Synthesis of 5-ortho-carboranylsalicylaldehyde and an indolinospirobenzopyran

Article abstract of DOI:10.1080/00397910902883694

5-ortho-Carboranylsalicylaldehyde was prepared from 5-iodosalicylaldehyde in six steps in 18% overall yield, and also from 5-iodosalicylic acid in seven steps in 45% overall yield. The reaction of 5-ortho-carboranylsalicylaldehyde with Fischer's base gave

Full text of DOI:10.1080/00397910902883694

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Synthesis of 5-ortho-
Carboranylsalicylaldehyde and
an Indolinospirobenzopyran
Seung Hwan Lee a , Young Bum Kwon a & Cheol Min
Yoon a
a Department of Advanced Material Chemistry, Korea
University, Seoul, South Korea
Version of record first published: 16 Oct 2009.
To cite this article: Seung Hwan Lee , Young Bum Kwon & Cheol Min Yoon (2009):
Synthesis of 5-ortho-Carboranylsalicylaldehyde and an Indolinospirobenzopyran,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 39:22, 4069-4078
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Synthetic Communications1, 39: 4069–4078, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902883694
Synthesis of 5-ortho-Carboranylsalicylaldehyde
and an Indolinospirobenzopyran
Seung Hwan Lee, Young Bum Kwon, and Cheol Min Yoon
Department of Advanced Material Chemistry, Korea University,
Seoul, South Korea
Abstract: 5-ortho-Carboranylsalicylaldehyde was prepared from 5-iodosalicylal-
dehyde in six steps in 18% overall yield, and also from 5-iodosalicylic acid in seven
steps in 45% overall yield. The reaction of 5-ortho-carboranylsalicylaldehyde with
Fischer’s base gave a spiropyran in 63% yield.
Keywords: Coumarin, indolinospirobenzopyran, ortho-carborane, salicylaldehyde
Salicylaldehydes (2-hydroxybenzaldehydes) are key substrates for the
synthesis of benzofurans, salen ligands, coumarins, and indolinospiro-
benzopyrans, which are very important skeletons in organic chemistry,
medicinal chemistry, and=or material chemistry. The benzofurans are
highly valuable molecular motifs often found in various natural products
and in molecules, showing a variety of pharmacological properties.[1] The
salen ligands have received considerable attention in various asymmetric
organic reactions[2] since Zhang et al.[3] and Irie et al.[4] reported signifi-
cant success in asymmetric epoxidation of unfunctionalized olefins.
Coumarins are found widely in nature[5] and have numerous applications
in perfumery,[5] as dyes in laser technology,[6a] and as fluorescent
indicators.[6b] Certain coumarins show inhibitory activity against several
enzymes such as acetylcholinesterase, aromatase, and squalene cyclase.[7]
Received December 16, 2008.
Address correspondence to Cheol Min Yoon, Department of Advanced
Material Chemistry, Korea University, Seoul, South Korea. E-mail: cmyoon@
korea.ac.kr
4069

