Sequential removal of photolabile protecting groups for carbonyls with controlled wavelength

Article abstract of DOI:10.1021/jo8008275

(Chemical Equation Presented) A group of robust and easy-to-make photolabile protecting groups (PPGs) for carbonyl compounds has been developed. Sequential removal of different PPGs is achieved via control of irradiation wavelength.

Full text of DOI:10.1021/jo8008275

Sequential Removal of Photolabile Protecting Groups for Carbonyls
with Controlled Wavelength
Pengfei Wang,* Yun Wang, Huayou Hu, Cierra Spencer, Xing Liang, and Lurong Pan
Department of Chemistry, UniVersity of Alabama at Birmingham, Birmingham, Alabama 35294
wangp@uab.edu
ReceiVed April 16, 2008
A group of robust and easy-to-make photolabile protecting groups (PPGs) for carbonyl compounds has
been developed. Sequential removal of different PPGs is achieved via control of irradiation wavelength.
Introduction
herein we report our work on other PPGs for carbonyls. With
this extension of our previous work, we were able to sequentially
release carbonyl compounds protected with different PPGs by
controlling the irradiation wavelength.
Protecting groups are essential tools in organic chemistry.1
Among various protecting groups, photolabile protecting groups
(PPGs) have very valuable features, including their neutral
removal by light without the use of any chemical reagent and
the capability of releasing substrates in a spatially and temporally
controlled manner. These advantages are appealing to both basic
and applied sciences, and development of practically useful
PPGs is highly sought.1,2
As a reactive functionality, carbonyl groups often need to be
protected in the course of a multistep synthesis. The search for
practically useful PPGs for carbonyl groups was initiated several
decades ago. Despite progress in the field, inherent drawbacks
of the early approaches hindered their wide utilization in
synthetic chemistry and other disciplines.3
Recently, we have developed two novel PPGs for carbonyl
protection, R,R-diphenyl-5-methoxysalicyl alcohol (1),4 evolved
from the triphenylmethyl dye photochemistry, and 3,5-dimethox-
ysalicyl alcohol (2),5 designed on the basis of the excited-state
meta effect.6 To further enrich the PPG tool box for carbonyl
protection and to provide more options for different applications,
Results and Discussion
The first new addition to the toolbox is R,R-diphenyl-3,5-
dimethoxysalicyl alcohol (3),7 another robust PPG for carbonyl
protection. When the protection procedures developed for 1 were
adopted for 3, protection of carbonyl compounds 4a-4e led to
acetals/ketals (5a-5e) in excellent yields (Table 1). These
protection procedures require an acid catalyst. For example, the
(3) (a) Hebert, J.; Gravel, D. Can. J. Chem. 1974, 52, 187. (b) Gravel, D.;
Herbert, J.; Thoraval, D. Can. J. Chem. 1983, 61, 400. (c) Gravel, D.; Murray,
S.; Ladouceur, G. J. Chem. Soc., Chem. Commun. 1985, 24, 1828. (d) Friedrich,
E.; Lutz, W.; Eichenauer, H.; Enders, D. Synthesis 1977, 12, 893. (e) Hoshino,
O.; Sawaki, S.; Umezawa, B. Chem. Pharm. Bull. 1979, 27, 538. (f) Aurell,
M. J.; Boix, C.; Ceita, M. L.; Llopis, C.; Tortajada, A.; Mestres, R. J. Chem.
Res. Synop. 1995, 12, 452. (g) Ceita, L.; Maiti, A. K.; Mestres, R.; Tortajada,
A. J. Chem. Res. Synop. 2001, 10, 403. (h) McHale, W. A.; Kutateladze, A. G.
J. Org. Chem. 1998, 63, 9924. (i) Lu, M.; Fedoryak, O. D.; Moister, B. R.;
Dore, T. M. Org. Lett. 2003, 5, 2119. (j) Blanc, A.; Bochet, C. G. J. Org. Chem.
2003, 68, 1138. (k) Kantevari, S.; Narasimhaji, C. V.; Mereyala, H. B.
Tetrahedron 2005, 61, 5849.
(1) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic Synthesis;
Wiley: New York, 1999.
(4) Wang, P.; Hu, H.; Wang, Y. Org. Lett. 2007, 9, 1533.
(5) (a) Wang, P.; Hu, H.; Wang, Y. Org. Lett. 2007, 9, 2831. (b) Irradiation
of acetals formed by 4a with salicyl alcohol, 5-methoxysalicyl alcohol, and 2
afforded 4a in 51%, 51%, and 73% yield, respectively, when the photoreactions
were carried out in CH3CN/water for 1 h with a 450 W medium pressure mercury
lamp equipped with a Vycor filter sleeve.
(2) For reviews and monographs, see: (a) Pillai, V. N. R. Synthesis 1980, 1.
(b) Binkley, R. W.; Flechtner, T. W. In Synthetic Organic Photochemistry;
Horspool, W. M., Ed.; Plenum: New York, 1984; p 375. (c) Pillai, V. N. R.
Org. Photochem. 1987, 9, 225. (d) Givens, R. S.; Kueper, L. W., III Chem. ReV.
1993, 93, 55. (e) Pirrung, M. C. Chem. ReV. 1997, 97, 473. (f) Guillier, F.;
Orain, D.; Bradley, M. Chem. ReV. 2000, 100, 2091. (g) Bochet, C. G. J. Chem.
Soc., Perkin Trans. 1 2002, 125. (h) Pelliccioli, A. P.; Wirz, J. Photochem.
Photobiol. Sci. 2002, 1, 441. (i) Dynamic Studies in Biology; Goeldner, M.,
Givens, R. S., Eds.; Wiley-VCH: Weinheim, Germany, 2005. (j) Mayer, G.;
Heckel, A. Angew. Chem., Int. Ed. 2006, 45, 4900.
(6) (a) Zimmerman, H. E.; Sandel, V. R. J. Am. Chem. Soc. 1963, 85, 915.
(b) Zimmerman, H. E.; Somasekhara, S. J. Am. Chem. Soc. 1963, 85, 922. (c)
Zimmerman, H. E. J. Am. Chem. Soc. 1995, 117, 8988. (d) Zimmerman, H. E.
