A self-immolative spacer that enables tunable controlled release of phenols under neutral conditions

Article abstract of DOI:10.1021/jo300400q

A current challenge in the area of responsive materials is the design of reagents and polymers that provide controlled release of phenols in environments that are less polar than water. In these contexts, a molecular strategy that enables release of nearl

Full text of DOI:10.1021/jo300400q

Article
pubs.acs.org/joc
A Self-Immolative Spacer That Enables Tunable Controlled Release of
Phenols under Neutral Conditions
Kyle M. Schmid, Lasse Jensen, and Scott T. Phillips*
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
S
* Supporting Information
ABSTRACT: A current challenge in the area of responsive
materials is the design of reagents and polymers that provide
controlled release of phenols in environments that are less polar
than water. In these contexts, a molecular strategy that enables
release of nearly any phenol with predictable and tunable rates
and without complication from background hydrolysis would
substantially increase the precision with which materials can be
designed to respond to a particular signal. This Article addresses
this problem at the fundamental level by describing the design,
synthesis, and physical-organic characterization of two small
molecule self-immolative spacers that are capable of releasing
phenols in organic and mixed organic−aqueous solutions. The rate of release from these small molecule model systems is
predictable and tunable, such that nearly any type of phenol, regardless of pKa value, can be released in neutral solutions without
complications from nonspecific background release due to hydrolysis. Furthermore, the release properties of the spacers can be
predicted from bond length and conformation data (obtained from crystal structures). On the basis of these results, it should
now be possible to incorporate these design elements into materials to enable precise response properties in environments that
are not 100% aqueous.
when the phenol is acidic. We also have recognized the need for
highly tunable spacer groups that enable predictable rates of
release of any phenol in response to a specific stimulus;
predictable rates of release would enhance the number of
applications to which these types of disassembling materials can
be applied, and a tunable spacer would enable release of any
type of phenol, rather than being limited to acidic phenols.
Solutions to both of these issues (i.e., background hydrolysis
and tunable spacers) will improve the precision with which
responsive materials/reagents perform their designed func-
tion.30
In an effort to address these challenges, we now describe the
design, synthesis, and physical-organic characterization of two
spacers (Figure 1) that are capable of releasing phenols without
complications from nonspecific background release reactions
and with tunable rates of release. These spacers function in a
variety of solvents (organic to mixed organic−aqueous) and are
capable of releasing nearly all types of phenols. In this Article,
we characterize the response properties of these spacers in
model systems with the objective that the results of these
studies can be used in future efforts to guide the rational design
of stimuli-responsive materials.30
INTRODUCTION
■
Effective molecular strategies are needed for releasing phenols
in response to specific stimuli in organic and mixed organic−
aqueous solutions without complication from background
hydrolysis and with precise control over the rate of release.
Solutions to this problem will be useful in diverse areas,
including responsive dendrimers,1−7 molecular sensors,8 and
smart nano- and micrometer-scale capsules9−11 that operate in
coatings, self-healing materials, and other environments that are
substantially less polar than water. Often in these types of
responsive materials, a phenol is attached to a portion of a
polymer or small molecule or integrated into the polymer to
form the backbone of the material. When these types of
materials are exposed to a specific stimulus, the phenol is
released in a disassembly process that translates detection of the
stimulus into a specific response of the material.
Phenols (and alcohols) frequently are attached to polymers
and small molecules of this type through a spacer group12−16
that enables effective translation of reaction with the stimulus to
release of the phenol; the functionality used to attach the
phenol to the spacer can be a carbonate,17 ester,18 acetal,19
ether,20−23 hemiaminal ether,24 carbamate,11,16,25−27 or related
functionalities.28,29 In these contexts, however, we19 and
others20 have observed substantial background release of
phenols from the spacer groups due to hydrolysis (even in
neutral, mixed organic−aqueous solutions) when the phenols
are connected to the spacer as an ester, carbonate, or acetal.
Furthermore, the hydrolysis reaction is particularly problematic
Design of the Spacers. In our designs (Figure 1), one end
of the spacer is connected to a reaction-based detection unit
(e.g., a substrate for an enzyme; this unit is referred to as a
Received: February 24, 2012
Published: April 11, 2012
© 2012 American Chemical Society
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organic−aqueous solutions; and (v) accessible via a short,
efficient, and modular synthesis, thus facilitating variation of
both the reaction-based detection unit and the pendant phenol.
Figure 1 illustrates two related spacers that were designed
with these criteria in mind. These spacers rapidly release
phenols with pKa values <9.2 (spacer 1) and <11.5 (i.e., nearly
all types of phenols) (spacer 2). Although similar to spacer 1,
spacer 2 possesses two methyl ethers at strategic positions on
the central benzene ring. We hypothesized that the addition of
methyl ethers ortho to the benzylic ether would increase the
energy of the HOMO of the aromatic ring, thus increasing the
strength of the HOMO−LUMO interaction between π and
σ*C−O. This orbital interaction would raise the ground state
energy of the controlled release reagent and thus increase the
rate of the release reaction. Moreover, stronger orbital
interactions between π and σ*C−O would, in theory, lengthen
the benzylic C−O bond and shorten the Cbenzene−Cbenzylic bond.
Hence, we reasoned that the addition of methyl ethers on the
spacer would weaken the ether bond and enable rapid rates of
release for any type of phenol.32−34 Our efforts to develop these
designs and test this hypothesis are described below.
Figure 1. Two spacers described in this Article for releasing phenols in
response to specific stimuli in organic and mixed organic−aqueous
solutions. The phenol is connected to the spacer through an ether
bond to minimize background release caused by nonspecific
hydrolysis, and the methyl ethers are included in entry 2 to increase
the rate of release of the phenol (i.e., they provide the ability to tune
the release rate).
RESULTS AND DISCUSSION
■
Preparation and Analysis of a Spacer for the
Controlled Release of Acidic Phenols (pKa Values
<9.2). To evaluate the effectiveness of spacer 1, we employed
an allyloxycarbonyl (Alloc) group as a model reaction-based
detection unit, which would detect Pd(0) as the model
chemical signal. Five derivatives were prepared via an efficient
three-step synthesis (see Scheme 1 for the synthesis of reagent
trigger in some literature13), and the other end is attached to
the phenol through a hydrolytically stable ether bond.31 The
presence of the specific chemical signal cleaves the bond
between the reaction-based detection unit and the spacer, thus
revealing an aniline or phenol that initiates release of the
pendant phenol via a presumed azaquinone methide or quinone
methide intermediate, respectively (see the Abstract image for
the general disassembly reaction that occurs).
Scheme 1. Synthetic Route to Reagent 3 (a Derivative of
Spacer 1 in Figure 1), Which Contains 2-Chlorophenol
Attached to the Spacer
Only a handful of previous studies20−23 have linked phenols
to spacers (similar to those shown in Figure 1) via ether bonds
and have demonstrated that phenols with pKa values of <9.8
can be released under neutral conditions. These studies were
conducted in aqueous solutions in which the high polarity of
the solvent accelerates the rate of the release reaction (vide
infra), presumably by stabilizing dipoles that are formed in the
transition state. When the same type of release reaction is
performed in organic or even mixed organic−aqueous
solutions, the release rate is substantially slowed (vide infra).
An alternative strategy (than shown in Figure 1) for
controlling the release rate of phenols that are linked to
spacers as ethers is to change reaction conditions to favor the
rate of release. This approach works particularly well when
basic reaction conditions are employed and when the spacer
proceeds through quinone methide.1−6 Because basic reaction
conditions are not always feasible in the context of stimuli-
responsive materials, we sought a more general strategy that
involved modifying the spacer, rather than adjusting the
conditions for the release reaction.
In order to release phenols from stimuli-responsive
materials/reagents in organic and mixed organic−aqueous
solutions, the ideal spacer would be (i) stable over days or
even months in aqueous or mixed organic−aqueous solutions
without background release; (ii) capable of releasing the
pendant alcohol only when exposed to a specific signal; (iii)
designed to enable predictable and tunable rates of release so
that the reagent can be modified to release any phenol at any
desired rate; (iv) capable of releasing phenols under neutral
conditions (i.e., pH 7.0 and 25 °C), in polar organic or mixed
3) to ascertain a range of phenols that can be released from this
first-generation spacer.
The rate of release of phenol from each spacer was measured
as follows: (i) The controlled-release reagent was exposed to
8.9 mol % Pd(PPh3)4, excess Bu3SnH, and excess AcOH in
THF for 3 min (Figure 2a). Quantitative deprotection of the
Alloc group occurred, but no alcohol was released in this
nonpolar solvent. (ii) A 10-μL aliquot of this reaction mixture
then was diluted with 1 mL of 1:1 CH3CN/water (pH 7.1).
(iii) The release of the pendant alcohol was monitored over
time by repetitive injections (20 min intervals) into an HPLC
connected to a mass spectrometer (LC−MS) (Figure 2b).
The half-life for the release of phenol from this spacer is
exponentially dependent on the pKa of the alcohol (Figure 3).
In other words, to achieve a reasonable rate of release (which
we are defining to be t1/2 ≤ 3 h), only alcohols with pKa values
less than 9.2 can be used under the specific release conditions.
Given this pKa constraint, spacer 1 is useful only for the
controlled release of relatively acidic phenols under these
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38 days. On the basis of these results, we conclude that spacer 1
will be useful in situations in which it is desirable to release
acidic phenols without complications from background release
due to hydrolysis.
Effect of Solvent Polarity on the Rate of Release from
Spacer 1. As indicated in the Introduction, qualitative
observations suggest that the polarity of the environment in
which the release reaction occurs can have a substantial effect
on the rate of the release reaction. Responsive materials (such
as responsive capsules) that operate in purely aqueous solutions
have substantially lower polarity environments within the shell
wall of the capsule and at the surface of the capsule (where the
release reaction occurs) as compared to the bulk solvent.36,37
The consequence of the low polarity of these local environ-
ments on slowing the rate of the release reaction likely is
substantial, thus leading to slow responses in the stimuli-
responsive material.38,30
To determine the consequence of polarity on the rate of
release of the spacers described herein, we performed a
quantitative release experiment using compound 7 as a model
system. The experiment involved repeating the release reaction
shown in Figure 2a, with the exception that the solvent
composition (and, hence, the solvent polarity) was varied in
step 2 of the reaction. Figure 4 shows that, as predicted, there is
Figure 2. Method for measuring the release of phenols from the self-
immolative spacers shown in Figure 1. (a) Reaction conditions used
for measuring the rate of release of each alcohol in response to Pd(0).
(b) Example of a stacked LC−MS plot over the course of the release
reaction (step 2). This example is for compound 7, where R = 3-
trifluoromethylphenyl. The rate of release of the alcohol was measured
over time by following the disappearance of the aniline intermediate B
at 330 nm.
reaction conditions. It is noteworthy that in the absence of
Pd(0) (the model analyte) even derivative 3 (which contains
the most acidic phenol, pKa = 8.5135) shows no signs of
background release when stored in 1:1 MeCN/buffered water
(pH 7) at 25 °C (i.e., the conditions of step 2 in Figure 2a) for
Figure 4. Effect of solvent polarity on the half-life for the release of 3-
trifluoromethylphenol (pKa = 9.0435) from compound 7 using the
release experiment outlined in Figure 2a. The solvent polarity was
varied in step 2 of the reaction in Figure 2a. The release reactions were
performed in triplicate; the average values and standard deviations
from the average are shown in the graph.
a direct relationship between solvent polarity and rate of
release, i.e., as the polarity increases, the rate of release increases
proportionally. The rapid rate of release in 70% H2O/MeCN is
further corroborated by the recent release studies reported by
Cohen et al. in 100% water.20 This graph makes clear that to
enable rapid release of 7 in a nonpolar environment (such as in
the shell of a capsule), further structural changes must be made
to the linker to enhance the rate of release. The following
sections describe spacer 2 that provides a solution to this issue.
