Expedient Approach to 6-Bromo-2-isopropylidenecoumaranone, a Potential Intermediate for the Synthesis of TMC-120B, Pseudodeflectusin, and Their Congeners

Article abstract of DOI:10.1002/hlca.201500525

A straightforward approach toward 6-bromo-2-isopropylidenecoumaranone, a potential intermediate toward alkaloid TMC 120-B, pseudodeflectusin, and other natural products, was reported. The synthetic sequence involved the reaction of 3-bromosalicylaldehyde with chloroacetone and cyclization of the resulting ether to a 2-acetylcoumaranol intermediate. This was followed by sequential methyl Grignard addition and Jones' oxidation to the corresponding coumaranone, which was dehydrated to the final product with the methanesulfonyl chloride/pyridine reagent. The protection of the coumaranol as the corresponding THP-ether resulted in improved product yields.

Full text of DOI:10.1002/hlca.201500525

398
Helv. Chim. Acta 2016, 99, 398 – 404
FULL PAPER
Expedient Approach to 6-Bromo-2-isopropylidenecoumaranone, a Potential
Intermediate for the Synthesis of TMC-120B, Pseudodeflectusin, and Their Congeners
by Jorgelina L. Pergomet, Teodoro S. Kaufman, and Andrea B. J. Bracca*
Institute of Chemistry of Rosario (IQUIR, CONICET-UNR) and School of Biochemical and Pharmaceutical Sciences,
National University of Rosario, Suipacha 531, S2002LRK, Rosario, Argentina (phone: +54-341-4370477, ext. 103,
e-mail: bracca@iquir-conicet.gov.ar)
A straightforward approach toward 6-bromo-2-isopropylidenecoumaranone, a potential intermediate toward alkaloid TMC
20-B, pseudodeflectusin, and other natural products, was reported. The synthetic sequence involved the reaction of
-bromosalicylaldehyde with chloroacetone and cyclization of the resulting ether to a 2-acetylcoumaranol intermediate. This
1
3
was followed by sequential methyl Grignard addition and Jones’ oxidation to the corresponding coumaranone, which was
dehydrated to the final product with the methanesulfonyl chloride/pyridine reagent. The protection of the coumaranol as the
corresponding THP-ether resulted in improved product yields.
Keywords: 6-Bromo-2-isopropylidenecoumaranone, TMC-120B, Pseudodeflectusin, Natural product synthesis, Proline-
mediated cyclization.
reflecting their defensive role against herbivorous
insects. Finally, the 4,6-dimethoxy derivative 10 was iso-
The benzofuran framework, consisting of fused benzene lated from the little shrub Calea peckii grown in Costa
Introduction
and furan rings, has been identified as a privileged core
structure [1]. Naturally occurring 2-methylene-3-benzofur-
anones comprise a series of compounds, widely spread in
Rica [11].
On the other hand, the related 7-chloro derivative 11
was employed as key intermediate for the synthesis of
species of higher plants [2 – 4], which display interesting analogs of the antifungal agent, griseofulvin [12], and the
biological activities; among them, they are antiprotozoan
[5] and anti-cancer [6] agents.
The more elaborated 2-isopropylidenecoumaranone
4-hydroxy compound 12 was synthesized as an intermedi-
ate toward heterocyclic derivatives containing polysubsti-
tuted alkyl ethers that have been patented as antitumor
and antimetastatic agents, with activity against the uroki-
nase-type plasminogen activator (uPA) [13].
motif is present in a smaller range of natural products iso-
lated, to date, exclusively from the Asteraceae family of
plants. In addition, some 2-isopropylidenecoumaranones
were obtained from fungi, whereas compounds bearing
this feature have also been used as valuable synthetic
intermediates.
Another member of this family is the linear furo-
coumarin 13, which was obtained from the related, natu-
rally occurring peucedanin and oreoselone [14], and was
Thus, among the plant-derived compounds, the hete- employed as an intermediate toward the synthesis of
rocyclic alcohols 1 and 2 were found in Verbesina luetsel-
hurgii MATTF. and Oyedaea boliviana, respectively [4][7],
polyazamacrocycles.
In addition, the 2-isopropylidene-substituted hetero-
whereas the related ester 3 was obtained from the leaves cyclic motif has also been found among the fungal
of both, Enceliopsis couillei and E. argophylla [3][8]. The metabolites, pseudodeflectusin (14), ustusorane C (15),
latter plant also provided the congeneric esters 4 – 7.