J. Phys. Chem. A 1998, 102, 5616.
(7) PPG 3 was readily synthesized from the known 3,5-dimethoxysalicylic
acid.4
6152 J. Org. Chem. 2008, 73, 6152–6157
10.1021/jo8008275 CCC: $40.75 2008 American Chemical Society
Published on Web 07/23/2008

Sequential RemoVal of Photolabile Protecting Groups
TABLE 1. Protection and Photorelease of Carbonyl Compounds
f
entry
carbonyls
protection yield (%)
deprotection yield (%)d
recovered 3 (%)
irradiation time (min)
1
2
3
4
5
4a
4b
4c
4d
4e
99a
93b
99c
99c
99c
92e
82
86
88
91
35
0
39
30
46
30
44
25
25
25
a PPG 3 (0.23 mmol), 4a (0.2 mmol), and pTsOH (0.02 mmol) in 0.8 mL of benzene, 23 °C, 20 h. b PPG 3 (0.3 mmol), 4b (0.2 mmol), pTsOH (0.01
mmol), and MgSO4 (0.8 mmol) in 1.0 mL of benzene, 23 °C, 24 h. c PPG 3 (0.3 mmol), carbonyl compound (0.2 mmol), pTsOH (0.01 mmol), and
d
P2O5 (0.4 mmol) in 1.0 mL of benzene, 23 °C, 1 h. Compound 5 (8.0 × 10-4 M) in CH3CN with 4-10% (v/v) H2O was irradiated with a 450 W
medium pressure mercury lamp equipped with a Pyrex filter sleeve (<280 nm) without excluding air. e Isolated as the oxime derivative due to the
volatile nature of 4a. The acetal 5a is stable under the derivatization conditions. f Isolated yields.
TABLE 2. Comparison of Photochemical Efficiency
SCHEME 1. Mechanism of Deprotection Reactions
deprotection
yield (%)
irradiation
time (min)
c,d
entry
PPG
ꢀ(λ) of acetala
Φb
1
2
3
1
2
3
4737 (296 nm)
3241 (290 nm)
4169 (297 nm)
0.11
0.03
0.17
90
81
92
60
240
30
a Extinction coefficient (M-1 cm-1) of the acetal of 4a. b Quantum
yields for producing of 4a in MeCN/H2O (9:1) upon irradiation with
monochromatic light (centered at 285 nm). c Acetal in MeCN/H2O (9:1)
irradiated with a 450 W medium pressure mercury lamp equipped with a
Pyrex filter sleeve (>280 nm) without excluding air. d Isolated as the
oxime derivative due to the volatile nature of 4a.
The other improvement of the new PPG is that various
amounts of PPG 3 were recovered from Pyrex-filtered irradiation
of 5 when water was used as a cosolvent. On the contrary, there
were no detectable amounts of 1 or 2 in the corresponding
photochemical deprotection reactions under the same conditions.
Several factors influenced the amounts of recovered 3. For
example, the yield of 3 increased with more water present in
the reaction solution, but the yields of obtained carbonyl
compounds were essentially not affected. Irradiation of 5a and
5e in MeCN/H2O (9:1) led to 3 in 35% and 46% yield,
respectively; the recovery of 3 from 5a increased to 58% in
MeCN/H2O (3:1) and to 68% from 5e in MeCN/H2O (1:1). We
hypothesized that 3 was produced in the reaction of water with
the intermediate 7 generated from fragmentation of zwitterion
6 (Scheme 1). Extended exposure of 3 to light caused severe
decomposition. For example, irradiation of 5a in MeCN/H2O
(3:1) for 40 min led to only 23% recovered 3, significantly lower
than 58% from 30 min of irradiation. Decomposition of 3 via
7 could be a possible pathway, since benzophenone formed in
both photoreactions of 5 and pure PPG 3 without deoxygen-
ation.10 Pisova and co-workers observed formation of ben-
zophenone upon irradiation of various o-fuchsones, which was
attributed to [8 + 2] cycloaddition of molecular oxygen to the
quinonoid trienone π-system and the subsequent fragmentations
aliphatic aldehyde 4a was conveniently protected in an excellent
yield in the presence of 5-10 mol % of pTsOH and a slight
excess of 3 (Table 1, entry 1). For ketones, the dehydrating
reagent (P2O5) was necessary for a fast and quantative protection
(Table 1, entries 3-5).
With ready access to acetals/ketals (5a-5e), we studied the
photochemical removal of the PPG from 5. In the cases
examined (Table 1), photochemical reactions went smoothly to
release aldehydes and ketones in high yields, similar to the
results obtained with PPGs 1 and 2.4,5 It is noteworthy that there
are two major improvements of PPG 3 when compared with 1
and 2. One is that the rate of removing 3 was faster than that of
removing 1 and 2 under the same irradiation conditions (Table
2). The quantum yields of releasing 4a from protection of 1, 2,
and 3 were 0.11, 0.03, and 0.17, respectively.8,9 In preparative
runs, it took less than 30 min to remove 3, whereas removal of
1 and 2 typically took 60-80 min and 3-4 h, respectively.4,5
(8) (a) Quantum yields were determined by chemical actinometry. Defoin,
A.; Defoin-Straatmann, R.; Hildenbrand, K.; Bittersmann, E.; Kreft, D.; Kuhn,
H. J. J. Photochem. 1986, 33, 237. (b) The monochromatic light centering at
285 nm (and opaque above 325 nm and below 250 nm) was obtained by passing
light from a 450 W medium pressure mercury lamp through three quartz cuvettes
containing 2 M NiSO4 in 5% H2SO4 (cell 1), 0.8 M CoSO4 in 5% H2SO4 (cell
2), and 2.46 × 10-4 M BiCl3 in concentrated HCl/H2O (2:3) (cell 3).9. (c) The
monochromatic light centering at 330 nm (and opaque above 368 nm and below
292 nm) was obtained by passing light from a 450 W medium pressure mercury
lamp through a filter solution in a quartz cuvette. The filter solution was prepared
by dissolving NiSO4 · 7H2O (11.2 g), CoSO4 · 7H2O (5.5 g), CuSO4 · 5H2O, and
KNO3 (0.5 g) in 25 mL of 10% H2SO4.9
(10) PPG 3 (0.2 mmol) in 250 mL of CH3CN/H2O (9:1) was irradiated with
a Pyrex-filtered 450 W medium pressure mercury lamp for 10 min, and an
unknown compound formed (unknown/3 ) 1:1). The characteristic 1H NMR
peaks of this unknown are 5.98 (d, J ) 2.6 Hz, 1 H), 5.74 (d, J ) 2.6 Hz, 1 H),
3.70 (s, 3 H), and 3.54 (s, 3 H). After another 15 min of irradiation, the unknown
compound decomposed and a significant amount of benzophenone formed, along
with a complex mixture of other unknowns.
