Efficient synthesis of resin-bound α-TMSdiazoketones and their use in solid-phase organic synthesis

Article abstract of DOI:10.1016/S0040-4020(00)00440-3

α-TMSdiazoketones on a solid support could be simply and efficiently prepared by reaction of the corresponding resin-bound acid chlorides with excess TMSdiazomethane, without any bases. These α-TMSdiazoketones were used via carbenes or carbenoids for a variety of solid-phase reactions. These useful solid-phase reactions allow efficient construction of diverse compound libraries by use of combinatorial chemistry, due to the high reactivity and wide applications of the carbenes or carbenoids. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00440-3

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 5353±5361
Ef®cient Synthesis of Resin-Bound a-TMSdiazoketones and Their
Use in Solid-Phase Organic Synthesis
*
Yasuyoshi Iso, Hirohisa Shindo and Hiroshi Hamana
Shionogi Research Laboratories, Shionogi & Co. Ltd., Fukushima-ku, Osaka 553-0002, Japan
Received 20 April 2000; accepted 22 May 2000
AbstractÐa-TMSdiazoketones on a solid support could be simply and ef®ciently prepared by reaction of the corresponding resin-bound
acid chlorides with excess TMSdiazomethane, without any bases. These a-TMSdiazoketones were used via carbenes or carbenoids for a
variety of solid-phase reactions. These useful solid-phase reactions allow ef®cient construction of diverse compound libraries by use of
combinatorial chemistry, due to the high reactivity and wide applications of the carbenes or carbenoids. q 2000 Elsevier Science Ltd. All
rights reserved.
Introduction
that TMSdiazomethane could successfully convert acid
chlorides to a-TMSdiazoketones without any bases on a
solid support and moreover, the molecular diversity could
be increased by use of the C±Si bond remaining in a
resin-bound substrate after subsequent reactions using
a-TMSdiazoketone.
Diazo compounds as precursors of carbenes or carbenoids,
including a-diazoketones, have a long history of useful
applications in organic chemistry1 and have been an impor-
tant and interesting theme for modern organic synthesis.2 In
solid-phase organic synthesis, some examples using diazo
compounds were recently reported, such as cyclopropene
synthesis,3 furan synthesis via 1,3-dipolar cycloaddition,4
OH-insertion reaction5 and the `diazo linker' method.6
However, few synthetic methods for a-diazoketones on a
solid support have been reported and the only synthesis
required diazo formation of resin-bound 1,3-diketone with
tosyl azide and subsequent deacylation of the 2-diazo-1,3-
diketone with pyrrolidine.5 In this route, the resin-bound
1,3-diketone must ®rst be prepared as a starting material
via a dif®cult procedure, and substances containing sensitive
functional groups or protecting groups cannot be used
because strong bases such as pyrrolidine must be used in
deacylation.
Results and Discussion
The preparation of resin-bound a-TMSdiazoketone 6 is
shown in Scheme 1. After attachment of the Wang resin
(1) and 4-hydroxy benzoic acid allyl ester (2) as a substrate
under Mitsunobu conditions,9 the allyl group was depro-
tected with Pd(PPh3)4 to give resin-bound carboxylic acid
4.10 The carboxyl group was converted into acid chloride 5
by oxalyl chloride under heating.11 Next, resin 5 was reacted
with TMSdiazomethane and triethylamine in the mixture
solvent of THF/MeCN (1/1) at room temperature for 50 h
to furnish resin-bound a-TMSdiazoketone 6, which had IR
absorption at 2102 cm21 resulting from the formed diazo
group. Another kind of resin-bound a-TMSdiazoketone 60
containing an aliphatic substrate was also obtained without
protection from azelaic acid (20) instead of a phenol deriva-
tive, under the same reaction conditions as above. However,
in order to use resin 6 in various reactions via a carbene or
carbenoid, the yield of 6 must be as high as possible. We
therefore optimized the reaction conditions from 5 to 6.
We thus tried to develop a method which could directly
give resin-bound a-diazoketones from resin-bound acid
chlorides and diazomethane, as generally performed in solu-
tion reaction.7 However, problems arise due to the highly
toxic and explosive diazomethane used in the solid-phase
reaction. The risk increases with a long reaction time and
static electricity which can be generated by rubbing of poly-
styrene. To avoid this problem, we used TMSdiazomethane
which is safer than diazomethane with respect to both toxi-
city and the possibility of explosion.8 As a result, we found
The yield of 6 was determined by comparing the nitrogen
content of 6 by elemental analysis with the calculated value
and the result is shown in Table 1. The mixture of THF/
MeCN (1/1) was better than only THF as the reaction
solvent and 50 h was better than 24 h for the reaction
time. With respect to the reagents, the quantity of triethyl-
amine greatly affected the reaction yield, with the less used,
Keywords: diazo compound; carbene and carbenoid; solid-phase synthesis;
combinatorial chemistry.
* Corresponding author. Tel.: 181-6-6458-5861; fax: 181-6-6458-0987;
e-mail: yasuyoshi.isou@shionogi.co.jp
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00440-3

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Y. Iso et al. / Tetrahedron 56 (2000) 5353±5361
Scheme 1. Synthetic route for preparation of resin-bound a-TMSdiazoketone (6 or 60). (i) ADDP (5 equiv.), n-Bu3P (5 equiv.) in THF, room temperature, 4 h.
(ii) Pd(PPh3)4 (1 equiv.), AcOH (excess), 4-methylmorpholine (excess) in CH3Cl3, room temperature, 3 h. (iii) (COCl)2 (10 equiv.), re¯uxed in benzene, 16 h.