Further, the 5-acetylcoumaranone derivative 8 has (18), as well as among other ustusoranes. Finally, the fea-
been isolated from the perennial herbs Ligularia
ture is also characteristic of the much studied furo[3,2-h]
kongkalingensis and L. nelumbifolia, which grow in the isoquinoline alkaloid TMC-120B (19) [15].
pergillin (16), penicisochroman A (17), and ustusorane A
Chinese provinces of Wuminhshan and Gansu, respec-
Pseudodeflectusin (14) was isolated from the fungus
tively [9]. The related phenolic ether 9 was obtained Aspergillus pseudodeflectus and from the sea fan-derived
from the rhizomatous Heliopsis helianthoides, collected fungus Penicillium sp. PSU-F40. The natural product
in Mexico [10]. However, high concentrations of some
of these benzofurans were found in the leaves, probably
exhibits cytotoxicity toward several human cancer cell
lines. On the other hand, tricycle 19 was isolated from
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Helv. Chim. Acta 2016, 99, 398 – 404
399
Aspergillus ustus TC 1118 and has shown moderate inhibi-
tory activity against the interleukin-5 mediated prolonga- Williamson etherification of aldehyde 22 was performed
tion of eosinophil survival [16]. Further, we have recently with freshly prepared monochloroacetone [23] in acetone,
reported that aspergillitine, the alkaloid obtained from employing K CO as base.
directly, by way of an aldol reaction. To that end, the
2
3
Aspergillus versicolor, isolated from the marine sponge
Xestospongia exigua, to which an angular tricyclic chro-
monic skeleton was assigned, is actually TMC-120B [17].
The interesting bioactivity of the latter compounds has
To be successful, the reaction had to be conducted at
temperatures below 40 °C, in order to avoid reduced
yields due to the concomitant uncontrolled base-catalyzed
cyclization of the resulting acetonyl ether to afford alco-
attracted considerable attention, and their total syntheses hol 24 and its diasteromer 24a, and the generation of
unwanted side products [24]. Under these conditions, the
yield of 23 was 82%.
have been reported [18].
In view of the widespread occurrence of the 2-isopro-
pylidenecoumaranone motif among natural products and
taking into account our previous efforts related to TMC-
The next step was the 5-enolexo-exo-trig aldolization
process toward 24. In order to have better control of the
cyclization, the O-acetonylsalicylaldehyde 23 was exposed
to catalytic amounts of L-proline in DMF, to which 1.0
1
6
20B [17], herein, we report an efficient approach toward
-bromo-2-isopropylidenecoumaranone (20) from 3-bro-
mophenol (21). The former is a potential intermediate
toward pseudodeflectusin (14), related natural products 84% of aldol 24 as a single diasteromer, after 36 h at
equivalent of H O was added. These conditions furnished
2
(
15 – 18) and alkaloid TMC-120B (19).
room temperature [25]. The stereochemistry of the result-
ing solid product was ascertained as cis by analysis of the
coupling constants between H–C(2) and H–C(3)
Results and Discussion
(J = 6.6 Hz).
The synthesis was initiated with the transformation of com-
It was postulated that the reaction may proceed
mercial 3-bromophenol (21) into the known salicylalde- through an intramolecular version of a Houk–List-type
hyde derivative 22 [19] (Scheme). The reaction, following transition-state model; this may explain the cis-configura-
Casiraghi’s protocol [20] with paraformaldehyde in reflux- tion observed [25].
ing toluene under SnCl catalysis, afforded the aldehyde in
4
Interestingly, carrying the cyclization reaction in the
presence of catalytic amounts of K CO enabled the for-
2
7% yield; however, better results (75%) were obtained
2
3
under the conditions of Skatebol [21] with paraformalde- mation of inseparable mixtures of cyclized products,
hyde, strictly anhyd. MgCl , and Et N, in refluxing THF. containing variable amounts of the anti-isomer 24a
Despite other alternatives are available that would (JH–C(2) – H–C(3) = 4.5 Hz). The latter proved to be unsta-
require extensive protection and deprotection steps [22], ble, becoming dehydrated at room temperature with rela-
it was opted to access the cyclized product 24 more tive ease.
2
3
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400
Helv. Chim. Acta 2016, 99, 398 – 404
Scheme. Synthesis of 6-bromo-2-isopropylidenecoumaranone (20).
