Intramolecular Direct Arylation of 3-Halo-2-pyrones and 2-Coumarins

Article abstract of DOI:10.1021/acs.joc.5b02027

Direct arylation represents a favorable alternative to traditional cross-coupling and has found widespread use with simple aryls and robust heterocycles. Herein a direct arylation protocol has been optimized and applied to 2-pyrones, which are delicate an

Full text of DOI:10.1021/acs.joc.5b02027

Article
pubs.acs.org/joc
Intramolecular Direct Arylation of 3‑Halo-2-pyrones and
2‑Coumarins
Marie-T. Nolan, Leticia M. Pardo, Aisling M. Prendergast, and Gerard P. McGlacken*
Department of Chemistry and Analytical and Biological Chemistry Research Facility, University College Cork, College Road, Cork,
Ireland
S
* Supporting Information
ABSTRACT: Direct arylation represents a favorable alternative to traditional cross-coupling and has found widespread use with
simple aryls and robust heterocycles. Herein a direct arylation protocol has been optimized and applied to 2-pyrones, which are
delicate and privileged biological motifs. Regioselective halogenation at the 3-position allows intramolecular coupling by
activation of a pyrone C−Br or C−Cl bond and a phenoxy C−H bond. Importantly, electron-poor phenoxy substrates also
worked well. The methodology was extended to 2-coumarins and applied to the synthesis of flemichapparin C and a novel
analogue. Deuterium isotope effects, typical of a concerted metalation−deprotonation (CMD) mechanism, were observed in the
case of a bromopyrone, but a highly unusual, inverse kinetic isotope effect was evident using a chlorocoumarin, implying that a
different mechanism is operating.
provide access to an array of chemical products and
intermediates.12 Finally, the 2-pyrone moiety displays reactivity
reminiscent of that of aromatic compounds,13 dienes,14 and
enones,15 and its framework can ring-open under some cross-
coupling conditions,16 thus bestowing 2-pyrones with challeng-
ing and rewarding properties. The related 2-coumarins
(especially 4-hydroxy variants) display a similarly remarkable
biological profile.17,18 The coumestan subgroup exhibits
impressive biological activities,19 and thus a number of novel
synthetic methods have been developed for constructing the
coumestan and related ring systems.19a,c,20
The intramolecular direct arylation of 2-pyrones involving
the formation of five-membered21 (Scheme 1) and six-
membered rings22 (not shown) has been reported. In these
cases coupling occurred between a C−H on the pyrone/
coumarin and a C−X on the phenoxy/benzyloxy moiety, which
presumably occurs via trouble-free oxidative addition to the
phenyl halide followed by C−H activation of the pyrone. The
INTRODUCTION
■
The formation of aryl−heteroaryl (Ar−HetAr) bonds is an
important transformation in organic synthesis1 due to the
abundance of the Ar−HetAr moiety in natural products and
pharmaceuticals.2 The most widely used methods for its
formation involve Suzuki−Miyaura,3 Stille,4 Negishi,5 and
similar reactions.6 More recently the development of direct
arylation protocols which involve at least one C−H activation
event has emerged and offers a number of advantages over
traditional cross-coupling.7 The 2-pyrone substrate, specifically
4-hydroxy-based 2-pyrones,8 represents a privileged biological
scaffold with broad spectrum biological activity,8,9 spanning
cytotoxic, antibiotic, and antifungal activity. For example,
radicinin (Figure 1) demonstrates inhibitory activity toward
the growth of some Gram-positive bacteria.10 Other appro-
priate examples include neo-tanshinlactone analogues which
display antibreast cancer activity.11 Additionally, 2-pyrones are a
promising class of biorenewable platform chemicals that
Scheme 1. Previous Studies and This Work
Figure 1. Biologically active examples of 4-alkoxy-2-pyrone and 2-
coumarin.
Received: August 31, 2015
© XXXX American Chemical Society
A
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Table 1. General Procedure for Intramolecular Direct Arylation Reaction of Pyrone 1 to 2
entry
X
Pd (mol %)
ligand (mol %)
base (equiv)
solvent
additive (equiv)
PivOH (0.3)
conversn (%)
yield (%)
1
I
Pd2dba3 (5.0)
PPh3 (10)
Na2CO3 (3.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (3.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
Cs2CO3 (1.1)
K2CO3 (3.0)
NMP
0
0
2
I
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
Pd(OAc)2 (2.0)
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
PCy3·HBF4 (10)
PCy3·HBF4 (10)
PPh3 (5.0)
DMA
DMA
DMA
xylene
xylene
xylene
xylene
xylene
xylene
xylene
3
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
43
4
53
5
SPhos (4.0)
PPh3 (15)
25
6
100
100
40
80
88
7
PPh3 (15)
PivOH (0.3)
8
PPh3 (15)
9
PPh3 (15)
PivOH (0.3)
12
10
11
PCy3·HBF4 (15)
PCy3·HBF4 (15)
100
100
63
79
Scheme 2. Effect of Substituents on Phenoxy Group
C3−H site of such compounds is known to be acidic,21a and
thus base-assisted proton removal is probably facile.
partners, by invoking a mechanism involving C−H cleavage of
an electron-poor substrate.25 The last point has proven to be a
limitation of previous studies21a (see Scheme 1).
A more challenging approach would be to locate the halide
on the pyrone and develop a methodology to activate the C−H
bond of the phenoxy-based coupling partner.23 This should (1)
facilitate complete regioselectivity (pyrone-C3 vs -C5 aryla-
tion),24 (2) avoid the use of a halogenated site on the phenoxy
coupling partner, thus providing easier access to di- and
trisubstituted products via cheaper substituted phenols, and (3)
improve yields when using electron-poor phenoxy coupling
RESULTS AND DISCUSSION
■
We initially prepared the 4-phenoxy-3-iodopyrone 1a via
iodination of the phenoxy pyrone in a completely regioselective
manner (only iodination at C-3).26 A variety of conditions were
tried, but disappointingly no cyclization was observed and only
starting material and significant amounts of dehalogenated
B
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product were isolated (Table 1, entries 1 and 2). Surprised by
these results, we then tested the corresponding bromides
(entries 3−7). A direct comparison of the iodo and bromo
substrates (entries 2 and 3) showed that only the latter afforded
product. Optimized conditions involved Pd(OAc)2, PPh3, and
K2CO3 in xylenes. The addition of pivalic acid27 improved the
yield from 80 (entry 6) to 88% (entry 7). However, the
increase in yield was not considered sufficient to warrant
inclusion of 30 mol % of PivOH going forward. We then
challenged our optimized conditions by using chlorinated
pyrone 1c as a substrate, which was easily and regioselectively
prepared by chlorination of the parent pyrone. The reaction
proved sluggish (entries 8 and 9) using the previously
optimized conditions. However, changing the ligand to a
bulkier variant28 facilitated complete conversion of starting
material in both Cs2CO3 (entry 10) and K2CO3 (entry 11) in
good isolated yields.
Scheme 4. Synthesis of Flemichapparin C (31) and 32
The reaction worked well with a number of electron-rich
substrates (Scheme 2, 5−10 to 16−21). It also displayed some
regioselectivity (10a was converted to 21 in 60% yield) and
substrate tolerance (see chloro analogue 15).
Scheme 5. Intramolecular Deuterium Isotope Studies in the
Pyrone System
To our delight, electron-poor phenoxy substrates worked
very well (Scheme 2, forming 14, 15, and 22−24). Cyclized
product 24 was isolated in excellent yields of 90% and 60%
using the bromide and chloride substrates 13a,b, respectively,
in sharp contrast to previous studies21a (Scheme 1).