(iv) TMSCHN2 (3 equiv.), Et3N (1 equiv.) in THF/MeCNˆ1/1, room temperature, 50 h (this reaction condition is not optimized; see Table 1).
Table 1. Optimization of reaction conditions from 5 to 6 (all reactions were performed at room temperature)
Entry
Solvent
TMSCHN2 (equiv.)
Et3N (equiv.)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
9
10
THF/MeCNˆ1/1
THF/MeCNˆ1/1
THF/MeCNˆ1/1
THF/MeCNˆ1/1
THF/MeCNˆ1/1
THF/MeCNˆ1/1
THF/MeCNˆ1/1
THF/MeCNˆ1/1
THF
1.3
1.3
2
2
3
3
3
3
2
1.3
1.3
2
2
0
0
0.5
1
2
0
24
50
24
50
50
50
50
50
50
50
40.1
48.2
±
38.5
41.0
80.5
71.5
61.0
25.7
45.0
THF
3
a The yield of 6 was determined by comparing the nitrogen content of 6 in elemental analysis with the calculated value.
leading to a higher yield. As a result, the conditions of entry
6 in the absence of triethylamine were the best even on
further optimization of the reaction conditions. The
advantage of entry 6 was also supported by both the
strength of IR absorption at 2102 cm21 and the yield after
the subsequent Arndt±Eistert reaction12 and cleavage.
Comparing the above data about 6 and 60 with time
dependence, we found that resin-bound a-TMSdiazoke-
tones were stable for at least a month in a desiccator
shielded from light kept under reduced pressure, even at
room temperature.
proceeded smoothly to give the corresponding methylene-
inserted ester resin 7-1 or 7-2 in the reaction of resin 6 with
alcohols 1 or 2 as a nucleophile, in the presence of 2,4,6-
trimethylpyridine as an additive, without solvent at 1808C
for 20 min. In this case, the TMS group would be removed
by the action of a nucleophile on resin 6.12a Resin 7-1 or 7-2
was cleaved with a 50% (v/v) solution of TFA in CH2Cl2 to
furnish the expected 8-1 or 8-2 in 63 or 61% total yield from
Wang resin (1), respectively (entry 1 and 2). Resin 60 also
gave methylene-inserted ester 80-1 in 46% total yield by the
same method as above (entry 4). Moreover, methylene-
inserted amide 8-3 was obtained in 60% total yield, by the
reaction of amine 3 with resin 6 in the absence of 2,4,6-
trimethylpyridine under the same reaction conditions and
the subsequent cleavage (entry 3). The above reactions did
not proceed successfully under photochemical conditions.
Next, we studied the various types of solid-phase reactions
via carbenes or carbenoids, using resin-bound a-TMSdiazo-
ketones 6 and 60 prepared as above. First, we tried the
Arndt±Eistert reaction, which is a classical and typical
methylene insertion reaction via a carbene from a-diazo-
ketones or a-TMSdiazoketones in solution reaction.12
Table 2 shows that the solid-phase Arndt±Eistert reaction
The results of the a-substitution reaction2,5,13 using resin-
bound a-TMSdiazoketones 6 and 60 are shown in Table 3.

Y. Iso et al. / Tetrahedron 56 (2000) 5353±5361
5355
Table 2. Solid-phase Arndt±Eistert reaction
Entry
Nucleophile (excess)
(HO± or H2N±R)
Additive
Reaction conditions
Total yield (%) of 8 or
80 from Wang resin
(1)
1
2
3
20 min, 1808C
20 min, 1808C
20 min, 1808C
63
61
60
±
4
20 min, 1808C
46
The solid-phase a-substitution (SH-,13a OH-5,13b or NH-13c
insertion) reaction via a carbenoid proceeded successfully
by the reaction of resin 6 with thiol 1, alcohol 2, or amine 3.
After the reaction of resin 6 with thiol 1 or amine 3 using
rhodium(II) acetate as a catalyst in benzene under heating
and the subsequent cleavage, the expected a-substituted
ketone 10-1 or 10-3 was obtained in 64 or 51% total yield
from Wang resin (1), respectively (entry 1 and 3). a-Substi-
tuted ketone 100-1 was also obtained in 41% total yield from
resin 60 and thiol 1 under the same reaction conditions as
Table 3. Solid-phase a-substitution (SH, OH or NH-insertion) reaction
Entry
Reactant (excess)
Catalyst
Solvent
Reaction conditions
Total yield (%) of 10
or 100 from Wang
resin (1)
1
2
Rh2(OAc)4
BF3´Et2O
Benzene
CH2Cl2
2 h, 508C
64
52
H±O±Et (2)
1 h, rt
3
Rh2(OAc)4
Benzene
2 h, 858C
51
4
Rh2(OAc)4
Benzene
2 h, 508C
41

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Y. Iso et al. / Tetrahedron 56 (2000) 5353±5361
Table 4. Oxazole synthesis via ylide formation with aryl nitrile and subsequent 1,5-cyclization
Entry
Aryl nitrile (excess)
Solvent
Total yield (%) of 12 or 120 from
Wang resin (1)
1
2
±
66
46
Benzene
3
Benzene
60
4
±
48
Scheme 2. Further modi®cations using C±Si bond of resin (11-1): (i) 50% TFA in CH2Cl2; (ii) Br2 (6 equiv.); Pyridine (3 equiv.) in CH2Cl2, 08C; (iii) p-
Tolylboronic acid (2.7 equiv.), Pd(PPh3)4 (cat.), aqueous Na2CO3 (2 M, 3.6 equiv.), re¯uxed in DME, 17 h.

