Photochemical Cleavage of Benzylic C-O Bond Facilitated by an Ortho or Meta Amino Group

Article abstract of DOI:10.1021/acs.joc.7b00927

The excited state meta effect, also known as the meta-ortho effect, results from selective electron transmission from an electron-donating group to the meta and ortho sites on an aromatic ring in its first excited singlet state. This effect facilitates photochemical cleavage of benzylic C-O or C-N bond to release the corresponding alcohol, carboxylic acid, or amine when an electron-donating amino group is at the meta position, as demonstrated in our recent work of using a 3-diethylaminobenzyl (DEABn) group as an effective photolabile protecting group (PPG). Herein, we demonstrate that an ortho amino group can also facilitate benzylic C-O bond cleavage to release an alcohol or carboxylic acid. However, an amino group at the meta position results in a PPG with better overall chemical and photochemical properties.

Full text of DOI:10.1021/acs.joc.7b00927

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Article
Photochemical Cleavage of Benzylic C-O Bond
Facilitated by an Ortho or Meta Amino Group
Xiong Ding, and Pengfei Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00927 • Publication Date (Web): 23 Jun 2017
Downloaded from http://pubs.acs.org on June 23, 2017
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Photochemical Cleavage of Benzylic C-O Bond
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Facilitated by an Ortho or Meta Amino Group
Xiong Ding, and Pengfei Wang*
Department of Chemistry, University of Alabama at Birmingham, 901 14th Street South,
Birmingham, AL 35294
wangp@uab.edu
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
ABSTRACT The excited state meta effect, also known as the meta-ortho effect, results from
selective electron transmission from an electron-donating group to the meta and ortho sites on
an aromatic ring in its first excited singlet state. This effect facilitates photochemical cleavage
of benzylic C-O or C-N bond to release the corresponding alcohol, carboxylic acid, or amine
when an electron-donating amino group is at the meta position, as demonstrated in our recent
work of using a 3-diethylaminobenzyl (DEABn) group as an effective photolabile protecting
group (PPG). Herein we demonstrate that an ortho amino group can also facilitate benzylic
C-O bond cleavage to release an alcohol or carboxylic acid. However, an amino group at the
meta position results in a PPG with better overall chemical and photochemical properties.
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INTRODUCTION
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Photolabile protecting groups are valuable to a wide range of research areas, owing to their
chemical-reagent-free removal that can be achieved with high temporal and spatial precision.
Their photochemistry and broad applications have been frequently reviewed.1-8 Continuously
increasing interests in PPG applications have attracted more efforts in developing new PPGs to
complement the existing ones. Recently, our lab developed a number of structurally simple
PPGs for protection of carbonyl, hydroxyl, diol, carboxyl, and amino functionalities.8-9 These
new PPGs are designed on the basis of the excited state meta effect which is also known as the
excited state meta-ortho effect. Zimmerman’s MO computation revealed a selective
transmission of electron density to the meta and ortho positions on an aromatic ring in the first
excited singlet state.10-13 As demonstrated in our PPGs, the meta effect facilitates
photochemical cleavage of a benzylic C-O or C-N bond to release various functionalities. The
particular meta amino group has been studied for its role in the meta effect,14-19 and has been
utilized in PPG designs. Toscano et al. demonstrated release of diazeniumdiolates from
3-(dimethylamino) benzyl protection,20 and Falvey et al. showed photochemical heterolysis of
3,5-bis(dimethylamino)benzyl ester to release carboxylic acids.21 The most recent example is
the 3-diethylaminobenzyl (DEABn) PPG which can efficiently release hydroxyl, carboxyl, and
amino functionalities (Scheme 1).22-25 We notice that the DEABn PPG differs from the known
3,5-dimethoxy-benzyl (DMBn) PPG which was also based on the meta effect.26 The latter is
known for only releasing good leaving groups such as carboxylate, carbonate, and carbamate
while the DEABn PPG directly releases various alcohols and amines via effective cleavage of
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the benzylic C-O or C-N bond in the excited state (Scheme 1). We infer that similar benzylic
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bond cleavage can be facilitated by an ortho amino group, leading to new PPGs.
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Scheme 1. DEABn PPG for Protection of Different Functionalities
RESULTS AND DISCUSSION
To examine feasibility of releasing substrates from the benzylic position ortho to an amino
substituent, we planned to compare photolysis of benzyl esters 2-4, with a dimethylamino
(DMA) group at the ortho, meta, and para position respectively (Figure 1). Unsubstituted and
commercially available benzyl ester 5 would be used as a control.
Figure 1. Benzyl esters for photolysis.
Esters 2-4 were easily synthesized (Scheme 2). Thus, reduction of commercially available
methyl N,N-dimethylanthranilate 6 with LiAlH4 led to 2-dimethylaminobenzyl alcohol 7,
which is also commercially available, in 91% yield. Its reaction with octanoyl chloride
provided ester 2 in 84% yield. Preparation of ester 3 and 4 was carried out in a similar manner
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from commercially available 3-dimethylaminobenzoic acid 8 and methyl 4-aminobenzoate 9,
respectively. However, para-substituted benzyl ester 4 was thermally unstable and decomposed
during column chromatographic purification while the esters 2 and 3 both remained stable at up
to 80 oC for 30 min in MeCN/water (4:1) or methanol.
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Scheme 2. Synthesis of Esters 2-4a
o
aReagents and conditions: (a) LiAlH4, THF, 0–50 C, 93%; (b) octanoyl chloride, DMAP,
Et3N, DCM, 86%; (c) LiAlH4, THF, r.t., 97%; (d) octanoyl chloride, DMAP, Et3N, DCM,
95%; (e) paraformaldehyde, NaBH3CN; LiAlH4, THF, 83%; (f) octanoyl chloride, DMAP,
Et3N, DCM.
To compare photochemical properties of 2 and 3, we irradiated 2-DMABn ester 2 and
3-DMABn ester 3 under the same conditions, against unsubstituted benzyl ester 5 as the
control. Compounds 2 and 3 have significantly different UV absorption profiles. Due to the
steric interaction between the adjacent dimethylamino and methylene groups in 2, conjugation
of the dimethylamino group to the benzene ring cannot be achieved as completely as in 3. As
consequence, the UV absorption of 2 does not have a distinct peak at ~313 nm as in the
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3-dialkylaminobenzyl counterparts; instead the peak at 252 nm of the 2-DMABn group has a
shoulder extending to ~330 nm. Irradiation of these compounds was carried out with a 450W
medium pressure mercury lamp equipped with a Pyrex filter sleeve (>300 nm) without
deaeration. For 10 min irradiation in CD3CN/D2O (4:1), 2 released the acid in 73% yield while
3 released the same acid in a lower yield of 55% (Table 1, entries 1 and 2). Irradiation for an
additional 10 min increased the yield to 83% for 2 and 70% for 3, respectively. The data
showed that the 2-DMABn is more efficient than 3-DMABn in releasing acid in CD3CN/D2O.