Preparation and Analysis of a Spacer for the
Controlled Release of All Phenols. As shown in Figure
3b, phenols with pKa values >9.2 are released slowly from
spacer 1. In order to facilitate release of these less acidic
phenols, our second spacer design (spacer 2, Figure 1) includes
two methyl ether substituents positioned ortho to the benzylic
position where the phenol is attached. According to our
Figure 3. Controlled release of ether-linked phenols from spacer 1 in
Figure 1. (a) Structures used to create the graph in (b). The pKa values
were obtained from reference 35. The reaction conditions used for
measuring the rate of release of each alcohol in response to Pd(0) are
shown in Figure 2a. The rate of release was quantified using LC−MS
as shown in Figure 2b. (b) Correlation between release half-life and
the pKa value of the pendant phenol. All kinetics experiments were
performed in triplicate; most error bars are the size of the data points
or smaller.
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a
hypothesis, the addition of these methyl ethers would increase
the interaction between π and σ*C−O, thus lengthening the
benzylic C−O bond and enhancing the rate of release of a
pendant phenol. Experimental data for spacers containing zero,
one, and two methyl ethers, as well as calculations (NWChem
program package39 using B3LYP and the 6-311G* basis sets),
further support this hypothesis by way of predicted and
experimental bond lengths for the three model reagents (and
spacers) shown in Figure 5.
Scheme 3. Synthetic Route to Reagent 9
a
Reagents and conditions: (a) PPTS, ethylene glycol, benzene, 105
°C; (b) n-BuLi, DMF, THF, −78 °C (80% over 2 steps); (c) NaBH4,
CH2Cl2/MeOH; (d) TMAD, Bu3P, phenol, benzene, 0 °C (76% over
2 steps); (e) TsOH, THF; (f) NaClO2, NaH2PO4, acetone/water; (g)
DPPA, TEA, allyl alcohol, benzene, 85 °C (62% over 3 steps).
(Figure 5), as well as a corresponding decrease in the C1−C2
bond length. (The experimental bond lengths are shown in
parentheses below the theoretical values in Figure 5.)
On the basis of the results in Figure 5, we hypothesized that
even the least acidic phenols would likely release effectively
from spacer 2, and therefore, this spacer could serve as a
general spacer for the release of all types of phenols. Using the
general synthetic route shown in Scheme 3, we prepared
derivatives 9−19 (Figure 6) and tested them using the Pd(0)-
detection and LC−MS analysis procedure described in Figure
2a. The results of these experiments reveal that phenols with
pKa values up to ∼11.5 (i.e., the least acidic types of phenols)
can be released at reasonable rates (t1/2 ≤ 3 h) (Figure 6b). In
Figure 5. Effect of methyl ethers (orange) on the rate of release of
phenol (green). The t1/2 values were obtained using the experimental
conditions outlined in Figure 2a. Bond lengths were obtained both
from theoretical calculations and from X-ray analysis of crystals (the
experimental values are in parentheses).
To test the theoretical prediction, derivatives 4, 8, and 9
(syntheses of 8 and 9 are shown in Schemes 2 and 3) were
a
Scheme 2. Synthetic Route to Reagent 8
a
Reagents and conditions: (a) DIAD, PPh3, phenol, 0 °C (49%); (b)
n-BuLi, CO2, −78 °C; (c) DPPA, Et3N, allyl alcohol, 85 °C (84% over
2 steps).
subjected to the same experimental conditions shown in Figure
2a. The half-life data for these reagents reveals a clear and
striking trend (Figure 5): addition of one methyl ether to the
linker (compound 8) increases the rate of release of phenol 39-
fold relative to that of 4, and addition of a second methyl ether
(compound 9) increases the rate 35-fold relative to that of 8. In
other words, reagent 9 releases phenol >103 times faster than
reagent 4. Of equal importance is the observation that none of
these compounds exhibited background release over a period of
1 month when exposed only to the conditions in step 2 (Figure
2a) (i.e., when not exposed to Pd(0) in step 1).
Figure 6. Controlled release of phenols using a spacer that contains
two methyl ethers ortho to the benzylic ether (i.e., entry 2 in Figure
1). (a) Structure and pKa value for the phenol. (b) Correlation
between the pKa value for phenol and the half-life for the release
reaction (orange data points). The experimental procedure for
studying the release reaction is shown in Figure 2a. The black data
points correspond to the data from Figure 3b and are included to
compare the effects of two methyl ethers on release rate with the
spacer that lacks methyl ethers. Experimental and estimated pKa values
were obtained from the following sources: 16,35 17,35 18,40 and 19.40
All kinetics experiments were performed in triplicate; most error bars
are smaller than the data points.
X-ray crystallographic data for compounds 4, 8, and 9
support the theoretical calculations by revealing that each
methyl ether results in an increase in the C2−O3 bond length
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other words, the presence of two methyl ethers on the spacer
molecule enables the release of pendant phenols that are 23-
fold less acidic (2.3 pKa units higher) than is possible when the
methyl ethers are absent. This spacer now allows nearly any
phenol to be released in mixed organic−aqueous solutions.
Attempt To Prepare a Spacer for the Rapid Controlled
Release of Alcohols (Other than Phenols) with pKa
Values >11.5. The results shown in Figures 5 and 6 suggest
that additional methyl ether substituents might further enhance
the rate of release of a pendant phenol in low polarity
environments and might even enable the release of other types
of alcohols that are connected to the spacer through an ether
bond (the synthesis of an example derivative is shown in
Scheme 4). In contrast to this prediction, we found that
Comparison of Azaquinone Methide and Quinone
Methide Spacers. The spacers discussed up to this point all
have released phenols through a presumed azaquinone methide
intermediate, but the release should be possible via quinone
methide as well. To determine the effectiveness of release via
quinone methide, we prepared reagent 23 (Scheme 5). Reagent
Scheme 5. Synthetic Route to 23, Which Releases 2-tert-
a
Butylphenol through Quinone Methide
Scheme 4. Synthetic Route to Reagent 20 (a Tetramethyl
a
Ether Spacer)
a
Reagents and conditions: (a) allyl chloroformate, pyridine, CH2Cl2
(84%); (b) NaBH4, MeOH−CH2Cl2; (c) TMAD, Bu3P, 2-tert-
butylphenol, benzene (40% over 2 steps).
23 is analogous to reagent 17, with the exception that 23
releases 2-tert-butylphenol via a quinone methide intermediate,
whereas 17 proceeds through a presumed azaquinone methide
intermediate. The rate of release of 2-tert-butylphenol from 23
was measured using the same experimental conditions
described in Figure 2a.
The half-life for release of 2-tert-butylphenol from 23 is 158
14 min, while the half-life for release of the same phenol from
17 is 37 4 min. This result indicates that, in mixed organic−
aqueous solutions at pH 7, a phenol spacer (Figure 1) is ∼4.3×
slower to release phenols than an aniline spacer, which is
consistent with the general sentiment in the literature.14 As the
pH of the solution is raised, however, this difference in release
rate is likely to diminish as the phenol intermediate (i.e., the
precursor to quinone methide) becomes deprotonated.1
a
Reagents and conditions: (a) Na2S2O4) MeOH/water; (b) MeI,
K2CO3, DMF; (c) n-BuLi, DMF, THF, −78 °C; (d) NaBH4, CH2Cl2/
MeOH; (e)TMAD, Bu3P, 2-tert-butylphenol, benzene, 0 °C (20% over
5 steps); (f) n-BuLi, DMF, THF, −78 °C; (g) NaClO2, Na2HPO4,
acetone/water; (h) DPPA, TEA, allyl alcohol, benzene, 85 °C (54%
over 3 steps).
additional methyl ethers on the spacer introduce unfavorable
nonbonding interactions between adjacent methyl ethers, thus
positioning the oxygen lone-pairs out of alignment with π* on
the aromatic ring (Figure 7a). Hence, the methyl ethers no
CONCLUSION
■
In conclusion, we have developed a general set of self-
immolative spacers for the controlled release of phenols (with
pKa values ≤11.5) in neutral, mixed organic−aqueous solutions
without background release due to nonspecific hydrolysis. The
syntheses of these spacers are modular and should enable ready
access to reagents that contain different reaction-based
detection units and that release various types of phenols. The
choice of which spacer to use depends on the type of phenol
being released, but in general, as the number of methyl ethers
on the spacer increases (i) the rate of release of a given phenol
increases and (ii) a broader range of phenols can be released,
including relatively nonacidic phenols. However, synthetic
accessibility may be a consideration as well when choosing a
spacer: the spacer with no methyl ethers is prepared in
approximately half the number of synthetic steps as the spacer
with two methyl ethers. Overall, the appropriate choice of
spacer depends on the pKa value of the phenol, the desired rate
of release, and synthetic accessibility. Taken together, the
results of this study now provide a framework for guiding the
rational design of responsive materials/reagents that release
phenols in environments that are less polar than water.
Figure 7. X-ray crystal structures of spacers that contain four methyl
ethers (a) and two methyl ethers (b). The oxygen lone pairs on the
methyl ethers in panel b are aligned for interactions with π*aromatic
whereas in panel a they are not.
,
longer significantly donate electron density through lone-
pair−π*aromatic interactions. The consequence of this con-
formation is apparent not only by comparison of X-ray
crystallographic data (Figure 7) but also by rates of release of
2-tert-butylphenol: using the conditions shown in Figure 2a, the
half-life for release of 2-tert-butylphenol from reagent 20
(Figure 7a) is 110 5 h, whereas the corresponding one- (58)
and two-methyl (9) ether derivatives released 2-tert-butylphe-
nol with half-lives of 9.2 0.5 h (12× faster) and 0.62 0.07 h
(177× faster), respectively.
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mL). Triethylamine (0.30 mL, 2.1 mmol, 1.3 equiv) and
diphenylphosphoryl azide (0.46 mL, 2.1 mmol, 1.3 equiv) were
added to the reaction mixture. The solution was heated to 80 °C for 2
h, and then allyl alcohol (0.33 mL, 4.9 mmol, 3.0 equiv) was added to
the hot solution. The solution was heated to 90 °C for 3 h, was
allowed to cool to 23 °C, and was concentrated by rotary evaporation.
The residue was purified by silica gel flash column chromatography
(20% ethyl acetate in hexanes, increasing to 40% ethyl acetate in
hexanes) to afford (4) as a white solid (0.33 mg, 1.2 mmol, 56% over
three steps): mp 92−95 °C; IR (cm−1) 3295, 1695, 1537; 1H NMR δ
7.51−7.32 (m, 7H), 7.07−7.02 (m, 3H), 6.08−5.97 (m, 1H), 5.47 (dd,
1H, J = 18, 1.2 Hz), 5.41 (dd, 1H, J = 10.5, 0.9 Hz), 5.06 (s, 2H), 4.76
(d, 2H, J = 5.4 Hz); 13C NMR δ 159.2, 153.9, 138.2, 132.9, 132.5,
130.0, 128.9, 121.4, 119.4, 118.7, 115.4, 70.0, 66.4; MS (TOF MS AP
+, m/z) 306.2 (M + Na+). HRMS (TOF MS AP+) calcd for
EXPERIMENTAL SECTION
■
General Experimental Methods. All reactions were performed in
flame-dried glassware under a positive pressure of argon unless
otherwise noted. Air- and moisture-sensitive liquids were transferred
via syringe or stainless steel cannula. Organic solutions were
concentrated by rotary evaporation (25−40 mmHg) at ambient
temperature. All reagents were purchased commercially and were used
as received. Acetonitrile (MeCN), dichloromethane, N,N-dimethyl-
formamide, benzene, triethylamine, and tetrahydrofuran were purified
by the method of Pangborn et al.41 Flash-column chromatography was
performed as described by Still et al.,42 employing silica gel (60-Å pore
size, 32−63 μm, standard grade). Thin-layer chromatography was
carried out on silica gel TLC (20 m × 20 cm w/h, F-254, 250 μm).