We then turned our attention to the important coumarin
class. Surprisingly, bromination of coumarin 25 failed under the
conditions which had previously worked for the 2-pyrones. A
diverse set of bromination conditions such as Br2, NBS, NBS/
TBAB, and NBS/CF3COOH also failed to give any
bromination. Bromination of the parent 4-hydroxy-coumarin
did occur using Br2/TBAB (72%, Supporting Information), but
the subsequent conditions tested to install the phenyl group
(e.g., PhB(OH)2, Cu(OAc)2, Et3N)29 failed.
We then attempted to chlorinate the 3-position. Using NCS
and CF3COOH, this reaction proceeded smoothly, giving the
chlorocoumarin 26 in 67% yield (Scheme 3). Subsequent
intramolecular direct arylation proceeded very well in 90%
yield.
of two runs) was observed, which represents a kinetically
significant C−H activation event (although not necessarily a
rate-determining C−H activation step32), typical of a CMD/
AMLA mechanism, as reported in the literature.33
Next we applied the same protocol to chlorocoumarin 35. An
intramolecular KIE experiment revealed a remarkable KIE value
of 0.47 (average of two runs) (Scheme 6), indicating that an
entirely different mechanism is at play with chlorocoumarin 35
in comparison to that for bromopyrone 33, at least under the
conditions used.
Scheme 6. Intramolecular Deuterium Isotope Studies in the
Coumarin System
Scheme 3. Cyclization of the Coumarin Variant
This good yield prompted us to attempt to access the
coumestan group of natural products.19 Commercially available
4-hydroxy-2-coumarin 28 (Scheme 4) was brominated at the 4-
position in good yield (29; 72%), coupled with sesamol and
chlorinated (30; 54% over two steps). Intramolecular arylation
occurred to form flemichapparin C (31) and its regioisomer
(32) (in 98% overall yield), which were easily separated using
silica gel chromatography. This represents a rapid four-step
route to these compounds, in comparison to more complex
chemical30 or enzyme-mediated routes.31
The absence of a large, positive KIE in this experiment rules
out a CMD/AMLA mechanism. At this stage we considered a
number of mechanistic scenarios which would result in a
significant inverse KIE. The most likely scenario involves
reversible Pd insertion into the C−H bond followed by a
kinetically significant subsequent step: e.g., slow oxidative
addition into the coumarin−Cl bond (possibly invoking
Pd(II)/Pd(IV))34 (Scheme 7). Alternatively oxidative addition
into the coumarin−Cl bond occurs first. In either case, a
reversible C−H activation will result in the buildup of the more
stable Pd−D species (in comparison to Pd−H).35 A slow
subsequent step would then result in more product arising from
We then turned our attention to the mechanism. An
intramolecular kinetic isotope effect (KIE) experiment was
undertaken with pyrone 33 (Scheme 5). A KIE of 3.3 (average
C
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product, 4-bromo-6-methyl-2-pyrone, was isolated as an orange solid
(6.40 g, 85%): mp 72−74 °C (lit. mp 73−74 °C); δH (CDCl3, 300
MHz) 2.25 (d, J = 0.5, 3H), 6.19 (t, J = 0.8, 1H), 6.46 (t, J = 0.7, 1H);
δC (CDCl3, 75.5 MHz) 19.7, 108.4, 114.8, 141.1, 160.6, 162.1; m/z
(ES+) 188 (98).
Scheme 7. Plausible Mechanistic Cycle for the
Chlorocoumarin System
General Procedure for Preparation of 4-Phenoxy-6-methyl-
2-pyrones. A solution of 4-bromo-6-methyl-2-pyrone (1.0 equiv),
phenol (1.5 equiv), and K2CO3 (1.8 equiv) in acetone (4.0 mL/mmol
starting material) was heated to 65 °C and stirred for 16 h. Upon
cooling, the reaction mixture was diluted with water (10 mL) and
EtOAc (20 mL). The mixture was extracted with EtOAc (2 × 20 mL),
and the combined organic layers were washed with aqueous NaOH
(10% w/v, 2 × 20 mL). The organic layer was then dried over MgSO4,
filtered, and concentrated under reduced pressure. The residues were
purified by recrystallization from EtOH.
4-Phenoxy-6-methyl-2-pyrone.39 yellow solid (1.69 g, 71%), mp
86 °C (lit. 89−91 °C); δH (CDCl3, 300 MHz) 2.26 (s, 3H), 5.21 (d, J
= 2.1, 1H), 5.96−5.97 (m, 1H), 7.07 (d, J = 8.0, 2H), 7.29 (t, J = 7.3,
1H), 7.43 (t, J = 7.8, 2H); δC (CDCl3, 75.5 MHz) 20.0, 91.0, 99.9,
121.1, 126.5, 130.2, 152.4, 163.3, 164.6, 170.8; m/z (ES+) 203 (100).
4-(4-Fluorophenoxy)-6-methyl-2-pyrone. yellow solid (0.39 g,
84%), mp 75−76 °C; νmax/cm−1 (NaCl) 3079, 1732, 1649, 1596,
1406, 1322, 1242, 1091; δH (CDCl3, 300 MHz) 2.26 (s, 3H), 5.17 (d, J
= 2.2, 1H), 5.96 (d, J = 1.5, 1H), 7.01−7.16 (m, 4H); δC (CDCl3, 75.5
MHz) 20.0, 91.0, 100.0, 117.0 (d, J = 24), 122.7 (d, J = 9), 148.2 (d, J
= 3), 160.6 (d, J = 247), 163.5, 164.4, 170.8; δF (CDCl3, 282 MHz)
−115.3; m/z (ES+) 220 (15); HRMS (ESI) exact mass calculated for
C12H10O3F [M + H+] 221.0614, found 221.0618.
4-(4-Chlorophenoxy)-6-methyl-2-pyrone. pale yellow solid (0.41
g, 82%), mp 76−77 °C; νmax/cm−1 (NaCl) 3055, 1731, 1646, 1609,
1485, 1448, 1405, 1341; δH (CDCl3, 300 MHz) 2.26 (s, 3H), 5.20 (d, J
= 2.2. 1H), 5.9 (t, J = 1.4, 1H), 6.99−7.05 (m, 2H), 7.36−7.43 (m,
2H); δC (CDCl3, 75.5 MHz) 20.1, 91.2, 99.2, 122.5, 130.4, 132.0,
150.8, 163.6, 164.3, 170.4; HRMS (ESI) exact mass calculated for
C12H10O3Cl [M + H+] 237.0318, found 237.0310.
4-(4-Methoxyphenoxy)-6-methyl-2-pyrone. white solid (0.38 g,
78%), mp 105−106 °C; νmax/cm−1 (NaCl) 2838, 1731, 1646, 1568,
1446, 1405, 1322, 1299; δH (CDCl3, 300 MHz) 2.25 (t, J = 0.7, 3H),
3.82 (s, 3H), 5.19 (dd, J = 2.2, 0.4, 1H), 5.95 (overlapping dd, J = 2.2,
1.0, 1H), 6.89−6.94 (m, 2H), 6.96−7.03 (m, 2H); δC (CDCl3, 75.5
MHz) 20.0, 55.7, 90.7, 99.9, 115.2, 122.0, 145.8, 157.8, 163.2, 164.1,
171.3; Exact mass calculated for C13H13O4 [M + H+] 233.0814, found
233.0810.
