.9, 60.0, 32.0; IR (neat) 3466, 3037, 2915, 1722, 1455, 1362,
1270, 1020, 1010, 972, 847, 725; HRMS (ESI) m/e calcd for
C37H42O7Na 621.2828, found 621.2829.
4-(Dimethylamino)-2-(diphenyl(3-phenylpropoxy)methyl)-
phenyl Acetate (12). To a stirred solution of 11 (44 mg, 0.10 mmol)
in dichloromethane (0.1 mL) were added acetyl chloride (8 μL, 0.11 mmol)
and pyridine (9 μL, 0.11 mmol). The reaction mixture was stirred at
40 °C for 6 h. The solvent was removed and the residue was purified with
flash column chromatography (petroleum ether/ethyl acetate = 5/1) to
provide 12 (39 mg, 81%) as a white solid: Rf 0.4 (petroleum ether/ethyl
acetate = 5/1); 1H NMR (300 MHz, CDCl3) δ 7.43 (m, 4 H), 7.26ꢀ
7.04 (m, 12 H), 6.85 (d, J = 8.8 Hz, 1 H), 6.60 (dd, J = 3.1, 8.8 Hz, 1 H),
3.04 (t, J = 6.3 Hz, 2 H), 2.84 (s, 6 H), 2.66 (m, 2 H), 1.86 (m, 2 H), 1.47
(s, 3 H); 13C NMR (75 MHz, CDCl3) δ 169.2, 148.1, 143.6, 142.3,
138.8, 135.6, 128.4, 128.3, 127.8, 127.7, 126.7, 125.7, 124.6, 113.8, 112.2,
100.0, 84.9, 63.0, 41.0, 32.6, 20.5; IR (neat) 3353, 3039, 2785, 2771,
2105, 2083, 1758, 1606, 1499, 1454, 1366, 1209, 747; HRMS (ESI) m/e
calcd for C32H34NO3 480.2539, found 480.2535.
Preparation of 33aꢀc: Representative Procedure for Pre-
paring 33a. In a reaction vessel, 32a (98 mg, 0.2 mmol) and
(3-(dimethylamino)phenyl)diphenylmethyl acetate (DMATr PPG)
(104 mg, 0.3 mmol) in toluene (50 μL) were heated at 120 °C under
argon protection for 3 h. The reaction mixture was directly purified with
column chromatography (petroleumether/ethyl acetate = 5/1) to provide
33a (139 mg, 89%): Rf 0.4 (petroleum ether/ethyl acetate = 5/1);
1H NMR (300 MHz, CDCl3) δ 7.48ꢀ7.07 (m, 26 H), 6.86 (s, 1 H),
6.75 (d, J = 7.8 Hz, 1 H), 6.59 (dd, J = 2.1, 8.1 Hz, 1 H), 4.93 (d, J =
10.8 Hz, 1 H), 4.71 (m, 3 H), 4.62 (d, J = 10.9 Hz, 1 H), 4.55 (s, 2 H),
3.64 (m, 6 H), 3.12 (m, 2 H), 2.85 (s, 6 H), 1.82 (m, J = 6.4 Hz, 2 H),
1.29 (d, J = 5.9 Hz, 3 H);); 13C NMR (75 MHz, CDCl3) δ 150.1, 144.8,
3-(((2R,3R,4R,5S,6S)-3,4,5-Tris(benzyloxy)-6-methyltetra-
hydro-2H-pyran-2-yl)oxy)propan-1-ol (32a). BH3 Me2S (2 M,
3
0.3 mL) was added dropwise at 0 °C to a stirred solution of 3,4,5-
tris(benzyloxy)-2-methyl-6-pent-4-enyloxytetrahydropyran (0.608 g,
5879
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FEATURED ARTICLE
144.6, 144.5, 138.7, 138.66, 138.4, 128.8, 128.7, 128.28, 128.26, 127.9,
127.8, 127.5, 127.4, 126.7, 117.6, 113.3, 111.1, 97.8, 86.6, 80.5, 80.3, 75.3,
75.0, 72.7, 72.1, 67.9, 64.5, 60.3, 40.7, 30.1, 18.0; IR (neat) 3034, 2925,
2808, 1600, 1491, 1452, 1354, 1267, 1211, 1142, 1020, 974, 745, 699;
HRMS (ESI) m/e calcd for C51H56NO6 778.4108, found 778.4115.