Y. Iso et al. / Tetrahedron 56 (2000) 5353±5361
5357
Scheme 3. Solid-phase intramolecular Buchner reaction: (i) Rh2(OAc)4 (cat.), re¯uxed in CHCl3, 40 min; (ii) 50% TFA in CH2Cl2.
entry 1 (entry 4). In the same way, alcohol 2 gave the corre-
sponding a-alkoxy ketone 10-2 in 52% total yield using
BF3´Et2O as a catalyst in CH2Cl2 at room temperature
(entry 2).
Conclusion
We have developed a simple and ef®cient method for
preparing a-TMSdiazoketones from carboxylic acid deriva-
tives on a solid support under mild conditions. Using these
resin-bound a-TMSdiazoketones which have diverse
substrates including various kinds of phenols and aliphatic
dicarboxylic acids, we successfully performed a variety of
solid-phase reactions containing the Arndt±Eistert reaction,
the a-substitution reaction, the oxazole synthesis via ylide
formation with aryl nitrile and subsequent 1,5-cyclization,
and the intramolecular Buchner reaction via carbenes or
carbenoids. The use of these solid-phase reactions with
combinatorial chemistry should contribute greatly to ef®-
cient construction of diverse compound libraries to search
for interesting compounds for new drugs.
Next, the ylide formation of resin-bound a-TMSdiazo-
ketones with aryl nitriles via carbenoids and the subsequent
1,5-cyclization14 proceeded successfully to give various
oxazole derivatives on a solid support as shown in
Table 4. After the reaction of resin 6 with aryl nitriles
1, 2, or 3 using rhodium(II) acetate as a catalyst in
benzene or without solvent under heating for 2.5 h
and the subsequent cleavage accompanied with desylila-
tion, 2,5-substituted oxazole derivatives 12-1, 12-2, or
12-3 were obtained in 66, 46 or 60% total yield from
Wang resin (1), respectively (entry 1, 2 and 3). Resin 60
also furnished 2,5-substituted oxazole derivative 120-1
in 48% total yield by the same method (entry 4). More-
over, we could perform further modi®cations using the
C±Si14b bond of resin 11-1 (Scheme 2). Bromination of
resin-bound oxazole derivative 11-1 at the position of
the C±Si bond using bromine and pyridine15 gave 13,
which furnished 2,5-substituted-4-bromo oxazole 14 in
50% total yield from Wang resin (1) after cleavage.
Further Suzuki reaction16 of resin 13 with p-tolylboronic
acid and catalytic Pd(PPh3)4 furnished 15, which also
gave 2,4,5-substituted oxazole derivative 16 in 41%
total yield from Wang resin (1) after cleavage. This
means that a series of reactions allow a diverse substi-
tuent to be introduced at all carbons on the oxazole and
the molecular diversity could be expanded more.
Experimental
General methods
Reagents were purchased from Aldrich, Tokyo Kasei (TCI-
JP), and Kanto Chemical and used as received. Solvents
were dried over appropriate molecular sieves. Particularly,
THF was distilled under N2 from lithium aluminum hydride,
MeCN was dried by distillation from phosphorus pentoxide,
and CHCl3 was partitioned with conc. H2SO4 and water,
dried over CaCl2, and distilled, immediately prior to use.
Wang resin was purchased from NovaBiochem. Compound
puri®cation by preparative TLC was carried out on plates
(20 cm£20 cm, 0.5 mm thick) precoated with silica gel
60F254 (Merck).
Formation of the fused ring system by intramolecular
Buchner reaction17 using resin-bound a-TMSdiazoketones
600 proceeded successfully as shown in Scheme 3. At
®rst, 600 was synthesized as above from Wang resin
(1) and 3-(4-hydroxyphenyl) propionic acid allyl ester
(200). Resin 600 was re¯uxed with catalytic rhodium(II)
acetate in CHCl3 for 40 min to give 17 having the
A Barnes analytical/spectra-tech diffuse re¯ectance acces-
sory was used for the infrared measurement of resins, and
diffuse re¯ectance infrared Fourier transform (DRIFT)
spectra of resins were obtained with a Nicolet 20SXB spec-
trometer with KBr optics.
bicyclo[5.3.0]decane skeleton via
a
transient nor-
caradiene-like intermediate. Cleavage, rearrangement
and desilylation of resin 17 occurred spontaneously
with a 50% (v/v) solution of TFA in CH2Cl2 to furnish
7-hydroxy-2-tetralone (18) in 60% total yield from
Wang resin (1).
4-Hydroxybenzoic acid allyl ester (2). THF (10 ml) was
added to a suspension of 4-hydroxybenzoic acid (5.0 g,
36.2 mmol), thionyl chloride (3.95 ml, 54.3 mmol) and
DMF (0.42 ml, 5.43 mmol) in CH2Cl2 (50 ml), and the reac-
tion mixture was stirred for 30 min at room temperature.

5358
Y. Iso et al. / Tetrahedron 56 (2000) 5353±5361
After allyl alcohol (5.5 ml, 81.45 mmol) was added drop-
wise to the obtained clear solution containing the acid
chloride, the reaction mixture was stirred for 2 h at room
temperature. Then, saturated aqueous NaHCO3 (150 ml)
was added, and the reaction mixture was stirred for
30 min more. CHCl3 (150 ml) and water (100 ml) were
added, and the organic layer was taken, washed with
water, dried (MgSO4), evaporated in vacuo, and recrystal-
lized from hexane to give 2 as white crystals (6.25 g, 97%).
was agitated at room temperature for 50 h. The resin was
®ltered and washed with anhydrous THF (3£2 ml), MeCN
(3£2 ml), CH2Cl2 (3£2 ml), and ether (3£2 ml) (52.0 mg).