Next, the installation of the isopropylidene feature
(Table, Entry 1). Increasing the temperature to ꢀ50 °C
proved to be detrimental to the yield, despite 4.0 equiv-
alents MeMgI were added (Entry 2). However, using
diglyme as solvent afforded 31% of the expected diol
after 60 min at 0 °C (Entry 3) and running the transfor-
was undertaken, and a Grignard addition-alcohol elimina-
tion sequence seemed to be the most straightforward
approach. However, this transformation proved challeng-
ing from the beginning, due to the instability [26] and
poor solubility of the starting material in the reaction
mation in Et O/diglyme in the presence of 1.0 equiva-
2
medium, in addition, to the marked proneness to enoliza- lent of Bu NBr as additive, the outcome to 49% yield
4
tion of the carbonyl moiety.
Thus, the reaction of 24 with MeMgI gave 26% of
of 25 (Entry 4) was improved. A further improvement
to 54% was achieved when 1.1 equivalents of LiCl was
diol 25 when performed in Et O at ꢀ78 °C for 30 min. added (Entry 5).
2
Table. Grignard addition to the carbonyl moieties of 24 and 27
Entry
MeMgI [equiv.]
Solvent
Additive [equiv.]
Temp. [°]
Time [min]
Prod.
Yield [%]
1
2
3
4
5
2.0
4.0
3.0
3.0
2.0
2.0
3.0
Et
Et
2
O
O
–
–
–
Bu
Bu
ꢀ78
ꢀ50
0
30
30
60
90
30
30
30
25
25
25
25
25
29
28
26
10
31
49
54
90
89
2
Diglyme
Et
2
Et
2
Et
2
Et
2
O/Diglyme
O/Diglyme
4
NBr (1.0)
NBr (1.0), LiCl (1.1)
0
4
0
6
a
O
O
CeCl
–
3
(1.0)
0
7
)
ꢀ20
a
)
The reaction was performed with THP ether 27.
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Helv. Chim. Acta 2016, 99, 398 – 404
401
This reagent mixture enabled to activate the C=O This work was financially supported by the Argentine
group, improve substrate solubility, and optimize Grig- National Research Council (CONICET, PIP 2012-0471)
nard reactivity [27]. However, the use of 1.0 equivalents
of anhyd. CeCl gave 90% of benzofuran 29 as the sole
product (Entry 6).
However, due to the not so unexpected instability of
and the National Agency for the Promotion of Science
and Technology (ANPCyT, PICT 2011-0399). JLP also
thanks ANPCyT for her fellowship.
3
the 1,3-diol 25 and in order to ensure access to a stable Experimental Part
heterocycle, the latter was immediately subjected to a
Jones’ oxidation at ꢀ20 °C, which enabled to get the General
ketone 26 in 70% yield.
All the reactions were carried out under dry N2 or Ar
This outcome prompted to explore modifications in
the reaction conditions toward 26. In order to increase
the solubility of the substrate, alcohol 24 was tetrahy-
dropyranylated under mild standard conditions to afford
atmospheres, employing oven-dried glassware. Anhyd.
THF, anhyd. Et O, and anhyd. diglyme were obtained by
2
reflux of the AR solvent over Na metal (benzophenone as
indicator), followed by distillation. Anhys. CH Cl2 were
2
70% of the diasteromeric THP-ethers 27, which without
separation furnished 89% yield of the expected com-
obtained from a solvent purification and dispenser system
(M. Braun, Stratham, New Hampshire, USA). Anhyd. ace-
pound 28 upon exposure to MeMgI at ꢀ20 °C during
tone was prepared by refluxing 4 h the AR grade product
over K CO and distilling the solvent at atmospheric pres-
sure. Anhyd. Et N was prepared by a 4 h reflux of the sol-
3
0 min (Entry 7). The spectral complexities of the latter
2
3
were simplified after reaction with Jones’ reagent, which
enabled in situ deprotection of the THP-ether moiety
and oxidation of the benzylic alcohol, providing 70%
of 26.
3
vent over CaH2 followed by atmospheric pressure
distillation. Abs. EtOH was prepared by refluxing the pro-
duct over Mg turnings to which a crystal of iodine was
added, and distilling the solvent from the so formed mag-
nesium ethoxide. All other reagents were used as received.
M.p.: Ernst Leitz (Wetzlar, Germany) model 350 hot-stage
microscope and are reported uncorrected.