4070
S. H. Lee, Y. B. Kwon, and C. M. Yoon
Scheme 1.
They also show biological activities such as anti-HIV, antifungal,
anticlotting, and anticancer activity.[8] Photochromic indolinospiroben-
zopyran dyes have received considerable attention because of their poten-
tial application in many new technologies associated with equilibrium
between colorless spiropyran form and colored merocyanine form
(Scheme 1), including the area of rewritable optical memory and optical
switching, nonlinear optics, and real-time holography.[9–11] Because the
chemical, physical, and biological properties of these four important
compounds are highly dependent on the substituent, it is important to
develop the structural-change methods of the parent compounds of
benzofurans, salens, coumarins, and indolinospirobenzopyrans.
The ortho-carborane ring system is highly lipophilic (i.e., the hydro-
phobic parameter for ortho-carborane is þ 4.20)[12] with an extraordinary
chemical and thermal stability. ortho-Carborane exerts stronger electron-
withdrawing (ꢀI) effects (similar to that of cyano group).[13] The size of
ortho-carborane was only slightly larger than the size occupied by a phe-
nyl ring, rotating about its C1–C4 axis.[14] The reasons to introduce an
ortho-carborane as a substituent in salicylaldehyde are related to its
properties, such as the electronic effect, steric effect, and lipophilicity
of o-carborane ring, which might change the character of existing
benzofurans, salens, indolinospirobenzopyrans, and coumarins. Here,
we report the synthesis of 5-ortho-carboranylsalicylaldehyde from 5-
iodosalicylaldehyde and 5-iodosalicylic acid and its application as a
starting material for the synthesis of an indolinospirobenzopyran.
The first approach to synthesis of target molecule 5 from 5-iodosali-
cylaldehye is as follows (Scheme 2): Acetylenylsalicylaldehyde 2 was
synthesized by the reaction of 5-iodosalicylaldehyde 1 with trimethylsily-
lacetylene under Sonogashira cross-coupling condition in 80% yield. The
salicylaldehyde 2 was protected by methylation in refluxing methylene

S-ortho-Carboranylsalicylaldehyde
4071
Scheme 2. (a) TMSA, PdCl2, PPh3, CuI, Et3N in CH3CN at reflux, overnight,
80%; (b) MeI, K2CO3 in acetone at reflux, 0.5 h, 94%; (c) K2CO3 in methanol
at rt, 0.5 h, quantitative; (d) B10H14 in CH3CN=toluene at reflux, 1 h, 34.1%; (e)
PCC in CH2Cl2 at rt, 3 h, 92%; (f) BBr3 in DCM at 0ꢁC, 5 h, 75%.
chloride using methyl iodide[15] followed by desilylation[16] using potassium
carbonate at rt to give acetylene 4 in 94% and quantitative yields for each
step. The reason to protect the hydroxyl group is that the ortho-carborane
ring system was not formed without protection of acidic hydroxyl group of
2-hydroxybenzaldehyde under the reported reaction condition.[17] The
reaction of benzaldehyde 4 with decaborane in a refluxing solution of
acetonitrile and toluene gave ortho-carboranylbenzylalcohol 5 in 34.1%
yield. The alcohol functional group was reoxidized to aldehyde using
pyridinium chlorochromate(PCC)in methylene chloride[18] atrtto givealde-
hyde 6 in 92% yield, which was demethylated using BBr3 in tetrahydrofuran
(THF)[19] to give the final 5-ortho-carboranylsalicylaldehyde in 75% yields.
The overall yield of the synthesis of 5-ortho-carboranylsalicylaldehyde
from 5-iodosalicylaldehyde was poor (18%) due to the conversion step of
an acetylene 4 to ortho-carborane 5. Therefore, the alternative second
approach (Scheme 3) was attempted, starting from the commercially avail-
able 5-iodosalicylic acid, for the preparation of benzyl alcohol 5. 5-Iodo-
salicylic acid 8 was protected with a methyl group using methyl iodide
and potassium carbonate in acetonitrile followed by Sonogashira coupling
with trimethylsilylacetylene to give the coupling product 10 in 91% and
quantitative yields, respectively. Compound 10 was desilylated using
potassium carbonate in methanol to give terminal acetylene 11 in 89%
yield, which in turn coupled with decaborane to afford ortho-carboranyl
compound 12 in 82% yield. The reduction of ester 12 using lithium alumi-
num hydride gave benzyl alcohol 5 in 99% yield. The overall yield of this
second approach is 45%, which is better than that of the first approach.
5-ortho-Carboranylsalicylaldehyde might be an intermediate for the
synthesis of benzofurans, indolinospirobenzopyrans, coumarins, and
salens. As an example, ortho-carboranylspiropyran 13, which can not