33b. Prepared from 32b (96 mg, 0.2 mmol) and (3-(dimethylamino)-
phenyl)diphenylmethyl acetate (DMATr PPG) (104 mg, 0.3 mmol) in
toluene (50 μL) by using the procedure of 33a. The reaction mixture was
directly purified with column chromatography (petroleum ether/ethyl
acetate =5/1) to provide 33b (140 mg, 91%): Rf 0.4 (petroleum ether/
ethyl acetate = 5/1). 1H NMR (300 MHz, CDCl3) δ 7.46 (d, J = 8.3 Hz,
4 H), 7.40ꢀ7.10 (m, 22 H), 6.89 (s, 1 H), 6.76 (d, J = 8.4 Hz,
1 H), 6.59 (dd, J = 2.1, 8.2 Hz, 1 H), 4.86 (q, J = 10.8 Hz, 2 H), 4.68
(m, 3 H), 4.57 (d, J = 12.3 Hz, 2 H), 3.83 (m, 2 H), 3.54 (m, 4 H), 3.40
(dd, J = 3.6, 9.6 Hz, 1 H), 3.20 (t, J = 6.1 Hz, 2 H), 2.86 (s, 6 H), 1.96
(m, 2 H); 13C NMR (75 MHz, CDCl3) δ 150.1, 144.9, 144.6, 144.5,
139.0, 138.37, 138.35, 128.8, 128.7, 128.33, 128.32, 128.28, 128.25,
128.0, 127.9, 127.73, 127.68, 127.66, 127.54, 127.47, 126.70, 126.69,
117.6, 113.2, 111.1, 97.0, 86.7, 81.3, 79.7, 78.2, 75.7, 73.4, 73.1, 65.3,
60.6, 59.9, 40.6, 30.2; IR (neat) 3032, 2925, 2881, 1602, 1495, 1456,
1364, 746, 698; HRMS (ESI) m/e calcd for C50H54NO6 764.3951,
found 764.3944.
33c. Prepared from 32c (120 mg, 0.2 mmol) and (3-(dimethylamino)-
phenyl)diphenylmethyl acetate (DMATr PPG) (104 mg, 0.3 mmol) in
toluene (50 μL) by using the procedure of 33a. The reaction mixture was
directly purified with column chromatography (petroleum ether/ethyl
acetate =9/1) to provide 33c (162 mg, 91%): Rf 0.1(petroleum ether/
ethyl acetate = 9/1); 1H NMR (300 MHz, CDCl3) δ 7.44 (d, J = 7.2 Hz,
4 H), 7.39ꢀ7.00 (m, 27 H), 6.85 (s, 1 H), 6.76 (d, J = 8.1 Hz, 1 H), 6.56
(dd, J = 2.3, 8.1 Hz, 1 H), 4.87 (dd, J = 4.6, 6.2 Hz, 2 H), 4.67 (m, 3 H),
4.50 (m, 4 H), 4.01 (t, J = 9.5 Hz, 1 H), 3.77 (m, 6 H), 3.53 (m, 1 H), 3.13
(m, 2 H), 2.82 (s, 6 H), 1.84 (m, 2 H); 13C NMR (75 MHz, CDCl3)
δ 150.0, 144.7, 144.5, 144.4, 138.5, 138.4, 138.3, 128.7, 128.6, 128.20,
128.18, 128.14, 128.12, 127.8, 127.7, 127.6, 127.5, 127.4, 127.3, 126.6,
117.5, 113.2, 111.0, 97.7, 86.6, 80.3, 74.9, 74.8, 73.3, 72.4, 72.0, 71.7,
69.1, 64.5, 60.2, 40.5, 30.0; IR (neat) 3036, 2925, 2874, 2806, 1600,
1495, 1453, 1359, 1267, 1211, 1141, 1013, 973, 729; HRMS (ESI) m/e
calcd for C58H62NO7 884.4526, found 884.4542.