Deionized water was purified using a Millipore purification system.
Kinetics experiments were carried out in 2-mL HPLC vials.
+
C17H21N2O3 (M + NH4 ) 301.1552, found 301.1548.
Proton nuclear magnetic resonance (1H NMR) spectra were
recorded using an NMR spectrometer at 25 °C. Proton chemical shifts
are expressed in parts per million (ppm) and are referenced to residual
protium in the NMR solvent (CHCl3, δ 7.24 ppm).43 Data are
represented as follows: chemical shift, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet and/or multiple
resonances), integration, and coupling constant (J) in hertz. Carbon
nuclear magnetic resonance spectra (13C NMR) were recorded on a 75
MHz NMR spectrometer at 25 °C. Carbon chemical shifts are
expressed in parts per million and are referenced to the carbon
resonances of the NMR solvent (CDCl3, δ 77.0). Kinetics and rate of
release studies were performed using an HPLC with a UV detector
and a 150 mm × 2.1 mm betasil phenyl-hexyl column. The column
was equilibrated in 9:1 H2O/MeCN at 1 mL/min flow rate. After
injection of the sample, a solvent gradient was established by ramping
to 1:9 H2O/MeCN over 15 min. Low resolution and high resolution
mass spectra were acquired using mobile phases containing 5 mM
ammonium formate.
Methyl 4-((3-Methoxyphenoxy)methyl)benzoate (29). Tributyl-
phosphine (0.30 mL, 1.2 mmol, 1.2 equiv) was added to a solution of
N,N,N′,N′-tetramethylazodicarboxamide (TMAD) (0.21 g, 1.2 mmol,
1.2 equiv) in benzene (5 mL) at 0 °C, and the mixture was stirred at 0
°C for 15 min. 4-(Hydroxymethyl) benzoate (0.17 g, 1.0 mmol, 1
equiv) and 3-methoxyphenol (0.13 mL, 1.2 mmol, 1.2 equiv) were
added as a solution in benzene (5 mL). The resulting reaction mixture
was stirred at 23 °C for 1 h. The product mixture was diluted with
ethyl acetate (20 mL), and the solution was washed with saturated
aqueous sodium chloride solution (2 × 20 mL). The organic layer was
dried over sodium sulfate, the sodium sulfate was removed by
filtration, and the solvent was removed by rotary evaporation. The
resulting oil was filtered through a plug of silica gel (5% ethyl acetate
in hexanes, increasing to 20% ethyl acetate in hexanes) to provide
compound 29, which was used without further purification.
Potassium 4-((3-Methoxyphenoxy)methyl)benzoate (30). Com-
pound 29 (0.18 g, 0.65 mmol, 1 equiv) and potassium
trimethylsilanolate (91 mg, 0.71 mmol, 1.1 equiv) were dissolved in
diethyl ether (12 mL), and the resulting solution was stirred at 23 °C
for 16 h. The reaction mixture was filtered, and the white solid was
washed with a 3:1 mixture of ether−hexanes (3 × 20 mL). The white
solid (30) was dried under reduced pressure and was used without
further purification.
Synthesis Procedures.
4-Phenoxymethyl-bromobenzene (27). Phenol (0.56 g, 6.0 mmol,
3.0 equiv) and tetrabutylammonium iodide (73 mg, 0.20 mol, 0.1
equiv) were dissolved in tetrahydrofuran (10 mL), and the reaction
mixture was cooled to 0 °C. Sodium hydride (99%, 0.14 g, 7.0 mmol,
3.5 equiv) was added to the reaction solution, and the suspension was
stirred for 15 min at 0 °C. 4-Bromobenzyl bromide (0.50 g, 2.0 mmol,
1 equiv) was added, and the suspension was stirred at 23 °C for 16 h.
Ethyl acetate (30 mL) was added to the reaction mixture, followed by
dropwise addition of 1 M aqueous sodium hydroxide solution (1 mL).
The layers were separated, and the organic layer was washed with 1 M
aqueous sodium hydroxide solution (3 × 30 mL), followed by
saturated aqueous sodium chloride solution (1 × 30 mL). The organic
layer was dried over sodium sulfate, the solid sodium sulfate was
removed by filtration, and the dried solution was concentrated by
rotary evaporation. 4-Phenoxymethyl-bromobenzene (27, colorless
oil) was used without further purification.
4-Phenoxymethylbenzoic Acid (28). Compound 27 (0.53 g, 2.0
mmol, 1 equiv) was dissolved in tetrahydrofuran (10 mL), and the
solution was cooled to −78 °C. n-Butyllithium (1.6 mL, 2.4 M in
hexanes, 2.0 equiv) was added dropwise to the −78 °C solution, and
the resulting mixture was stirred for 5 min. Dry carbon dioxide was
bubbled through an 18-gauge metal needle into the reaction mixture
for 15 min, and then the reaction mixture was allowed to warm to 23
°C. Aqueous sodium hydroxide solution (1 N, 1 mL) was added to the
reaction mixture, followed by ethyl acetate (20 mL). The layers were
separated, and the organic layer was extracted with 1 M aqueous
sodium hydroxide (2 × 20 mL). The combined aqueous layers were
acidified to pH 2 by addition of concentrated hydrochloric acid. The
acidic aqueous solution was extracted with ethyl acetate (2 × 20 mL).
The combined organic extracts were dried over sodium sulfate, and the
solid sodium sulfate was removed by filtration. The solvent was
removed by rotary evaporation to afford compound 28 as a white
solid, which was used without further purification.
Allyl 4-((3-Methoxyphenoxy)methyl)phenylcarbamate (5). Trie-
thylamine (44 μL, 0.32 mmol, 1.2 equiv) and diphenylphosphoryl
azide (70 μL, 0.32 mmol, 1.2 equiv) were added to a solution of
compound 30 (78 mg, 0.26 mmol, 1 equiv) in benzene (1.5 mL) at 23
°C. The reaction mixture was heated to 80 °C. After 2 h of stirring at
80 °C, allyl alcohol (90 μL, 1.3 mmol, 5.0 equiv) was added. The
solution was heated to 90 °C, held at 90 °C for 3 h, and allowed to
cool to 23 °C. The solvent was removed by rotary evaporation, and the
residue was dissolved in ethyl acetate (8 mL) and sequentially washed
with water (10 mL) and a saturated sodium chloride solution (10 mL).
The organic layer was dried over sodium sulfate, and the solid sodium
sulfate was removed by filtration. The solvent was removed by rotary
evaporation, and the residue was purified by silica gel flash column
chromatography (10% ethyl acetate in hexanes, increasing to 30%
ethyl acetate in hexanes) to afford compound 5 as a white solid (0.11
1
g, 0.35 mmol, 35% over 3 steps). IR (cm−1) 3322, 1711, 1599; H
NMR δ 7.40−7.34 (m, 4H), 7.07 (td, 3H, J = 7.6, 1.1 Hz), 6.68 (s,
1H), 6.56−6.49 (m, 4H), 6.00−5.90 (m, 1H), 5.38 (dd, 1H, J = 17.2,
1.5 Hz), 5.27 (dd, 1H, J = 10.4, 1.3 Hz), 4.97 (s, 2H), 4.66 (d, 2H, J =
5.7 Hz); 13C NMR δ 160.8, 159.9, 137.5, 132.3, 132.0, 129.9, 128.5 (2
carbons), 118.7, 118.3, 106.9, 106.6, 101.3, 69.6, 65.9, 55.2; MS (TOF
MS AP+, m/z) 336.1 (M + Na+). HRMS (TOF MS AP+) calcd for
+
C18H23N2O4 (M + NH4 ) 331.1646, found 331.1658.
Methyl 4-((3-Fluorophenoxy)methyl)benzoate (31). Compound
31 (white solid) was prepared using the same conditions as those
described for compound 29 with the exception that 3-fluorophenol
was used instead of 3-methoxyphenol. The quantities of reagents used
were N,N,N′,N′-tetramethylazodicarboxamide (0.21 g, 1.2 mmol, 1.2
equiv), tributylphosphine (0.30 mL, 1.2 mmol, 1.2 equiv) 4-
(hydroxymethyl)benzoate (0.17 g, 1.0 mmol, 1 equiv), and 3-
fluorophenol (0.11 mL, 1.2 mmol, 1.2 equiv).
(4-Phenoxymethylphenyl)carbamic Acid Allyl Ester (4). Com-
pound 28 (0.37 g, 1.6 mmol, 1 equiv) was dissolved in benzene (6.5
4368
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Article
Potassium 4-((3-Fluorophenoxy)methyl)benzoate (32). Com-
pound 32 (white solid) was prepared using the same conditions as
those described for compound 30. The quantities of reagents used
were 31 (0.18 g, 0.62 mmol, 1 equiv) and potassium trimethylsila-
nolate (87 mg, 0.68 mmol, 1.1 equiv).
MS (TOF MS AP+, m/z) 318.2 (M + H+). HRMS (TOF MS AP+)
calcd for C17H20N2O3Cl (M + NH4 ) 335.1162, found 335.1153.
+
3-Methoxy-4-phenoxymethyl-bromobenzene (11). Diisopropyl
azodicarboxylate (0.30 mL, 1.0 mmol, 1.5 equiv) was dissolved in
benzene (5 mL), and the reaction mixture was cooled to 0 °C.
Triphenylphosphine (0.39 g, 1.5 mmol, 1.5 equiv) was added to the
reaction mixture, and the solution was stirred at 0 °C for 10 min. 4-
Bromo-2-methoxybenzyl alcohol (10) (0.22 g, 1.0 mmol, 1 equiv) and
phenol (0.14 g, 1.5 mmol, 1.5 equiv) were then added as a solution in
benzene (5 mL), and the reaction mixture was stirred at 23 °C for 2 h.
The solvent was removed by rotary evaporation, and the resulting oil
was purified by silica gel flash column chromatography (30% ethyl
acetate in hexanes, increasing to 60% ethyl acetate in hexanes) to
afford compound 11 as an oil (0.14 g, 0.49 mmol, 49%). IR (cm−1)
2931, 1590, 1495; 1H NMR δ 7.33−7.26 (m, 3H), 7.11 (d, 1H, J = 8.0
Hz), 6.98−6.93 (m, 3H), 5.04 (s, 2H,), 3.84 (s, 3H); 13C NMR δ
158.6, 157.2, 129.5, 129.4, 124.6, 123.5, 122.0, 120.9, 114.7, 113.8,
64.4, 55.6.