(9) (a) Zimmerman, H. E.; Nuss, J. M.; Tantillo, A. W. J. Org. Chem. 1988,
53, 3792. (b) Zimmerman, H. E. Mol. Photochem. 1971, 3, 281.
J. Org. Chem. Vol. 73, No. 16, 2008 6153

Wang et al.
TABLE 3. Stability of 5a under Various Conditions
TABLE 4. Evaluation of Different PPGs
entry
reagenta
solvent
conditions
5a (%)c
1
2
3
4
5
PhLib
LiAlH4
THF
THF
THF
THF
MeCN
-78 to 23 °C, 6 h
23 °C, 24 h
23 °C, 24 h
23 °C, 18 h
23 °C, 24 h
80 °C, 2 h
23 °C, 24 h
80 °C, 2 h
23 °C, 24 h
80 °C, 2 h
23 °C, 24 h
80 °C, 2 h
23 °C, 24 h
80 °C, 2 h
23 °C, 24 h
80 °C, 2 h
23 °C, 24 h
80 °C, 2 h
100
100
100
100
100
100
100
94
NaBH4
H2, Pd/Cd
t-BuOK
yields (%) of obtained 4aa,b
5a
8
9
10
11
87d
12
99d
6
DDQ
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Pyrex
Vycor
92c
88c
5c
<1c
96e
99e
92e
82e
7
CAN
0
0
a Irradiated with a 450 W medium pressure mercury lamp equipped
with a Pyrex or a Vycor filter sleeve without excluding air, with the
substrate concentration of 8.0 × 10-4 M in CH3CN/H2O (9:1) (v/v).
b Isolated as the oxime. c 30 min of irradiation. d 16 min of irradiation.
e 10 min of irradiation.
8
AcOH
TFA
100
100
100
91
100
65
9
10
11
HCl (37%)
pTsOH
47
0
a Acetal 5a (0.01 mmol) in 1.0 mL of MeCN or THF treated with
reagent (>0.20 mmol). b Acetal 5a (0.05 mmol) in 1.0 mL of dry THF
treated with 0.4 mL of PhLi (2.0 M in Bu2O) under argon. c Yields
determined by H NMR. d Acetal 5a (0.02 mmol) in 2.0 mL of THF.
1
of the resulting 1,2,3-trioxanaphthalene.11 When the photore-
actions were conducted under nitrogen, the production of
benzophenone from 5 and 3 diminished. With 5b, PPG 3 was
not observed after 44 min of irradiation (Table 1, entry 2) and
was observed in only <10% (based on released 4b) after 10
min of irradiation (with conversion of 5b > 50%). Presumably,
the decomposition pathway of 3 was altered in the presence of
4b. Indeed, irradiation of PPG 3 with 1 equiv of 4b in CD3CN/
D2O (9:1) for only 10 min led to decomposition of more than
80% 3 to a complex mixture.12 Without 4b, only 37% 3 was
consumed under the same irradiation conditions and was
converted mainly to an unknown compound that was also
observed in a larger scale run.10
The obtained acetals/ketals (5a-5e) displayed a useful range
of dark stability toward various chemical reagents and were
stable under laboratory lighting (Table 3, exemplified with 5a).
Acetal 5a withstood mild acid conditions (Table 3, entries 8-10)
yet was susceptible in the presence of excess pTsOH (entry 11).
However, the electron-rich aromatic system of 5a did not survive
strong oxidation conditions, and the acetal completely decom-
posed upon treatment with cerium ammonium nitrate (CAN).
Structural modification of the salicyl alcohol chromophore
by changing the position and nature of the substituents resulted
in more PPGs with considerably different photochemical pro-
perties. For comparison, acetals of 3-phenylpropanal (4a) with
these PPGs were prepared and studied (Table 4). Irradiation
with Pyrex-filtered light for 30 min released more 4a from 5a
(with two meta methoxyl groups) than from 8 (with one meta
methoxyl group).4 Without a meta methoxyl group, acetal 9
released much less 4a (only 5%). For acetal 10, most of the
acetal (>99%) was recovered under the same irradiation
conditions. However, 10 min of irradiation with Vycor-filtered
light (>210 nm) led to efficient release of 4a from acetals 5a
and 8-10 in high yields. With a dimethylamino auxochrome
in the PPGs, there is a notable bathochromic shift of the UV
bands of both acetal 11 (with a para amino group) and 12 (with
FIGURE 1. UV spectra of acetals.
a meta amino group), when compared with their counterparts
having a methoxyl auxochrome (9 and 8, Figure 1). Pyrex-
filtered irradiation of 11 and 12 for 16 min provided 4a in 87%
and 99% yield, respectively. These data along with the UV
spectra of the acetals (Figure 1, c ) 2.0 × 10-5 M) suggested
that the auxochrome(s) located at different position(s) of the
salicyl alcohol skeleton mainly affected the photolysis by
changing chromophore absorption profiles. Nonetheless, the
meta effect also influenced the reaction outcome to some extent,
as shown in the photoreaction of 12 versus 11 (99% vs 87%)
and 8 versus 9 (99% vs 92%) under the same conditions. Since
the photochemical removal of 2 to release 4a (Table 1) was
significantly slower than the photoreactions of acetals 5a and
8-12, the two benzylic phenyl groups of the salicyl alcohol
skeleton seemed to have a more important role in facilitating
the benzylic C-O bond cleavage than the meta effect.
Among various new PPGs studied, R,R-diphenyl-5-(dimethy-
lamino)salicyl alcohol (14) used in acetal 12 appeared to be
more robust, with higher potential for biological applications
due to its longer absorption wavelength and good photochemical
efficiency (Φ ) 0.13).8,9 PPG 14 was readily prepared from
the commercially available 5-aminosalicylic acid (13) (Scheme
2). Installation of 14 onto 4a was relatively inefficient at room
temperature, but reflux in toluene afforded the desired acetal
12 in 94% yield.
As anticipated, on one hand, acetal 12 was more stable than
5a upon acid treatment (Table 5). Presumably the inductive
effect from protonated dimethylamino group in 12 made acid-
activation of acetal oxygens and subsequent heterolysis of a
C-O bond more difficult. On the other hand, acetal 12 became
more susceptible toward oxidants, degrading completely upon
the DDQ treatment at room temperature, whereas 5a remained
intact under the same conditions.