However, in CD3OD, 2-DMABn becomes less efficient than 3-DMABn. Although irradiation
for 10 min led to similar yields of releasing the acid from 2 (68%) and 3 (71%), 20 min
irradiation led to a more drastic difference between 2 (75%) and 3 (94%). This
solvent-dependent reactivity change is probably related to solvent effect on a proposed single
electron transfer (SET) process (vide infra),24 the resulting charge-transfer state, and
subsequent decay pathways.14-15 Control compound 5 was stable under the reaction conditions
due to its lack of UV absorption at  > 300 nm; it remained stable upon irradiation with a Vycor
filter sleeve (>220 nm).
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Table 1. Photochemical Release of Acid or Alcohol from Amino-Substituted Benzyl Groupa
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Releasing yield, 10 min Releasing yield, 20 min
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compound
entry
CH3CN/D2O
(4:1)
CH3CN/D2O
(4:1)
CD3OD
CD3OD
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aA 5.0 mM solution in 5 mm NMR tubes was irradiated with a 450W medium pressure mercury lamp equipped with a Pyrex filter sleeve (>
300 nm) without deaeration. The yields were determined by 1H NMR analysis.
Interestingly, for releasing alcohols, the 2-DMABn PPG showed comparable efficiency as
for releasing acid in both CD3CN/D2O and CD3OD (Table 1, entry 3), albeit alkoxide being a
poorer leaving group compared with carboxylate. On the other hand, comparison between
2-DMABn (as in 10) and 3-DMABn (as in 11a) in releasing 3-phenyl-1-propanol showed that
3-DMABn is better than 2-DMABn. Within 10 min, the alcohol was released from 11a in
nearly quantitative yield in both CD3CN/D2O and CD3OD (Table 1, entry 4), much higher than
that of the corresponding 2-DMABn. We also compared the photoreaction of 11a and 11b22
under the same conditions, and confirmed that the DMABn (in 11a) and DEABn PPG (in 11b)
have similar efficiency (Table 1, entries 4 and 5), showing that alkyl substitution on the aniline
amino group did not alter the photoreaction outcomes. Ethers 10 and 11a were prepared from
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the respective benzyl alcohols and 3-phenylpropyl tosylate while 11b was prepared from
3-phenyl-1-propanol and the corresponding benzyl chloride in good yields.22
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The data in Table 1 clearly showed that release of alcohol by 3-DMABn is more efficient
than release of acid (Table 1, entries 2 and 4), which is consistent with our early observations
with the 3-DEABn PPG.22 We postulated that with the presence of the ester moiety, a SET
process between the aromatic amino group and the ester functional group, and the subsequent
decay, might serve as an internal filtering process, which reduces the efficiency of
photochemical C-O bond cleavage. Similar SET from a meta amino group is known in
literature.14-17, 19, 21
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A relevant observation is that not only is an acid slower to be cleaved from the PPG than an
alcohol, but also the presence of a benzyl ester moiety slows down the release of alcohol, as
demonstrated in the photoreactions of 12-14. Since deprotection of DEABn does not destroy
the working chromophore, we previously demonstrated that release of two alcohol substrates
from one PPG chromophore could be achieved in high yield.22 We thus synthesized diether 12,
diester 13, and mixed ether and ester 14 to compare their efficiency in releasing the respective
substrates. The synthesis was straightforward, starting from commercially available
5-dimethylamino-1,3-benzenedimethanol diol 15a or 15b,22 as shown in Scheme 3.
Scheme 3. Synthesis of Compounds 12-14 that Release Two Substrates from One
Chromophorea
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aReagents and conditions: (a) NaH, Ph(CH2)3OTs, DMF, 0 oC to rt, 43% for 12a; (b) SOCl2,
o
o
DCM, -10 C to rt; Ph(CH2)3OH, NaH, Bu4NBr, DMF, 0 C to rt, 85% for 12b; (c) octanoyl
chloride, DMAP, Et3N, DCM, 93% for 13a and 95% for 13b; (d) NaH, Ph(CH2)3OTs; DMF, rt
to 50 oC, 37%; (e) octanoyl chloride, DMAP, Et3N, DCM, 90%.
With 3-phenyl-1-propanol as the leaving alcohol substrate, irradiation of 12a and 12b (313
nm (MeCN) = 3000 M-1 cm-1,  = 0.20) in CD3CN/D2O (4:1) for 10 min resulted in releasing of the
alcohol in a quantitative yield (Table 2, entries 1 and 2), consistent with our earlier results.22
Irradiation of 13 under the same conditions led to slower release of the acid substrate (Table 2,
entries 3 and 4). Based on the results of 12 and 13, we expected that irradiation of 14 would
lead to sequential release of two different substrates from the same PPG, i.e., the alcohol would
be released first, followed by the acid. However, under the same photoreaction conditions,
compound 14 only released the alcohol in 35% yield after 10 min of irradiation and 76% yield
after another 10 min of irradiation (Table 2, entry 5), much slower than 12. It appeared that the
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presence of the benzylic ester moiety interfered with the release of the alcohol occurring at the
other meta position. Presumably, the hypothesized SET process between the aromatic amino
group and the ester functional group and the subsequent decay process might again serve as an
internal filtering process to reduce the efficiency of photochemical C-O bond cleavage on the
other side of the chromophore.
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Table 2. Photoreaction of 12-14a,b
Releasing yield, 10 min Releasing yield, 20 min
compound
entry
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alcohol
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100%
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acid
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alcohol
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100%
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12b
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35%
76%
aA 5.0 mM solution (in CD3CN/D2O 4:1) in 5 mm NMR tubes was irradiated with a 450W medium pressure mercury lamp equipped with a
Pyrex filter sleeve (>300 nm) without deaeration. The yields were determined by 1H NMR analysis. bYield = released substrate/total substrate
expected to be released.
Encouraged by the highly efficient release of alcohols from structurally simple diether 12,
we went on to examine the feasibility of releasing alcohols from diethers 17 and 18 (Scheme 4).
Diether 17 was synthesized from commercially available 3-aminophthalic acid 19 through diol
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intermediate 20, and diether 18 was synthesized from commercially available dimethyl
aminoterephthalate 21 through diol intermediate 22 which is also commercially available.