IR (KBr): 2102 (±C(±TMS)±N2), 1720 (±CO±) cm21. Anal
calcd for resin 6: N, 1.59. Found: N, 1.28. Substrate loading
of 6 was determined to be 0.54 mmol/g by the above result
and total yield from Wang resin (1) was also determined to
be 80.5%.
IR (CHCl3): 3280, 1700, 1610 cm21. H NMR (200 MHz,
Preparation of resin 60. Resin 60 was prepared by the same
method as above from commercially available azelaic acid
(20) as a starting material. IR (KBr): 2102 (±C(±TMS)±N2),
1717 (±CO±) cm21. Anal calcd for resin 60: N, 1.54. Found:
N, 0.95. Substrate loading of 60 was determined to be
0.41 mmol/g by the above result and total yield from
Wang resin (1) was also determined to be 61.7%.
1
CDCl3): d 4.81 (dd, Jˆ5.6 Hz, Jˆ1.6 Hz, 2H), 5.28 (dd,
Jˆ10.2 Hz, Jˆ1.8 Hz, 1H), 5.41 (dd, Jˆ16.2 Hz, Jˆ
1.8 Hz, 1H), 5.93 (br s, 1H (±OH)), 5.94±6.14 (m, 1H),
6.88 (d, Jˆ8.2 Hz, 2H), 7.99 (d, Jˆ8.2 Hz, 2H). 13C NMR
(75 MHz, CDCl3): 165.1, 163.4, 137.0, 132.2, 122.0, 115.8,
115.5, 66.7. Anal calcd for C10H10O3: C, 67.41; H, 5.66.
Found: C, 67.01; H, 5.60.
4-Hydroxyphenylacetic acid benzyl ester (8-1). Resin 6
(52 mg, ,0.028 mmol) was suspended in 1:1 (v/v)
anhydrous benzyl alcohol/2,4,6-trimethylpyridine (2 ml),
and the reaction mixture was agitated at 1808C for 20 min.
Resin 7-1 was ®ltered, washed with anhydrous CH2Cl2
(3£2 ml), THF (3£2 ml), and ether (3£2 ml), and dried in
vacuo. A 50% (v/v) solution of TFA in CH2Cl2 (2 ml) was
added to the above resin, and the reaction mixture was
agitated at room temperature for 30 min. After the resin
was ®ltered and washed with CH2Cl2 (2 ml), the combined
®ltrates were concentrated, and puri®ed by preparative TLC
(ethyl acetate/toluene) to give 8-1 (5.1 mg) in 63% yield
Preparation of resin 3. Tributylphosphine (0.834 ml,
3.35 mmol), 2 (1.2 g, 6.7 mmol), 1,10-(Azodicarbonyl)di-
piperidine (ADDP; 846 mg, 3.35 mmol) were added to a
suspension of Wang resin (1) (0.67 mmol, i.e. 1.0 g of
resin, hydroxy group loading 0.67 mmol/g) in anhydrous
THF (50 ml), and the reaction mixture was agitated at
room temperature for 4 h. The resin was ®ltered, washed
with anhydrous THF (3£40 ml), DMF (3£40 ml), MeOH
(3£40 ml), CH2Cl2 (3£40 ml), and ether (3£40 ml), and
dried in vacuo (1.12 g).
1
Preparation of resin 4. Resin 3 (1.12 g, ,0.67 mmol) was
suspended in anhydrous CHCl3 (50 ml), and acetic acid
(4 ml, 70 mmol), 4-methylmorpholine (2 ml, 18 mmol),
and Pd(PPh3)4 (774 mg, 0.67 mmol) were added. The reac-
tion mixture was agitated under N2 at room temperature for
3 h. The resin was ®ltered, washed with 1% (w/v) diiso-
propylethylamine/DMF (3£40 ml), 1% (w/v) diethyldithio-
carbamic acid sodium salt/DMF (3£40 ml), anhydrous
DMF (3£40 ml), MeOH (3£40 ml), CH2Cl2 (3£40 ml),
and ether (3£40 ml), and dried in vacuo (1.09 g). Genera-
tion of resin 4 and substrate loading of 4 were checked by
cleavage of a part of the obtained resin.
from 1. IR (CHCl3): 3300, 1720, 1610 cm21. H NMR
(200 MHz, CDCl3): d 3.60 (s, 2H), 5.13 (s, 2H), 5.33 (br
s, 1H (±OH)), 6.78 (d, Jˆ8.4 Hz, 2H), 7.15 (d, Jˆ8.4 Hz,
2H), 7.30±7.40 (m, 5H). 13C NMR (75 MHz, CDCl3): d
171.0, 157.7, 130.6, 128.0, 125.7, 116.3, 66.2, 42.1.
HR-FABMS: m/z calcd for MH1 (C15H15O3) 243.1021,
found 243.1022.