4072
S. H. Lee, Y. B. Kwon, and C. M. Yoon
Scheme 3. (a) MeI, K2CO3, acetone, 6 h, 91%; (b) TMSA, PdCl2, PPh3, CuI,
Et3N, 2 h, quantitative; (c) K2CO3, MeOH, 0.5 h, 89%; (d) B10H14, acetonitrile=
toluene, 4 h, 82%; (e) LiAlH4, DCM, 30 min, 99%.
be prepared by the direct reaction of acetylenylspiropyran 14 with
decaborane under reflux condition, was prepared by the reaction of
5-ortho-carboranylsalicylaldehyde with Fischer’s base in ethanol under
reflux condition in 63% yield (Scheme 4). The reaction of acetylenylspir-
opyran 14 with decaborane in a solution of acetonitrile and toluene at
reflux gave a black precipitate, which was not identifiable.
In conclusion, 5-ortho-carboranylsalicylaldehyde, which might be
good substrate of benzofurans, indolinospirobenzopyrans, salen ligands,
and coumarins, was prepared from 5-iodosalicylaldehyde in six steps in
18% overall yield and also from 5-iodosalicylic acid in seven steps in
45% overall yield. The 5-ortho-caboranylsalicylaldehyde reacted with
Fischer’s base in ethanol at reflux to afford an ortho-carboranylind-
olinospirobenzopyran in 63% yield.
EXPERIMENTAL
5-(Trimethylsilylacetylenyl)salicylaldehyde (2)
A solution of 5-iodosalicylaldehyde 1 (10.0 g, 40.3 mmol), trimethylsilyla-
cetylene (8.55 mL, 60.5 mmol, 1.5 equiv.), PdCl2 (358 mg, 2.02 mmol,
5 mol%), Ph3P (1.06 g, 4.03 mmol, 10 mol%), CuI (0.19 g, 1.01 mmol,
2.5 mol%), and triethylamine (39.4 mL, 282 mmol, 7 equiv.) was heated
at reflux under an argon atmosphere. After 3 h of reflux, the reaction
Scheme 4. Synthesis of ortho-carboranylindolinospirobenzopyran.

S-ortho-Carboranylsalicylaldehyde
4073
mixture was filtered through a celite pad. The filtrate was concentrated
under reduced pressure and chromatographed on silica gel using a
solution of ethyl acetate and hexane (1:4) to afford 5-(trimethylsilylacety-
lenyl)salicylaldehyde 2 (7.04 g, 32.3 mmol, 80.0%) as a yellow-brown
1
solid: mp 94–96ꢁC. H NMR (CDCl3, 300 MHz): d 11.10 (s, 1H), 9.86
(s, 1H), 7.71 (s, 1H), 7.61 (d, J ¼ 8.8 Hz, 1H), 6.94 (d, J ¼ 8.8 Hz, 1H),
0.23 (s, 9H). Anal. calcd. for C12H14O2Si: C, 66.02; H, 6.46. Found: C,
65.64; H, 6.43.
2-Methoxy-5-(trimethylsilylacetylenyl)benzaldehyde (3)
Methyl iodide (0.69 ml, 11 mmol, 2 equiv.) was added to a heterogeneous
solution of a salicylaldehyde 2 (1.2 g, 5.5 mmol) and potassium carbonate
(3.8 g, 27.5 mmol) in acetonitrile (20 ml). The resulting solution was
stirred at reflux under argon atmosphere. After 30 min of reflux, the
mixture was cooled down and filtered through filter paper to remove
salts. The filtrate was concentrated under reduced pressure and purified
by column chromatography on silica gel (ethyl acetate and hexane¼ 1:20)
to give 2-methoxybenzaldehyde 3 (1.20 g, 5.18 mmol, 94.2%) as an ivory
1
solid: mp 111–112ꢁC. H NMR (CDCl3, 300MHz): d 10.40 (s, 1H), 7.93
(s, 1H), 7.62 (d, J ¼ 8.8 Hz, 1H), 6.92 (d, J ¼ 8.8Hz, 1H), 3.94 (s, 3H),
0.23 (s, 9H). Anal. calcd. for C13H16O2Si: C, 67.20; H, 6.94. Found: C,
65.00; H, 7.04.
5-Acetylenyl-2-methoxybenzaldehyde (4)
A solution of a 2-methoxybenzaldehyde 3 (1.0 g, 4.3 mmol) and K2CO3
(0.9 g, 6.5 mmol, 1.5 equiv.) in methanol (20 mL) was stirred for 30 min
at rt. After the concentration of the reaction mixture under reduced
pressure, ethyl acetate (20 ml) was added and filtered through filter paper,
and the filtrate was concentrated and chromatographed on silica gel
(ethylacetate–hexane ¼ 1:4) to give aldehyde 4 (689 mg, 4.30 mmol, quan-
titative) as a yellow-colored solid: mp 82–83ꢁC. 1H NMR (CDCl3,
300 MHz): d 10.42 (s, 1H), 7.95 (s, 1H), 7.66 (d, J ¼ 8.8 Hz, 1H), 6.96
(J ¼ 8.8 Hz, 1H), 3.96 (s, 3H), 3.03 (s, 1H).
5-(1,2-Dicarba-closo-dodecaboranyl)-2-methoxybenzylalcohol (5)
A solution of decaborane (1.8 g, 15.0 mmol, 1.2 equiv.) in dry acetonitrile
(20 mL) was heated at reflux for 5 h under argon atmosphere. A solution