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Scheme 4. Synthesis of Diethers 17 and 18a
aReagents and conditions: (a) K2CO3, CH3I, DMF, rt, 35%; (b) LiAlH4, THF, 0 to 60 oC, 59%;
(c) NaH, Ph(CH2)3OTs, DMF, 0 oC to rt, 77%; (d) K2CO3, CH3I, DMF, 30 oC, 34%; (e) LiAlH4,
THF, 0 to 60 oC, 86%; (f) NaH, Ph(CH2)3OTs, DMF, 0 oC to rt, 83%;
Under the same irradiation conditions, 12a released all the alcohols within 10 min, while
17 and 18 only released 27% and 29%, respectively (Table 3). At the end of 30 min of
irradiation, there was only 58% of alcohol released from 17 and 54% from 18. This reduced
chemical efficiency of 17 and 18 can perhaps also be attributed to the reduced conjugation of
the dimethylamino group with the benzene ring in 17 and 18 due to the steric interaction
between the amino group and the ortho methylene group. The reduced conjugation affects not
only release of alcohol from the ortho benzylic position as shown in 10 (Table 1, entry 3) but
also cleavage of the meta benzylic C-O bond in 17 and 18.
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Table 3. Photoreaction of Diethers 12a, 17, and 18a,b
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entry
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compound
12a
10 min
100%
27%
20 min
30 min
100%
58%
100%
33%
48%
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29%
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aA 5.0 mM solution (in CD3CN/D2O 4:1) in 5 mm NMR tubes was irradiated with a 450W medium pressure mercury lamp equipped with a
Pyrex filter sleeve (>300 nm) without deaeration. The yields were determined by 1H NMR analysis. bYield = released substrate/total substrate
expected to be released.
Based on these results as well as the fact that access to 12 is much easier than to17 and 18,
we decided to continue the study of releasing multiple substrates from one molecule with the
bifunctional PPG in 12. We next examined the efficiency of releasing four alcohols from a
single molecule. Synthesis of the PPG carrier started with commercially available dimethyl
5-aminoisophthalate 23 (Scheme 5). Its ethylation and subsequent reduction with LAH led to
5-(N-ethylamino)-1,3-benzenedimethanol 24. Two 24 molecules were then joined together to
provide the tetraol 25 in 75% yield. It was then converted to new PPG reagent 26 in 84% yield
by treating with thionyl chloride. Reaction of the new PPG reagent with alcohol substrate, i.e.,
commercially available diacetone-D-glucose, loaded four monosaccharides to the
photoresponsive carrier to provide 27 in 76% yield. Upon irradiation of a 5.0 mM solution of
27 (317 nm (MeCN) = 4300 M-1 cm-1,  = 0.09) in CH3CN/H2O (4:1), the monosaccharide was
released completely within 20 min, and an isolated yield of 90% (obtained ROH/all expected
ROH) was achieved, consistent with the yield determined by NMR.
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Scheme 5. Photorelease of Multiple Substrates from One Chromophorea
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aReagents and conditions: (a) Na2HPO4, EtI, DMF, 60 oC, 44%; (b) LiAlH4, THF, 0 to 60
oC, 82%; (c) K2CO3, I(CH2)2O(CH2)2O(CH2)2I, MeCN, 95 oC, 75%; (d) SOCl2, MeCN, 0 oC to
rt, 84%; (e) diacetone-D-glucose, NaH, Bu4NBr, DMF, 0 oC to rt, 76%; (f) h, MeCN/H2O 4:1,
90% (released ROH/all ROH expected to be released).
In summary, we provided experimental evidence to show that an ortho amino group can
indeed facilitate benzylic C-O bond cleavage to release alcohol and carboxyl acid. We
compared the efficiency of cleaving benzylic C-O bond in 2-DMABn and 3-DMABn, and
concluded that amino group at the meta position results in a PPG with better overall chemical
and photochemical properties. We further demonstrated that by joining two PPGs as shown in
Scheme 5, four alcohol substrates can be released from one molecule in high efficiency.
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Experimental Section
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General. Organic solutions were concentrated by rotary evaporation at ca. 12 Torr. Flash
column chromatography was performed employing 230-400 mesh silica gel. Thin-layer
chromatography was performed using glass plates pre-coated to a depth of 0.25 mm with
230-400 mesh silica gel impregnated with a fluorescent indicator (254 nm). Infrared (IR) data
are presented as frequency of absorption (cm-1). Proton and carbon-13 nuclear magnetic
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resonance (1H NMR or C NMR) spectra were recorded on 300, 400 and 700 MHz NMR
spectrometers; Chemical shifts are expressed in parts per million (δ scale) downfield from
tetramethylsilane and are referenced to residual protium in the NMR solvent (CHCl3: δ 7.26).
Data are presented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet,
q = quartet, quint = quintet, m = multiplet and/or multiple resonances), coupling constant in
Hertz (Hz), integration. HRMS was conducted with ESI ionization method and with TOF
mass analyser.
Materials. Anhydrous solvents Tetrahydrofuran (THF), dimethylformamide (DMF), and
dichloromethane (DCM) were used without distillation. Solvents for workup and column
chromatography, such as petroleum ether (PE), ethyl acetate (EA), methanol (MeOH), and
triethylamine (TEA), and other chemicals were obtained from commercial vendors and used
without further purification.
Synthesis of 2-(N,N-dimethylamino)benzyl octanoate 2: To methyl 2-(dimethylamino)
benzoate (3.580 g, 20.0 mmol) in THF (100.0 mL) was added LiAlH4 (0.912 g, 24.0 mmol) at
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0 C under nitrogen atmosphere. The reaction was stirred at 50 C for 3 h and was then
quenched with H2O and treated with 10% NaOH (aq) and water. The precipitate was removed
through filtration and the filtrate was concentrated under reduced pressure to give a yellow oil
which was purified by column chromatography (PE/EA 3:1) to provide benzyl alcohol 7 (2.802
g, 93%, Rf = 0.15). To benzyl alcohol 7 (76.0 mg, 0.500 mmol), octanoyl chloride (0.082 mL,
0.480 mmol), and DMAP (1.0 mg, 0.005 mmol) in DCM (2.0 mL) was added triethylamine
(0.174 mL, 1.250 mmol). The reaction mixture was stirred for 2 h and quenched with statured
NaHCO3 aqueous solution. The organic layer was washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The crude product was purified with column
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chromatography (PE/EA 20:1, Rf = 0.8) to provide 3 (115.0 mg, 86%) as a colorless oil. H
NMR (700 MHz, CDCl3) δ 7.36 (d, J = 7.6 Hz, 1 H), 7.28 (t, J = 7.7 Hz, 1 H), 7.12 (d, J =
7.7 Hz, 1 H), 7.06 (t, J = 7.7 Hz, 1 H), 5.25 (s, 2 H), 2.70 (s, 6 H), 2.37 (t, J = 7.7 Hz, 2 H),
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1.66 (quint, J = 7.0 Hz, 2 H), 1.33-1.24 (m, 8 H), 0.89 (t, J = 7.0 Hz, 3 H); C NMR (176
MHz, CDCl3) δ 174.0, 153.0, 130.4, 129.6, 128.9, 123.1, 119.3, 62.5, 45.2, 34.5,
31.7,29.1,29.0, 25.0, 22.6, 14.1; IR (neat) 2927, 2857, 2830, 2785, 1734, 1494, 1454; HRMS
(ESI-TOF) m/e: [M+H]+ calcd for C17H28NO2 278.2120; found 278.2126.