Allyl 4-((3-Fluorophenoxy)methyl)phenylcarbamate (6). Com-
pound 6 (white solid, 2% over three steps) was prepared using the
same conditions as those described for compound 4. The quantities of
reagents used were 32 (77 mg, 0.27 mmol, 1 equiv), diphenylphos-
phoryl azide (70 μL, 0.32 mmol, 1.2 equiv), triethylamine (45 μL, 0.32
mmol, 1.2 equiv) and allyl alcohol (92 μL, 1.4 mmol, 5.0 equiv). IR
1
(cm−1) 3328, 1703, 1590; H NMR δ 7.40−7.33 (m, 4H), 7.24−7.16
(m, 1H), 6.73−6.71 (m, 1H), 6.68−6.62 (m, 3H), 5.99−5.90 (m, 1H),
5.37 (dd, 1H, J = 17.3, 1.5 Hz), 5.27 (dd, 1H, J = 10.4, 1.2 Hz), 4.97
(s, 2H), 4.66 (d, 2H, J = 5.7 Hz); 13C NMR δ 137.7, 132.3, 131.5,
130.2, 130.1, 128.5, 118.3, 110.6, 110.5, 107.8, 107.6 102.7, 102.4, 69.8,
65.9; MS (TOF MS AP+, m/z) 302.1 (M + H+). HRMS (TOF MS
+
AP+) calcd for C17H20N2O3F (M + NH4 ) 319.1458, found 319.1441.
Methyl 4-((3-(Trifluoromethyl)phenoxy)methyl)benzoate (33).
Compound 33 (white solid) was prepared using the same conditions
as those described for compound 29 with the exception that 3-
trifluoromethylphenol was used instead of 3-methoxyphenol. The
quantities of reagents used were N,N,N′,N′-tetramethylazodicarbox-
amide (0.21 g, 1.2 mmol, 1.2 equiv), tributylphosphine (0.30 mL, 1.2
mmol, 1.2 equiv) methyl 4-(hydroxymethyl)benzoate (0.17 g, 1.0
mmol, 1 equiv), and 3-trifluoromethylphenol (0.15 mL, 1.2 mmol, 1.2
equiv).
Potassium 4-((3-(Trifluoromethyl)phenoxy)methyl)benzoate (34).
Compound 34 (white solid) was prepared using the same conditions
as those described for compound 30. The quantities of reagents used
were 33 (0.16 g, 0.58 mmol, 1 equiv) and potassium trimethylsila-
nolate (90 mg, 0.71 mmol, 1.1 equiv).
3-Methoxy-4-phenoxylmethylbenzoic Acid (12). n-Butyllithium
(0.39 mL from 2.5 M in hexanes, 0.98 mmol, 2.0 equiv) was added
dropwise to a solution of compound 11 (0.14 g, 0.49 mmol, 1 equiv)
in tetrahydrofuran (5 mL) at −78 °C. The reaction solution was
stirred for 5 min at −78 °C. Dry carbon dioxide was bubbled into the
reaction mixture for 15 min, and then the solution was allowed to
warm to 23 °C. Aqueous sodium hydroxide (1 M, 0.5 mL) was added
dropwise to the solution, and the resulting mixture was diluted with
ethyl acetate (15 mL). The organic phase was separated from the
aqueous layer and was washed with 1 M aqueous sodium hydroxide (2
× 20 mL). The aqueous layers were combined and acidified to pH 2
by addition of concentrated aqueous hydrochloric acid. The aqueous
layer was extracted with ethyl acetate (2 × 20 mL). The combined
organic layers were dried over sodium sulfate, and the sodium sulfate
was removed by filtration. The solvent was removed by rotary
evaporation to afford compound 12 as a white solid, which was used
without further purification.
Allyl (4-((3-(Trifluoromethyl)phenoxy)methyl)phenyl)carbamate
(7). Compound 7 (pale yellow solid, 29% over three steps) was
prepared using the same conditions as those described for compound
4. The quantities of reagents used were 34 (0.13 g, 0.44 mmol, 1
equiv), diphenylphosphoryl azide (0.11 mL, 0.53 mmol, 1.2 equiv),
triethylamine (75 μL, 0.53 mmol, 1.2 equiv) and allyl alcohol (0.15
(3-Methoxy-4-phenoxylmethylphenyl)carbamic Acid Allyl Ester
(8). Triethylamine (66 μL, 0.47 mmol, 1.2 equiv) and diphenylphos-
phoryl azide (0.10 mL, 0.47 mmol, 1.2 equiv) were added to a solution
of compound 12 (0.10 g, 0.40 mmol, 1 equiv) in benzene (2 mL) at 23
°C. The solution was heated to 80 °C. After 2 h of stirring at 80 °C,
allyl alcohol (0.80 mL, 1.2 mol, 3.0 equiv) was added to the reaction
mixture, and the solution was heated to 90 °C. After 3 h of stirring at
90 °C, the solution was allowed to cool to 23 °C, and the solvent was
removed by rotary evaporation. The residue was purified by silica gel
flash column chromatography (20% ethyl acetate in hexanes,
increasing to 40% ethyl acetate in hexanes) to afford 8 as a waxy
white solid (0.10 g, 0.33 mmol, 84% over two steps): mp 86−89 °C;
1
mL, 2.2 mmol, 5.0 equiv). IR (cm−1) 3323, 1712, 1600; H NMR δ
7.42−7.34 (m, 5H), 7.21−7.19 (m, 2H), 7.11 (d, 1H, J = 9.4), 6.69 (s,
1H), 6.01−5.90 (m, 1H), 5.38 (dd, 1H, J = 17.2, 1.5 Hz), 5.27 (dd,
1H, J = 10.4, 1.3 Hz), 5.02 (s, 2H), 4.67 (d, 2H, J = 5.7 Hz); 13C NMR
δ 158.8, 137.8, 132.3, 132.0 131.2, 129.9, 128.6, 118.7, 118.3, 118.2,
117.6, 117.5, 111.7, 111.6, 69.9, 65.9; MS (TOF MS AP+, m/z) 352.0
(M + H+). HRMS (TOF MS AP+) calcd for C18H20N2O3F3 (M +
+
NH4 ) 369.1432, found 369.1426.
Methyl 4-((2-Chlorophenoxy)methyl)benzoate (1). Compound 1
(white solid) was prepared using the same conditions as those
described for compound 29 with the exception that 2-chlorophenol
was used instead of 3-trifluoromethylphenol. The quantities of
reagents used were N,N,N′,N′-tetramethylazodicarboxamide (0.21 g,
1.2 mmol, 1.2 equiv), tributylphosphine (0.30 mL, 1.2 mmol, 1.2
equiv) methyl 4-(hydroxymethyl)benzoate (0.17 g, 1.0 mmol, 1
equiv), and 2-chlorophenol (0.12 mL, 1.2 mmol, 1.2 equiv).
Potassium 4-((2-Chlorophenoxy)methyl)benzoate (2). Com-
pound 2 (white solid) was prepared using the same conditions as
those described for compound 30. The quantities of reagents used
were 1 (0.16 g, 0.58 mmol, 1 equiv) and potassium trimethylsilanolate
(0.11 g, 0.87 mmol, 1.5 equiv).
1
IR (cm−1) 3318, 1707, 1601; H NMR δ 7.41−7.26 (m, 5H), 7.04−
6.96 (m, 3H), 6.88 (s, 1H), 6.18−5.8 (m, 1H), 5.47 (dd, 1H, J = 9.0,
3.0 Hz), 5.44 (dd, 1H, J = 18, 1.5 Hz), 5.33 (dd, 1H, J = 10.5, 1.2 Hz),
5.09 (s, 2H), 4.72 (d, 2H, J = 6.0 Hz), 3.88 (s, 3H); 13C NMR δ 159.4,
158.0, 153.5, 139.3, 132.8, 130.2, 129.84, 129.7, 121.2, 120.8, 118.7,
115.3, 102.5, 66.3, 65.2, 55.9; MS (TOF MS AP+, m/z) 313.2 (M+).
HRMS (TOF MS AP+) calcd for C18H20NO4 (M + H)+ 314.1397,
found 314.1392.
2-(4-Bromo-3,5-dimethoxyphenyl)-[1,3]dioxolane (35). 4-Bromo-
3,5-dimethoxybenzaldehyde (13) (2.5 g, 10 mmol, 1 equiv),
pyridinium p-toluenesulfonate (0.50 g, 2.0 mmol, 0.2 equiv), and
ethylene glycol (2.2 mL, 40 mmol, 4.0 equiv) were dissolved in
benzene (50 mL). A Dean−Stark apparatus was affixed to the reaction
flask, and the solution was heated to 105 °C. After 5 h of stirring at
105 °C, the product solution was cooled to 23 °C. Benzene was
removed by rotary evaporation, and the residue was dissolved in ethyl
acetate (50 mL). The resulting solution was washed sequentially with
saturated aqueous sodium bicarbonate solution (1 × 50 mL) and
saturated aqueous sodium chloride solution (1 × 50 mL). The organic
layer was dried over sodium sulfate. The sodium sulfate was removed
by filtration, and the solution was concentrated by rotary evaporation
to yield compound 35 as a white solid, which was used without further
purification.
Allyl (4-((2-Chlorophenoxy)methyl)phenyl)carbamate (3). Com-
pound 3 (white solid, 35% over three steps) was prepared using the
same conditions as those described for compound 4. The quantities of
reagents used were 2 (0.15 g, 0.51 mmol, 1 equiv), diphenylphos-
phoryl azide (0.13 mL, 0.60 mmol, 1.2 equiv), triethylamine (85 μL,
0.60 mmol, 1.2 equiv) and allyl alcohol (0.17 mL, 23.6 mmol, 5.0
1
equiv). IR (cm−1) 3322, 1704, 1596; H NMR δ 7.38−7.34 (m, 5H),
7.18 (t, 1H, J = 8.3), 6.94−6.86 (m, 2H), 6.69 (s, 1H), 6.00−5.90 (m,
1H), 5.37 (d, 1H, J = 17.9 Hz), 5.26 (d, 1H, J = 10.4 Hz), 5.08 (s, 2H),
4.66 (d, 2H, J = 5.7 Hz); 13C NMR δ 154.2, 137.6, 132.4, 131.6, 130.4,
128.2 (2 carbons), 127.7, 123.3, 121.7, 118.8, 118.4, 114.3, 70.5, 65.9;
4369
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4[1,3]Dioxolan-2-yl-2,6-dimethoxybenzaldehyde (14). n-Butyl-
lithium (8.0 mL, 2.5 M in hexanes, 20 mmol, 2.0 equiv) was added
dropwise to a −78 °C solution of compound 35 (2.9 g, 10 mmol, 1
equiv) in tetrahydrofuran (50 mL). The mixture was allowed to stir for
5 min at −78 °C, and then N,N-dimethylformamide (3.9 mL, 50
mmol, 5.0 equiv) was added. The reaction solution was stirred for 30
min at −78 °C and then was allowed to warm to 23 °C. After 1 h of
stirring at 23 °C, the solution was slowly diluted with water (dropwise
addition) (5 mL), followed by ethyl acetate (100 mL) and then
saturated aqueous sodium bicarbonate solution (1 × 150 mL). The
layers were separated, and the organic layer was washed with saturated
aqueous sodium chloride (1 × 150 mL). The organic layer was dried
over sodium sulfate, and the sodium sulfate was removed by filtration.
The solvent was removed by rotary evaporation, and the residue was
purified by silica gel flash column chromatography (40% ethyl acetate
in hexanes, increasing to 80% ethyl acetate in hexanes), yielding
compound 14 (1.9 g, 8.0 mmol, 80% over two steps) as a pale yellow
solid: mp 74−76 °C; IR (cm−1) 3506, 2942, 2884, 1676, 1613, 1566;
1H NMR δ 10.43 (s, 1H), 6.66 (s, 2H), 5.73 (s, 1H), 4.07−4.00 (m,
4H), 3.86 (s, 6H); 13C NMR δ 189.0, 162.1, 146.0, 114.3, 102.6, 101.6,
65.2, 56.0; MS (TOF MS AP+, m/z) 261.2 (M + Na+). HRMS (TOF
MS AP+) calcd for C12H15O5 (M + H)+ 239.0919, found 239.0914.