4074
S. H. Lee, Y. B. Kwon, and C. M. Yoon
of 5-ethynyl-2-methoxybenzaldehyde 4 (2.0 g, 12.5 mmol) in benzene
(60 mL) was added dropwise to this solution. The mixture was heated
at reflux for 80 h. The reaction mixture was concentrated and chroma-
tographed on silica gel (methanol and methylene chloride ¼ 2:98) to give
a ortho-carboranyl benzylalcohol 5 (2.98 g, 10.6 mmol, 34.1%) as a white
solid: mp 121–122ꢁC. 1H NMR (CDCl3, 300 MHz): d 7.41–7.44 (m,
2H), 6.80 (d, J ¼ 9.6 Hz, 1H), 4.66 (s, 2H), 3.91 (br s, 1H), 3.86 (s,
3H). Anal. calcd. for C10H20B10O2: C, 42.84; H, 7.19. Found: C,
42.83; H, 7.30.
5-(1,2-Dicarba-closo-dodecaboranyl)-2-methoxybenzaldehyde (6)
Pyridium chlorochromate (2.3 g, 10.7 mmol, 3 equiv.) was added to a
solution of benzylalchol 5 (1.0 g, 3.57 mmol) in dichloromethane
(30 mL) at room temperature. After the heterogeneous reaction
solution was stirred at room temperature for 3 h, it was diluted
with dichloromethane (50 ml) and filtered through a celite pad.
The filtrate was concentrated and chromatographed on silica gel
using a solution of ethyl acetate and hexane (1:4) to give a benzal-
dehyde
6 (912 mg, 3.28 mmol, 91.9%) as a yellow solid: mp
108–109ꢁC. 1H NMR (CDCl3, 300 MHz): d 10.41 (s, 1H), 7.87 (s,
1H), 7.73 (d, J ¼ 8.8 Hz, 1H), 6.97 (d, J ¼ 8.8 Hz, 1H), 3.96 (s,
3H), 3.87 (br s, 1H). Anal. calcd. for C10H18B10O2: C, 43.15; H,
6.52. Found: C, 43.22; H, 6.50.
5-(1,2-Dicarba-closo-dodecaboranyl)-2-hydroxybenzaldehyde (7)
A solution of boron tribromide (5.8 mL, 5.8 mmol, 2 equiv.) in
dichloromethane was added dropwise to a solution of compound 6
(800 mg, 2.87 mmol) in dichloromethane (50 mL) at ꢀ78ꢁC (in a dry
ice=2-propanol bath) under argon. The cold bath was removed, and
the reaction mixture was stirred for 4 h under an argon atmosphere,
poured into ice water, stirred for 30 min, saturated with NaCl, and
extracted with dichloromethane. The extract was dried with anhy-
drous magnesium bromide, concentrated, and chromatographed on
silica gel (ethyl acetate and hexane ¼ 1:10) to give the product 7
(570 mg, 2.16 mmol, 75%) as a white solid: mp 165–166ꢁC. 1H
NMR (CDCl3, 300 MHz): d 11.12 (s, 1H), 9.90 (s, 1H), 7.73 (s,
1H), 7.65 (d, J ¼ 8.8 Hz, 1H), 6.97 (d, J ¼ 8.8 Hz, 1H), 3.89 (br s,
1H). Anal. calcd. for C9H16B10O2: C, 40.89; H, 6.10. Found: C,
38.92; H, 5.78.