(m, 1 H), 6.76 (d, J = 7.8 Hz, 1 H), 6.62 (dd, J = 2.6, 8.2 Hz, 1 H), 3.08 (s,
3 H), 2.88 (s, 6 H); 13C NMR (75 MHz, CDCl3) δ 150.1, 144.4, 144.2,
128.7, 128.2, 127.5, 126.7, 117.7, 113.4, 111.1, 87.3, 52.1, 40.6; IR (neat)
3052, 2940, 2823, 1695, 1597, 1490, 1446, 1349, 1223, 1179, 858, 741;
HRMS (ESI) m/e calcd for C22H24NO 318.1858, found 318.1854.
(3-(Dimethylamino)phenyl)diphenylmethanol (39): 1H NMR
(300 MHz, CDCl3) δ 7.35ꢀ7.20 (m, 10 H), 7.14 (t, J = 8.0 Hz, 1 H),
6.71 (m, 1 H), 6.64 (dd, J = 2.6, 8.2 Hz, 1 H), 6.51 (d, J = 7.7 Hz, 1 H),
2.84 (s, 6 H); 13C NMR (75 MHz, CDCl3) δ 150.2, 147.7, 147.0, 128.4,
127.9, 127.7, 127.0, 116.7, 112.4, 111.4, 82.2, 40.5; IR (neat) 3455, 3066,
2886, 2804, 1719, 1602, 1490, 1446, 1349, 1150, 853, 746; HRMS (ESI)
m/e calcd for C21H22NO 304.1701, found 304.1696.
3-Benzhydryl-N,N-dimethylaniline (40): 1H NMR (300 MHz,
CDCl3) δ 7.32ꢀ7.10 (m, 11 H), 6.60 (dd, J = 2.5, 7.8 Hz, 1 H), 6.52
(m, 1 H), 6.46 (d, J = 8.0 Hz, 1 H), 5.50 (s, 1 H), 2.87 (s, 6 H); 13C NMR
(75 MHz, CDCl3) δ 150.5, 144.6, 144.1, 129.4, 128.8, 128.1, 126.1,
118.0, 114.0, 110.5, 57.2, 40.5; IR (neat) 2803, 1656, 1490, 1442, 1349,
1135, 828; HRMS (ESI) m/e calcd for C21H22N 288.1752, found
288.1753.
General Procedure of Deprotection of 33aꢀd and 34 with
Sunlight. The Pyrex test tubes (16 ꢁ 150 mm) containing the solution
of 33aꢀd or 34 (5 mM in MeOH/MeCN = 14/1, MeOH or MeOH/
H2O = 1/1) were kept in a water bath (20ꢀ30 °C) and placed outdoors
under sunlight in clear weather. After 4.5 h, the reaction mixture was
concentrated, and the residue was purified with column chromatography
to provide 32aꢀd or 37.
Deprotection of 33a. Compound 33a (58.3 mg, 0.075 mmol) was
irradiated by using the general deprotection procedure to produce 32a
(29.8 mg, 84%) after column chromatography (petroleum ether/ethyl
acetate = 1/1).
Deprotection of 33b. Compound 33b (80 mg, 0.105 mmol) was
irradiated by using the general deprotection procedure. The residue was
purified with column chromatography (petroleum ether/ethyl acetate = 1/1)
to provide 32b (42.1 mg, 84%).