(4[1,3]Dioxolan-2-yl-2,6-dimethoxyphenyl)methanol (36). So-
dium borohydride (0.30 g, 8.0 mmol, 1.0 equiv) was added to a
solution of compound 14 (1.9 g, 8.0 mmol, 1 equiv) in a mixture of
dichloromethane (20 mL) and methanol (20 mL) at 23 °C. The
reaction mixture was stirred for 5 min at 23 °C and then was slowly
diluted (dropwise addition) with saturated aqueous ammonium
chloride solution (5 mL). Dichloromethane (50 mL) and saturated
aqueous ammonium chloride solution (80 mL) were added, and the
layers were separated. The organic layer was washed with saturated
aqueous sodium chloride solution (1 × 80 mL) and was dried over
sodium sulfate. The sodium sulfate was removed by filtration, and the
solvent was removed by rotary evaporation to provide compound 36
as a pale yellow solid, which was used without further purification.
2-(3,5-Dimethoxy-4-phenoxymethylphenyl)-[1,3]dioxolane (15).
Tributylphosphine (0.16 mL, 0.65 mmol, 1.3 equiv) was added to a
solution of N,N,N′,N′-tetramethylazodicarboxamide (TMAD) (0.11 g,
0.65 mmol, 1.3 equiv) in benzene (2.5 mL) at 0 °C, and the mixture
was immersed in a 0 °C bath and stirred for 15 min. To this mixture
was added a solution of compound 36 (0.12 g, 0.50 mmol, 1 equiv)
and phenol (61 mg, 0.65 mmol, 1.3 equiv) in benzene (2.5 mL). The
resulting reaction mixture was allowed to warm to 23 °C and then was
stirred at 23 °C for 1 h. The mixture was diluted with ethyl acetate (10
mL), and the solution was washed with saturated aqueous sodium
chloride (2 × 15 mL). The organic layer was dried over sodium sulfate,
the sodium sulfate was removed by filtration, and the solvent was
removed by rotary evaporation. The resulting oil was purified by silica
gel flash column chromatography (30% ethyl acetate in hexanes,
increasing to 60% ethyl acetate in hexanes) to afford compound 15 as
a white solid (0.12 g, 0.38 mmol, 76% over two steps). IR (cm−1)
2942, 2884, 1595; 1H NMR δ 7.30 (t, 2H, J = 8.0 Hz), 7.04 (d, 2H, J =
8.0 Hz), 6.93 (t, 1H, J = 7.6 Hz), 6.73 (s, 2H), 5.82 (s, 1H), 5.12 (s,
2H), 4.13−4.01 (m, 4H), 3.84 (s, 6H); 13C NMR δ 160.0, 159.8,
140.9, 129.7, 120.8, 115.5, 113.9, 103.9, 102.3, 65.6, 59.5, 56.4; MS
(TOF MS AP+, m/z) 317.2 (MH+). HRMS (TOF MS AP+) calcd for
C18H21O5 (M + H)+ 317.1389, found 317.1377.
rotary evaporation to afford compound 37, which was used without
further purification.
3,5-Dimethoxy-4-phenoxymethylbenzoic Acid (38). Compound
37 (0.10 g, 0.37 mol, 1 equiv) and 2-methyl-2-butene (0.24 mL, 2.2
mmol, 6.0 equiv) were dissolved in acetone (3 mL). A solution of
sodium dihydrogen phosphate monohydrate (0.31 g, 2.3 mmol, 6.0
equiv) and sodium chlorite (0.20 g, 2.3 mmol, 6.0 equiv) in water (3
mL) was added to the reaction mixture. The suspension was stirred
vigorously for 30 min at 23 °C. Acetone was removed by rotary
evaporation, and the aqueous solution was diluted with ethyl acetate
(13 mL). The layers were separated, and the organic layer was washed
sequentially with 1 M hydrochloric acid (1 × 10 mL), saturated
aqueous sodium chloride (2 × 10 mL), saturated aqueous sodium
thiosulfate (1 × 10 mL), and saturated aqueous sodium chloride (1 ×
10 mL). The organic layer was dried over sodium sulfate, and the
sodium sulfate was removed by filtration. The solvent was removed by
rotary evaporation to afford compound (38) as a white solid, which
was used without further purification.
(3,5-Dimethoxy-4-phenoxymethylphenyl)carbamic Acid Allyl
Ester (9). Triethylamine (0.10 mL, 0.77 mmol, 1.2 equiv) and
diphenylphosphoryl azide (0.17 mL, 0.77 mmol, 1.2 equiv) were
added to a solution of compound 38 (0.19 g, 0.64 mmol, 1 equiv) in
benzene (3 mL) at 23 °C. The reaction mixture was heated to 80 °C.
After 2 h of stirring at 80 °C, allyl alcohol (0.13 mL, 1.9 mmol, 3.0
equiv) was added. The solution was heated to 90 °C, was held at 90
°C for 3 h, and then was allowed to cool to 23 °C. The solvent was
removed by rotary evaporation, and the residue was purified by silica
gel flash column chromatography (10% ethyl acetate in hexanes,
increasing to 30% ethyl acetate in hexanes) to afford compound 9 as a
pale yellow solid (0.17 g, 0.49 mmol, 62% over 3 steps): mp 91−94
1
°C; IR (cm−1) 3318, 2942, 1731, 1607; H NMR δ 7.37−7.25 (m,
2H), 7.08−6.95 (m, 4H), 6.72 (s, 2H), 5.97 (m, 1H), 5.41 (d, 1H, J =
16.8 Hz), 5.30 (d, 1H, J = 10.4 Hz), 5.10 (s, 2H), 4.69 (d, 2H, J = 4.8
Hz), 3.78 (s, 6H); 13C NMR δ 159.7, 159.4, 153.0, 140.1, 132.3, 129.2,
120.3, 118.0, 114.9, 107.8, 94.6, 65.7, 59.0, 55.7; MS (TOF MS AP+,
m/z) 366.2 (M + Na+). HRMS (TOF MS AP+) calcd for
C19H21NO5Na (M + Na+) 366.1317, found 366.1332.
2-[3,5-Dimethoxy-4-(4-methoxyphenoxymethyl)phenyl]-[1,3]-
dioxolane (39). Compound 39 (pale yellow oil, 64% two steps) was
prepared using the same conditions as described for compound 15
with the exception that 4-methoxyphenol was used instead of phenol.
The quantities of reagents used were N,N,N′,N′-tetramethylazodicar-
boxamide (0.23 g, 1.3 mmol, 1.3 equiv), tributylphosphine (0.33 mL,
1.3 mmol, 1.3 equiv), 36 (0.25 g, 1.0 mmol, 1 equiv), and 4-
methoxyphenol (0.17 g, 1.3 mmol, 1.3 equiv). IR (cm−1) 2942, 1584;
1H NMR δ 6.96 (d, 2H, J = 8.8 Hz), 6.82 (d, 2H, J = 8.8 Hz), 6.70 (s,
2H), 5.80 (s, 1H), 5.04 (s, 2H), 4.11−4.00 (m, 4H), 3.82 (s, 6H), 3.75
(s, 3H); 13C NMR δ 159.8, 154.2, 154.1, 140.8, 116.8, 114.8, 114.2,
103.8, 102.4, 65.6, 60.4, 56.5, 56.5; MS (TOF MS AP+, m/z) 347.2
(MH+). HRMS (TOF MS AP+) calcd for C19H23O6 (M + H)+
347.1495, found 347.1496.
3,5-Dimethoxy-4-(4-methoxyphenoxymethyl)benzaldehyde (40).
Compound 40 (white solid) was prepared using the same conditions
as those described for compound 37. The quantities of reagents used
were 39 (0.22 g, 0.64 mmol, 1 equiv) and p-toluenesulfonic acid
monohydrate (24 mg, 0.13 mmol, 0.2 equiv).
3,5-Dimethoxy-4-(4-methoxyphenoxymethyl)benzoic Acid (41).
Compound 41 (white solid) was prepared using the same conditions
as those described for compound 38. The quantities of reagents used
were 40 (0.19 g, 0.64 mmol, 1 equiv), NaClO2 (0.46 g, 5.1 mmol, 8.0
equiv), NaH2PO4 monohydrate (0.70 g, 5.1 mmol, 8.0 equiv) and 2-
methyl-2-butene (0.20 mL, 1.9 mmol, 3.0 equiv).
3,5-Dimethoxy-4-phenoxymethylbenzaldehyde (37). Compound
15 (0.12 g, 0.38 mmol, 1 equiv) was dissolved in tetrahydrofuran (3
mL). p-Toluenesulfonic acid monohydrate (7.0 mg, 38 μmol, 0.1
equiv) was added to the reaction mixture as a solution in water (0.5
mL). The resulting solution was stirred at 23 °C for 14 h.
Triethylamine (16 μL, 0.11 mmol, 0.3 equiv) was added to the
reaction mixture, and the solvent was removed by rotary evaporation.
The residue was dissolved in ethyl acetate (10 mL), and the organic
solution was washed with saturated aqueous ammonium chloride
solution (1 × 10 mL) followed by saturated aqueous sodium chloride
(1 × 10 mL). The organic layer was dried over sodium sulfate, and the
sodium sulfate was removed by filtration. The solvent was removed by
[3,5-Dimethoxy-4-(4-methoxyphenoxymethylphenyl)]carbamic
Acid Allyl Ester (16). Compound 16 (pale yellow film, 32% over three
steps) was prepared using the same conditions as those described for
compound 9. The quantities of reagents used were 41 (80 mg, 0.25
mmol, 1 equiv), diphenylphosphoryl azide (70 μL, 0.33 mmol, 1.3
equiv), triethylamine (45 μL, 0.33 mmol, 1.3 equiv) and allyl alcohol
(51 μL, 0.75 mmol, 3.0 equiv). IR (cm−1) 3325, 2938, 1732, 1609; 1H
NMR δ 6.96 (d, 2H, J = 9.0 Hz), 6.82−6.79 (m, 3H), 6.66 (s, 2H),
4370
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5.95−5.89 (m, 1H), 5.37 (dd, 1H, J = 17.1, 1.2 Hz), 5.27 (dd, 1H, J =
10.5, 1.2 Hz), 4.98 (s, 2H), 4.65 (d, 2H, J = 5.7 Hz), 3.76 (s, 6H), 3.75
(s, 3H); 13C NMR δ 159.7, 153.7, 152.9, 139.9, 132.3, 118.2, 116.1,
114.4, 108.2, 94.5, 65.8, 59.9, 55.8, 55.7; MS (TOF MS AP+, m/z)
396.3 (M + Na+). HRMS (TOF MS AP+) calcd for C20H24NO6 (M +
H)+ 374.1604, found 374.1598.