4-(4-Methylphenoxy)-6-methyl-2-pyrone. cream solid (0.45 g,
79%), mp 53 °C; νmax/cm−1 (NaCl) 3056, 1736, 1644, 1569, 1452,
1324, 1271; δH (CDCl3, 300 MHz) 2.25 (s, 3H), 2.37 (s, 3H), 5.20 (d,
J = 2.1, 1H), 5.95 (t, J = 1.0, 1H), 6.94 (d, J = 8.5, 2H), 7.21 (d, J = 8.2,
2H); δC (CDCl3, 75.5 MHz) 20.0, 20.9, 90.8, 99.9, 120.8, 130.7, 136.3,
150.1, 163.2, 164.7, 171.0; m/z (ES-): 216 (16); HRMS (ESI) exact
mass calculated for C13H13O3 [M + H+] 217.0865, found 217.0869.
4-(4-Ethylphenoxy)-6-methyl-2-pyrone. cream solid (0.57 g, 88%),
mp 54−55 °C; νmax/cm−1 (NaCl) 2966, 2932, 2873, 1732, 1651, 1603,
1447, 1321, 1231; δH (CDCl3, 300 MHz) 1.25 (t, J = 7.6, 3H), 2.25 (s,
3H), 2.66 (dd, J = 15.2, 7.62, 2H), 5.20 (d, J = 2.2, 1H), 5.96
(overlapping dd, J = 2.2, 0.9, 1H), 6.94−6.99 (m, 2H), 7.21−7.26 (m,
2H); δC (CDCl3, 75.5 MHz) 15.6, 20.0, 28.3, 90.9, 100.0, 120.9, 129.5,
142.7, 150.3, 163.7, 164.7, 171.0; m/z (ES+) 230 (100); HRMS (ESI)
exact mass calculated for C14H15O3 [M + H+] 231.1021, found
231.1021.
the greater amount of Pd−D intermediate. Other mechanistic
routes involving an electrophilic aromatic process36 were
considered less likely, as inverse KIEs associated with this
mechanism are secondary and thus of lower magnitude. Finally,
observation of an inverse KIE arising from a faster reductive
elimination or β-elimination37 is also considered unlikely. First,
the presence of only one D atom37 would not affect the
electron density on palladium sufficiently, and in any case we
consider it unlikely that either reductive elimination or β-
elimination would be the rate-determining step.
CONCLUSION
■
In conclusion, we report intramolecular direct arylation of
brominated and chlorinated pyrones. Yields are very good, and
importantly, electron-withdrawing substituents on the phenoxy
ring are tolerated. The analogous 2-coumarin works well,
facilitating access to flemichapparin C and an analogue in four
steps. Deuterium isotope experiments show a large, positive
KIE for a bromopyrone typical of a CMD/AMLA mechanism,
whereas an unusually large inverse kinetic isotope effect is
observed for a chlorocoumarin, indicating that a different
mechanism is at play.
EXPERIMENTAL SECTION
■
Melting point determinations were performed by the open capillary
method and are reported uncorrected. 1H and 13C NMR spectra were
recorded at 25 °C in CDCl3 at 300 and 75.5 MHz with a spectrometer
unless otherwise specified, with TMS as the internal standard.
Chemical shifts (δH, δC, and δF) were expressed as parts per million
(ppm), positive shifts being downfield from TMS; coupling constants
(J) are expressed in hertz (Hz). High-resolution mass spectra (HRMS)
were obtained on a TOF MS instrument with an ESI source. High-
resolution mass spectra were recorded only for new compounds.
Literature citations are provided for known compounds, along with
representative characterization data. IR spectra were recorded on an
FT-IR spectrometer as a thin film (liquid samples) or applied as a
solution in chloroform, and the chloroform was allowed to evaporate
(solid samples). Column chromatography was carried out using 60 Å
(35−70 μm) silica.
4-(3-Methylphenoxy)-6-methyl-2-pyrone. cream solid (0.46 g,
81%), mp 59−60 °C; νmax/cm−1 (NaCl) 3099, 1731, 1646, 1612,
1586, 1487, 1321, 1249; δH (CDCl3, 300 MHz) 2.26 (m, 3H), 2.37 (s,
3H), 5.21 (dd, J = 2.2, 0.4, 1H), 5.96 (dd, J = 2.2, 0.9, 1H, app), 6.84−
6.89 (m, 2H), 7.08−7.11 (m, 1H), 7.29 (td, J = 7.6, 1.0, 1H); δC
(CDCl3, 75.5 MHz) 20.0, 21.3, 91.0, 100.0, 118.0, 121.6, 127.3, 129.9,
140.6, 152.3, 163.2, 164.7, 170.8; m/z (ES+) 216 (14); HRMS (ESI)
exact mass calculated for C13H13O3 [M + H+] 217.0865, found
217.0868.
4-Bromo-6-methyl-2-pyrone.38 A solution of 4-hydroxy-6-
methyl-2-pyrone (5.00 g, 39.7 mmol), TBAB (14.80 g, 46.0 mmol),
and P2O5 (13.5 g, 95.2 mmol) in toluene (4.0 mL/mmol starting
material) was stirred at 94 °C for 1.5 h. Upon cooling, the reaction
mixture was washed with toluene (2 × 30 mL). The combined organic
extracts were then washed with saturated aqueous NaHCO3 (2 × 20
mL) and H2O (2 × 20 mL). The organic layer was then dried over
MgSO4, filtered, and concentrated under reduced pressure. The
4-(2-Methylphenoxy)-6-methyl-2-pyrone. cream solid (0.38 g,
66%), mp 59−60 °C; νmax/cm−1 (NaCl) 1731, 1643, 1567, 1447,
D
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1404, 1232; δH (CDCl3, 300 MHz) 2.15 (s, 3H), 2.24 (s, 3H), 5.06 (d,
J = 2.2, 1H), 6.00 (dd, J = 2.2, 0.9, 1H), 6.97 (dd, J = 7.5, 1.7, 1H),
7.14−7.21 (m, 2H), 7.22−7.28 (m, 1H); δC (CDCl3, 75.5 MHz) 20.0,
21.3, 91.0, 100.0, 118.0, 121.6, 127.3, 129.9, 140.6, 152.3, 163.2, 164.7,
170.8; m/z (ES+) 216 (100); HRMS (ESI) exact mass calculated for
C13H13O3 [M + H+] 217.0865, found 217.0863.
4-(3-Methoxyphenoxy)-6-methyl-2-pyrone. off-white solid (0.53 g,
86%), mp 100 °C; νmax/cm−1 (NaCl) 3097, 1732, 1647, 1608, 1489,
1446, 1404, 1321, 1285; δH (CDCl3, 300 MHz) 2.26 (s, 3H), 3.81 (s,
3H), 5.26 (d, J = 2.1, 1H), 5.96 (dd, J = 2.1, 0.9, 1H), 6.61 (t, J = 2.3,
1H), 6.66 (dd, J = 8.0, 2.2, 1H), 6.83 (dt, J = 8.4, 2.0, 1H), 7.32 (t, J =
8.2, 1H); δC (CDCl3, 75.5 MHz) 20.0, 55.7, 90.7, 99.9, 115.2, 122.0,
145.8, 157.8, 163.2, 164.1, 171.3; m/z (ES+) 232 (100); HRMS (ESI)
exact mass calculated for C13H13O4 [M + H+] 233.0814, found
233.0813.