Synthesis of 3-(N,N-dimethylamino)benzyl octanoate 3: To 3-(dimethylamino)benzoic acid
(8.870 g, 54.0 mmol) in THF (150.0 mL) was added LiAlH4 (4.104 g, 108.0 mmol) under N2
at room temperature. The reaction mixture was stirred overnight and quenched with water
(3.8 mL) followed by treatment with 10% NaOH aqueous solution. The precipitate was
filtered off and the filtrate was concentrated under reduced pressure. The crude reaction
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product was purified by column chromatography (PE/EA 3:1, Rf = 0.20) to provide oil
intermediate 3-(dimethylamino)benzyl alcohol (7.897 g, 97%). To the alcohol (100.0 mg,
0.662 mmol), octanoyl chloride (0.142 mL, 0.828 mmol), and DMAP (1.0 mg, 0.007 mmol) in
DCM (5.0 mL) was added triethylamine TEA (0.184 mL, 1.665 mmol) at room temperature.
After 5 h, the reaction was quenched with statured NaHCO3 (aq). The organic layer was
washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The reaction
mixture was purified by column chromatography (PE/EA 95:5, Rf = 0.5) to provide 4 as a
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colorless oil (174.0 mg, 95%). H NMR (700 MHz, CDCl3) δ 7.24 (t, J = 8.0 Hz, 1 H),
6.71-6.69 (m, 3 H), 5.07 (s, 2 H), 2.95 (s, 6 H), 2.35 (t, J = 7.7 Hz, 2 H), 1.64 (quint, J = 7.4
Hz, 2 H), 1.30-1.25 (m, 8 H), 0.87 (t, J = 6.7 Hz, 3 H); 13C NMR (176 MHz, CDCl3) δ 173.8,
150.7, 136.9, 129.3, 116.3, 112.4, 112.2, 40.6, 34.4, 31.7, 29.1, 29.0, 25.0, 22.6, 14.1; IR
(neat) 2953, 2926, 2855, 2805, 1733, 1606, 1583, 1500, 1459, 1351; HRMS (ESI-TOF) m/e:
[M+H]+ calcd for C17H28NO2 278.2120; found 278.2125.
Synthesis of 2-(N,N-dimethylamino)benzyl 3-phenyl-1-propyl ether 10: To the solution of 7
(181.0 mg, 1.2 mmol) in DMF (2.0 mL) was added sodium hydride (60% dispersion in
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mineral oil, 120.0 mg, 3.0 mmol) at 0 C. The reaction mixture was stirred at 40 C for 20
min before 3-phenylpropyl 4-methylbenzenesulfonate (290.0 mg 1.0 mmol) was added. After
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3 h at 40 C, the reaction was quenched with saturated NaHCO3 (aq) at 0oC and extracted
with Et2O. The organic layer was washed with water and brine, dried over Na2SO4, and
concentrated under reduced pressure. The crude mixture was purified by column
chromatography (PE/EA 30:1, Rf = 0.6) to provide 10 (208.0 mg, 77%) as a colorless oil. 1H
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NMR (700 MHz, CDCl3) δ 7.46 (dd, J = 7.4, 1.2 Hz, 1 H), 7.29-7.25 (m, 2 H), 7.20-7.17 (m,
3 H), 7.08-7.05 (m, 2 H), 4.59 (s, 2 H), 3.54 (t, J = 6.3 Hz, 2 H), 2.73 (t, J = 7.7 Hz, 2 H),
2.70 (s, 6 H), 1.96 (m, 2 H); 13C NMR (176 MHz, CDCl3) δ 152.4, 142.1, 132.5, 129.4, 128.5,
128.3, 128.1, 125.6, 122.9, 118.6, 69.9, 68.8, 45.1, 32.5, 31.5; IR (neat) 2935, 2857, 2782,
1594, 1489, 1449; HRMS (ESI-TOF) m/e: [M+H]+ calcd for C18H24NO 270.1858; found
270.1863.
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Synthesis of 3-(N,N-dimethylamino)benzyl 3-phenyl-1-propyl ether 11a: To the solution of
3-(N,N-dimethylamino)benzyl alcohol (38.0 mg, 0.250 mmol) in DMF (1.5 mL) was added
sodium hydride (60% dispersion in mineral oil, 20.0 mg, 0.500 mmol) at room temperature.
The reaction mixture was stirred for 90 min before 3-phenylpropyl 4-methylbenzenesulfonate
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(80.0 mg, 0.280 mmol) was added. After stirred at 50 C overnight, the reaction was
quenched with saturated NaHCO3 (aq) at 0oC and extracted with Et2O. The organic layer was
washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure.
The crude mixture was purified by column chromatography (PE/EA 20:1, Rf = 0.4) to provide
11a (51.0 mg, 76%) as a colorless oil. 1H NMR (700 MHz, CDCl3) δ 7.28-7.17 (m, 6 H), 6.74
(s, 1 H), 6.70 (d, J = 7.4 Hz, 1 H), 6.67 (d, J = 7.7 Hz, 1 H), 4.48 (s, 2 H), 3.49 (t, J = 6.3 Hz,
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2 H), 2.95 (s, 6 H), 2.72 (t, J = 7.7 Hz, 2 H), 1.93 (quint, J = 7.7 Hz, 2 H); C NMR (176
MHz, CDCl3) δ 150.8, 142.1, 139.4, 129.1, 128.5, 128.3, 125.8, 116.1, 111.9, 111.8, 73.4,
69.4, 40.7, 32.5, 31.5; IR (neat) 2932, 2853, 2799, 1603, 1496, 1350; HRMS (ESI-TOF) m/e:
[M+H]+ calcd for C18H24NO 270.1858; found 270.1866.