4-Hydroxyphenylacetic acid 3-cyclohexylpropyl ester
(8-2). Resin 6 (52 mg, ,0.028 mmol) was suspended in
1:1 (v/v) anhydrous 3-cyclohexyl-1-propanol/2,4,6-tri-
methylpyridine (2 ml), and the reaction mixture was
agitated at 1808C for 20 min. The product (5.6 mg) was
isolated as above in 61% yield from 1. IR (CHCl3): 3300,
After 50% (v/v) TFA/CH2Cl2 (2 ml) was added to the above
resin (109 mg, ,0.67 mmol), and the reaction mixture was
agitated at room temperature for 30 min, the resin was
®ltered and washed with CH2Cl2 (2 ml). The combined
®ltrates were concentrated and gave 4-hydroxybenzoic
acid as a starting substrate after recrystallization from
CHCl3/ether, whose spectrum data were identical with
those of an authentic sample (9.0 mg, 0.0652 mmol, 97%).
Substrate loading of 4 was determined to be 0.65 mmol/g by
the above result.
1
1715 cm21. H NMR (200 MHz, CDCl3): d 1.17±1.24 (m,
12H), 1.58±1.70 (m, 3H), 3.51 (s, 2H), 4.05 (t, Jˆ6.6 Hz,
2H), 5.37 (br s, 1H (±OH)), 6.76 (d, Jˆ8.4 Hz, 2H), 7.09 (d,
Jˆ8.4 Hz, 2H). 13C NMR (75 MHz, CDCl3): d 171.0, 157.8,
130.8, 125.4, 116.2, 64.8, 41.8, 35.8, 33.4, 33.1, 29.5, 27.3,
26.9. HR-FABMS: m/z calcd for MH1 (C17H25O3)
277.1804, found 277.1806.
2-(4-Hydroxyphenyl)N-phenylacetamide (8-3). Resin 6
(52 mg, ,0.028 mmol) was suspended in aniline (2.5 ml),
and the reaction mixture was agitated at 1808C for 20 min.
The product (4.6 mg) was isolated as above in 60% yield
from 1. IR (CHCl3): 3500, 3300, 1710, 1600 cm21. 1H NMR
(200 MHz, CDCl3): d 3.67 (s, 2H), 5.38 (br s, 1H (±OH)),
6.87 (d, Jˆ8.8 Hz, 2H), 6.92 (d, Jˆ8.8 Hz, 2H), 7.11 (d,
Jˆ8.0 Hz, 1H), 7.24 (br s, 1H (±NH±)), 7.62 (t, Jˆ8.4 Hz,
2H), 7.80 (d, Jˆ8.4 Hz, 2H). 13C NMR (75 MHz, CDCl3): d
169.8, 157.3, 140.2, 130.5, 128.7, 127.3, 124.1, 119.6,
117.1, 44.9. HR-FABMS: m/z calcd for MH1
(C14H14NO2) 228.1025, found 228.1028.
Preparation of resin 6 via resin 5 (entry 6). Oxalyl
chloride (0.283 ml, 3.25 mmol) was added to a suspension
of resin 4 (500 mg, ,0.325 mmol) in anhydrous benzene
(30 ml), and the reaction mixture was agitated at 858C for
16 h. Resin 5 was ®ltered, washed with anhydrous CH2Cl2
(3£30 ml), THF (3£30 ml), and ether (3£30 ml), and dried
in vacuo (506 mg). TMSdiazomethane (ca. 10% solution in
hexanes, 0.11 ml, ca. 0.098 mmol) was added to a suspen-
sion of resin 5 (50.6 mg, ,0.0325 mmol) in 1:1 (v/v)
anhydrous THF/MeCN (2 ml), and the reaction mixture

Y. Iso et al. / Tetrahedron 56 (2000) 5353±5361
5359
Decanedioic acid monobenzyl ester (80-1). Resin 60
(57 mg, ,0.023 mmol) was suspended in 1:1 (v/v) anhy-
drous benzyl alcohol/2,4,6-trimethylpyridine (2 ml), and
the reaction mixture was agitated at 1808C for 20 min.
The product (4.5 mg) was isolated as above in 46% yield
(0.1 ml, 0.97 mmol) and Rh2(OAc)4 (2 mg, 0.0045 mmol)
were added to
suspension of resin 60 (57 mg,
a
,0.023 mmol) in anhydrous benzene (2 ml), and the reac-
tion mixture was agitated 508C for 2 h. The product
(4.0 mg) was isolated as above in 41% yield from 1. IR
from 1. IR (CHCl3): 3400±2800, 1730 cm21
.
1H NMR
(CHCl3): 3350±2800, 1710 cm21 1H NMR (200 MHz,
.
(200 MHz, CDCl3): d 1.22±1.30 (m, 12H), 2.35 (t,
Jˆ7.6 Hz, 4H), 5.12 (s, 2H), 7.27±7.35 (m, 5H). 13C
NMR (75 MHz, CDCl3): d 179.1, 173.3, 135.7, 128.6,
128.3, 128.2, 66.6, 34.2, 29.2, 29.0, 24.8. HR-FABMS: m/
z calcd for MH1 (C17H25O4) 293.1753, found 293.1758.
CDCl3): d 1.23±1.54 (m, 10H), 2.28±2.39 (m, 4H), 3.62
(s, 2H), 7.10±7.35 (m, 5H). 13C NMR (75 MHz, CDCl3):
d 202.4, 179.2, 135.8, 129.2, 128.4, 126.0, 43.0, 42.1, 34.4,
29.3, 29.2, 24.9, 24.0. HR-FABMS: m/z calcd for MH1
(C16H23O3S) 295.1368, found 295.1372.