7.09 (d, J = 7.9, 2H), 7.32 (t, J = 7.4, 1H), 7.42−7.49 (m, 2H); δC
(CDCl3, 75.5 MHz) 20.0, 91.0, 97.6, 120.9, 126.5, 130.4, 152.9, 160.9,
162.3, 165.5; m/z (ES+) 281 (100); HRMS (ESI) exact mass
calculated for C12H10O3Br [M + H+] 280.9813, found 280.9816.
3-Bromo-4-(4-fluorophenoxy)-6-methyl-2-pyrone (3a): white
solid (0.11 g, 81%), mp 119−120 °C; νmax/cm−1 (NaCl) 1725,
1644, 1501, 1498, 1311, 1267, 1083; δH (CDCl3, 300 MHz) 2.19 (s,
3H), 5.60 (s, 1H), 7.06−7.18 (m, 4H); δC (CDCl3, 75.5 MHz) 20.4,
91.1, 97.5, 117.2 (d, JC−F = 24), 122.6 (d, JC−F = 9), 148.8 (d, JC−F
=
3), 160.6 (d, JC−F = 246), 160.8, 162.6, 165.5; δF (CDCl3, 282 MHz)
−115.1; HRMS (ESI) exact mass calculated for C12H9O3FBr [M +
H+] 298.9716, found 298.9717.
3-Bromo-4-(4-chlorophenoxy)-6-methyl-2-pyrone (4a): white
solid (0.09 g, 83%), mp 127−128 °C; νmax/cm−1 (NaCl) 1728,
1644, 1592, 1443, 1382, 1315; δH (CDCl3, 300 MHz) 2.18 (s, 3H),
5.61 (s, 1H), 7.02−7.07 (m, 2H), 7.39−7.45 (m, 2H); δC (CDCl3,
75.5 MHz) 20.0, 91.4, 97.4, 122.2, 130.4, 132.0, 151.4, 160.7, 162.5,
165.1; m/z (ES+) 315 (100); HRMS (ESI) exact mass calculated for
C12H9O3ClBr [M + H+] 314.9424, found 314.9426.
3-Bromo-4-(4-methoyphenoxy)-6-methyl-2-pyrone (5a): white
solid (0.10 g, 78%), mp 143−145 °C; νmax/cm−1 (NaCl) 2838,
1723, 1643, 1442, 1385, 1316; δH (CDCl3, 300 MHz) 2.16 (d, J = 0.7,
3H), 3.84 (s, 3H), 5.61 (d, J = 0.7, 1H), 6.95 (d, J = 9.0, 2H), 7.03 (d,
J = 9.0, 2H); δC (CDCl3, 75.5 MHz) 20.0, 55.7, 90.1, 97.3, 115.2,
122.0, 146.3, 157.9, 160.9, 162.2, 166.0; m/z (ES+) 311 (100); HRMS
(ESI) exact mass calculated for C13H12O4Br [M + H+] 310.9919,
found 310.9926.
3-Bromo-6-methyl-4-(4-methylphenoxy)-2-pyrone (6a): white
solid (0.20 g, 73%), mp 147−148 °C; νmax/cm−1 (NaCl) 1727,
1639, 1441, 1382, 1315; δH (CDCl3, 300 MHz) 2.15 (s, 3H), 2.39 (s,
3H) 5.62 (d, J = 0.6, 1H), 6.95−6.99 (m, 2H, m), 7.24 (d, J = 8.3,
2H); δC (CDCl3, 75.5 MHz) 20.0, 20.9, 90.5, 97.5, 120.7, 130.8, 136.4,
150.7, 160.9, 162.2, 165.8; m/z (ES+) 295 (100); HRMS (ESI) exact
mass calculated for C13H12O3Br [M + H+] 294.9970, found 294.9972.
3-Bromo-4-(4-ethylphenoxy)-6-methyl-2-pyrone (7a): white solid
(0.19 g, 71%), mp 109−110 °C; νmax/cm−1 (NaCl) 3060, 3044, 1728,
1669, 1646, 1443, 1386, 1380; δH (CDCl3, 300 MHz) 1.27 (t, J = 7.6,
3H), 2.16 (d, J = 0.8, 3H), 2.69 (q, J = 7.6, 2H), 5.63 (d, J = 0.8, 1H),
6.97−7.02 (m, 2H), 7.26 (d, J = 8.6, 2H); δC (CDCl3, 75.5 MHz) 15.5,
20.0, 28.3, 90.5, 97.6, 120.7, 129.6, 142.7, 150.8, 160.9, 162.2, 165.8;
m/z (ES+) 309 (100); HRMS (ESI) exact mass calculated for
C14H14O3Br [M + H+] 309.0126, found 309.0135.
4-(2-Fluorophenoxy)-6-methyl-2-pyrone. yellow solid (0.40 g,
70%), mp 52−53 °C; νmax/cm−1 (NaCl) 1732, 1648, 1609, 1448,
1322, 1264, 1192; δH (CDCl3, 300 MHz) 2.25 (s, 3H), 5.18 (s, 1H),
6.03 (s, 1H), 7.13−7.31 (m, 4H); δC (CDCl3, 75.5 MHz) 19.9, 90.5,
99.4, 117.4 (d, JC−F = 18), 123.4, 125.2 (d, JC−F = 4), 127.9 (d, JC−F
=
7), 139.3 (d, JC−F = 12), 153.9 (d, JC−F = 251), 163.5, 164.3, 170.0; δF
(CDCl3, 282 MHz) −129.1; m/z (ES+) 220 (100); HRMS (ESI)
exact mass calculated for C12H10O3F [M + H+] 221.0614, found
221.0611.
4-(3-Fluorophenoxy)-6-methyl-2-pyrone. yellow solid (0.39 g,
83%), mp 77−80 °C; νmax/cm−1 (NaCl) 1732, 1646, 1605, 1447,
1404, 1322, 1228; δH (CDCl3, 300 MHz) 2.27 (s, 3H), 5.25 (d, J = 2.3,
1H), 5.96−5.97 (m, 1H), 6.83 (dt, J = 9.1, 2.3, 1H), 6.89 (dd, J = 8.2,
2.1, 1H), 7.02 (m, 1H), 7.36−7.44 (m, 1H); δC (CDCl3, 75.5 MHz)
20.1, 91.4, 99.7, 109.3 (d, JC−F = 24), 113.7 (d, JC−F = 21), 116.9 (d,
JC−F = 4), 131.2 (d, JC−F = 9), 153.2 (d, JC−F = 11), 163.3 (d, JC−F
=
249), 163.6, 164.3, 170.2; δF (CDCl3, 282 MHz) −109.2; m/z (ES+)
220 (100); HRMS (ESI) exact mass calculated for C12H10O3F [M +
H+] 221.0614, found 221.0614.
4-(4-Trifluoromethylphenoxy)-6-methyl-2-pyrone. brown oil
(0.22 g, 76%); νmax/cm−1 (NaCl) 1732, 1646, 1612, 1448, 1407,
1323, 1233; δH (CDCl3, 300 MHz) 2.28 (s, 3H), 5.23 (d, J = 2.3, 1H),
5.98 (dd, J = 2.2, 0.9, 1H), 7.21 (d, J = 8.4, 2H), 7.72 (d, J = 8.4, 2H);
δC (CDCl3, 75.5 MHz) 20.1, 91.7, 99.6, 121.6, 127.6, 127.7, 127.8,
163.8, 164.1, 169.8; δF (CDCl3, 282 MHz) −62.3; m/z (ES+) 270
(100); HRMS (ESI) exact mass calculated for C13H10O3F3 [M + H+]
271.0582, found 271.0587.