(11) Pisova, M.; Soucek, M. Collect. Czech. Chem. Commun. 1982, 47, 3318.
(12) The small scale runs were conducted in quartz cuvettes, with 3 (2.7
mg, 8 × 10-3 mmol) in 2.0 mL of solvent with Pyrex-filtered light from a 450
W medium pressure mercury lamp.
6154 J. Org. Chem. Vol. 73, No. 16, 2008

Sequential RemoVal of Photolabile Protecting Groups
SCHEME 2. Synthesis and Application of PPG 14
afforded the methyl ester. The ester (2.19 g, 10 mmol) in 15 mL
of THF was treated with PhLi (22.5 mL, 2.0 M in Bu2O) slowly
and stirred at -78 °C under Ar for 1.5 h. The reaction mixture
was quenched with saturated aqueous NH4Cl and extracted with
ethyl acetate (30 mL × 2). The combined organic layers were dried
over Na2SO4, filtered, and concentrated. The residue was purified
with flash chromatography (petroleum ether/ethyl acetate ) 3:1,
1
Rf 0.5) to provide 3 in 99% yield. H NMR (CDCl3, 300 MHz) δ
7.33-7.24 (m, 10 H), 6.47 (d, J ) 2.7 Hz, 1 H), 5.92 (s, 1 H),
5.70 (d, J ) 2.7 Hz, 1 H), 5.07 (s, 1 H), 3.86 (s, 3 H), 3.54 (s, 3
H); 13C NMR (CDCl3, 75 MHz) δ 152.2, 147.4, 145.9, 137.5, 132.7,
127.84, 127.79, 127.3, 106.8, 98.2, 82.3, 56.2, 55.5; IR (neat) 3502,
3059, 2941, 2838, 1600, 1490, 1449, 1429, 1372, 1317, 1229;
HRMS (ESI) m/z calcd for C21H20O4Na (M + Na+) 359.1259, found
359.1258.
Preparation of Acetal 5a. PPG 3 (79.0 mg, 0.23 mmol),
3-phenylpropanal (4a) (27.8 µL, 0.20 mmol), and pTsOH (3.8 mg,
0.02 mmol) in 1 mL of benzene were stirred at room temperature
for 20 h. The reaction mixture was concentrated for flash column
chromatography (petroleum ether/ethyl acetate ) 7/1, Rf 0.33) to
yield 5a (92 mg, 99%). 1H NMR (CDCl3, 300 MHz) δ 7.44-7.12
(m, 13 H), 7.01 (dd, J ) 7.5, 1.5 Hz, 2 H), 6.41 (d, J ) 2.7 Hz, 1
H), 5.97 (d, J ) 2.7 Hz, 1 H), 5.02 (dd, J ) 6.6, 3.6 Hz, 1 H), 3.88
(s, 3 H), 3.60 (s, 3 H), 2.87-2.79 (m, 1 H), 2.70-2.60 (m, 1 H),
2.33-2.21 (m, 2 H); 13C NMR (CDCl3, 75 MHz) δ 152.7, 149.0,
146.0, 144.2, 141.4, 136.8, 129.5, 128.4, 128.24, 128.18, 128.05,
127.9, 127.5, 125.9, 125.7, 104.6, 98.8, 94.7, 84.3, 56.0, 55.5, 35.9,
29.7; IR (neat) 3059, 3027, 2935, 2837, 1602, 1491, 1450, 1402,
1359, 1338, 1280, 1233; HRMS (ESI) m/z calcd for C30H29O4 (M
+ H+) 453.2066, found 453.2070.
TABLE 5. Stability of 12 under Acidic Conditions
a
entry
reagent
solvent
conditions
12 (%)b
1
2
AcOH
TFA
MeCN
MeCN
23 °C, 24 h
23 °C, 24 h
80 °C, 2 h
23 °C, 24 h
80 °C, 2 h
23 °C, 24 h
80 °C, 2 h
100
100
99
96
91
3
4
HCl (37%)
MeCN
MeCN
pTsOH
89
44
a Acetal 12 (0.01 mmol) in 1.0 mL of MeCN treated with reagent
b
1
(>0.2 mmol). Yields determined by H NMR.
SCHEME 3. Selective Removal of PPG
Preparation of Acetal 5b. PPG 3 (103 mg, 0.30 mmol),
4-phenoxybenzaldehyde (4b) (37.5 µL, 0.20 mmol), pTsOH (1.9
mg, 0.01mmol), and MgSO4 (100 mg, 0.80 mmol) in 1.0 mL of
benzene were stirred at room temperature for 24 h. The reaction
mixture was concentrated for flash column chromatography (pe-
troleum ether/ethyl acetate ) 7/1, Rf 0.60) to yield 5b (95 mg, 93%).
1H NMR (CDCl3, 400 MHz) δ 7.54 (d, J ) 8.8 Hz, 2 H), 7.48-7.45
(m, 2 H), 7.39-7.21 (m, 10H), 7.08 (t, J ) 7.3 Hz, 1 H), 7.02-6.98
(m, 4 H), 6.44 (d, J ) 2.7 Hz, 1 H), 6.00 (d, J ) 2.7 Hz, 1 H),
5.91 (s, 1 H), 3.85 (s, 3 H), 3.60 (s, 3 H); 13C NMR (CDCl3, 100
MHz) δ 157.9, 157.0, 152.8, 149.2, 145.6, 144.0, 136.8, 132.3,
129.7, 129.3, 128.3, 128.2, 128.1, 127.9, 127.6, 125.8, 123.3, 119.0,
118.6, 104.5, 98.8, 94.5, 85.1, 56.0, 55.5; IR (neat) 3059, 2937,
2837, 1592, 1510, 1490, 1386, 1357, 1280, 1236, 1200; HRMS
(ESI) m/z calcd for C34H28NaO5 (M + Na+) 539.1834, found
539.1832.