1-(4-Hydroxyphenyl)-2-phenylthioethanone (10-1). Thio-
phenol (0.1 ml, 0.97 mmol) and Rh2(OAc)4 (2 mg,
0.0045 mmol) were added to a suspension of resin 6
(52 mg, ,0.028 mmol) in anhydrous benzene (2 ml), and
the reaction mixture was agitated at 508C for 2 h. Resin
9-1 was ®ltered, washed with anhydrous CH2Cl2 (3£2 ml),
THF (3£2 ml), and ether (3£2 ml), and dried in vacuo. A
50% (v/v) solution of TFA in CH2Cl2 (2 ml) was added to
the above resin, and the reaction mixture was agitated at
room temperature for 30 min. After the resin was ®ltered,
and washed with CH2Cl2 (2 ml), the combined ®ltrates were
concentrated, and puri®ed by preparative TLC (ethyl
acetate/toluene) to give 10-1 (5.2 mg) in 64% yield from
4-(2-Phenyloxazol-5-yl)phenol (12-1). Rh2(OAc)4 (2 mg,
0.0045 mmol) was added to a suspension of resin 6
(52 mg, ,0.028 mmol) in benzonitrile (1 ml, 9.8 mmol),
and the reaction mixture was agitated at 658C for 2.5 h.
Resin 11-1 was ®ltered, washed with anhydrous CH2Cl2
(3£2 ml), THF (3£2 ml), and ether (3£2 ml), and dried in
vacuo. A 50% (v/v) solution of TFA in CH2Cl2 (2 ml) was
added to the above resin, and the reaction mixture was
agitated at room temperature for 30 min. After the resin
was ®ltered, and washed with CH2Cl2 (2 ml), the combined
®ltrates were concentrated, and puri®ed by preparative TLC
(ethyl acetate/toluene) to give 12-1 (5.2 mg) in 66% yield
1
from 1. IR (CHCl3): 3290, 1730, 1610 cm21. H NMR
1. IR (CHCl3): 3250, 1710, 1610 cm21
.
1H NMR
(200 MHz, CDCl3): d 5.10 (br s, 1H (±OH)), 6.93 (d,
Jˆ8.0 Hz, 2H), 7.33 (s, 1H), 7.40±7.60 (m, 3H), 7.63 (t,
Jˆ8.0 Hz, 2H), 8.10 (d, Jˆ8.0 Hz, 2H). 13C NMR (75 MHz,
CDCl3): d 160.4, 157.2, 150.8, 131.9, 129.1, 127.8, 127.1,
126.7, 125.7, 121.7, 116.0. HR-FABMS: m/z calcd for MH1
(C15H12NO2) 238.0868, found 238.0869.
(200 MHz, CDCl3): d 4.23 (s, 2H), 5.42 (br s, 1H (±OH)),
7.00 (d, Jˆ8.8 Hz, 2H), 7.30±7.45 (m, 5H), 7.90 (d,
Jˆ8.8 Hz, 2H). 13C NMR (75 MHz, CDCl3): d 194.3,
162.8, 135.5, 130.5, 129.2, 128.7, 127.0, 115.4, 37.8. HR-
FABMS: m/z calcd for MH1 (C14H13O2S) 245.0636, found
245.0640.
4-[2-(4-Chlorophenyl)oxazol-5-yl]phenol (12-2). p-Chloro-
benzonitrile (0.1 g, 0.73 mmol) and Rh2(OAc)4 (2 mg,
0.0045 mmol) were added to a suspension of resin 6
(52 mg, ,0.028 mmol) in anhydrous benzene (2 ml), and
the reaction mixture was agitated at 658C for 2 h. The
product (4.2 mg) was isolated as above in 46% yield from
1. IR (CHCl3): 3310, 1720, 1600 cm21. 1H NMR (200 MHz,
CDCl3): d 5.14 (br s, 1H (±OH)), 6.92 (d, Jˆ8.2 Hz, 2H),
7.38 (s, 1H), 7.80 (d, Jˆ8.2 Hz, 2H), 7.90±8.10 (m, 4H). 13C
NMR (75 MHz, CDCl3): d 160.3, 157.2, 150.8, 135.0,
130.6, 128.6, 127.1, 126.9, 125.6, 121.8, 116.2. HR-
FABMS: m/z calcd for MH1 (C15H11ClNO2) 272.0478,
found 272.0481.
2-Ethoxy-1-(4-hydroxyphenyl)ethanone (10-2). Ethanol
(0.1 ml, 1.7 mmol) and BF3´Et2O (4 ml, 0.031 mmol) were
added to a suspension of resin 6 (52 mg, ,0.028 mmol) in
anhydrous CH2Cl2 (1 ml), and the reaction mixture was
agitated at room temperature for 1 h. The product
(3.1 mg) was isolated as above in 52% yield from 1. IR
(CHCl3): 3260, 1710, 1600 cm21 1H NMR (200 MHz,
.
CDCl3): d 1.28 (t, Jˆ7.0 Hz, 3H), 3.63 (q, Jˆ7.0 Hz, 2H),
4.67 (s, 2H), 5.40 (br s, 1H (±OH)), 6.88 (d, Jˆ8.8 Hz, 2H),
7.92 (d, Jˆ8.8 Hz, 2H). 13C NMR (75 MHz, CDCl3): d
194.3, 163.4, 129.6, 126.1, 115.5, 73.7, 68.0, 14.8. HR-
FABMS: m/z calcd for MH1 (C10H13O3) 181.0865, found
181.0869.