Preparation of 3-Iodo-4-phenoxy-6-methyl-2-pyrone (1a).26
A solution of 4-phenoxy-6-methyl-2-pyrone (1.00 g, 4.9 mmol), iodine
(0.63 g, 4.9 mmol), and [Bu4N]2[S2O8] (3.35 g, 4.9 mmol) in
acetonitrile (10 mL/mmol) was stirred in darkness at room
temperature (ca. 17 °C) for 120 h. The reaction mixture was diluted
with 10% aqueous Na2S2O3 (25 mL) and EtOAc (25 mL). The
mixture was extracted with EtOAc (2 × 25 mL), and the combined
organic extracts were washed with H2O (3 × 25 mL). The organic
layer was then dried over MgSO4, filtered, and concentrated under
reduced pressure. The residues were purified by silica gel
chromatography using 5% EtOAc in hexane as eluent. The product,
3-iodo-4-phenoxy-6-methyl-2-pyrone, was isolated as a white solid
(0.38 g, 23%): mp 151−153 °C (lit. mp 142 °C); δH (CDCl3, 300
MHz) 2.17 (d, J = 0.8, 3H), 5.55 (d, J = 0.8, 1H), 7.06−7.11 (m, 2H),
7.29−7.35 (m, 1H), 7.42−7.49 (m, 2H); δC (CDCl3, 75.5 MHz) 19.9,
64.9, 97.3, 120.9, 126.5, 130.4, 153.1, 161.8, 163.6, 169.4; m/z (ES+)
327 (<10); HRMS (ESI) exact mass calculated for C12H10O3I [M +
H+] 328.9675, found 328.9674.
General Procedure for Preparation of 3-Bromo-4-phenoxy-
6-methyl-2-pyrones via Br2 (1b, 3−13a). A solution of 4-phenoxy-
6-methyl-2-pyrone (1.0 equiv) and bromine (1.1 equiv) in DCM (5.0
mL/mmol starting material) was stirred in darkness at room
temperature (ca. 17 °C) for 2 h. The reaction mixture was
concentrated under reduced pressure. The residues were purified by
recrystallization from EtOH to afford the title products.
3-Bromo-4-phenoxy-6-methyl-2-pyrone (1b): white solid (0.75 g,
83%), mp 94−95 °C; νmax/cm−1 (NaCl) 3102, 1728, 1646, 1590,
1443, 1314, 1230; δH (CDCl3, 300 MHz) 2.17 (s, 3H), 5.62 (s, 1H),
3-Bromo-4-(3-methylphenoxy)-6-methyl-2-pyrone (8a): white
solid (0.22 g, 80%), mp 147−148 °C; νmax/cm−1 (NaCl) 3055,
1724, 1648, 1609, 1436, 1422, 1386; δH (CDCl3, 300 MHz) 2.17 (s,
3H), 2.39 (s, 3H), 5.63 (s, 1H), 6.87−6.90 (m, 2H), 7.12 (d, J = 7.6,
1H), 7.32 (t, J = 7.7, 1H); δC (CDCl3, 75.5 MHz) 20.0, 21.3, 90.8,
97.7, 117.8, 121.4, 127.8, 130.0, 140.9, 152.9, 160.9, 162.2, 165.6; m/z
(ES+) 295 (100); HRMS (ESI) exact mass calculated for C13H12O3Br
[M + H+] 294.9970, found 294.9960.
3-Bromo-4-(2-methylphenoxy)-6-methyl-2-pyrone (9a): white
solid (0.13 g, 76%), mp 82−83 °C; νmax/cm−1 (NaCl) 3102, 1723,
1646, 1584, 1384, 1237; δH (CDCl3, 300 MHz) 2.15 (d, J = 0.6, 3H),
2.20 (s, 3H), 5.51 (d, J = 0.6, 1H,), 7.01 (dd, J = 7.4, 1.8, 1H), 7.20−
7.33 (m, 3H); δC (CDCl3, 75.5 MHz) 15.9, 20.1, 90.0, 97.0, 121.3,
126.8, 127.7, 130.4, 132.0, 151.2, 160.9, 162.4, 165.6; m/z (ES+) 295
(100); HRMS (ESI) exact mass calculated for C13H12O3Br [M + H+]
294.9970, found 294.9978.
Preparation of 3-bromo-4-(3-methoxyphenoxy)-6-methyl-2-py-
rone via NBS (10a). A solution of 4-(3-methoxyphenoxy)-6-methyl-2-
pyrone (0.21 g, 0.9 mmol) and N-bromosuccinimide (0.20 g, 1.1
mmol) in CHCl3 (5.0 mL/mmol starting material) was stirred in
darkness at 50 °C for 18 h. Upon cooling, the reaction mixture was
washed with aqueous saturated NaHCO3 (2 × 20 mL), and H2O (2 ×
20 mL). The organic layer was then dried over MgSO4, filtered, and
concentrated under reduced pressure. The residues were purified by
recrystallization from acetic acid. The product, 3-bromo-4-(3-
methoxyphenoxy)-6-methyl-2-pyrone, was isolated as a white solid
(0.17 g, 62%): mp 179−180 °C; νmax/cm−1 (NaCl) 3070, 1720, 1642,
1605, 1440, 1314, 1266; δH (CDCl3, 300 MHz) 2.17 (s, 3H), 3.83 (s,
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Article
3H), 5.67 (s, 1H), 6.64−6.69 (m, 2H), 6.86 (dd, J = 8.4, 2.2, 1H), 7.34
(t, J = 8.1, 1H); δC (CDCl3, 75.5 MHz) 20.0, 55.6, 91.0, 97.7, 106.9,
112.2, 112.8, 130.7, 153.9, 160.9, 161.2, 162.2, 165.4; m/z (ES+) 311
(100); HRMS (ESI) exact mass calculated for C13H12O4Br [M + H+]
310.9919, found 310.9904.
3-Bromo-4-(2-fluorophenoxy)-6-methyl-2-pyrone (11a; via Br2
procedure): white solid (0.44 g, 83%), mp 118−119 °C; νmax/cm−1
(NaCl) 3055, 1728, 1644, 1444, 1422, 1383, 1348, 1266; δH (CDCl3,
300 MHz) 2.18 (s, 3H), 5.59 (s, 1H), 7.18−7.36 8 (m, 4H); δC
(CDCl3, 75.5 MHz) 20.0, 90.6, 96.7, 117.6 (d, JC−F = 18), 123.3, 125.3
(d, JC−F = 4), 128.0 (d, JC−F = 7), 140.1 (d, JC−F = 12), 154.0 (d, JC−F
= 251), 160.8, 162.5, 165.2; δF (CDCl3, 282 MHz) −129.3; m/z (ES
+) 299 (100); HRMS (ESI) exact mass calculated for C12H9O3FBr [M
+ H+], 298.9719, found 298.9722.