To end the proposed synthesis, dehydration of aldol
6 was required. The use of dimethylformamide dimethyl
2
acetal smoothly furnished 54% yield of 20 after refluxing
in Et O for 42 h [28]. However, the transformation exhib-
2
ited poor reproducibility and was difficult to be scaled-up,
probably due to its ability to form a vinylogous enami-
none from the resulting vinylogous methyl ketone prod- Chromatographic Methods
uct. Luckily, slightly better but highly reproducible yields
The flash column chromatographies were run with silica
gel 60 H (SiO ; Merck, Darmstadt, Germany), eluting with
(
61%) were achieved with the use of the MsCl/pyridine
2
reagent system at 40 °C [29].
Interestingly, a Pd-catalyzed reaction of iodoarenes
with
hexane/AcOEt mixtures, under positive pressure and
employing gradient of solvent polarity techniques. All new
compounds gave single spots on TLC plates (silica gel 60
GF254) run in different hexane/AcOEt solvent systems.
The chromatographic spots were detected by exposure to
3-aryl-1-(2-tert-butyldimethylsilyloxy)phenyl-2-pro-
pyn-1-ones toward differentially substituted 2-alkylidene-
coumaranones has also been reported [30]. However, the
only example given on the use of 3-alkyl instead of 3-aryl
substituted starting materials, afforded a 2-alkyl chrome-
none instead of the expected 2-alkylidenecoumaranone,
being this approach unsuitable for targets like 20.
2
anisaldehyde/H SO reagent and final careful heating of
54 nm UV light, followed by spraying with ethanolic p-
2
4
the plates for improving selectivity. IR spectra: Shimadzu
Prestige 21 (Shimadzu, Kyoto, Japan) IR spectrophotome-
ter, as thin films held between NaCl cells for oils or as solid
dispersions in KBr disks, for solid samples. Absorption fre-
Conclusions
ꢀ1 1
quencies (m) are in cm . H-NMR spectra: 300.13 MHz in
CDCl on a Bruker Avance 300 (Bruker, Rheinstetten,
A straightforward synthesis of 6-bromo-2-isopropylidene
coumaranone (20) as a potential key intermediate toward
pseudodeflectusin (14), its congeneric angular tricyclic
naturally occurring coumaranones 15 – 18, and alkaloid
TMC-120B (19), was carried out. The synthesis featured
an L-proline-catalyzed aldolization to form the hetero-
cyclic ring, and a Grignard addition – alcohol oxidation
and dehydration sequence in order to install the isopropy-
lidene side chain. The OH group protection of the aldol
intermediate enabled an improved yield of the final prod-
uct. The synthesis took place in seven steps and 13.7%
overall yield from the commercially available 3-bromo-
phenol (21), or six steps and 10.8% yield, when omitting
the protection stage.
TM
3
Germany) NMR spectrometer. Chemical shifts are
reported in ppm on the d scale; w1/2 and J-values are given
in Hz. The residual solvent peak (CHCl in CDCl , d(H)
3
3
1
3
7
were recorded at 75.48 MHz on a Bruker Avance spec-
.26) was used as the internal standard. C-NMR spectra
trometer. The solvent peak (CDCl , d(C) 77.0) was used as
3
the internal standard. In special cases, 2D-NMR experi-
ments (HMBC and HSQC) were also employed to aid the
interpretation and assignment of the spectra. HR-MS: Bru-
ker MicroTOF-Q II instrument (Bruker Daltonics, Biller-
ica, MA, USA). Detection of the ions was performed in
electrospray ionization, positive ion mode.
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402
Helv. Chim. Acta 2016, 99, 398 – 404
4
3
-Bromo-2-hydroxybenzaldehyde (22).
-bromophenol (21, 1100 mg, 6.3 mmol) and anhyd. Et N
A
solution of 1-[(2S*,3S*)-6-Bromo-2,3-dihydro-3-hydroxy-1-benzofuran-
2-yl]ethanone (24a). K CO (7 mg, 0.05 mmol) was added
2 3
3
(1.8 ml) in dry THF (13 ml) was treated with anhyd.