The relatively distinct absorption maximum of acetal 12 at
327 nm (ꢀ )3.38 × 103 M-1 cm-1) compared with others below
310 nm (Figure 1) suggested that selective removal of 14 in
the presence of other PPGs such as 3 could be feasible by control
of the irradiation wavelength. Indeed, irradiation of 5a at 350
nm in MeCN/H2O (9:1) for 20 min in a Rayonet reactor only
led to recovery of unreacted 5a in 97% yield. Under the same
conditions, released aldehyde 4a from 12 was obtained in 96%
yield (after conversion to its oxime derivative due to the volatile
nature of 4a). A mixture of 5b and 12 (1:1) in MeCN/H2O (9:
1) was also irradiated at 350 nm for 20 min, leading to 4a in
89% yield after derivatization and recovered 5b in 98% yield
(Scheme 3). Interestingly, the same selectivity could be achieved
with sunlight, even though acetal 12 was stable as a solid and
in solutions under laboratory lighting. Thus, 5b and 12 (1:1)
in MeCN/H2O (9:1) were exposed to sunlight for 3 h,
resulting in 96% released 4a from 12 (after derivatizing) and
98% recovered 5b.
General Procedure for the Preparation of Ketals 5c, 5d,
and 5e under Acidic Condition with a Dehydrating Reagent.
PPG 3 (103 mg, 0.30 mmol), ketone 4c-4e (0.20 mmol), pTsOH
(1.9 mg, 0.01 mmol), and P2O5 (60 mg, 0.40 mmol) in 1.0 mL of
benzene were stirred at room temperature for 1 h. The mixture was
poured into saturated aqueous NaHCO3 and extracted with CH2Cl2
(15 mL × 2). The combined organic layers were dried over Na2SO4,
filtered, and concentrated for flash column chromatography.
5c (isomer A): 74%, Rf 0.50 (petroleum ether/ethyl acetate )
In summary, a group of structurally simple PPGs for carbonyl
compounds have been developed. These PPGs were readily
prepared, demonstrated high protection/deprotection efficiencies,
and furthermore displayed excellent dark stability. The diversity
of new PPGs allowed highly efficient sequential removal of
PPGs by control of the irradiation wavelength.
1
9/1); H NMR (CDCl3, 300 MHz) δ 7.36-7.15 (m, 15 H), 6.44
(d, J ) 2.7 Hz, 1 H), 6.00 (d, J ) 2.8 Hz, 1 H), 3.86 (s, 3 H), 3.60
(s, 3 H), 2.49 (tt, J ) 12.3, 3.5 Hz, 1 H), 2.13 (d, J ) 12.6 Hz, 2
H), 1.93 (qd, J ) 13.0, 3.1 Hz, 2 H), 1.71 (d, J ) 10.8 Hz, 2 H),
1.56 (td, J ) 13.2, 4.0 Hz, 2 H); 13C NMR (CDCl3, 75 MHz) δ
153.2, 150.3, 146.8, 146.4, 134.3, 128.6, 128.39, 128.37, 127.8,
127.4, 126.9, 126.5, 126.1, 104.9, 101.4, 99.1, 81.5, 56.3, 55.6,
43.2, 36.3, 30.6; IR (neat) 3060, 3027, 2936, 2862, 2838, 1604,
1492, 1447, 1336, 1284, 1230, 1200; HRMS (ESI) m/z calcd for
C33H33O4 (M + H+) 493.2379, found 493.2380.
Experimental Section
Preparation of r,r-Diphenyl-3,5-dimethoxysalicyl Alcohol
(3). The known compound 3,5-dimethoxysalicylic acid5 was
refluxed in MeOH in the presence of concentrated H2SO4 for 3
days. The reaction mixture was cooled and concentrated. Flash
chromatography (petroleum ether/ethyl acetate ) 7:1, Rf 0.37)
5c (isomer B): 25%, Rf 0.30 (petroleum ether/ethyl acetate )
9/1); 1H NMR (CDCl3, 300 MHz) δ 7.45-7.41 (m, 4 H), 7.34-7.23
(m, 8 H), 7.19-7.09 (m, 3H), 6.43 (d, J ) 2.7 Hz, 1 H), 6.08 (d,
J ) 2.7 Hz, 1 H), 3.89 (s, 3 H), 3.63 (s, 3 H), 2.51 (tt, J ) 11.2,
J. Org. Chem. Vol. 73, No. 16, 2008 6155

Wang et al.
4.4 Hz, 1 H), 2.23 (dd, J ) 10.8, 3.0 Hz, 2 H), 1.78 (dt, J ) 13.0,
4.7 Hz, 2 H), 1.59-1.43 (m, 4 H); 13C NMR (CDCl3, 75 MHz) δ
153.0, 149.9, 146.7, 146.6, 134.4, 128.6, 128.2, 127.7, 127.4, 127.2,
126.8, 125.9, 104.5, 101.4, 98.8, 81.3, 56.1, 55.5, 43.3, 35.9, 29.8;
IR (neat) 3059, 3026, 2935, 2861, 1604, 1492, 1449, 1337, 1284,
1240, 1200; HRMS (ESI) m/z calcd for C33H33O4 (M + H+)
493.2379, found 493.2381.
5d: 99%, Rf 0.47 (petroleum ether/ethyl acetate ) 9/1); 1H NMR
(CDCl3, 400 MHz) δ 7.41 (dd, J ) 8.2, 1.8 Hz, 2 H), 7.28-7.22
(m, 8 H), 6.41 (d, J ) 2.7 Hz, 1 H), 6.02 (d, J ) 2.8 Hz, 1 H),
3.85 (s, 3 H), 3.61 (s, 3 H), 1.82-1.78 (m, 2 H), 1.43-1.39(m, 2
H), 1.30-1.16 (m, 31 H), 0.88 (t, J ) 6.8 Hz, 3 H); 13C NMR
(CDCl3, 100 MHz) δ 152.9, 150.2, 147.6, 146.5, 135.0, 128.9,
128.7, 128.2, 128.1, 127.7, 127.6, 126.5, 105.2, 103.0, 99.1, 81.4,
56.5, 55.9, 41.2, 32.4, 30.2, 30.1, 30.04, 29.97, 29.8, 25.2, 24.1,
23.2, 14.6; IR (neat) 2923, 2852, 1595, 1491, 1466, 1379, 1340,
1248, 1200; HRMS (ESI) m/z calcd for C40H57O4 (M + H+)
601.4257, found 601.4266.
the PPG R,R-diphenyl- 4-methoxysalicyl alcohol (911 mg, 99%).