3-Bromo-4-(3-fluorophenoxy)-6-methyl-2-pyrone (12a; via Br2
procedure): white solid (0.10 g, 75%), mp 173−174 °C; νmax/cm−1
(NaCl) 1725, 1639, 1604, 1484, 1383, 1371, 1198; δH (CDCl3, 300
MHz) 2.19 (s, 3H), 5.66 (s, 1H), 6.83−6.92 (m, 2H), 7.04 (td, J = 8.3,
2.2, 1H), 7.39−7.46 (m, 1H); δC (CDCl3, 75.5 MHz) 20.1, 91.8, 97.6,
108.8 (d, JC−F = 24), 113.6 (d, JC−F = 21), 116.4 (d, JC−F = 3), 131.3
cooled. Pyrone (1 equiv), Pd(OAc)2 (5 mol %), and PPh3 (15 mol %)
were then added. The reagents were then stirred under vacuum, and
the Schlenk tube was refilled with N2. This procedure was repeated
twice more. Xylenes (1 mL/0.25 mmol) was then added. The reaction
mixture was heated to 130 °C and stirred for 16 h. Upon cooling, the
reaction mixture was diluted with water (15 mL) and EtOAc (15 mL).
The mixture was extracted with EtOAc (2 × 15 mL). The organic
layer was then dried over MgSO4, filtered, and concentrated under
reduced pressure. The residues were purified by silica gel
chromatography using 6% EtOAc in hexane as eluent to afford the
title products.
Conditions B: Coupling of 3-Chloro-4-phenoxypyrones 1c, 10b,
and 13b. K2CO3 (3.0 equiv) was placed in a Schlenk tube. The
Schlenk tube was then heated under vacuum using a heat gun and
refilled with N2. This procedure was repeated twice more, and the
Schlenk tube was cooled. Pyrone (1.0 equiv), Pd(OAc)2 (5 mol %),
and PCy3·HBF4 (15 mol %) were then added. The reagents were then
stirred under vacuum, and the Schlenk tube was refilled with N2. This
procedure was repeated twice more. Xylenes (1 mL/0.25 mmol) was
then added. The reaction mixture was heated to 130 °C and stirred for
14 h. Upon cooling, the reaction mixture was diluted with water (15
mL) and EtOAc (15 mL). The mixture was extracted with EtOAc (2 ×
15 mL). The organic layer was then dried over MgSO4, filtered, and
concentrated under reduced pressure. The residues were purified by
silica gel chromatography using 3% EtOAc in hexane as eluent to
afford the title products.
(d, JC−F = 10), 153.8 (d, JC−F = 11), 160.7, 162.5, 163.3 (d, JC−F
=
251), 165.5; δF (CDCl3, 282 MHz) −108.9; HRMS (ESI) exact mass
calculated for C12H9O3FBr [M + H+] 298.9719, found 298.9712.
3-Bromo-4-(4-trifluoromethylphenoxy)-6-methyl-2-pyrone (13a;
via Br2 procedure): white solid (0.10 g, 40%), mp 148−150 °C; νmax
/
cm−1 (NaCl) 1732, 1645, 1609, 1543, 1323; δH (CDCl3, 300 MHz)
2.20 (d, J = 0.8, 3H), 5.64 (d, J = 0.9, 1H), 7.21 (d, J = 8.3, 2H), 7.73
(d, J = 8.3, 2H); δC (CDCl3, 75.5 MHz) 20.0, 92.7, 97.8, 120.8, 121.8,
127.7, 127.8 (q, JC−F = 3.8), 155.5, 160.5, 162.7, 164.4; δF (CDCl3, 282
MHz) −62.3; m/z (ES+) 349 (100); HRMS (ESI) exact mass
calculated for C13H9O3F3Br [M + H+] 348.9687, found 348.9693.
General Procedure for Preparation of 3-Chloro-4-phenoxy-
6-methyl-2-pyrones (1c, 10b, 13b). A solution of 4-phenoxy-6-
methyl-2-pyrone (1.0 equiv), N-chlorosuccinimide (1.2 equiv), and
TFA (1.2 equiv) in CHCl3 (5.0 mL/mmol starting material) was
stirred at 55 °C for 23 h. The reaction mixture was then washed with
aqueous saturated NaHCO3 (2 × 20 mL) and H2O (2 × 20 mL). The
organic layer was then dried over MgSO4, filtered, and concentrated
under reduced pressure. The residues were purified by recrystallization
from EtOH to afford the title products.
3-Methyl-1H-pyrano[4,3-b]benzofuran-1-one (2):21a white solid
(from 1b, conditions A, 0.03 g, 80%; from 1c, conditions B, 0.07 g,
79%), mp 187−188 °C (lit. 188−190 °C); νmax/cm−1 (NaCl) 2922,
1727, 1626, 1446, 1284, 1104; δH (CDCl3, 300 MHz) 2.42 (s, 3H),
6.53 (s, 1H), 7.34−7.37 (m, 2H), 7.51−7.59 (m, 1H), 8.02−8.06 (m,
1H); δC (CDCl3, 75.5 MHz) 20.6, 95.9, 103.7, 111.5, 121.3, 122.9,
124.9, 126.1, 154.9, 159.5, 162.9, 164.5; m/z (ES+) 200 (99); HRMS
(ESI) exact mass calculated for C12H9O3 [M + H+], 201.0552, found
201.0554.
8-Fluoro-3-methyl-1H-pyrano[4,3-b]benzofuran-1-one (14):
(conditions A) white solid (0.06 g, 77%), mp 124−125 °C; νmax
/
cm−1 (NaCl) 3055, 2923, 2850, 1741, 1634, 1574, 1502, 1453, 1265;
δH (CDCl3, 300 MHz) 2.43 (s, 3H), 6.52 (s, 1H), 7.11 (dd, J = 9.0,
2.7, 1H), 7.48 (dd, J = 9.0, 3.9, 1H), 7.69 (dd, J = 8.0, 2.7, 1H); δC
(CDCl3, 75.5 MHz) 20.7, 95.8, 103.2, 107.5 (d, JC−F = 26), 112.3 (d,
3-Chloro-4-phenoxy-6-methyl-2-pyrone (1c): pale cream solid
(1.73 g, 67%), mp 96−97 °C; νmax/cm−1 (NaCl) 1730, 1590, 1444,
1232, 1153; δH (CDCl3, 300 MHz) 2.18 (s, 3H), 5.67 (s, 1H), 7.07−
7.11 (m, 2H), 7.32 (t, J = 7.4, 1H), 7.42−7.49 (m, 2H); δC (CDCl3,
75.5 MHz) 20.0, 97.6, 101.9, 120.8, 126.5, 130.4, 152.9, 160.9, 161.3,
163.6; m/z (ES+) 236 (100); HRMS (ESI) exact mass calculated for
C12H10O3Cl [M + H+] 237.0318, found 237.0314.
3-Chloro-4-(3-methoxyphenoxy)-6-methyl-2-pyrone (10b): white
solid (0.11 g, 50%), mp 155−158 °C; νmax/cm−1 (NaCl) 1714, 1546,
1319; δH (CDCl3, 300 MHz) 2.18 (dd, J = 5.0, 0.9, 3H), 3.83 (s, 3H),
5.69 (d, J = 0.9, 1H), 6.6−6.69 (m, 2H), 6.82−6.89 (m, 1H), 7.30−
7.38 (m, 1H); δC (CDCl3, 75.5 MHz) 20.0, 55.6, 97.7, 101.9, 106.8,
112.2, 112.8, 130.7, 153.9, 160.8, 161.2, 161.3, 163.5; m/z (ES+) 266
(10); HRMS (ESI) exact mass calculated for C13H12O4Cl [M + H+]
267.0424, found 267.0415.