4-(2-Naphthalen-1-yloxazol-5-yl)phenol (12-3). 1-Naphtho-
nitrile (0.5 g, 3.26 mmol) and Rh2(OAc)4 (2 mg,
0.0045 mmol) were added to a suspension of resin 6
(52 mg, ,0.028 mmol) in anhydrous benzene (2 ml), and
the reaction mixture was agitated at 658C for 2 h. The
product (5.8 mg) was isolated as above in 60% yield from
1. IR (CHCl3): 3290, 1710, 1610 cm21. 1H NMR (200 MHz,
CDCl3): d 5.11 (br s, 1H (±OH)), 6.87 (d, Jˆ8.0 Hz, 2H),
6.96 (d, Jˆ8.0 Hz, 2H), 7.48 (s, 1H), 7.55±7.62 (m, 2H),
7.69 (d, Jˆ8.2 Hz, 2H), 7.97 (d, Jˆ8.2 Hz, 2H), 8.29 (d,
Jˆ8.0 Hz, 1H). 13C NMR (75 MHz, CDCl3): d 157.2, 150.9,
131.3, 131.1, 130.9, 130.5, 130.0, 128.5, 127.9, 127.1,
126.8, 125.6, 123.4, 122.8, 116.2. HR-FABMS: m/z calcd
for MH1 (C19H14NO2) 288.1025, found 288.1029.
1-(4-Hydroxyphenyl)-2-phenylaminoethanone
(10-3).
Aniline (0.1 ml, 1.1 mmol) and Rh2(OAc)4 (2 mg,
0.0045 mmol) were added to a suspension of resin 6
(52 mg, ,0.028 mmol) in anhydrous benzene (1 ml), and
the reaction mixture was agitated 858C for 2 h. The product
(3.9 mg) was isolated as above in 51% yield from 1. IR
.
(CHCl3): 3480, 3290, 1710, 1600 cm21 1H NMR
(200 MHz, CDCl3): d 3.68 (br s, 1H (±NH±)), 5.27 (s,
2H), 5.37 (br s, 1H (±OH)), 6.92 (d, Jˆ8.8 Hz, 2H), 7.16
(d, Jˆ8.0 Hz, 2H), 7.37 (t, Jˆ7.4 Hz, 1H), 7.62 (d,
Jˆ8.0 Hz, 2H), 7.81 (d, Jˆ8.8 Hz, 2H). 13C NMR
(75 MHz, CDCl3): d 195.6, 161.8, 147.1, 132.4, 129.2,
127.9, 118.8, 115.5, 113.3, 47.8. HR-FABMS: m/z calcd
for MH1 (C14H14NO2) 228.1025, found 228.1029.
8-(2-Phenyloxazol-5-yl)octanoic acid (120-1). Rh2(OAc)4
(2 mg, 0.0045 mmol) was added to a suspension of resin
9-Oxo-10-phenylthiodecanoic acid (100-1). Thiophenol

5360
Y. Iso et al. / Tetrahedron 56 (2000) 5353±5361
60 (57 mg, ,0.023 mmol) in benzonitrile (1 ml, 9.8 mmol),
and the reaction mixture was agitated at 658C for 2.5 h. The
product (4.6 mg) was isolated as above in 48% yield from 1.
CDCl3): d 2.62 (t, Jˆ8.0 Hz, 2H), 2.90 (t, Jˆ8.0 Hz, 2H),
4.57 (dd, Jˆ5.6 Hz, Jˆ1.8 Hz, 2H), 4.68 (br s, 1H (±OH)),
5.22 (dd, Jˆ9.8 Hz, Jˆ1.8 Hz, 1H), 5.28 (dd, Jˆ16.2 Hz,
Jˆ1.8 Hz, 1H), 5.80±5.99 (m, 1H), 6.75 (d, Jˆ8.8 Hz, 2H),
7.07 (d, Jˆ8.8 Hz, 2H). 13C NMR (75 MHz, CDCl3): d
172.7, 155.4, 132.7, 131.8, 129.5, 117.8, 115.5, 65.1, 35.8,
30.0. HR-FABMS: m/z calcd for MH1 (C12H15O3)
207.1021, found 207.1022.
IR (CHCl3): 3450±2850, 1730, 1600 cm21 1H NMR
.
(200 MHz, CDCl3): d 1.18±1.51 (m, 10H), 2.37 (t,
Jˆ7.6 Hz, 2H), 2.76 (t, Jˆ7.6 Hz, 2H), 7.36 (s, 1H),
7.35±7.46 (m, 3H), 7.98±8.10 (m, 2H). 13C NMR
(75 MHz, CDCl3): d 178.6, 155.0, 149.1, 131.8, 128.6,
127.0, 123.3, 34.1, 30.6, 30.5, 29.3, 28.1, 25.9, 24.8. HR-
FABMS: m/z calcd for MH1 (C17H22NO3) 288.1600, found
288.1605.
Preparation of Resin 600. Resin 600 was synthesized by the
same route and conditions as the preparation of resin 6. IR
(KBr): 2103 (±C(±TMS)±N2), 1741 (±CO±) cm21. Anal
calcd for resin 600: N, 1.56. Found: N, 1.26. Substrate load-
ing of 600 was determined to be 0.54 mmol/g by the above
result and total yield from Wang resin (1) was also deter-
mined to be 80.6%.
4-(4-Bromo-2-phenyloxazol-5-yl)phenol (14). Bromine
(8.6 ml, 0.168 mmol) and pyridine (6.8 ml, 0.084 mmol)
were added to a suspension of resin 11-1 (54 mg,
,0.028 mmol) in CH2Cl2 (3 ml) under ice cooling, and
the reaction mixture was agitated at 08C for 2 h. Resin 13
was ®ltered, washed with anhydrous CH2Cl2 (5£2 ml), and
dried in vacuo. A 50% (v/v) solution of TFA in CH2Cl2
(2 ml) was added to the above resin, and the reaction
mixture was agitated at room temperature for 30 min.