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Synthesis of diether 12a: To the solution of dimethyl 5-(N,N-dimethylamino)isophthalate
(2.373 g, 10.0 mmol) in THF (100.0 mL) was added LiAlH4 (0.912 g, 24.0 mmol) at 0 oC under
nitrogen atmosphere. The reaction mixture was refluxed for 3 h, and then was quenched with
H2O (0.912 mL) and 10% NaOH aqueous (2 x 0.912 mL). The precipitate was filtered off and
the filtrate was evaporated under reduced pressure. The crude reaction mixture was purified by
column chromatography (DCM/MeOH 20:1, Rf = 0.2) to provide diol 15a (1.445 g, 80%). To
the solution of 15a (13.0 mg, 0.072 mmol) in DMF (1.0 mL) was added sodium hydride (60%
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dispersion in mineral oil, 9.0 mg, 0.215 mmol) at 0 C. The reaction mixture was stirred for
30 min at room temperature before 3-phenylpropyl 4-methylbenzenesulfonate (46.0 mg,
0.160 mmol) was added. After stirred at room temperature overnight, the reaction was
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quenched with water 0 C and concentrated under reduced pressure. The crude mixture was
purified by column chromatography (PE/EA 20:1, Rf = 0.2) to provide 12a (13.0 mg, 43%). 1H
NMR (700 MHz, CDCl3) δ 7.27-7.26 (m, 4 H), 7.19-7.17 (m, 6 H), 6.68-6.67 (m, 3 H), 4.48
(s, 4 H), 3.49 (t, J = 6.3 Hz, 4 H), 2.96 (s, 6 H), 2.72 (t, J = 7.7 Hz, 4 H), 1.93 (quint, J = 6.7
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Hz, 4 H); C NMR (176 MHz, CDCl3) δ 151.0, 142.1, 139.5, 128.5, 128.3, 125.7, 115.5,
111.1, 73.3, 69.4, 40.7, 32.5, 31.5; IR (neat) 2929, 2854, 1600, 1487, 1449, 1361; HRMS
(ESI-TOF) m/e: [M+H]+ calcd for C28H36NO2 418.2746; found 418.2740.
Synthesis of diether 12b: To the solution of dimethyl 5-aminoisophthalate (5.0 g, 23.9 mmol)
and Na2HPO4 (20.4 g, 143.4 mmol) in dry DMF (75.0 mL) was added iodoethane (7.68 mL,
95.6 mmol). The reaction mixture was stirred at 60 oC for 36 h, and then diluted with 250 mL of
water, extracted with EtOAc (50 mL x 3). The combined organic layers were washed with
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water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified with
flash column chromatography (PE/EA 9:1) to provide dimethyl 5-(N,N-diethylamino)-
isophthalate (5.14 g, 81%) as a pale yellow solid. To the solution of dimethyl
5-(N,N-diethylamino)isophthalate (530.0 mg, 2.0 mmol) in THF was added LiAlH4 (152.0 mg,
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4.0 mmol) at -10 ̊C, and the mixture was warmed to room temperature and stirred overnight.
The reaction was quenched by water (160 μL), 10% NaOH (aq, 320 μL), and then water (480
μL). The organic layer was concentrated and purified by flash column chromatography
(DCM/MeOH 10:1) to provide 15b (343.0 mg, 82%) as a pale yellow waxy solid. Rf 0.50
(PE/EA 1:4). To a solution of 15b (299.0 mg, 1.430 mmol) in DCM was added thionyl chloride
(310 µL, 4.290 mmol) at -10 ̊C. After 30 min, the reaction mixture was warmed to room
temperature and stirred for 4 h. The crude mixture was concentrated and purified by column
chromatography (DCM) to the corresponding dichloride (320.0 mg, 91%) as a pale yellow
solid. Rf 0.50 (PE/EA 19:1). To the solution of 3-phenylpropan-1-ol (60.0 mg, 0.440 mmol) in
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under N2 atmosphere. After stirred at room temperature for 30 mins, a solution of the
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dichloride (49.0 mg, 0.2 mmol) in DMF (0.5 mL) was added at 0 C, followed by Bu4NBr
(32.0 mg, 0.1 mmol). After stirred at room temperature overnight, the reaction was quenched
with ice water. The organic solvent was evaporated and the crude mixture was purified by
column (PE/EA 40:1, Rf = 0.2) to provide 12b (76.0 mg, 85%) as a clear oil. 1H NMR (700
MHz, CDCl3) δ 7.27-7.25 (m, 4 H), 7.18-7.16 (m, 6 H), 6.61 (s, 2 H), 6.59 (s, 1 H), 4.45 (s, 4
H), 3.49 (t, J = 6.4 Hz, 4 H), 3.36 (q, J = 7.1 Hz, 4 H), 2.71 (t, J = 7.7 Hz, 4 H), 1.93 (quint, J
= 6.6 Hz, 4 H), 1.16 (t, J = 7.1 Hz, 6 H); 13C NMR (176 MHz, CDCl3) δ 148.2, 142.1, 139.7,
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128.51, 128.50, 128.46, 128.32, 128.28, 125.72, 125.71, 114.34, 114.30, 110.32, 110.28, 73.4,
69.4, 44.4, 32.5, 31.5, 12.7, 12.6; IR (neat) 2929, 2856, 1598, 1480, 1405; HRMS (ESI-TOF)
m/e: [M+H]+ calcd for C30H40NO2 446.3059; found 446.3068.
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Synthesis of diester 13a: To the solution of 15a (80.0 mg, 0.442 mmol), octanoyl chloride
(0.189 mL, 1.105 mmol) and DMAP (0.6 mg, 0.004 mmol) in DCM (5.0 mL) was added
triethylamine (0.246 mL, 1.768 mmol) at room temperature. The reaction was stirred overnight
and quenched with statured NaHCO3 (aq). The layer of DCM was washed with brine, dried
over Na2SO4, and concentrated under reduced pressure. The crude reaction mixture was
purified by column chromatography (PE/EA19:1, Rf = 0.2) to provide 13a (179.0 mg, 93%) as
a colorless oil. 1H NMR (700 MHz, CDCl3) δ 6.69 (s, 1 H), 6.65 (s, 2 H), 5.06 (s, 4 H), 2.96
(s, 6 H), 2.35 (t, J = 7.7 Hz, 4 H), 1.65 (quint, J = 7.1 Hz, 4 H), 1.32-1.25 (m, 16 H), 0.87 (t, J
= 7.0 Hz, 6 H); 13C NMR (176 MHz, CDCl3) δ 173.8, 150.8, 137.3, 115.9, 111.9, 66.4, 40.5,
34.4, 31.7, 29.1, 29.0, 25.0, 22.6, 14.1; IR (neat) 2954, 2926, 2855, 1733, 1604, 1491, 1459;
HRMS (ESI-TOF) m/e: [M+H]+ calcd for C26H44NO4 434.3270; found 434.3264.
Synthesis of diester 13b: To the solution of 15b (100.0 mg, 0.478 mmol), octanoyl chloride
(0.204 mL, 1.196 mmol) and DMAP (0.5 mg, 0.005 mmol) in DCM (5.0 mL) was added
triethylamine (0.266 mL, 1.912 mmol) at room temperature. After stirred overnight the
reaction was quenched with statured NaHCO3 (aq). The layer of DCM was washed by brine,
dried over Na2SO4, and concentrated under reduced pressure. The crude reaction mixture was
purified by column chromatography (PE/EA19:1, Rf = 0.6) to provide 13b (209.0 mg, 95%) as
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a colorless oil. 1H NMR (700 MHz, CDCl3) δ 6.60 (s, 1 H), 6.58 (s, 2 H), 5.04 (s, 4 H), 3.35
(q, J = 7.0 Hz, 4 H), 2.35 (t, J = 7.7 Hz, 4 H), 1.64 (quint, J = 7.0 Hz, 4 H), 1.31-1.25 (m, 16
H), 1.16 (t, J = 7.0 Hz, 6 H), 0.87 (t, J = 7.0 Hz, 6 H); 13C NMR (176 MHz, CDCl3) δ 173.8,
148.1, 137.4, 114.8, 111.1, 66.6, 44.4, 34.4, 31.7, 29.1, 29.0, 25.0, 22.6, 14.1, 12.5; IR (neat)
2956, 2926, 2856, 1733, 1603, 1487, 1466; HRMS (ESI-TOF) m/e: [M+H]+ calcd for
C28H48NO4 462.3583; found 462.3577.