3-Chloro-4-(4-trifluoromethylphenoxy)-6-methyl-2-pyrone (13b):
white powder (0.053 g, 57%), mp 134−136 °C; νmax/cm−1 (NaCl)
1735, 1551, 1322, 1242; δH (CDCl3, 300 MHz) 2.22 (d, J = 0.9, 3H),
5.68 (d, J = 0.9, 1H), 7.20 (d, J = 8.3, 2H), 7.73 (d, J = 8.3, 2H); δC
(CDCl3, 75.5 MHz) 20.0, 97.9, 103.6, 120.6, 123.6 (d, JC−F = 272),
125.4, 127.8 (d, JC−F = 3.7), 128.5 (d, JC−F = 33), 155.6, 160.5, 161.7,
162.4; δF (CDCl3, 282 MHz) −62.3; m/z (ES+) 304 (80); HRMS
(ESI) exact mass calculated for C13H9O3ClF3 [M + H+] 305.0192,
found 305.0202.
General Procedure for Phenoxy Intramolecular Coupling of
Pyrones 1 and 3−13: Synthesis of Compounds 2 and 14−24.
Conditions A: Coupling of 3-Bromo-4-phenoxypyrones 1b and 1−
13a. K2CO3 (3 equiv) was placed in a Schlenk tube. The Schlenk tube
was then heated under vacuum using a heat gun and refilled with N2.
This procedure was repeated twice more, and the Schlenk tube was
JC−F = 10), 113.6 (d, JC−F = 26), 124.1 (d, JC−F = 12), 150.9 (d, JC−F
=
1), 159.1, 160.3 (d, JC−F = 242), 163.6, 165.7; δF (CDCl3, 282 MHz)
−117.1; HRMS (ESI) exact mass calculated for C12H8O3F [M + H+]
219.0457, found 219.0448.
8-Chloro-3-methyl-1H-pyrano[4,3-b]benzofuran-1-one (15):
(conditions A) white solid (0.05 g, 45%), mp 181−182 °C; νmax
/
cm−1 (NaCl) 1743, 1631, 1573, 1439, 1258; δH (CDCl3, 300 MHz)
2.43 (s, 3H), 6.53 (s, 1H), 7.36 (dd, J = 8.8, 2.1, 1H), 7.46 (d, J = 8.8,
1H), 8.00 (d, J = 2.0, 1H); δC (CDCl3, 75.5 MHz) 20.7, 95.8, 103.2,
112.4, 121.1, 124.4, 126.3, 130.8, 153.3, 158.9, 163.8, 165.4; m/z (ES
+) 234 (34); HRMS (ESI) exact mass calculated for C12H8O3Cl [M +
H+] 235.0155, found 235.0162.
8-Methoxy-3-methyl-1H-pyrano[4,3-b]benzofuran-1-one (16):
(conditions A) white solid (0.06 g, 87%), mp 152−154 °C; νmax
/
cm−1 (NaCl) 1635, 1571, 1459, 1429, 1274, 1227; δH (CDCl3, 300
MHz) 2.42 (d, J = 0.7, 3H), 3.89 (s, 3H), 6.97 (d, J = 0.8, 1H), 6.97
(dd, J = 9.0, 2.7, 1H), 7.42 (d, J = 9.0, 1H), 7.48 (d, J = 2.6, 1H); δC
(CDCl3, 75.5 MHz) 20.6, 56.0, 96.0, 103.3, 103.9, 112.0, 115.1, 123.7,
149.6, 157.5, 159.6, 162.6, 165.0; m/z (ES+) 230 (99); HRMS (ESI)
exact mass calculated for C13H11O4 [M + H+] 231.0657, found
231.0661.
3,8-Dimethyl-1H-pyrano[4,3-b]benzofuran-1-one (17): (condi-
tions A) white solid (0.07 g, 93%), mp 159−160 °C; νmax/cm−1
(NaCl) 3089, 1715, 1615, 1572, 1448, 1422, 1265; δH (CDCl3, 300
MHz) 2.41 (d, J = 0.6, 3H), 2.48 (s, 3H), 6.49 (d, J = 0.8, 1H), 7.19
(dd, J = 8.4, 1.4, 1H), 7.39 (d, J = 8.5, 1H), 7.82 (s, 1H); δC (CDCl3,
75.5 MHz) 20.6, 21.3, 95.9, 103.5, 110.9, 121.2, 122.9, 127.2, 134.8,
153.3, 159.6, 162.6, 164.6; m/z (ES+) 214 (99); HRMS (ESI) exact
mass calculated for C13H11O3 [M + H+] 215.0708, found 215.0698.
F
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Article
8-Ethyl-3-methyl-1H-pyrano[4,3-b]benzofuran-1-one, (18): (con-
ditions A) white solid (0.07 g, 89%), mp 72−73 °C; νmax/cm−1 (NaCl)
2963, 1734, 1625, 1449, 1344, 1265; δH (CDCl3, 300 MHz) 1.29 (t, J
= 7.9, 3H), 2.41 (d, J 0 0.7, 3H), 2.78 (q, J = 7.6, 2H), 6.51 (d, J = 0.8,
1H), 7.23 (dd, J = 8.5, 1.8, 1H), 7.43 (d, J = 8.5, 1H), 7.85 (d, J = 1.2,
1H); δC (CDCl3, 75.5 MHz) 16.1, 20.6, 28.9, 96.0, 103.6, 111.0, 120.1,
122.9, 126.2, 141.4, 153.5, 159.7, 162.6, 164.6; m/z (ES+) 228 (100);
HRMS (ESI) exact mass calculated for C14H13O3 [M + H+] 229.0865,
found 229.0871.
127.8 (q, J = 33), 156.2, 158.8, 164.3, 165.7; δF (CDCl3, 282 MHz)
−61.2; m/z (ES+) 268 (100); HRMS (ESI) exact mass calculated for
C13H8O3F3 [M + H+], 269.0426, found 269.0428.
4-Bromo-2-coumarin.21a A solution of 4-hydroxy-2-coumarin
(1.0 equiv), TBAB (1.16 equiv), and P2O5 (2.4 equiv) in toluene (4.0
mL/mmol starting material) was stirred at 94 °C for 1.5 h. Upon
cooling, the reaction mixture was washed with toluene (2 × 30 mL).
The combined organic extracts were then washed with saturated
aqueous NaHCO3 (2 × 20 mL) and H2O (2 × 20 mL). The organic
layer was then dried over MgSO4, filtered, and concentrated under
reduced pressure. The product, 4-bromo-2-coumarin, was isolated as a
brown solid (3.00 g, 72%): mp 88−89 °C (lit. mp 92−93 °C); δH
(CDCl3, 300 MHz) 6.87 (s, 1H), 7.23−7.39 (m, 2H), 7.57−7.63 (m,
1H), 7.85 (dd, J = 7.9, 1.5, 1H); δC (CDCl3, 75.5 MHz) 117.0, 119.0,
119.6, 125.0, 128.1, 133.2, 141.5, 152.5, 158.7; m/z (ES+) 225 (76).