Deprotection of 33c. The compound 33c (133 mg, 0.15 mmol)
was irradiated by using the general deprotection procedure. The residue
was purified with column chromatography (petroleum ether/ethyl
acetate = 1/1) to provide 32c (74.0 mg, 82%).
(2R,3R,4S,5S,6S)-2-(Acetoxymethyl)-6-(3-hydroxypropoxy)-
tetrahydro-2H-pyran-3,4,5-triyl Triacetate (36). BF3 OEt2
Deprotection of 33d. The compound 33d (80 mg, 0.15 mmol)
was irradiated by using the general deprotection procedure. The residue
was purified with column chromatography (petroleum ether/ethyl
acetate = 3/1) to provide 32d (30.6 mg, 83%).
3
(0.8 mL, 6.3 mmol) was added to the solution of 35 (0.8 g, 2.1 mmol)
and 1,3-propanediol (0.346 g, 4.6 mmol) in DCM/CH3CN (13 mL, 1:1,
V/V) at 0 °C. The mixture was stirred at room temperature for 57 h. Workup
as usual followed by flash chromatography (DCM/ethyl acetate =1/1,
Rf 0.3) to afford the title compound 36 (0.157 g, 18%).
Deprotection of 34
1 Compound 34 (80 mg, 0.153 mmol) was irradiated by using the
general deprotection procedure. The residue was purified with column
chromatography to provide 38 (18.9mg, 39%), 39 (2.1mg,5%),and40
(4.8 mg, 11%) (eluted with petroleum ether/ethyl acetate = 9/1) and 37
(30.9 mg, 84%) (eluted with dichloromethane/methanol = 5/1).
2 A 26.7 mL solutionof34 (70 mg, 0.134 mmol) in MeOH in two Pyrex
test tubes was irradiated by using the general deprotection procedure.
The residue was purified with column chromatography to provide 38
(18.2 mg, 43%), 39 (2.0 mg, 5%) and 40 (4.3 mg, 11%) (eluted with
petroleum ether/ethyl acetate = 9/1) and 37 (27.8 mg, 87%) (eluted
with dichloromethane/methanol =5/1).
3 A 30 mL solution of 34 (80 mg, 0.153 mmol) in MeOH/H2O = 1/1
in two Pyrex test tubes was irradiated by using the general deprotec-
tion procedure. The residue was purified with column chromato-
graphy to provide 38 (19.8 mg, 41%), 39 (12.4 mg, 27%) and 40
(1.8 mg, 4%) (eluted with petroleum ether/ethyl acetate = 9/1) and
37 (35.4 mg, 97%) (eluted with dichloromethane/methanol =5/1).
34. The mixture of 36 (0.134 g, 0.32 mmol) and DMATr PPG (0.157 g,
0.51 mmol) was heated at 120 °C for 3 h. The reaction mixture was purified
by flash column chromatography (petroleum ether/ethyl acetate =5/2,
Rf 0.3) to afford the desired PPG protected product (0.223 g, 99%). The
above obtained product (0.200 g, 0.28 mmol, 1 equiv) was stirred with
K2CO3 (0.120 g, 0.87 mmol) in methanol for 135 min. The solvent was
removed, and the residue was extracted with ethyl acetate. The
combined extracts were dried (Na2SO4) and concentrated. The residue
was purified by flash chromatography to afford the title compound 34
(0.142 g, 96%): Rf 0.4 (DCM/ethyl acetate = 6/1); 1H NMR (300 MHz,
CDCl3) δ 7.42 (d, J = 7.7 Hz, 4 H), 7.29ꢀ7.07 (m, 7 H), 6.83 (s, 1 H),
6.74 (d, J = 7.6 Hz, 1 H), 6.60 (dd, J = 2.1, 8.2 Hz, 1 H), 4.75 (s, 1 H),
3.65 (m, 9 H), 3.11 (m, 2 H), 2.82 (s, 6 H), 1.81 (m, 1 H); 13C NMR
(75 MHz, CDCl3) δ 150.1, 144.7, 144.5, 144.4, 128.6, 128.3, 127.6,
126.8, 118.0, 113.7, 111.5, 86.7, 72.0, 71.4, 70.9, 66.1, 65.0, 60.8, 60.7,
60.1, 40.8, 30.0; IR (neat) 3392, 2925, 1603, 1392, 1139, 675; HRMS
(ESI) m/e calcd for C30H38NO7 524.2648, found 524.2649.