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Synthesis of intermediate 16 and 14: To a solution of 15b (105.0 mg 0.5 mmol) in DMF (3.0
mL) was added NaH (60% dispersion in mineral oil 40.0 mg, 1.0 mmol) at room temperature.
The reaction mixture was stirred for 30 min, and 3-phenylpropyl 4-methylbenzenesulfonate
(29.0 mg 0.1 mmol) in DMF (1.0 mL) was added at room temperature. After stirring at 50 oC
overnight, the reaction was quenched with water at 0 oC, and extracted with ethyl acetate. The
organic layer was washed with water, brine, dried over Na2SO4, and concentrated under
reduced pressure. The crude reaction mixture was purified by column chromatography (PE/EA
5:1, Rf = 0.3) to provide 16 (12.0 mg, 37%) as a colorless oil. 1H NMR (700 MHz, CDCl3) δ
7.28-7.25 (m, 2 H), 7.19-7.17 (m, 3 H), 6.62-6.61 (m, 3 H), 4.62 (s, 2 H), 4.45 (s, 2 H), 3.49
(t, J = 6.4 Hz, 2 H), 3.36 (q, J = 7.0 Hz, 4 H), 2.72 (t, J = 7.7 Hz, 2 H), 1.94 (quint, J = 6.4 Hz,
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2 H), 1.16 (t, J = 7.1 Hz, 6 H); C NMR (176 MHz, CDCl3) δ 148.3, 142.2, 142.1, 140.0,
128.5, 128.3, 125.7, 113.4, 110.3, 109.6, 73.4, 69.5, 66.1, 44.4, 32.4, 31.4, 12.6; IR (neat)
3401, 2967, 2926, 2861, 1598, 1471, 1403, 1354, 1289; HRMS (ESI-TOF) m/e: [M+H]+
calcd for C21H30NO2 328.2277; found 328.2277.
To a solution of 16 (33.0 mg, 0.10 mmol), octanoyl chloride (0.018 mL, 0.105 mmol) and
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DMAP (0.6 mg, 0.005 mmol) in DCM (1.0 mL) was added triethylamine (0.028 mL, 0.20
mmol) at room temperature. After stirred for 3 hours, the reaction was quenched with water.
The layer of DCM was washed by brine, dried over Na2SO4, and concentrated under reduced
pressure. The crude reaction mixture was purified by column chromatography (PE/EA20:1, Rf
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= 0.3) to provide 14 (41.0 mg, 90%) as a colorless oil. H NMR (700 MHz, CDCl3) δ
7.28-7.25 (m, 2 H), 7.19-7.17 (m, 3 H), 6.63 (s, 1 H), 6.60 (s, 1 H), 6.56 (s, 1 H), 5.05 (s, 2 H),
4.45 (s, 2 H), 3.49 (t, J = 6.3 Hz, 2 H), 3.36 (q, J = 7.0 Hz, 4 H), 2.72 (t, J = 7.7 Hz, 2 H),
2.34 (t, J = 7.6 Hz, 2 H), 1.93 (quint, J = 7.0 Hz, 2 H), 1.64 (quint, J = 7.0 Hz, 2 H),
1.31-1.24 (m, 8 H), 1.17 (t, J = 7.0 Hz, 6 H), 0.85 (t, J = 6,8 Hz, 6 H); 13C NMR (176 MHz,
CDCl3) δ 173.8, 148.1, 142.0, 139.9, 137.1, 128.5, 128.3, 125.7, 114.5, 110.62, 110.57, 73.2,
69.4, 66.7, 44.3, 34.4, 32.4, 31.6, 31.5, 29.1, 28.9, 25.0, 22.6, 14.1, 12.6; IR (neat) 2926,
2856, 1734, 1601, 1457, 1408, 1375; HRMS (ESI-TOF) m/e: [M+H]+ calcd for C29H44NO3
454.3321; found 454.3321.
Synthesis of diether 17 and intermediate 20: To a stirred solution of 3-aminophthalic acid (1.0
g, 5.5 mmol) and potassium carbonate (5.320 g, 38.6 mmol) in DMF (20.0 mL), methyl
iodide (10.940 g, 77.1 mmol) was added. The reaction mixture was stirred at room
temperature for 24 h, and then was diluted with H2O (100 mL) and extracted with EA (50 mL
x 3). The combined organic layers were washed with H2O (50 mL x 3), dried with Na2SO4,
filtered, and concentrated. The crude product was purified by column chromatography
(PE/EA 15:1) to provide corresponding dimethyl 3-(N,N-dimethylamino)phthalate (0.460 g,
35%). Rf = 0.6 (PE/EA 3:1). To a suspension of LiAlH4 (0.170 g, 4.2 mmol) in THF (15.0
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sequential addition of H2O (0.170 mL), 10% NaOH aqueous solution (2 x 0.170 mL), and
H2O (3 x 0.170 mL), and stirred for 15 minutes. The resulting white precipitate was filtered
off, the filtrate was concentrated, and then diluted with H2O (100 mL) and extracted with EA
(50 mL x 3). The combined organic layers were washed with H2O (50 mL x 3), dried with
Na2SO4, filtered, and concentrated. The crude product was purified by column
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chromatography (PE/EA 1:1, Rf = 0.4) to provide 20 (0.158 g, 59%). H NMR (700 MHz,
CDCl3) δ 7.25 (t, J = 8.3 Hz, 1 H), 7.15 (d, J = 8.1 Hz, 1 H), 7.08 (d, J = 7.4 Hz, 1 H), 4.91 (s,
13
2 H), 4.68 (s, 2 H), 2.74 (s, 6 H); C NMR (176 MHz, CDCl3) δ 153.3, 140.2, 134.0, 128.4,
124.8, 119.8, 64.3, 59.3, 45.3; IR (neat) 2939, 2866, 2830, 2785, 1584, 1468, 1455, 1312;
HRMS (ESI-TOF) m/e: [M+H]+ calcd for C10H16NO2 182.1181; found 182.1185.
To a solution of 20 (22.0 mg, 0.484 mmol) in DMF (1.0 mL) at 0oC was added sodium
hydride (60% dispersion in mineral oil, 19.0 mg 0.121 mmol). After stirred for 30 min at room
temperature, 3-phenylpropyl 4-methylbenzenesulfonate (105.0 mg 0.363 mmol) was added.