MgCl2 (1200 mg, 12.6 mmol). After stirring for 10 min.,
to a solution of 23 (50 mg, 0.20 mmol) in AcOEt (25 ml),
and the solvent was slowly evaporated in a rotary evapo-
(
CHO)n (572 mg, 18.69 mmol) was added and heated rator at 40 °C. AcOEt (10 ml) was added to the residue,
under reflux for 10 h. The mixture was then cooled to
room temperature, 5% aq. HCl was added, and the pro-
duct extracted with CH Cl . The combined organic matographed, furnishing an inseparable mixture of
the solid was filtered off, and the solvent was evaporated
under reduced pressure. The residue was chro-
2
2
extracts were washed with brine, dried (Na SO ), and cyclized compounds containing 24 and 24a (35 mg, 70%),
2
4
concentrated under reduced pressure. The chromatogra- as an oil. Compound 24a: R = 0.39; hexane/AcOEt 70:30.
f
1
phy of the residue gave 22 (950 mg, 75%), as a pale yel-
H-NMR: 7.24 (d, J = 8.0, 1 H, H–C(4)); 7.14 (d, J = 1.5,
low solid. M.p.: 42 °C. Lit.: 50 – 51.5 °C [21]. R = 0.66; 1 H, H–C(7)); 7.14 (dd, J = 8.0, 1.5, 1 H, H–C(5)); 5.50
f
hexane/AcOEt 85:15. IR (KBr): 3381, 2924, 2850, 1651,
(br. d, J = 4.5, 1 H, H–C(3)); 4.89 (d, J = 4.5, 1 H, H–C
557, 1479, 1304, 1188, 1067, 907, 862, 799. H-NMR: (2)); 2.25 (s, 3 H, COCH ); 1.55 (br. s, 1 H, OH). C-
1
13
1
1
3
1.11 (s, 1 H, OH); 9.85 (s, 1 H, COH); 7.41 (d, J = 8.1, 1
NMR: 206.4 (COCH ); 160.1 (C(7a)); 125.2 (C(4)); 126.0
3
H, H–C(6)); 7.19 (d, J = 1.6, 1 H, H–C(3)); 7.16 (dd, (C(3a)); 125.2 (C(5)); 124.5 (C(6)); 114.4 (C(7)); 94.6 (C
1
3
J = 8.1, 1.6, 1 H, H–C(5)). C-NMR: 195.8 (COH); 161.9
(
(
(2)); 74.6 (C(3)); 26.6 (COCH ). HR-ESI-TOF-MS:
3
+
þ
C(2)); 134.5 (C(6)); 132.0 (C(4)); 123.5 (C(5)); 121.1 (C
3)); 119.5 (C(1)).
278.9628 ([M + Na] , C10H9BrNaO ; calc. 278.9633).
6-Bromo-2,3-dihydro-2-(1-hydroxypropan-2-yl)-1-benzo-
3
4
of aldehyde 22 (800 mg, 3.11 mmol) in dry acetone was
-Bromo-2-(2-oxopropoxy)benzaldehyde (23). A solution furan-3-ol (25). A mixture of MeMgI (1.5 ml, 1.38 mmol),
Bu NBr (27 mg, 0.092 mmol), and LiCl (21 mg,
4
treated with K CO (644 mg, 4.67 mmol), ClCH COMe
2
0.51 mmol) in a mixture of anhyd. Et O (1.4 ml) and
2
2
3
(
2.42 ml, 4.04 mmol), and a catalytic amount of KI. The
anhyd. diglyme (0.17 ml, 1.14 mmol) was stirred for
reaction was stirred for 4 h at 30 °C. After cooling to
room temperature, the K CO was filtered off, the solvent (125 mg, 0.46 mmol) in ether (0.5 ml) was added and the
30 min at 0 °C. Then, a solution of methyl ketone 24
2
3
was evaporated, and the residue was chromatographed, mixture was allowed to warm to room temperature. After
furnishing compound 23 (655 mg, 82%), as a yellow oil. 1 h, the reaction was quenched with saturated solution of
R = 0.22; hexane/AcOEt 85:15. IR (film): 3454, 1732, NH Cl (5 ml) and extracted with CH Cl (4 9 20 ml).