1H NMR (CDCl3, 300 MHz) δ 8.21 (s, 1 H), 7.35-7.32 (m, 6 H),
7.23-7.19 (m, 4 H), 6.49 (d, J ) 2.7 Hz, 1 H), 6.40 (d, J ) 8.1
Hz, 1 H), 6.29 (dd, J ) 8.1, 2.4 Hz, 1 H), 3.77 (s, 3 H), 3.48 (s, 1
H); 13C NMR (CDCl3, 75 MHz) δ 160.8, 157.4, 145.0, 130.7, 128.2,
128.0, 127.7, 122.4, 105.1, 102.7, 84.3, 55.3; IR (neat) 3455, 3178,
2962, 1614, 1587, 1515, 1491, 1432, 1377, 1297, 1235; HRMS
(ESI) m/z calcd for C20H18NaO3 (M + Na+) 329.1154, found
329.1154.
The obtained PPG R,R-diphenyl-4-methoxysalicyl alcohol (92
mg, 0.30 mmol), 3-phenylpropanal 4a (27.8 µL, 0.20 mmol), and
pTsOH (1.9 mg, 0.01mmol) in 1.0 mL of benzene were stirred at
room temperature for 15 h. The mixture was poured into saturated
aqueous NaHCO3 and extracted with CH2Cl2 (15 mL × 2). The
combined organic layers were dried over Na2SO4, filtered, and
concentrated for flash column chromatography (petroleum ether/
1
ethyl acetate ) 20/1, Rf 0.28) to yield 9 (83 mg, 98%). H NMR
(CDCl3, 400 MHz) δ 7.37-7.33 (m, 5 H), 7.26-7.21 (m, 5 H),
7.19 (d, J ) 7.2 Hz, 2H), 7.12 (t, J ) 7.6 Hz, 1H), 7.06 (d, J ) 7.0
Hz, 2H), 6.71(d, J ) 8.6 Hz, 1H), 6.45 (d, J ) 2.5 Hz, 1H), 6.41
(dd, J ) 8.6, 2.6 Hz, 1 H), 5.03 (dd, J ) 5.9, 4.1 Hz, 1H), 3.74 (s,
3 H), 2.86 - 2.67 (m, 2 H), 2.25- 2.09 (m, 2H); 13C NMR (CDCl3,
100 MHz) δ 160.0, 153.7, 146.8, 144.9, 141.9, 130.9, 129.9, 128.84,
128.78, 128.5, 128.4, 128.3, 127.9, 126.3, 118.2, 108.1, 101.7, 95.1,
84.5, 55.7, 36.6, 30.0; IR (neat) 3448, 3060, 3028, 2932, 1620,
1583, 1501, 1447, 1399, 1359, 1327, 1258, 1201; HRMS (ESI)
m/z calcd for C29H27O3(M + H+) 423.1960, found 423.1957.
Preparation of Acetal 10. Commercially available 2,3,4-
trihydroxybenzoic acid (0.47 g, 2.75 mmol), K2CO3 (1.52 g, 11
mmol), and MeI (1.03 mL, 16.5 mmol) were stirred in 10 mL of
dry DMF at room temperature for 68 h. The reaction mixture was
adjusted to pH 4-5 with 1 N HCl, extracted with EtOAc (50 mL
× 2), dried over Na2SO4, filtered, and concentrated for flash column
chromatography (petroleum ether/ethyl acetate ) 5/1, Rf 0.28) to
yield methyl 2-hydroxy-3,4-dimethoxy-benzoate (234 mg, 40%).
Into a solution of PhLi (2.1 mL, 2 M in Bu2O) was added a
solution of the obtained methyl 2-hydroxy-3,4-dimethoxy-benzoate
(222 mg, 1.05 mmol) in 3 mL of freshly distilled THF dropwise at
-78 °C under argon. The reaction mixture was stirred at -78 °C
for 1 h and at room temperature for 2 h and then was quenched
with ice-cooled saturated aqueous NH4Cl. The mixture was
extracted with ethyl acetate (30 mL × 2), and the combined organic
layers were was dried over Na2SO4, filtered, and concentrated for
flash column chromatography (petroleum ether/ethyl acetate ) 3/1,
Rf 0.33) to yield the PPG R,R-diphenyl-3,4-dimethoxysalicyl alcohol
(346 mg, 98%). 1H NMR (CDCl3, 400 MHz) δ 7.27-7.21 (m, 10
H), 6.86 (s, 1H), 6.25 (d, J ) 8.9 Hz, 1H), 6.15 (d, J ) 8.8 Hz,
1H), 4.97 (s, 1 H), 3.81 (s, 3 H), 3.76 (s, 3 H); 13C NMR (CDCl3,
100 MHz) δ 152.5, 148.0, 146.5, 136.5, 128.32, 128.29, 128.26,
127.7, 126.4, 125.0, 102.9, 82.7, 61.4, 56.2; IR (neat) 3370, 2955,
2845, 1677, 1630, 1593, 1512, 1439, 1369, 1297, 1251, 1233, 1212;
HRMS (ESI) m/z calcd for C21H20NaO4 (M + Na+) 359.1259, found
359.1255.
5e, 99%, Rf 0.57 (petroleum ether/ethyl acetate ) 5/1); 1H NMR
(CDCl3, 400 MHz) δ 7.42 (dd, J ) 7.8, 1.4 Hz, 2 H), 7.30-7.22
(m, 8 H), 7.01 (d, J ) 8.6 Hz, 2 H), 6.78 (d, J ) 8.6 Hz, 2 H),
6.42 (d, J ) 2.7 Hz, 1 H), 6.01 (d, J ) 2.8 Hz, 1 H), 3.86 (s, 3 H),
3.75 (s, 3 H), 3.61 (s, 3 H), 2.83-2.66 (m, 2 H), 2.18-2.05 (m, 2
H), 1.31 (s, 3 H); 13C NMR (CDCl3, 100 MHz) δ 156.6, 151.7,
148.8, 146.0, 144.8, 133.3, 133.0, 128.3, 127.4, 127.2, 126.7, 126.4,
126.3, 125.5, 112.6, 103.7, 101.2, 97.7, 80.2, 55.0, 54.5, 54.2, 41.7,
28.0, 24.0; IR (neat) 2998, 2938, 2835, 1609, 1512, 1491, 1465,
1376, 1339, 1279, 1245, 1200; HRMS (ESI) m/z calcd for
C32H32NaO5 (M + Na+) 519.2147, found 519.2144.