2-[4-(2-tert-Butylphenoxymethyl)-3,5-dimethoxyphenyl]-[1,3]-
dioxolane (42). Compound 42 (waxy white solid, 83% two steps) was
prepared using the same conditions as those described for compound
15 with the exception that 2-tert-butylphenol was used instead of
phenol. The quantities of reagents used were N,N,N′,N′-tetramethy-
lazodicarboxamide (0.24 g, 1.4 mmol, 1.4 equiv), tributylphosphine
(0.35 mL, 1.4 mmol, 1.4 equiv), 36 (0.24 g, 1.0 mmol, 1 equiv), and 2-
tert-butylphenol (0.21 mL, 1.4 mmol, 1.4 equiv). IR (cm−1) 2954,
2872, 1595; 1H NMR δ 7.26−7.23 (m, 1H), 7.18 (t, 1H, J = 7.2 Hz),
7.10 (d, 1H, J = 10.8 Hz), 6.87 (t, 1H, J = 7.2 Hz), 6.71 (s, 2H), 5.79
(s, 1H), 5.08 (s, 2H), 4.15−4.05 (m, 4H), 3.81 (s, 6H), 1.27 (s, 9H);
13C NMR δ 159.3, 158.2, 139.8, 138.2, 126.8, 126.3, 119.7, 114.0,
112.2, 103.5, 101.7, 65.2, 58.6, 55.6, 34.7, 29.6; MS (TOF MS AP+, m/
z) 373.3 (M + H)+. HRMS (TOF MS AP+) calcd for C22H29O5 (M +
H)+ 373.2015, found 373.2013.
4-(2-tert-Butylphenoxymethyl)-3,5-dimethoxybenzaldehyde (43).
Compound 43 (white solid) was prepared using the same conditions
as those described for compound 37. The quantities of reagents used
were 42 (0.31 g, 0.82 mmol, 1 equiv), and p-toluenesulfonic acid
monohydrate (31 mg, 0.16 mmol, 0.2 equiv).
reagents used were 46 (0.21 g, 0.59 mmol, 1 equiv), NaClO2 (0.43 g,
4.7 mmol, 8.0 equiv), NaH2PO4 monohydrate (0.65 g, 4.7 mmol, 8.0
equiv) and 2-methyl-2-butene (0.19 mL, 1.8 mmol, 3.0 equiv).
[3,5-Dimethoxy-4-(2,2,2-trifluoro-1-phenylethoxymethyl)phenyl]-
carbamic Acid Allyl Ester (18). Compound 18 (pale yellow solid, 36%
three steps) was prepared using the same conditions as those
described for compound 9. The quantities of reagents used were 47
(0.20 g, 0.54 mmol, 1 equiv), triethylamine (90 μL, 0.65 mmol, 1.2
equiv), diphenylphosphoryl azide (0.14 mL, 0.65 mmol, 1.2 equiv),
and allyl alcohol (0.11 mL, 1.6 mmol, 3.0 equiv). IR (cm−1) 3328,
2941, 1735, 1609; 1H NMR δ 7.46−7.43 (m, 2H), 7.36−7.34 (m, 3H),
6.86 (s, 1H), 6.60 (s, 2H), 5.99−5.90 (m, 1H), 5.38 (dd, 1H, J = 17.4,
1.5 Hz), 5.27 (dd, 1H, J = 10.2, 1.2 Hz), 4.71−4.68 (m, 1H), 4.66−
4.64 (m, 3H), 4.57 (d, 1H, J = 10.5 Hz), 3.71 (s, 6H); 13C NMR δ
159.8, 153.0, 140.0, 133.6, 132.3, 129.0 (2 carbons), 128.4, 128.0 (2
carbons), 118.2, 107.9, 94.3, 78.5 (q), 65.8, 60.3, 55.5; MS (TOF MS
AP+, m/z) 426.2 (M + H)+. HRMS (TOF MS AP+) calcd for
C21H23NO5F3(M + H)+ 426.1528, found 426.1527.
(4-[1,3]Dioxolan-2-yl-2,6-dimethoxy-benzyloxy)-phenyl Acetic
Acid Methyl Ester (48). Compound 48 (white solid, 36%) was
prepared using the same conditions as those described for compound
15 with the exception that methyl DL-mandelate was used instead of
phenol. The quantities of reagents used were N,N,N′,N′-tetramethy-
lazodicarboxamide (0.25 g, 1.5 mmol, 1.5 equiv), tributylphosphine
(0.37 mL, 1.5 mmol, 1.5 equiv), 36 (0.24 g, 1.0 mmol, 1 equiv), and
methyl DL-mandalate (0.25 g, 1.5 mmol, 1.5 equiv). IR (cm−1) 2954,
1
4-(2-tert-Butylphenoxymethyl)-3,5-dimethoxybenzoic Acid (44).
Compound 44 (white solid) was prepared using the same conditions
as those described for compound 38. The quantities of reagents used
were 43 (0.16 g, 0.46 mmol, 1 equiv), NaClO2 (0.27 g, 2.7 mmol, 6.0
equiv), NaH2PO4 monohydrate (0.41 g, 2.7 mmol, 6.0 equiv) and 2-
methyl-2-butene (0.17 mL, 1.6 mmol, 3.5 equiv).
2884, 1742, 1584; H NMR δ 7.47 (m, 2H), 7.34 (m, 3H), 6.70 (s,
2H), 5.81 (s, 1H), 4.97 (s, 1H), 4.75 (s, 2H), 4.13−4.05 (m, 4H), 3.84
(s, 6H), 3.67 (s, 3H); 13C NMR δ 171.7, 159.5, 140.1, 137.2, 128.2 (2
carbons), 127.4, 113.9, 103.4, 101.8, 79.2, 65.1, 59.4, 55.7, 51.9; MS
+
(TOF MS AP+, m/z) 406.4 (M + NH4 ). HRMS (TOF MS AP+)
+
calcd for C21H28NO7 (M + NH4 ) 406.1866, found 406.1879.
[4-(2-tert-Butylphenoxymethyl)-3,5-dimethoxyphenyl]carbamic
Acid Allyl Ester (17). Compound 17 (waxy pale yellow solid, 34%
three steps) was prepared using the same conditions as those
described for compound 9. The quantities of reagents used were 44
(0.14 g, 0.40 mmol, 1 equiv), diphenylphosphoryl azide (0.10 mL, 0.47
mmol, 1.2 equiv), triethylamine (66 μL, 0.47 mmol, 1.2 equiv) and
allyl alcohol (80 μL, 1.2 mmol, 3.0 equiv). IR (cm−1) 3320, 2955,
1708, 1610; 1H NMR δ 7.32−7.24 (m, 2H), 7.15 (d, 1H, J = 8.0 Hz),
6.93−6.87 (m, 2H), 6.75 (s, 2H), 6.05−5.98 (m, 1H), 5.43 (d, 1H, J =
17.2 Hz), 5.33 (d, 1H, J = 10.4 Hz), 5.10 (s, 2H), 4.73 (d, 2H, J = 5.6
Hz), 3.81 (s, 6H), 1.34 (s, 9H); 13C NMR δ 159.7, 158.3, 153.1, 139.7,
138.3, 132.3, 126.8, 126.3, 119.6, 118.2, 112.4, 108.7, 94.5, 65.8, 58.6,
55.6, 34.7, 29.5; MS (TOF MS AP+, m/z) 322.2 (M + Na+). HRMS
(4-Formyl-2,6-dimethoxybenzyloxy)phenyl Acetic Acid Methyl
Ester (49). Compound 49 (white solid) was prepared using the
same conditions as those described for compound 37. The quantities
of reagents used were 48 (0.14 g, 0.36 mmol, 1 equiv) and p-
toluenesulfonic acid monohydrate (14 mg, 72 μmol, 0.2 equiv).
3,5-Dimethoxy-4-(methoxycarbonylphenyl-methoxymethyl)-
benzoic Acid (50). Compound 50 (white solid) was prepared using
the same conditions as those described for compound 38. The
quantities of reagents used were 49 (0.12 g, 0.36 mmol, 1 equiv),
NaClO2 (0.20 g, 2.2 mmol, 6.0 equiv), NaH2PO4 monohydrate (0.30
g, 2.2 mmol, 6.0 equiv) and 2-methyl-2-butene (0.12 mL, 1.1 mmol,
3.1 equiv).
(4-Allyloxycarbonylamino-2,6-dimethoxybenzyloxy)phenyl Ace-
tic Acid Methyl Ester (19). Compound 19 (oily pale yellow solid,
55% over three steps) was prepared using the same conditions as those
described for compound 9. The quantities of reagents used were
triethylamine (50 μL, 0.36 mmol, 1.3 equiv), diphenylphosphoryl
azide (77 μL, 0.36 mmol, 1.3 equiv), 50 (0.11 g, 0.28 mmol, 1 equiv),
and allyl alcohol (56 μL, 0.83, 3.0 equiv). IR (cm−1) 3333, 2951, 1732,
+
(TOF MS AP+) calcd for C23H33N2O5 (M + NH4 ) 417.2389, found
417.2399.
2-[3,5-Dimethoxy-4-(2,2,2-trifluoro-1-phenylethoxymethyl)-
phenyl]-[1,3]dioxolane (45). Compound 45 (yellow oil, 70% over two
steps) was prepared using the same conditions as those described for
compound 15 with the exception that α-(trifluoromethyl)benzyl
alcohol was used instead of phenol. The quantities of reagents used
were N,N,N′,N′-tetramethylazodicarboxamide (51 mg, 0.30 mmol, 1.5
equiv), tributylphosphine (75 μL, 0.3 mmol, 1.5 equiv), 36 (48 mg,
0.20 mmol, 1 equiv), and α-(trifluoromethyl)benzyl alcohol (42 μL,
1
1609; H NMR δ 7.46−7.43 (m, 2H), 7.30−7.28 (m, 3H), 6.04 (s,
1H), 6.61 (s, 2H), 5.95−5.89 (m, 1H), 5.37 (dd, 1H, J = 17.1, 1.5 Hz),
5.26 (dd, 1H, J = 11.4, 1.2 Hz), 4.96 (s, 1H), 4.64−4.62 (m, 3H), 3.71
(s, 6H), 3.65 (s, 3H); 13C NMR δ 171.8, 159.7, 153.05, 140.0, 137.2,
132.3, 128.3, 128.2, 127.4, 118.1, 108.1, 94.2, 79.3, 65.7, 59.5, 55.5,
1
0.30 mmol, 1.5 equiv). IR (cm−1) 2942, 2872, 1595; H NMR δ 7.44
(s, 2H), 7.37 (s, 3H), 6.67 (s, 2H), 5.77 (s, 1H), 4.72 (t, 2H, J = 7.2
Hz), 4.64 (d, 1H, J = 10.8 Hz), 4.11−3.99 (m, 4H), 3.79 (s, 6H); 13C
NMR δ 159.4, 140.4, 133.6, 128.9, 128.3, 128.0, 125.3, 122.6, 113.5,
103.3, 101.6 (2 carbons), 78.4 (q), 65.1, 60.2, 55.6; MS (TOF MS AP
+, m/z) 399.3 (M + H)+. HRMS (TOF MS AP+) calcd for
+
52.0; MS (TOF MS AP+, m/z) 433.4 (M + NH4 ). HRMS (TOF MS
+
AP+) calcd for C22H29N2O7 (M + NH4 ) 433.1975, found 433.1969.
2,5-Dimethoxybenzene-1,4-diol (51). To a stirred suspension of
2,5-dimethoxy-1,4-benzoquinone (1.6 g, 9.5 mmol, 1 equiv) in
methanol (60 mL) and water (120 mL) was added sodium
hydrosulfite (6.6 g, 38 mmol, 4.0 equiv). The reaction mixture was
stirred for 15 min at 23 °C, and then another portion of sodium
hydrosulfite (3.3 g, 19 mmol, 2.0 equiv) was added to the mixture. The
solution was stirred for 2 h at 23 °C. Methanol was removed by rotary
evaporation, and the aqueous solution was extracted with ethyl acetate
(2 × 120 mL). The combined organic layers were washed with
saturated sodium chloride (1 × 120 mL). The organic layer was dried
over sodium sulfate, and the sodium sulfate was removed by filtration.
+
C20H25NO5F3(M + NH4 ) 416.1685, found 416.1693.