S-ortho-Carboranylsalicylaldehyde
4075
Methyl 5-iodo-2-methoxybenzoate (9)
A solution of 5-iodosalicylic acid 8 (4.0 g, 15.15 mmol), potassium
carbonate (21.0 g, 152 mmol, 10 equiv.), and methyl iodide (9.4 ml,
152 mmol, 10 equiv.) in acetonitrile (50 ml) was heated at reflux under
argon. After 6 h of reflux, the mixture was cooled down, filtered through
filter paper, and concentrated under reduced pressure. The concentrate
was chromatographed on silica gel using a solution of ethyl acetate and
hexane (1:6) to give ester 9 (4.0267 g, 13.79 mmol, 91.0%) as a brown
1
solid: mp 47–48ꢁC. H NMR (CDCl3, 300 MHz): d 8.07 (s, 1H), 7.73
(d, J ¼ 8.4 Hz, 1H), 6.76 (d, J ¼ 8.4 Hz, 1H), 3.88 (s, 6H). Anal. calcd.
for C9H9IO3: C, 37.01; H, 3.11. Found: C, 37.04; H, 3.12.
Methyl 5-(trimethylsilylacetylenyl)-2-(methoxy)benzoate (10)
A solution of ester 9 (4.00 g, 13.7 mmol), trimethylsilylacetylene (2.9 ml,
21 mmol, 1.5 equiv.), palladium(II) chloride (121 mg, 0.685 mmol, 0.05
equiv.), triphenylphosphine (360 mg, 1.37 mmol, 0.1 equiv.), copper
iodide (65.2 mg, 0.025 equiv.), and triethylamine (13.4 mL, 95.9 mmol, 7
equiv.) in acetonitrile (100 mL) was heated at reflux. After 2 h of reflux,
it was filtered through celite pad, and the filtrate was concentrated and
chromatographed on silica gel using a solution of ethyl acetate and
hexane (1:10) to afford a coupling product 10 (3.59 g, 13.7 mmol, quanti-
1
tative) as sticky brown oil. H NMR (CDCl3, 300 MHz): d 7.92 (s, 1H),
7.56 (d, J ¼ 8.4 Hz, 1H), 6.90 (d, J ¼ 8.4 Hz, 1H), 3.91 (s, 3H), 3.88 (s,
3H), 0.24 (s, 9H).
Methyl 5-(acetylenyl)-2-(methoxy)benzoate (11)
A solution of compound 10 (1.0 g, 3.8 mmol) and K2CO3 (790 mg,
5.7 mmol, 1.5 equiv.) in methanol (10 mL) was stirred at room tempera-
ture for 30 min. After concentration, ethyl acetate (50 ml) and water
(20 ml) were added. The ethyl acetate layer was separated, washed with
water (20 ml ꢂ 2) and brine solution (20 ml), dried on anhydrous magne-
sium sulfate, and filtered. The filtrate was concentrated and chromato-
graphed on silica gel using a solution of ethyl acetate and hexane (1:5)
to give an acetylenylbenzoate 11 (646 mg, 3.39 mmol, 89.1%) as a yellow
1
solid: mp 61–62ꢁC. H NMR (CDCl3, 300 MHz): d 7.94 (s, 1H), 7.59 (d,
J ¼ 8.7 Hz, 1H), 6.93 (d, J ¼ 8.7 Hz, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.02
(s, 1H). Anal. calcd. for C11H10O3: C, 69.40; H, 5.30. Found: C, 69.19;
H, 5.49.