Photoreaction of Water-Soluble Compound 44. To the
stirred solution of 34 (181.4 mg, 0.346 mmol) in 4.7 mL of dichloromethane
was added succinic anhydride (175 mg, 1.732 mmol), followed by Et3N
(242 μL, 1.732 mmol). After 19 h, the reaction was complete. Formation of
3-(Methoxydiphenylmethyl)-N,N-dimethylaniline (38): 1H
NMR (300 MHz, CDCl3) δ 7.46 (m, 4 H), 7.34ꢀ7.10 (m, 7 H), 6.88
5880
dx.doi.org/10.1021/jo200692c |J. Org. Chem. 2011, 76, 5873–5881

The Journal of Organic Chemistry
FEATURED ARTICLE
the derivative 44 was confirmed by the characteristic peaks in the 1H NMR:
δ 6.84 (s, 1H), 6.74 (d, J = 7.7 Hz, 1H), 6.61 (dd, J = 2.4, 8.2 Hz, 1H), 5.40
(dd, J = 10.1, 10.1 Hz, 1H), 5.25 (dd, J = 3.4, 10.1 Hz, 1H), 5.16 (m, 1H),
4.18 (dd, J = 3.0, 12.6 Hz, 1H), 4.75 (s, 1H), 4.02 (d, J = 5.5 Hz, 1H). The
mixture was concentrated, and half of it was dissolved in water (34.6 mL)
with Na2CO3 (1.3 mg, 0.1 equiv) in a test tube. The obtained clear
solution was stirred under sunlight for 4.5 h and then was treated with
NaOH (279 mg, 7 mmol). Water was removed, and the residue was
subjected to flash column chromatography, eluted with PE/EA = 5:1 and
DCM/MeOH = 5:1, to provide 34 (33.8 mg, 37%), 37 (21.8 mg, 52%), 39
(14.6 mg, 27%), 40 (6.2 mg, 12%), 42 (3.7 mg, 7%), and 43 (3.4 mg, 7%).
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’ ASSOCIATED CONTENT
1
S
Supporting Information. General procedure; H NMR
b
and 13C NMR spectra of 4, 6ꢀ15, 32aꢀ32c, 33aꢀ33c, 36, and
38ꢀ40. This material is available free of charge via the Internet at
http://pubs.acs.org.
(6) Wang, P.; Zhou, L.; Zhang, X.; Liang, X. Chem. Commun. 2010,
46, 1514.
(7) (a) Zimmerman, H.; Sandel, V. J. Am. Chem. Soc. 1963, 85, 915.
(b) Zimmerman, H.; Somasekhara, S. J. Am. Chem. Soc. 1963, 85, 922.
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’ AUTHOR INFORMATION
(8) Solvent effects were examined.6 Among different solvents or
solvent combinations, methanol leads to cleaner reactions and better
yields of the released alcohols.
Corresponding Author
*E-mail: wangp@uab.edu.
(9) A trityl cation has long been known as a good hydride acceptor:
(a) Norris, J.; Young, R. J. Am. Chem. Soc. 1930, 52, 753. (b) Smith, H.;
Smith, R. J. Am. Chem. Soc. 1948, 70, 2400. (c) Bartlett, P.; McCollum, J.
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Chem. Soc. 1976, 98, 7882.
’ ACKNOWLEDGMENT
We thank the NSF for its support (CHE-0848489).
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