3,5-Dimethoxy-4-(2,2,2-trifluoro-1-phenylethoxymethyl)-
benzaldehyde (46). Compound 46 (off-white solid) was prepared
using the same conditions as those described for compound 37. The
quantities of reagents used were 45 (0.29 g, 0.69 mmol, 1 equiv) and
p-toluenesulfonic acid monohydrate (13 mg, 69 μmol, 0.1 equiv).
3,5-Dimethoxy-4-(2,2,2-trifluoro-1-phenylethoxymethyl)benzoic
Acid (47). Compound 47 (white solid) was prepared using the same
conditions as those described for compound 38. The quantities of
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+
The solvent was removed by rotary evaporation to provide compound
51 as a white solid, which was used without further purification.
1,2,4,5-Tetramethoxybenzene (52). Anhydrous potassium carbo-
nate (10.7 g, 76 mmol, 8.0 equiv) was added to a stirred solution of
compound 51 (1.6 g, 9.5 mmol, 1 equiv) in N,N-dimethylformamide
(40 mL). Iodomethane (4.7 mL, 76 mmol, 8.0 equiv) was added
dropwise to the reaction mixture. The reaction mixture then was
heated to 50 °C and was stirred at 50 °C for 16 h. The suspension was
cooled to 23 °C, and N,N-dimethylformamide was removed by rotary
evaporation. The residue was diluted with ethyl acetate (100 mL), and
the organic solution was washed with water (1 × 100 mL) and then
was washed with 2 M aqueous sodium hydroxide until the aqueous
layer remained colorless (6 × 100 mL). The organic layer then was
washed with saturated sodium chloride (1 × 100 mL). The organic
layer was dried over sodium sulfate, and the solid sodium sulfate was
removed by filtration. The solvent was removed by rotary evaporation
to give compound 52 as a pale yellow solid, which was used without
further purification.
2,3,5,6-Tetramethoxybenzaldehyde (21). n-Butyllithium (3.3 mL,
2.5 M in hexanes, 8.4 mmol, 2.0 equiv) was added dropwise to a −78
°C solution of compound 52 (0.83 g, 4.2 mmol, 1 equiv) in
tetrahydrofuran (20 mL). The mixture was allowed to stir for 5 min at
−78 °C and then was warmed to −10 °C. The reaction mixture was
stirred at −10 °C for 1 h and then was cooled to −78 °C. N,N-
Dimethylformamide (1.6 mL, 21 mmol, 5.0 equiv) was added to the
reaction solution, and the solution was allowed to warm to 23 °C.
After 1 h of stirring at 23 °C, the solution was slowly diluted (dropwise
addition) with 1 M hydrochloric acid solution (2 mL). Ethyl acetate
(100 mL) and saturated aqueous sodium bicarbonate (1 × 100 mL)
were added, and the layers were separated. The organic layer was
washed with saturated aqueous sodium chloride solution (1 × 100
mL) and was dried over sodium sulfate. The sodium sulfate was
removed by filtration. The solvent was removed by rotary evaporation,
and the residue was filtered through a plug of silica gel (30% ethyl
acetate in hexanes) to provide compound 21 (containing some
residual 52; ∼7:1 mixture of 21:52), which was used without further
purification.
(TOF MS AP+) calcd for C21H32NO5 (M + NH4 ) 378.2280, found
378.2264.
4-((2-tert-Butylphenoxy)methyl)-2,3,5,6-tetramethoxybenzalde-
hyde (54). n-Butyllithium (1.3 mL, 2.5 M in hexanes, 3.3 mmol, 1.75
equiv) was added dropwise to a −78 °C solution of compound 22
(0.67 g, 1.9 mmol, 1 equiv) in tetrahydrofuran (10 mL). The mixture
was stirred for 5 min at −78 °C and then was warmed to −10 °C. The
reaction mixture was stirred at −10 °C for 1 h and then was cooled to
−78 °C. N,N-Dimethylformamide (0.72 mL, 9.3 mmol, 5.0 equiv) was
added, and the solution was allowed to warm to 23 °C. After 1 h of
stirring at 23 °C, the solution was slowly diluted (dropwise addition)
with 1 M hydrochloric acid solution (1 mL). Ethyl acetate (50 mL)
and saturated aqueous sodium bicarbonate (50 mL) were added, and
the layers were separated. The organic layer was washed with saturated
aqueous sodium chloride (1 × 50 mL) and was dried over sodium
sulfate. Sodium sulfate was removed by filtration. The solvent was
removed by rotary evaporation, and the residue was filtered through a
plug of silica gel (20% ethyl acetate in hexanes) to provide crude
compound 54 (with residual 2, 6:1 mixture of 54:22), which was used
without further purification.
4-((2-tert-Butylphenoxy)methyl)-2,3,5,6-tetramethoxybenzoic
Acid (55). A solution of sodium dihydrogen phosphate monohydrate
(0.94 g, 5.1 mmol, 6.0 equiv) and sodium chlorite (0.62 g, 5.1 mmol,
6.0 equiv) in water (9 mL) was added to a solution of compound 54
(0.33 g, 0.85 mol, 1 equiv) and 2-methyl-2-butene (0.72 mL, 5.1
mmol, 6.0 equiv) in acetone (9.0 mL). The suspension was stirred
vigorously for 30 min at 23 °C. Acetone was removed by rotary
evaporation, and the aqueous reaction mixture was diluted with ethyl
acetate (20 mL) and 1 M hydrochloric acid (10 mL). The layers were
separated, and the organic layer was washed sequentially with
saturated aqueous sodium chloride (2 × 20 mL), saturated aqueous
sodium thiosulfate (1 × 20 mL), and saturated aqueous sodium
chloride solution (1 × 20 mL). The organic layer was dried over
sodium sulfate, and the sodium sulfate was removed by filtration. The
solvent was removed by rotary evaporation to afford compound 55 as
a white solid, which was used without further purification.
Allyl 4-((2-tert-Butylphenoxy)methyl)-2,3,5,6-tetramethoxyphe-
nylcarbamate (20). Triethylamine (0.12 mL, 0.85 mmol, 1.2 equiv)
and diphenylphosphoryl azide (0.18 mL, 0.85 mmol, 1.2 equiv) were
added to a solution of compound 55 (0.29 g, 0.71 mmol, 1 equiv) in
benzene (4 mL) at 23 °C. The reaction mixture was heated to 80 °C.
After 2 h of stirring at 80 °C, allyl alcohol (0.24 mL, 3.6 mmol, 5.0
equiv) was added. The solution was heated to 90 °C, was held at 90
°C for 3 h, and then was allowed to cool to 23 °C. The solvent was
removed by rotary evaporation, and the residue was purified by silica
gel flash column chromatography (10% ethyl acetate in hexanes,
increasing to 25% ethyl acetate in hexanes) to afford compound 20 as
a white solid (0.17 g, 0.36 mmol, 54% over 3 steps): mp 104−106 °C;
(2,3,5,6-Tetramethoxyphenyl)methanol (53). Compound 21 (0.79
g, 3.5 mmol, 1 equiv) was dissolved in dichloromethane (10 mL) and
methanol (10 mL). Sodium borohydride (0.13 mg, 3.5 mmol, 1.0
equiv) was added to the reaction mixture, and the solution was stirred
for 5 min at 23 °C. Saturated aqueous ammonium chloride (5 mL)
was added, and the reaction mixture was diluted with dichloromethane
(50 mL). The layers were separated, and the organic layer was washed
with saturated aqueous ammonium chloride (1 × 50 mL) and
saturated sodium chloride (1 × 50 mL). The organic layer was dried
over sodium sulfate, and the sodium sulfate was removed by filtration.
The solvent was removed by rotary evaporation to provide compound
53 as a white solid, which was used without further purification.
3-((2-tert-Butylphenoxy)methyl)-1,2,4,5-tetramethoxybenzene
(22). N,N,N′,N′-Tetramethylazodicarboxamide (0.63 g, 3.7 mmol, 1.3
equiv) was dissolved in benzene (14 mL), and the reaction mixture
was cooled to 0 °C. Tributylphosphine (0.92 mL, 3.7 mmol, 1.3 equiv)
was added to the reaction solution, and the mixture was stirred at 0 °C
for 15 min. A solution of compound 53 (0.64 g, 2.8 mmol, 1 equiv)
and 2-tert-butylphenol (0.56 mL, 3.7 mmol, 1.3 equiv) in benzene (14
mL) was added, and the resulting solution was allowed to warm to 23
°C over 1 h. The reaction mixture was diluted with ethyl acetate (50
mL), and the diluted solution was washed with water (1 × 50 mL) and
saturated aqueous sodium chloride solution (1 × 50 mL). The organic
layer was dried over sodium sulfate, and the sodium sulfate was
removed by filtration. The solvent was removed by rotary evaporation,
and the resulting oil was purified by silica gel flash column
chromatography (5% ethyl acetate in hexanes, increasing to 40%
ethyl acetate in hexanes) to afford compound 22 as a white solid (0.67
IR (cm−1) 3310, 2944, 1726; H NMR δ 7.30−7.20 (m, 2H), 7.1 (d,
1
1H, J = 8.2 Hz), 6.93 (t, 1H, J = 7.4), 6.25 (s, 1H), 6.02−5.92 (m,
1H), 5.38 (dd, 1H, J = 17.3, 1.6 Hz), 5.33 (dd, 1H, J = 10.4, 1.4 Hz),
5.02 (s, 2H), 4.69 (dt, 2H, J = 5.5, 1.4 Hz), 3.82 (s, 12H), 1.29 (s,
9H); 13C NMR δ 158.0, 154.4, 148.6, 144.4, 138.4, 132.5, 127.0, 126.6,
125.3, 122.5, 120.3, 117.9, 112.6, 66.2, 61.45, 60.7, 59.7, 34.7, 29.8; MS
(TOF MS AP+, m/z) 460.2 (M + H+). HRMS (TOF MS AP+) calcd
for C25H34NO7 (M + H+) 460.2335, found 460.2317.
4-Bromo-1-((2-tert-butylphenoxy)methyl)-2-methoxybenzene
(56). N,N,N′,N′-Tetramethylazodicarboxamide (0.27 g, 1.2 mmol, 1.2
equiv) was dissolved in benzene (10 mL), and the reaction mixture
was cooled to 0 °C. Tributylphosphine (0.30 mL, 1.2 mmol, 1.2 equiv)
was added to the reaction solution, and the mixture was stirred at 0 °C
for 15 min. A solution of 4-bromo-2-methoxybenzyl alcohol (0.22 g,
1.0 mmol, 1 equiv) and 2-tert-butylphenol (0.18 mL, 1.2 mmol, 1.2
equiv) in benzene (10 mL) was added. The resulting solution was
allowed to warm to 23 °C over 1 h and then was stirred at 23 °C for
16 h. The product solution was diluted with ethyl acetate (50 mL) and
then was washed with water (1 × 50 mL) and saturated sodium
chloride (1 × 50 mL). The organic layer was dried over sodium sulfate,
and the sodium sulfate was removed by filtration. The solvent was
removed by rotary evaporation, and the resulting oil was filtered
1
g, 1.9 mmol, 20% over 5 steps). IR (cm−1) 2954; H NMR δ 7.31−
7.16 (m, 3H), 6.93 (td, 1H, J = 16.1, 1.5 Hz), 6.62 (s, 1H), 5.08 (s,
2H), 3.88 (s, 6H), 3.78 (s, 6H), 1.31 (s, 9H); 13C NMR δ 158.1,
148.8, 142.1, 138.3, 127.0, 126.5, 124.6, 120.2, 112.7, 99.8, 61.7, 59.9,
56.3, 34.7, 29.9; MS (TOF MS AP+, m/z) 361.2 (M + H+). HRMS
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through a plug of silica gel (100% hexanes, increasing to 10% ethyl
acetate in hexanes) to afford compound 56 as a yellow oil, which was
used without further purification.
sodium chloride (1 × 20 mL). The organic layer was dried over
sodium sulfate, and the solid sodium sulfate was removed by filtration.