4076
S. H. Lee, Y. B. Kwon, and C. M. Yoon
Methyl 5-(1,2-dicarba-closo-dodecaboranyl)benzoate (12)
Decaborane (1.93 g, 15.8 mmol, 1.5 equiv.) in dry acetonitrile (20 mL)
was heated at reflux for 3 h under an argon atmosphere. A solution of
compound 11 (2.00 g, 10.5 mmol) in toluene (60 mL) was added to the
solution. After the resulting solution was refluxed for 4 h, it was concen-
trated and chromatographed on silica gel using a solution of ethyl acetate
and hexane (1:5) to give the product 12 (2.65 g, 8.6 mmol, 81.9%) as a
white solid: mp 150–151ꢁC. 1H NMR (CDCl3, 300 MHz): d 7.88 (s,
1H), 7.62 (d, J ¼ 8.7 Hz, 1H), 6.92 (d, J ¼ 8.7 Hz, 1H), 3.91–3.92 (m,
7H). Anal. calc. for C11H20B10O3: C, 42.84; H, 6.54. Found: C, 42.71;
H, 6.76.
5-(1,2-Dicarba-closo-dodecaboranyl)-2-methoxybenzylalcohol (5)
Lithium aluminum hydride (16 mL, 16 mmol, 1.0 M in ether) was
added dropwise to a solution of 12 (1.0 g, 3.2 mmol) in ether
(4 ml) at 0ꢁC with stirring. The mixture was stirred for 1 h at 0ꢁC.
After quenching with saturated aqueous ammonium chloride solu-
tion, the mixture was extracted with ether and dried over anhydrous
magnesium sulfate. Evaporation of the solvents followed by purifi-
cation using silica-gel column chromatography (ethyl acetate
and hexane ¼ 1:4) afforded 5 (886 mg, 3.16 mmol, 98.9%) as a white
solid.
6-(1,2-Dicarba-closo-dodecaboranyl)spiropyran (13)
A solution of 2-methylene-1,3,3-trimethylindoline (655 mg, 3.8 mmol,
1 equiv.) in ethanol (10 mL) was added dropwise to a solution of
5-ortho-carboranylsalicylaldehyde
7
(1.0 g, 3.8 mmol) in ethanol
(20 mL) under reflux. After the resulting solution was heated under
reflux for 2 h, the reaction mixture was concentrated and chromato-
graphed on silica gel using a solution of ethyl acetate and hexane
(1:10) to give a spiropyran 13 (1.00 g, 2.38 mmol, 63%) as a violet solid:
1
mp 201–202ꢁC. H NMR (CDCl3, 300 MHz): d 7.16–7.21 (m, 3H), 7.07
(d, J ¼ 7.2 Hz, 1H), 6.85 (t, J ¼ 7.5 Hz, 1H), 6.81 (d, J ¼ 10.5 Hz, 1H),
6.63 (d, J ¼ 8.4 Hz, 1H), 6.53 (d, J ¼ 7.8 Hz, 1H), 5.76 (d, J ¼ 10.2 Hz,
1H), 3.85 (br s, 1H), 2.71 (s, 3H), 1.23 (s, 3H), 1.16 (s, 3H). Anal. calcd.
for C21H29B10NO: C, 60.11; H, 6.97; N, 3.34. Found: C, 59.71; H, 7.21;
N, 3.09.

S-ortho-Carboranylsalicylaldehyde
4077
ACKNOWLEDGMENT
This work was supported by Korea University.
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