f
4
2
2
1
1
680, 1587, 1406, 1246, 1064, 889. H-NMR: 10.48 (s, 1 H, The combined organic extracts were washed with brine
COH); 7.73 (d, J = 8.4, 1 H, H–C(6)); 7.24 (dd, J = 8.4, (10 ml), dried (Na SO ), and concentrated under reduced
2
4
1
2
2
.5, 1 H, H–C(5)); 6.97 (d, J = 1.5, 1 H, H–C(3)); 4,69 (s, pressure. The residue was chromatographed, affording
1
3
H, CH COCH ); 2.33 (s, 3 H, CH COCH ). C-NMR: diol 25 (68 mg, 54%) as a brownish oil. R = 0.21; hexane/
2
3
2
3
f
02.8 (CH COCH ); 189.0 (COH); 159.9 (C(2)); 132.5 (C AcOEt 70:30. IR (film): 3377, 2924, 1603, 1472, 1225,
2
3
1
(
4)); 130.4 (C(6)); 125.5 (C(5)); 124.0 (C(1)); 116.6 (C(3));
3.2 (CH COCH ); 26.7 (CH COCH ). HR-ESI-TOF-
1005, 893. H-NMR: 7.26 (d, J = 7.5, 1 H, H–C(4)); 7.08
7
(dd, J = 7.5, 1.7, 1 H, H–C(5)); 7.06 (d, J = 1.7, 1 H, H–C
(7)); 5.27 (d, J = 6.2, 1 H, H–C(3)); 4.24 (d, J = 6.2, 1 H,
2
3
2
3
+
þ
MS: 278.9621 ([M+Na] , C10H9BrNaO ; calc. 278.9633).
3
1
2
1
1
-[(2R*,3S*)-6-Bromo-2,3-dihydro-3-hydroxy-1-benzofuran- H–C(2)); 4.03 (br. s, 1 H, OH–C(3)); 2.71 (br. s, 1 H, C
-yl]ethanone (24). To a solution of 23 (500 mg, (CH ) OH); 1.56 (s, 3 H, COHCH ); 1.50 (s, 3 H,
.95 mmol) in DMF (8.3 ml) was added H O (0.035 ml, COHCH3). C-NMR: 160.2 (C(7a)); 129.2 (C(3a)); 126.5
3
2
3
1
3
2
.95 mmol) and L-proline (44 mg, 0.39 mmol). The mixture (C(4)); 124.6 (C(5)); 123.7 (C(6)); 114.1 (C(7)); 89.7 (C
was stirred for 30 h at room temperature. After addition (2)); 72.8 (COHCH ); 72.4 (C(3)); 28.4 (COHCH ); 25.3
3
3
+
of brine (10 ml), the product was extracted with AcOEt (COHCH3). HR-ESI-TOF-MS: 294.9945 ([M+Na] ,
þ
(
sively washed with H O (5 9 10 ml) and brine (10 ml), 2-(6-Bromo-1-benzofuran-2-yl)propan-2-ol (29). To a solu-
4 9 25 ml). The organic extracts were combined, succes-
C11H13BrNaO ; calc. 294.9946).
3
2
dried (Na SO ), and concentrated under reduced pressure. tion of 24 (100 mg, 0.39 mmol) in ether (3 ml) was slowly
2
4
Chromatography of the residue gave 24 (421 mg, 84%), as added at 0 °C MeMgI (0.95 ml, 0.78 mmol) and CeCl3
white solid. M.p.: 130 – 132 °C (hexane/AcOEt). (96 mg, 0.39 mmol). After stirring the reaction at 0 °C for
a
R = 0.39; hexane/AcOEt 70:30. IR (KBr): 3439, 1714, 30 min it was quenched with NH Cl (5 ml) and extracted
f
4
1
1
604, 1448, 1286, 1180, 897. H-NMR: 7.28 (d, J = 7.2, 1
with CH Cl (4 9 20 ml). The combined organic extracts
2
2
H, H–C(4)); 7.15 (d, J = 1.7, 1 H, H–C(7)); 7.13 (dd, were washed with brine (10 ml), dried (Na SO ), and con-
2
4
J = 7.2, 1.7, 1 H, H–C(5)); 5.50 (d, J = 6.6, 1 H, H–C(3)); centrated under reduced pressure. The residue was chro-
.96 (d, J = 6.6, 1 H, H–C(2)); 2.35 (s, 3 H, COCH ); 1.55 matographed, affording 29 (89.5 mg, 90%) as a brownish
4
3
1
3
(
(
(
br. s, 1 H, OH). C-NMR: 205.8 (COCH ); 160.4 (C oil. R = 0.52; hexane/AcOEt 70:30. IR (film): 3381.2,
3 f
1
7a)); 126.9 (C(4)); 126.0 (C(3a)); 125.2 (C(5)); 124.6 (C 2982.0, 1606.7, 1452.0, 1273.0, 1168.9, 898.8. H-NMR:
6)); 114.5 (C(7)); 90.7 (C(2)); 72.4 (C(3)); 28.5 (COCH ). 7.61 (d, J = 1.6 Hz, 1 H, H–C(7)); 7.38 (d, J = 8.3, 1 H,
3
+
þ
HR-ESI-TOF-MS: 278.9628 ([M+Na] , C10H9BrNaO ;
calc. 278.9633).