The reaction was then stirred at room temperature overnight and quenched with water at 0 oC.
The crude product was purified by column chromatography (DCM/MeOH 100:1, Rf = 0.5) to
provide 17 (39.0 mg, 77%) as a colorless oil. 1H NMR (700 MHz, CDCl3) δ 7.27-7.26 (m, 5
H), 7.20-7.17 (m, 7 H), 7.04 (d, J = 7.7 Hz, 1 H), 4.67 (s, 2 H), 4.66 (s, 2 H), 3.54 (t, J = 6.2
13
Hz, 4 H), 2.73-2.68 (m, 10 H), 1.96-1.91 (m, 4 H); C NMR (176 MHz, CDCl3) δ 153.8,
142.1, 140.0, 130.0, 128.7, 128.51, 128.48, 128.37, 128.34, 128.32, 125.77, 125.75, 123.4,
118.3, 70.5, 70.1, 69.9, 65.4, 45.7, 32.6, 32.5, 31.50, 31.47; IR (neat) 2933, 2857, 2783, 1590,
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1460, 1357, 1311; HRMS (ESI-TOF) m/e: [M+H]+ calcd for C28H36NO2 418.2746; found
418.2746.
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Synthesis of diether 18: To the solution of dimethyl aminoterephthalate (0.500 g, 2.392 mmol)
and potassium carbonate (1.320 g, 9.570 mmol) in DMF (8.0 mL) was added methyl iodide
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(1.893 g, 14.340 mmol) under N2 atmosphere. After stirred at 30 C for 7 days, the reaction
mixture was diluted with 150.0 mL of H2O and extracted with EtOAc (50 mL x 3). The
combined organic layers were washed with H2O (50 mL x 3), brine, dried over Na2SO4, filtered,
and concentrated. The crude product was purified by column chromatography (PE/EA 10:1, Rf
= 0.4) to provide intermediate dimethyl (N,N-dimethylamino)terephthalate (0.194 g, 34%). To
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a suspension of LiAlH4 (63.0 mg, 1.671 mmol) in THF (10.0 mL) at 0 C, dimethyl
(N,N-dimethylamino) terephthalate (132.0 mg, 0.557 mmol) in THF (3.0 mL) was added.
After refluxed overnight, the reaction mixture was quenched by the sequential dropwise
addition of H2O (0.1 mL), 10% NaOH aqueous solution (2 x 0.1 mL), and H2O (3 x 0.1 mL).
The resulting white precipitate was filtered off, and the filtrate was concentrated, diluted with
H2O (50 mL), and extracted with EA (50 mL x 3). The combined organic layers were washed
with H2O (50 mL x 3), dried over Na2SO4, filtered, and concentrated. The crude product was
purified by column chromatography (PE/EA 3:2, Rf = 0.3) to provide 22 (86.0 mg, 86%). To
a solution of 22 (21.0 mg, 0.113 mmol) in DMF (1.0 mL) was added sodium hydride (60%
dispersion in mineral oil, 18.0 mg 0.452 mmol) at 0oC. After stirred for 30 min at room
temperature, 3-phenylpropyl 4-methylbenzenesulfonate (98.0 mg 0.339 mmol) was added at
0oC. The reaction was stirred at room temperature overnight and quenched with water at 0 oC.
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The crude product was purified by column chromatography (DCM, Rf = 0.2) to 18 (39.0 mg,
83%) as a colorless oil. 1H NMR (700 MHz, CDCl3) δ 7.43 (d, J = 7.7 Hz, 1 H), 7.28-7.26 (m,
4 H), 7.20-7.18 (m, 6 H), 7.07 (s, 1 H), 7.03 (d, J = 7.7 Hz, 1 H), 4.57 (s, 2 H), 4.48 (s, 2 H),
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3.54 (t, J = 6.3 Hz, 2 H), 3.49 (t, J = 6.3 Hz, 2 H), 2.80-2.71 (m, 10 H), 1.94 (m, 4 H); C
NMR (176 MHz, CDCl3) δ 152.5, 142.1, 142.0, 138.5, 131.6, 129.5, 128.5, 128.3, 125.75,
125.72, 122.1, 117.9, 72.9, 69.8, 69.4, 68.7, 45.0, 32.5, 32.4, 31.5, 31.4; IR (neat) 2933, 2854,
2783, 1603, 1494, 1452; HRMS (ESI-TOF) m/e: [M+H]+ calcd for C28H36NO2 418.2746;
found 418.2746.
Synthesis of tetraol 25: To the solution of dimethyl 5-aminoisophthalate (1.000 g, 4.780 mmol)
and Na2HPO4 (1.350 g, 9.560 mmol) in dry DMF (50.0 mL) was added iodoethane (0.198 mL,
4.780 mmol). The reaction mixture was stirred at 60 oC for 72 h, and then diluted with water,
extracted with EtOAc. The combined organic layers were washed with water and brine, dried
over Na2SO4, filtered, and concentrated. The residue was purified with flash column
chromatography (PE/EA 5:1) to provide dimethyl 5-(N-ethylamino)isophthalate (0.500 g, 44%)
as a pale yellow solid. To a solution of dimethyl 5-(N-ethylamino)isophthalate (1.329 g, 5.600
mmol) in THF (50.0 mL) was added LiAlH4 (638.0 mg, 16.8 mmol) at 0 ̊C. After refluxed for 3
h, the reaction was quenched with sequential addition of H2O (0.638 mL), 10% NaOH
aqueous (2 x 0.638 mL), and H2O (3 x 0.638 mL). The precipitate was filtered and the filtrate
was evaporated under reduced pressure. The residue was purified by column chromatography
(DCM/MeOH 10:1, Rf
=
0.20) to provide intermediate 5-(N-ethylamino)-
1,3-benzenedimethanol 24 (831.0 mg, 82%) as a yellow solid. 1H NMR (700 MHz, CDCl3) δ
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6.62 (s, 4 H), 6.49 (s, 2 H), 4.54 (s, 4 H), 3.14 (q, J = 7.0 Hz, 4 H), 1.24 (t, J = 7.0 Hz, 6 H);
13C NMR (176 MHz, CDCl3) δ 148.9, 142.5, 114.4, 110.6, 65.3, 38.6, 14.8; IR (neat) 3279,
3184, 2968, 2899, 2837, 1605, 1524, 1457, 1366, 1336, 1296; HRMS (ESI-TOF) m/e:
[M+H]+ calcd for C10H16NO2 182.1181; found 182.1189.