After the resin was ®ltered, and washed with CH2Cl2
(2 ml), the combined ®ltrates were concentrated, and puri-
®ed by preparative TLC (ethyl acetate/toluene) to give 14
(5.3 mg) in 50% yield from 1. IR (CHCl3): 3280, 1720,
7-Hydroxy-2-tetralone (18). Rh2(OAc)4 (2 mg, 0.0045
mmol) was added to a suspension of resin 600 (52 mg,
,0.028 mmol) in anhydrous CHCl3 (4 ml), and the reaction
mixture was re¯uxed for 40 min. Resin 17 was ®ltered,
washed with anhydrous CH2Cl2 (3£2 ml), THF (3£2 ml),
and ether (3£2 ml), and dried in vacuo. A 50% (v/v) solu-
tion of TFA in CH2Cl2 (2 ml) was added to the above resin,
and the reaction mixture was agitated at room temperature
for 30 min. After the resin was ®ltered, and washed with
CH2Cl2 (2 ml), the combined ®ltrates were concentrated,
and puri®ed by preparative TLC (ethyl acetate/toluene) to
give 18 (3.3 mg) in 60% yield from 1: IR (CHCl3) 3400±
1
1605 cm21. H NMR (200 MHz, CDCl3): d 5.12 (br s, 1H
(±OH)), 6.96 (d, Jˆ8.4 Hz, 2H), 7.46±7.51 (m, 3H), 7.91
(d, Jˆ8.4 Hz, 2H), 8.08 (d, Jˆ8.4 Hz, 2H). 13C NMR
(75 MHz, CDCl3): d 174.7, 158.2, 148.0, 131.1, 129.1,
128.2, 127.7, 126.7, 123.5, 116.8, 114.1. HR-FABMS: m/z
calcd for MH1 (C15H11BrNO2) 316.0173, found 316.0178.
1
2800, 1730 cm21; H NMR (200 MHz, CDCl3): d 2.54 (t,
Jˆ6.6 Hz, 2H), 2.99 (t, Jˆ6.6 Hz, 2H), 3.53 (s, 2H), 5.00 (br
s, 1H (±OH)), 6.75 (d, Jˆ8.0 Hz, 1H), 7.03 (s, 1H), 7.10 (d,
Jˆ8.0 Hz, 1H). 13C NMR (75 MHz, CDCl3): d 210.0, 154.3,
133.0, 129.6, 128.8, 115.7, 112.6, 44.9, 37.9, 27.7. HR-
FABMS: m/z calcd for MH1 (C10H11O2) 163.0759, found
163.0762.
4-(2-Phenyl-4-p-tolyloxazol-5-yl)phenol (16). p-Tolyl-
boronic acid (10.3 mg, 0.076 mmol), Pd(PPh3)4 (2.4 mg,
2.1 mmol), and aqueous Na2CO3 (2 M, 52 ml, 0.1 mmol)
were successively added to a suspension of resin 13
(56 mg, ,0.028 mmol) in DME (6 ml), and the reaction
mixture was re¯uxed for 17 h. After aqueous NH4OAc
(25%, w/v, 2 ml) was added and the reaction mixture was
agitated for 5 min, resin 15 was ®ltered, washed with DME/
H2O (1:1, 3£2 ml), diluted HCl (0.2 N, 3£2 ml), water
(3£2 ml), DME (3£2 ml), EtOAc (3£2 ml), EtOAc/MeOH
(1:1, 3£2 ml), and MeOH (3£2 ml), and dried in vacuo. A
50% (v/v) solution of TFA in CH2Cl2 (2 ml) was added to
the above resin, and the reaction mixture was agitated at
room temperature for 30 min. After the resin was ®ltered,
and washed with CH2Cl2 (2 ml), the combined ®ltrates were
concentrated, and puri®ed by preparative TLC (ethyl
acetate/toluene) to give 16 (4.5 mg) in 41% yield from 1.
References
1. (a) Curtius, T. Ber. Dtsch. Chem. Ges. 1883, 16, 2230. (b) Arndt,
F.; Eistert, B.; Amende, J. Ber. Dtsch. Chem. Ges. B 1928, 61,
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IR (CHCl3): 3300, 1725, 1615 cm21. H NMR (200 MHz,
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CDCl3): d 2.41 (s, 3H), 5.13 (br s, 1H (±OH)), 6.87 (d,
Jˆ8.0 Hz, 2H), 7.22 (d, Jˆ8.0 Hz, 2H), 7.46±7.64 (m,
7H), 8.15 (d, Jˆ8.0 Hz, 2H). 13C NMR (75 MHz, CDCl3):
d 160.4, 157.1, 145.5, 140.0, 134.9, 133.9, 133.3, 132.5,
130.2, 128.6, 127.6, 126.5, 126.4, 121.5, 116.3, 20.9. HR-
FABMS: m/z calcd for MH1 (C22H18NO2) 328.1338, found
328.1341.
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3-(4-Hydroxyphenyl) propionic acid allyl ester (200). The
product was obtained by the same method as the preparation
of 2, using 3-(4-hydroxyphenyl) propionic acid (6.02 g,
36.2 mmol) as a starting material (6.33 g, 85%). IR
10. (a) Nielsen, J.; Lyngso, L. O. Tetrahedron Lett. 1996, 37,
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(CHCl3): 3270, 1690, 1605 cm21 1H NMR (200 MHz,
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Y. Iso et al. / Tetrahedron 56 (2000) 5353±5361
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