General Procedure of Photolysis. Ketal/acetal 5 (0.20 mmol)
in 225 mL of acetonitrile and 25 mL of water was irradiated with
a 450 W medium pressure mercury lamp filtered with a Pyrex sleeve
without excluding air (for 5d, 240 mL of acetonitrile and 10 mL
of water were used because of the solubility limitation). The reaction
mixture was then concentrated, and the residue was subject to flash
column chromatography. For volatile 3-phenylpropanal (4a), de-
rivatization is necessary prior to chromatography. Thus, to the
reaction solution was added HONH2 ·HCl (1.112 g, 16.0 mmol)
and NaOAc (1.690 g, 19.2 mmol). The resulting mixture was stirred
at room temperature for 24 h, concentrated, and extracted with
CH2Cl2 (2 × 30 mL). The organic layers were combined, dried
over Na2SO4, filtered, and concentrated. The residue was purified
with flash column chromatography to provide the corresponding
oxime derivative.
Selective Removal of 14 with 350 nm Wavelength Irradi-
ation. In 225 mL of MeCN and 25 mL of H2O were dissolved 5b
(51.7 mg, 0.1 mmol) and 12 (43.6 mg, 0.1 mmol). The obtained
colorless solution was irradiated in a Rayonet photoreactor equipped
with 350 nm lamps for 20 min. The resulting purple color reaction
mixture was then derivatized with NaOAc and HONH2 · HCl as
describe above. The crude products were purified with flash column
chromatography, eluted with petroleum/ethyl acetate (5:1) to provide
the oxime of 4a (13 mg, 89%) and unreacted 5b (50 mg, 98%).
Selective Removal of 14 with Sunlight. In 225 mL of MeCN
and 25 mL of H2O were dissolved 5b (51.7 mg, 0.1 mmol) and 12
(43.5 mg, 0.1 mmol). The obtained colorless solution was exposed
to outdoor sunlight for 3 h, and a purple solution was obtained.
Derivatization and workup as described above afforded oxime of
4a (14 mg, 96%) and unreacted 5b (50 mg, 98%).
Preparation of Acetal 9. A solution of commercially available
methyl 2-hydroxy-4-methoxybenzoate (558 mg, 3.0mmol) in 8.0
mL of freshly distilled THF was added into PhLi (6.0 mL, 2 M in
Bu2O) dropwise at -78 °C under argon, and the mixture was stirred
at -78 °C for 1 h and at room temperature for 2 h. Ice-cooled
saturated aqueous NH4Cl was added to quench the reaction. The
reaction mixture was adjusted to slightly acidic and extracted with
ethyl acetate (50 mL × 2). The combined organic layers were dried
over Na2SO4, filtered, and concentrated for flash column chroma-
tography (petroleum ether/ethyl acetate ) 5/1, Rf 0.30) to yield
The PPG (103 mg, 0.30 mmol), 3-phenylpropanal 4a (27.8 µL,
0.20 mmol), and pTsOH (1.9 mg, 0.01 mmol) in 1.0 mL of benzene
were stirred at room temperature for 12.5 h. The mixture was poured
into saturated aqueous NaHCO3 and extracted with CH2Cl2 (15 mL
× 2). The combined organic layers were dried over Na2SO4, filtered,
and concentrated for flash column chromatography (petroleum ether/
1
ethyl acetate ) 9/1, Rf 0.50) to yield 10 (89 mg, 98%). H NMR
(CDCl3, 400 MHz) δ 7.37-7.33 (m, 5 H), 7.28-7.07 (m, 10 H),
6.50 (d, J ) 8.8 Hz, 1H), 6.42 (d, J ) 8.8 Hz, 1H), 5.06 (dd, J )
5.8, 4.1 Hz, 1H), 3.89 (s, 3 H), 3.80 (s, 3H), 2.86 - 2.73 (m, 2 H),
2.28 - 2.21 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 152.4, 147.1,
146.8, 144.8, 141.8, 137.3, 129.9, 128.84, 128.79, 128.54, 128.53,
128.49, 128.3, 127.9, 126.3, 124.7, 119.8, 104.6, 95.3, 84.5, 61.4,
56.4, 36.6, 30.1; IR (neat) 3060, 3027, 2934, 2835, 1610, 1498,
1460, 1400, 1355, 1289, 1259, 1238, 1209; HRMS (ESI) m/z calcd
for C30H29O4 (M + H+) 453.2066, found 453.2068.
6156 J. Org. Chem. Vol. 73, No. 16, 2008

Sequential RemoVal of Photolabile Protecting Groups
Preparation of Acetal 11. Commercially available 4-aminosali-
cylic acid (1.55 g, 10.0 mmol), NaHCO3 (4.2 g, 50.0 mmol) and
MeI (2.49 mL, 40.0 mmol) were stirred in 15 mL of DMF at room
temperature for 24 h. The reaction mixture was acidified with 1 N
HCl to pH 4-5, extracted with EtOAc (50 mL × 2), dried over
Na2SO4, filtered, and concentrated for flash column chromatography
(petroleum ether/ethyl acetate ) 5/1, Rf 0.28) to yield methyl
4-(dimethylamino)-2-hydroxybenzoate (777 mg, 40%). Into a
solution of PhLi (2.0 mL, 2 M in Bu2O) was added a solution of
methyl 4-(dimethylamino)-2-hydroxybenzoate (200 mg, 1.0 mmol)
in 3 mL freshly distilled THF dropwise, at -78 °C under argon.