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5-(N-ethylamino)-1,3-benzenedimethanol 24 (565.0 mg, 3.122 mmol) was mixed with
1,2-bis(2-iodoethoxy)ethane (565.0 mg 1.527 mmol) and K2CO3 (1.400 g 10.200 mmol) in
CH3CN (2.0 mL) in a sealed vial. The reaction was heated at 95 oC for 72 h, and then K2CO3
was filtered off and the filtrate was concentrated. The obtained crude product was purified by
column chromatography (DCM/MeOH 30:1, Rf = 0.2) to provide 25 (545.0 mg, 75%) as a
white solid. 1H NMR (700 MHz, MeOD-d4) δ 6.66 (s, 4 H), 6.62 (s, 2 H), 4.54 (s, 8 H), 3.66
(t, J = 6.2 Hz, 4 H), 3.63 (s, 4 H), 3.51 (t, J = 6.2 Hz, 4 H), 3.45 (q, J = 7.0 Hz, 4 H), 1.16 (t, J
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= 7.0 Hz, 6 H); C NMR (176 MHz, MeOD-d4) δ 148.1, 142.2, 113.0, 109.4, 70.4, 68.7,
64.4, 49.7, 45.1, 11.1; IR (neat) 3297, 2975, 2857, 1595, 1472, 1404, 1358, 1279; HRMS
(ESI-TOF) m/e: [M+H]+ calcd for C26H41N2O6 477.2965; found 477.2964.
Synthesis of tetrachloride 26: To a solution of 25 (540.0 mg, 1.133 mmol) in CH3CN (20.0
mL) was added SOCl2 (166 L, 2.278 mmol) at 0 oC. The reaction mixture was stirred for 4 h
o
at room temperature and quenched by saturated NaHCO3 (aq) at 0 C. After removal of
CH3CN, DCM was added to extract the product. The organic layer was washed with brine,
dried over NaSO4, concentrated, and purified by column chromatography (PE/EA 5:1, Rf =
0.40) to 26 (525.0 mg, 84%) as a white solid. 1H NMR (700 MHz, CDCl3) δ 6.68 (s, 1 H), 6.64
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(s, 2 H), 4.01 (s, 4 H), 3.64-3.62 (m, 4 H), 3.51 (t, J = 6.4 Hz, 2 H), 3.41 (q, J = 7.1, 2 H),
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1.16 (t, J = 7.0 Hz, 3 H); C NMR (176 MHz, CDCl3) δ 148.4, 139.0, 115.9, 111.7, 70.8,
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68.9, 50.0, 46.7, 45.4, 12.1; IR (neat) 2965, 2913, 2874, 1598, 1447, 1359; HRMS (ESI-TOF)
m/e: [M+H]+ calcd for C26H37Cl4N2O2 549.1609; found 549.1609.
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Synthesis of 27: To the solution of the commercially available diacetone-D-glucose (57.0 mg
0.220 mmol) in DMF (0.5 mL) was added sodium hydride (60% dispersion in mineral oil,
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18.0 mg, 0.440 mmol) at 0 C under N2 atmosphere. After the suspension was stirred at room
temperature for 30 min, compound 26 (28.0 mg, 0.050 mmol) in DMF (0.5 mL) was added,
followed by Bu4NBr (6.0 mg, 0.020 mmol). The reaction mixture was stirred for 22 h at room
temperature and quenched with water at 0oC. The reaction mixture was extracted with ethyl
acetate, and the organic layer was washed with water, brine, dried over Na2SO4, and
concentrated under reduced pressure. The crude product was purified by preparative TLC
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plate (DCM/MeOH 10:1, Rf = 0.6) to provide 27 (55.0 mg 76%) as a white foam. H NMR
(700 MHz, CDCl3) δ 6.58 (s, 2 H), 6.57 (s, 4 H), 5.89 (d, J = 3.5 Hz, 4 H), 4.60-4.56 (m, 12
H), 4.38-4.35 (q, J = 6.0, 4 H), 4.16 (dd, J = 7.5, 3.0 Hz, 4 H), 4.10 (t, J = 7.4 Hz, 4 H),
4.05-4.00 (m, 8 H), 1.49 (s, 12 H), 1.43 (s, 12 H), 1.36 (s, 12 H), 1.31 (s, 12 H), 1.15 (t, J =
7.0 Hz, 6 H); 13C NMR (176 MHz, CDCl3) δ 148.1, 139.0, 114,2, 111.8, 110.2, 108.9, 105.3,
82.6, 81.7, 81.2, 72.8, 72.7, 70.7, 68.9, 67.2, 50.0, 45.5, 29.7, 26.9, 26.8, 26.3, 25.5, 12.1; IR
(neat) 2980, 2930, 1731, 1600, 1472, 1372; HRMS (ESI-TOF) m/e: [M+H]+ calcd for
C74H113N2O26 1445.7528; found 1445.7513.
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Photoreaction in NMR tube in deuterated solvent: To a 5 mm NMR tube was added a stock
solution of the substrate (0.5 mL, 5.0 mM) in MeOD or CD3CN/D2O (4:1) with a micro
syringe. The NMR tube was sealed with PTFE tape, bound to the immersion well condenser
of the photoreactor, and irradiated for the indicated time. The conversion and yield of
reaction was calculated based on 1H NMR integration of the products.
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Larger scale Photoreaction in NMR tube in nondeuterated solvent: To 5 mm NMR tubes
were added solution of the substrate (0.5 mL, 5.0 mM) in CH3CN/H2O (4:1). The NMR tubes
were sealed with PTFE tape, bound to the immersion well condenser of the photoreactor, and
irradiated for 20 min. The reaction solutions in all NMR tubes were combined in a flask and
concentrated. The crude product was purified by column chromatograph.
Photoreaction of 27: To 5 mm NMR tubes were added solution of 27 (0.5mL x 14, 5.0 mM)
in CH3CN/H2O (4:1). The NMR tubes were sealed with PTFE tape and bound to the
immersion well condenser of the photoreactor and irradiated for 20 min. The reaction
solution in all NMR tubes were then combined, concentrated, and the reaction yield was
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estimated to be quantitative by H NMR. The crude product was purified by column
chromatography (DCM/ MeOH 60:1, Rf = 0.15) to provide the released diacetone-D-glucose
(33 mg) in 90% yield.
Quantum yield determination: A 5.0 mM solution of the sample and a 5.0 mM solution of
DEABn-protected 3-phenyl-1-propanol (with known quantum yield of 0.26) in NMR tubes
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were irradiated side-by-side under the same conditions. The yields of the photo reactions
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were determined by H NMR analysis, and the quantum yield of the new reaction was
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calculated based on the measured chemical yields of the two reactions, the known quantum
yield of the reference reaction, and the PPG chromophore UV absorption profiles.
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ACKNOWLEDGMENT. We thank the NSF (CHE 1404063) for financial support. We also
thank D. Devalankar for synthesizing 13a and 13b, D. Rountree for synthesizing 20, and W.
Lu for his early contribution.
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Supporting Information Available: H and C NMR spectra of new compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
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