H–C(4)); 7.32 (dd, J = 8.3, 1.6, 1 H, H–C(5)); 6.54 (s, 1
H, H–C(3)); 2.19 (br. s, w1/2 = 25 Hz, 1 H, OH); 1.66 (s, 6
3
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Helv. Chim. Acta 2016, 99, 398 – 404
403
1
H, COH(CH ) ). C-NMR: 163.7 (C(2)); 155.0 (C(7a));
3
A solution of MeMgI (0.65 ml, 0.56 mmol), in Et O
2
3
2
1
1
27.4 (C(3a)); 126.1 (C(5)); 121.9 (C(4)); 117.1 (C(6)); (0.6 ml) was slowly added at ꢀ20 °C to a solution of the
14.7 (C(7)); 100.3 (C(3)); 69.3 (COHCH3); 28.7 methyl ketone 27 (125 mg, 0.37 mmol) in anhyd. Et O
2
(
COHCH ); 28.7 (COHCH ). HR-ESI-TOF-MS: 292.9786 (0.4 ml) and the mixture was allowed to warm to room
3 3
+
þ
(
6
[M+Na] , C11H11BrNaO ; calc. 276.9840).
temperature. After 1 h, the reaction was quenched with
NH Cl (5 ml) and extracted with CH Cl (4 9 20 ml).
2
-Bromo-2-(1-hydroxypropan-2-yl)-1-benzofuran-3(2H)-one
4
2
2
(
26). Method A: A solution of chromium trioxide and sul- The pooled organic extracts were washed with brine
furic acid in acetone (Jones’ reagent, 0.083 ml, 0.66 mmol) (5 ml), dried (Na SO ), and concentrated under reduced
was slowly added to a stirred solution of diol 25 (60 mg, pressure. The residue was chromatographed to yield alco-
2
4
0
.22 mmol) in acetone (6 ml), cooled at ꢀ20 °C. The reac-
hol 28 (118 mg, 89%) as a brownish oil. R = 0.37; hex-
f
+
ane/AcOEt 80:20. HR-ESI-TOF-MS: 379.0511 ([M+Na] ,
tion was allowed to warm to 0 °C and the excess of Jones
reagent was quenched with isopropyl alcohol. Then, the
pH of the solution was adjusted to 4.0 with a saturated
þ
C16H21BrNaO ; calc. 379.0515).
A solution of Jones’ reagent (0.124 ml, 0.93 mmol)
4
solution of NaOAc, the solvent was evaporated under was slowly added to a stirred solution of protected alco-
reduced pressure and the product extracted with Et O hol 28 (110 mg, 0.31 mmol) in acetone (9 ml), cooled at
2
(
with brine (5 ml), dried (Na SO ), and concentrated under the excess of Jones’ reagent was quenched with PrOH.
4 9 20 ml). The combined organic extracts were washed ꢀ20 °C. The reaction was allowed to warm to 0 °C and
i
2
4
reduced pressure. Chromatography of the residue provided Then, the pH of the solution was adjusted to 4.0 with a
the ketone 26 (42 mg, 70%) as a brownish oil. R = 0.47; saturated solution of AcONa, the solvent was evaporated
f
hexane/AcOEt 70:30. IR (film): 3418, 2926, 1713, 1601, under reduced pressure, and the product extracted with
1
1
427, 1315, 1198, 1016, 883. H-NMR: 7.51 (d, J = 8.4, 1 H, Et O (4 9 20 ml). The combined organic extracts were
2
H–C(4)); 7.37 (d, J = 1.4, 1 H, H–C(7)); 7.24 (dd, J = 8.4, washed with brine (5 ml), dried (Na SO ), and concen-
2
4
1
OH); 1.35 (s, 3 H, COHCH ); 1.24 (s, 3 H, COHCH ). the residue provided the ketone 26 (59 mg, 70%) as a
.4, 1 H, H–C(5)); 4.39 (s, 1 H, H–C(2)); 2.96 (br. s, 1 H, trated under reduced pressure. The chromatography of
3
3
13
C-NMR: 199.8 (C(3)); 172.9 (C(7a)); 133.2 (C(6)); 126.2 brownish oil. The NMR and IR data of the product were
C(5)); 125.1 (C(4)); 120.1 (C(3a)); 117.0 (C(7)); 89.8 (C in agreement with those recorded for 26, when obtained
2)); 72.4 (COHCH ); 25.6 (COHCH ); 24.3 (COHCH ). from 25.