The reaction mixture was stirred at -78 °C for 1 h and at room
temperature for 2 h, and then was quenched with ice-cooled
saturated aqueous NH4Cl. The solution was extracted with ethyl
acetate (30 mL × 2). The combined organic layers were dried over
Na2SO4, filtered, and concentrated for flash column chromatography
(petroleum ether/ethyl acetate ) 3/1, Rf 0.20) to yield the PPG R,R-
diphenyl-4-(dimethylamino)salicyl alcohol (315 mg, 99%). 1H NMR
(CDCl3, 400 MHz) δ 8.00 (s, 1H), 7.37-7.29 (m, 6 H), 7.23-7.20
(m, 4H), 6.33 (d, J ) 8.6 Hz, 1H), 6.29 (d, J ) 2.5 Hz, 1 H), 6.10
Into the mixture of methyl 5-amino-2-hydroxybenzoate (1.50 g,
9.0 mmol), paraformaldehyde (2.70 g, 90 mmol), and NaBH3CN
(1.805 g, 27 mmol) was added AcOH (90 mL). The mixture was
stirred at room temperature for 4 h and then concentrated. Saturated
aqueous Na2CO3 was poured into the mixture to adjust the pH to
7-8. The mixture was extracted with CH2Cl2 (30 mL × 3). The
combined organic layers were dried over Na2SO4, filtered, and
concentrated to yield methyl 5-(dimethylamino)-2-hydroxybenzoate
(1.72 g, 98%)
Into a solution of PhLi (0.9 mL, 2 M in Bu2O) was added a
solution of methyl 5-(dimethylamino)-2-hydroxybenzoate (54 mg,
0.28mmol) in 1 mL of freshly distilled THF dropwise, at -78 °C
under argon. The mixture was stirred at -78 °C for 1 h and at
room temperature for 2 h and then was quenched with ice-cooled
saturated aqueous NH4Cl. The solution was extracted with ethyl
acetate (15 mL × 2). The combined organic layers were dried over
Na2SO4, filtered, and concentrated for flash column chromatography
(petroleum ether/ethyl acetate ) 5/1, Rf 0.43) to yield PPG 14, R,R-
diphenyl- 5-(dimethylamino)salicyl alcohol (81 mg, 92%). 1H NMR
(CD3SOCD3, 300 MHz) δ 9.04 (s, 1H), 7.33-7.18 (m, 10 H), 6.73
(s, 1H), 6.68 (d, J ) 8.7 Hz, 1H), 6.59 (dd, J ) 8.7, 3.0 Hz, 1H),
5.92 (d, J ) 2.7 Hz, 1 H), 3.35 (s, 6 H); 13C NMR (CD3SOCD3,
75 MHz) δ 146.9, 146.2, 143.4, 132.2, 127.5, 127.4, 126.8, 116.6,
115.2, 113.6, 81.9, 41.0; IR (neat) 3408, 3058, 2909, 1625, 1494,
1447, 1239; HRMS (ESI) m/z calcd for C21H22NO2 (M + H+)
320.1651, found 320.1647.
(dd, J ) 8.7, 2.4 Hz, 1H), 3.49 - 3.42 (m, 1 H), 2.92 (s, 6H); 13
C
NMR (CDCl3, 100 MHz) δ 156.9, 151.8, 145.5, 130.5, 128.1, 127.8,
127.7, 118.3, 103.3, 101.1, 84.2, 40.3, 31.0; IR (neat) 3164, 3058,
2909, 1621, 1565, 1528, 1487, 1445, 1366, 1300, 1236; HRMS
(ESI) m/z calcd for C21H22NO2 (M + H+) 320.1651, found
320.1649.
PPG 14 (128 mg, 0.40 mmol), 3-phenylpropanal 4a (27.8 µL,
0.20 mmol), and pTsOH (3.8 mg, 0.02 mmol) in 2.0 mL of toluene
were refluxed under Ar for 35 h. The mixture was poured into
saturated aqueous NaHCO3 and extracted with EtOAc (20 mL ×
2). The combined organic layers were dried over Na2SO4, filtered,
and concentrated for flash column chromatography (petroleum ether/
The PPG (98 mg, 0.30 mmol), 3-phenylpropanal 4a (27.8 µL,
0.20 mmol), pTsOH (1.9 mg, 0.01 mmol), and P2O5 (60 mg, 0.8
mmol) in 1.0 mL of benzene was stirred at room temperature for
1.5 h. The mixture was poured into saturated aqueous NaHCO3
and extracted with EtOAc (20 mL × 2). The combined organic
layers were dried over Na2SO4, filtered, and concentrated for flash
column chromatography (petroleum ether/ethyl acetate ) 20/1, Rf
1
ethyl acetate ) 5/1, Rf 0.50) to yield 12 (82 mg, 94%). H NMR
(CDCl3, 300 MHz) δ 7.49-7.07 (m, 15 H), 6.87 (d, J ) 9.0 Hz,
1H), 6.71 (dd, J ) 9.0, 3.0 Hz, 1H), 6.27 (d, J ) 3.0 Hz, 1H), 5.02
(dd, J ) 6.0, 4.2 Hz, 1H), 2.91 - 2.67 (m, 8 H), 2.29- 2.09 (m,
2H); 13C NMR (CDCl3, 75 MHz) δ 146.4, 144.8, 144.7, 144.6,
141.6, 129.5, 128.4, 128.3, 128.1, 128.0, 127.9, 127.8, 127.3, 125.7,
125.4, 117.3, 114.8, 114.4, 94.3, 84.4, 41.5, 36.2, 29.7; IR (neat)
3060, 3028, 2929, 2884, 2795, 1620, 1504, 1447, 1400, 1361, 1240;
HRMS (ESI) m/z calcd for C30H30NO2 (M + H+) 436.2277, found
436.2276.
1
0.25) to yield 11 (43 mg, 49%). H NMR (CDCl3, 300 MHz) δ
7.42-7.04 (m, 15 H), 6.66 (dd, J ) 6.9, 2.4 Hz, 1H), 6.26 - 6.23
(m, 2H), 5.03 (dd, J ) 6.0, 4.2 Hz, 1H), 2.88 - 2.65 (m, 8 H),
2.26 - 2.05 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 153.2, 150.7,
146.8, 145.0, 141.6, 130.3, 129.5, 128.5, 128.4, 128.1, 128.0, 127.9,
127.8, 127.3, 125.8, 113.8, 105.7, 99.8, 94.6, 84.1, 40.4, 36.4, 29.7;
IR(neat) 3059, 3027, 2929, 2802, 1623, 1564, 1516, 1492, 1447,
1399, 1366, 1314, 1278, 1240; HRMS (ESI) m/z calcd for
C30H30NO2 (M + H+) 436.2277, found 436.2276.
Acknowledgment. This work was supported by the Univer-
Preparation of Acetal 12. The commercially available 5-ami-
nosalicylic acid (1.55 g, 10.0 mmol) was refluxed in 10 mL of
MeOH in the presence of H2SO4 (0.3 mL) for 26 h. After solvent
was removed, saturated aqueous NaHCO3 was added into the
mixture to adjust the pH to 8-9.The mixture was extracted with
EtOAc (20 mL × 3), dried over Na2SO4, filtered and concentrated
to yield methyl 5-amino-2-hydroxybenzoate (162 mg, 96%).
sity of Alabama at Birmingham.
Supporting Information Available: UV, 1H NMR, and 13
NMR Spectra of 3, 5a-5e, 9-12, and 14. This material is
available free of charge via the Internet at http://pubs.acs.org.
C
JO8008275
J. Org. Chem. Vol. 73, No. 16, 2008 6157