The solvent was removed by rotary evaporation to yield 26 as a white
solid, which was used without further purification.
4-((2-tert-Butylphenoxy)methyl)-3-methoxybenzoic Acid (57).
Compound 56 (0.23 g, 0.64 mmol, 1 equiv) was dissolved in
tetrahydrofuran (6 mL), and the solution was cooled to −78 °C. n-
Butyllithium (0.52 mL, 2.4 M in hexanes, 2.0 equiv) was added
dropwise, and the resulting mixture was stirred at −78 °C for 5 min.
Dry carbon dioxide was bubbled through an 18 gauge metal needle
into the reaction mixture for 15 min, and then the reaction mixture
was allowed to warm to 23 °C. Aqueous sodium hydroxide solution (1
M, 1 mL) was added to the reaction mixture, followed by ethyl acetate
(20 mL). The layers were separated, and the organic layer was
extracted with 1 M aqueous sodium hydroxide (2 × 20 mL). The
combined aqueous layers were acidified to pH 2 by addition of
concentrated hydrochloric acid. The acidic aqueous solution was
extracted with ethyl acetate (2 × 20 mL). The combined organic
extracts were dried over sodium sulfate, and the solid sodium sulfate
was removed by filtration. The solvent was removed by rotary
evaporation to afford compound 57 as a white solid that was used
without further purification.
Carbonic Acid Allyl Ester 4-(2-tert-Butyl-phenoxymethyl)-3,5-
dimethoxy-phenyl Ester (23). Tributylphosphine (0.20 μL, 0.78
mmol, 1.4 equiv) was added to a 0 °C solution of diamide (0.13 g, 0.78
mmol, 1.4 equiv) in benzene (2.5 mL), and the resulting reaction
mixture was stirred at 0 °C for 15 min. To this cold solution was added
a solution of compound (26) (0.15 g, 0.56 mmol, 1 equiv) and 2-tert-
butylphenol (0.12 mL, 0.78 mmol, 1.4 equiv) in benzene (2.5 mL).
The resulting solution was allowed to warm to 23 °C over 1 h. The
solvent was removed by rotary evaporation, and the resulting oil was
purified by silica gel flash column chromatography (5% ethyl acetate in
hexanes, increasing to 20% ethyl acetate in hexanes) to afford
compound 23 (90 mg, 0.23 mmol, 40% over 2 steps) as a white solid:
mp 69−71 °C; IR (cm−1) 2955, 1763, 1607; 1H NMR δ 7.35 (dd, 1H,
J = 7.8, 1.8 Hz), 7.26 (t, 1H, J = 5.4 Hz), 7.18 (dd, 1H, J = 8.1, 0.9
Hz), 6.95 (td, 1H, J = 7.5, 1.2 Hz), 6.12−6.01 (m, 1H), 5.54 (dd, 1H, J
= 17.1, 1.2 Hz), 5.43 (dd, 1H, J = 10.5, 0.9 Hz), 5.14 (s, 2H), 4.83 (d,
2H, J = 5.7 Hz), 3.85 (s, 6H), 1.37 (s, 9H); 13C NMR δ 159.7, 158.2,
153.2, 152.7, 138.3, 131.0, 126.8, 126.3, 119.8, 119.6, 112.3, 111.2,
69.2, 58.5, 55.8, 34.7, 29.6; MS (TOF MS AP+, m/z) 423.3 (20, M +
Na), 251.3 (100). HRMS (TOF MS AP+) calcd for C23H32NO6 (M +
NH4) 418.2234, found 418.2230.
General Conditions for Measuring the Release Kinetics. An
Alloc-protected compound (0.01 mmol) and tetrakis-
(triphenylphosphine)palladium(0) (1.1 mg) were dissolved in 0.1
mL of tetrahydrofuran in a 2-mL vial. Acetic acid (1.5 μL) and
tributyltin hydride (5 μL) were added to the reaction mixture, and the
solution was shaken for 3 min. An aliquot (10 μL) of the solution was
added to an HPLC vial and was diluted with acetonitrile (0.5 mL) and
phosphate buffer (0.1 M, pH 7.1, 0.5 mL). The solution was shaken
for 10 s and then was filtered through a syringe filter (PTFE, 0.22 μm).
The release of the alcohol/phenol was inferred by monitoring the
disappearance of the aniline intermediate by HPLC using a UV
detector set at 254 nm or 330 nm. The relative quantity of the aniline
intermediate that is formed after Alloc deprotection was measured
over time by integration of the peak area at 254 nm or 330 nm. The
HPLC spectra showed clean conversion of this aniline intermediate
into the byproducts depicted in Figure 2. Identical kinetics data were
obtained when the quantity of phenol was measured over time (by
integration of the peak area at 254 nm or 330 nm), but for some
derivatives, the released phenol was too close to the solvent front for
accurate integration.
Allyl 4-((2-tert-Butylphenoxy)methyl)-3-methoxyphenylcarba-
mate (58). Triethylamine (90 μL, 0.65 mmol, 1.2 equiv) and
diphenylphosphoryl azide (0.14 mL, 0.65 mmol, 1.2 equiv) were
added to a solution of compound 57 (0.17 g, 0.54 mmol, 1 equiv) in
benzene (2.5 mL) at 23 °C. The reaction mixture was heated to 80 °C.
After 2 h of stirring at 80 °C, allyl alcohol (0.18 mL, 2.7 mmol, 5.0
equiv) was added. The solution was heated to 90 °C, was held at 90
°C for 3 h, and then was allowed to cool to 23 °C. The solvent was
removed by rotary evaporation, and the residue was purified by silica
gel flash column chromatography (5% ethyl acetate in hexanes,
increasing to 20% ethyl acetate in hexanes) to afford compound 58 as
a white solid (0.15 g, 0.41 mmol, 41% over 3 steps). IR (cm−1) 3323,
1
2955, 1708; H NMR δ 7.37−7.27 (m, 3H), 7.1 (td, 1H, J = 8.2, 1.7
Hz), 6.95 (dd, 1H, J = 8.2, 1.1), 6.9 (td, 1H, J = 7.5, 1.2 Hz), 6.73−
6.69 (m, 2H), 6.00−5.92 (m, 1H), 5.38 (dd, 1H, J = 19.1, 1.5 Hz),
5.28 (dd, 1H, J = 10.4, 1.3 Hz), 5.06 (s, 2H), 4.67 (d, 2H, J = 5.7 Hz),
3.84 (s, 3H), 1.37 (s, 9H); 13C NMR δ 157.8, 157.5, 153.2, 138.6,
138.2, 132.4, 129.1, 127.0, 126.6, 120.9, 120.3, 118.3, 112.6, 110.2,
101.4, 65.9, 65.1, 55.4, 34.9, 29.8; MS (TOF MS AP+, m/z) 392.2 (M
+
+ Na+). HRMS (TOF MS AP+) calcd for C22H31N2O4 (M + NH4 )
387.2284, found 387.2269.
Carbonic Acid Allyl Ester 4-Formyl-3,5-dimethoxy-phenyl Ester
(25). 4-Hydroxy-2,6-dimethoxybenzaldehyde (24) (0.18 g, 1.0 mmol,
1 equiv) was dissolved in dichloromethane (8.0 mL) and pyridine (1.6
mL, 20 mmol, 20 equiv), and the mixture was cooled to 0 °C. Allyl
chloroformate (1.1 mL, 10 mmol, 10 equiv) was added dropwise, and
the reaction solution was allowed to warm to 23 °C over 2 h. The
reaction mixture then was diluted with dichloromethane (20 mL) and
was washed sequentially with saturated aqueous ammonium chloride
solution (2 × 30 mL) saturated aqueous sodium chloride solution (1 ×
30 mL). The organic layer was dried over sodium sulfate, and the solid
sodium sulfate was removed by filtration. The solvent was removed by
rotary evaporation, and the residue was purified by flash chromatog-
raphy (20% ethyl acetate in hexanes, increasing to 60% ethyl acetate in
hexanes) to yield 25 as an opaque white film (0.22 g, 0.84 mmol,
General Procedure for Crystallizing Compounds 4, 8, 9, and
20. Compounds 4, 8, 9, and 20 were crystallized by vapor diffusion in
benzene and pentane. Each compound (∼10 mg) was dissolved in a
minimum amount of benzene. Pentane was allowed to diffuse into the
benzene solution through a pin-sized hole in an aluminum foil cover
over the course of 24−48 h. White, opaque needles were formed in all
cases.
ASSOCIATED CONTENT
■
1
84%). IR (cm−1) 2946, 1764, 1686, 1599; H NMR δ 10.36 (s, 1H),
S
* Supporting Information
6.42 (s, 2H), 5.98−5.90 (m, 1H), 5.41 (d, 1H, J = 17.2), 5.31 (d, 2H, J
= 10.4), 4.70 (d, 2H, J = 4.8), 3.82 (s, 6H); 13C NMR δ 187.9, 163.0,
156.7, 152.2, 130.6, 119.8, 112.1, 97.3, 69.4, 56.2; MS (TOF MS AP+,
m/z) 289.3 (14, M + Na), 267.3 (100, MH+). HRMS (TOF MS AP
+) calcd for C13H15O6 (MH+) 267.0862, found 267.0869.
Tables giving experimental data, figures giving crystallographic
1
data in CIF format, and figures giving H and 13C NMR
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
Carbonic Acid Allyl Ester 4-Hydroxymethyl-3,5-dimethoxy-phenyl
Ester(26). Sodium borohydride (32 mg, 0.84 mmol, 1.0 equiv) was
added to a solution of compound 25 (0.22 g, 0.84 mmol, 1 equiv) in
dichloromethane (4 mL) and methanol (4 mL). The reaction mixture
was stirred for 5 min and then was diluted with saturated aqueous
ammonium chloride (1 mL) and dichloromethane (20 mL). The
layers were separated, and the organic layer was washed with saturated
aqueous ammonium chloride (1 × 20 mL) and saturated aqueous
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sphillips@psu.edu.
Notes
The authors declare no competing financial interest.
4373
dx.doi.org/10.1021/jo300400q | J. Org. Chem. 2012, 77, 4363−4374

The Journal of Organic Chemistry
Article
we include the additional element of being able to tune the response
properties of the spacer to enable precise control over the rate of
release of a phenol that is linked to the spacer as an ether.
(32) A study on a new protecting group33 that was published during
the course of this work and a report by Rokita et al.34 provide further
support for this idea.
ACKNOWLEDGMENTS
■
This work was supported in part by the American Chemical
Society (PRF no. 51618-DNI7), the Arnold and Mabel
Beckman Foundation, the Camille and Henry Dreyfus
Foundation, Mr. Louis Martarano, and The Pennsylvania
State University. We thank Dr. Landy K. Blasdel for her
contributions to the preparation of the manuscript.
(33) Muranaka, K.; Ichikawa, S.; Matsuda, A. J. Org. Chem. 2011, 76,
9278−9293.
(34) Weinert, E. E.; Dondi, R.; Colloredo-Melz, S.; Frankenfield, K.
N.; Mitchell, C. H.; Freccero, M.; Rokita, S. E. J. Am. Chem. Soc. 2006,
128, 11940−11947.
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