(
(
3
3
3
þ
+
HR-ESI-TOF-MS: 292.9781 ([M+Na] , C11H11BrNaO ;
calc. 292.9789).
6-Bromo-2-(propan-2-ylidene)-1-benzofuran-3(2H)-one (20).
A solution of MsCl in CH Cl (2M, 0.9 ml, 1.8 mmol) was
3
2
2
6
(
-Bromo-2-(1-hydroxypropan-2-yl)-1-benzofuran-3(2H)-one
26). Method B: Dihydropyran (0.08 ml, 0.88 mmol), cam- 0.18 mmol) and DMAP (4.5 mg, 0.04 mmol) in anhyd. pyr-
phorsulfonic acid (6.8 mg, 0.030 mmol), and powdered idine (0.3 ml). The reaction was further stirred for 17 h at
dropwise added to a stirred solution of ketone 26 (50 mg,
ꢀ
4
A molecular sieves (100 mg) were successively added to 40 °C, when it was cooled to room temperature and the
a solution of 24 (150 mg, 0.59 mmol) in CH Cl (6 ml). pH was adjusted to 4 – 5 with a solution of HCl (10% w/
2
2
The reaction was stirred at room temperature for 2 h, v). Then, the product was extracted with CH Cl2
2
when brine (7 ml) was added, and the product was (4 9 20 ml), the combined organic extracts were washed
extracted with AcOEt (4 9 20 ml). The combined organic with water (5 ml), dried (Na SO ), and concentrated under
extracts were washed with brine (5 ml), dried (Na SO ), reduced pressure. The chromatography of the residue gave
2
4
2
4
and concentrated under reduced pressure. The residue was the coumaranone derivative 20 (25 mg, 61%) as a yellowish
chromatographed, giving 27 (140 mg, 70%) as a brownish solid. M.p.: 43 – 45 °C. R = 0.79; hexane/AcOEt 70:30. IR
f
oil. R = 0.68; hexane/AcOEt 70:30. IR (film) 2941, 1725, (KBr): 2924, 2359, 1745, 1703, 1651, 1599, 1427, 1313, 1117,
f
1
1
1
600, 1473, 1356, 1219, 1118, 1020, 891. H-NMR: 7.28 (d, 899. H-NMR: 7.60 (d, J = 8.3, 1 H, H–C(4)); 7.40 (d,
J = 8.4, 1 H, H–C(4)); 7.22 (d, J = 7.9, 1 H, H–C(4)); 7.15 J = 1.6, 1 H, H–C(7)); 7.27 (dd, J = 8.3, 1.6, 1 H, H–C(5));
1
3
(
m, 1 H, H–C(7)); 7.12 (m, 1 H, H–C(5)); 5.42 (d, J = 7.4, 2.35 (s, 3 H, CH ); 2.09 (s, 3 H, CH ). C-NMR: 182.7 (C
3 3
1
H, H–C(3)); 5.41 (d, J = 6.4, 1 H, H–C(3)); 4.95 (d, (3)); 164.5 (C(7a)); 145.0 (C(2)); 130.5 (C(6)); 126.0 (C(5));
J = 6.4, 1 H, H–C(2)); 4.91 (d, J = 7.4, 1 H, H–C(2)); 3.67 125.2 (C(4)); 122.5 (C(3a)); 116.1 (C(7)); 133.1 (C(CH ) );
3
2
0
m, 2 H, H–C(6 )); 2.36 (s, 3 H, COCH ); 2.28 (s, 3 H, 20.2 (CH ); 17.5 (CH ). HR-ESI-TOF-MS: 274.9667
3 3 3
(
0
0
+
þ
COCH ); 1.55 (m, 2 H, H–C(5 ); 1.53 (m, 2 H, H–C(4 );
([M+Na] , C11H9BrNaO ; calc. 274.9684).
3
2
0
.51 (m, 2 H, H–C(3 ). C-NMR: 206.2 (COCH ); 204.3
3
13
1
(
(
(
1
COCH3); 161.2 (C(7a)); 160.7 (C(7a)); 128.1 (C(4)); 127.9
C(3a)); 127.3 (C(3a)); 127.2 (C(4)); 125.3 (C(6)); 124.9 (C
5)); 124.7 (C(6)); 124.4 (C(5)); 114.7 (C(7)); 114.2 (C(7));
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Received December 15, 2015
Accepted February 15, 2016
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