4-Phenoxy-2-coumarin (25).40 A solution of 4-bromo-2-
coumarin (1.0 equiv), substituted phenol (1.5 equiv), and K2CO3
(1.8 equiv) in acetone (4.0 mL/mmol starting material) was heated to
65 °C and stirred for 16 h. Upon cooling, the reaction mixture was
diluted with water (10 mL) and EtOAc (20 mL). The mixture was
extracted with EtOAc (2 × 20 mL), and the combined organic layers
were washed with aqueous NaOH (10% w/v, 2 × 20 mL). The
organic layer was then dried over MgSO4, filtered, and concentrated
under reduced pressure. The residues were purified by recrystallization
from EtOH. The product 4-phenoxy-2-coumarin was isolated as a
yellow solid (1.40 g, 68%): mp 131−132 °C (lit. mp 133−134 °C); δH
(CDCl3, 300 MHz) 5.42 (s, 1H), 7.16−7.20 (m, 2H), 7.32−7.38 (m,
3H), 7.46−7.52 (m, 2H), 7.59−7.65 (dd, J = 8.7, 1.6, 1H), 8.03 (dd, J
= 8.0, 1.5, 1H); δC (CDCl3, 75.5 MHz) 93.5, 115.4, 116.9, 121.3,
123.1, 124.2, 126.0, 130.5, 132.9, 152.4, 153.7, 162.6, 166.4; m/z (ES
+) 239 (100).
7-Methyl-3-methyl-1H-pyrano[4,3-b]benzofuran-1-one (19):
(conditions A) white solid (0.03 g, 40%), mp 139−141 °C; νmax
/
cm−1 (NaCl) 2921, 1734, 1620, 1576, 1447, 1380, 1317; δH (CDCl3,
300 MHz) 2.41 (s, 3H), 2.49 (s, 3H), 6.50 (s, 1H), 7.22 (d, J = 7.9,
1H), 7.33 (s, 1H), 7.88 (d, J = 7.9, 1H); δC (CDCl3, 75.5 MHz) 20.6,
21.8, 95.9, 103.7, 111.7, 120.3, 120.8, 126.2, 136.7, 155.4, 159.6, 162.4,
164.2; m/z (ES+) 214 (100); HRMS (ESI) exact mass calculated for
C13H11O3 [M + H+] 215.0708, found 215.0702.
3,6-Dimethyl-1H-pyrano[4,3-b]benzofuran-1-one (20): (condi-
tions A) white solid (0.05 g, 74%), mp 169−170 °C; νmax/cm−1
(NaCl) 1725, 1642, 1571, 1434, 1263, 1204; δH (CDCl3, 300 MHz)
2.41 (d, J = 0.8, 3H), 2.54 (s, 3H), 6.52 (d, J = 0.8, 1H), 7.19 (d, J =
7.4, 1H), 7.29 (t, J = 7.6, 1H), 7.89 (d, J = 7.8, 1H); δC (CDCl3, 75.5
MHz) 14.9, 20.6, 95.9, 103.9, 118.7, 121.7, 122.4, 124.9, 127.2, 153.9,
159.6, 162.6, 164.2; m/z (ES+) 214 (99); HRMS (ESI) exact mass
calculated for C13H11O3 [M + H+] 215.0708, found 215.0702.
7-Methoxy-3-methyl-1H-pyrano[4,3-b]benzofuran-1-one (21):
white solid (from 10a, conditions A, 0.04 g, 60%; from 10b,
conditions B, 0.02 g, 57%), mp 158−159 °C; νmax/cm−1 (NaCl) 1716,
1642, 1618, 1427, 1376, 1327; δH (CDCl3, 300 MHz) 2.41 (s, 3H),
3.88 (s, 3H), 6.50 (d, J = 0.6, 1H), 7.02 (dd, J = 8.5, 2.2, 1H), 7.07 (d,
J = 2.1, 1H), 7.88 (d, J = 8.6, 1H); δC (CDCl3, 75.5 MHz) 20.5, 55.8,
95.9, 96.8, 103.9, 113.0, 115.9, 121.5, 156.1, 159.2, 159.6, 161.7, 164.0;
m/z (ES+) 230 (100); HRMS (ESI) exact mass calculated for
C13H11O4 [M + H+] 231.0657, found 231.0659.
3-Chloro-4-phenoxy-2-coumarin (26).41 A solution of 4-
phenoxy-2-coumarin (0.10 g, 0.42 mmol), N-chlorosuccinimide
(0.07 g, 0.50 mmol), and TFA (0.06 g, 0.50 mmol) in CHCl3 (5.0
mL/mmol starting material) was stirred in darkness at 55 °C for 72 h.
The reaction mixture was then washed with aqueous saturated
NaHCO3 (2 × 5 mL) and H2O (2 × 5 mL). The organic layer was
then dried over MgSO4, filtered, and concentrated under reduced
pressure. The residues were purified by silica gel chromatography
using 2% EtOAc in hexane as eluent. The product, 3-chloro-4-
phenoxy-2-coumarin, was isolated as a brown solid (0.08 g, 67%): mp
74−75 °C (lit. mp 88.8−90.4 °C); νmax/cm−1 (NaCl) 3057, 1735,
1611, 1563, 1451, 1351, 1266; δH (CDCl3, 300 MHz) 6.97−7.01 (m,
2H), 7.15 (tt, J = 7.4, 1.1, 1H), 7.26−7.39 (m, 3H), 7.43 (dd, J = 8.4,
0.7, 1H), 7.57−7.60 (m, 1H), 7.66 (dd, J = 8.0, 1.7, 1H); δC (CDCl3,
75.5 MHz) 112.0, 116.1, 116.8, 117.0, 123.8, 124.1, 124.9, 130.1,
132.7, 151.7, 155.6, 158.3, 158.8; m/z (ES+) 272 (100); HRMS (ESI)
exact mass calculated for C15H10O3Cl [M + H+] 273.0318, found
273.0311.
6-Fluoro-3-methyl-1H-pyrano[4,3-b]benzofuran-1-one (22):
(conditions A) white solid (0.06 g, 57%), mp 221−223 °C; νmax
/
cm−1 (NaCl) 3096, 1734, 1616, 1572, 1435, 1272, 1260; δH (CDCl3,
300 MHz) 2.44 (s, 3H), 6.57 (s, 1H), 7.13−7.19 (m, 1H), 7.31−7.38
(t, J = 8.0, 1H), 7.79 (d, J = 7.8, 1H); δC (CDCl3, 75.5 MHz) 20.7,
95.8, 103.8, 112.8 (d, JC−F = 16), 116.9 (d, JC−F = 4), 125.9 (d, JC−F
=
6), 126.3 (d, JC−F = 3), 141.6 (d, JC−F = 12), 147.7 (d, JC−F = 251),
159.0, 163.8, 164.9; δF (CDCl3, 282 MHz) −136.3; m/z (ES+) 218
(16); HRMS (ESI) exact mass calculated for C12H8O3F [M + H+]
219.0457, found 219.0452.
9-Fluoro-3-methyl-1H-pyrano[4,3-b]benzofuran-1-one (23a):
(conditions A) white solid (0.06 g, 54%), mp 183−185 °C; νmax
/
cm−1 (NaCl) 3055, 1741, 1647, 1623, 1436, 1373, 1266; δH (CDCl3,
300 MHz) 2.43 (d, J = 0.89, 3H), 6.51 (d, J = 0.8, 1H), 7.06−7.17 (m,
1H), 7.32−7.39 (m, 2H); δC (CDCl3, 75.5 MHz) 20.6, 95.4, 102.2 (d,
6H-Benzofuro[3,2-c]chromen-6-one (27).21a K2CO3 (0.06 g,
0.44 mmol) was placed in a Schlenk tube. The Schlenk tube was then
heated under vacuum using a heat gun and refilled with N2. This
procedure was repeated twice more, and the Schlenk tube was cooled.
3-Chloro-4-phenoxy-2-coumarin (26; 0.04 g, 0.15 mmol), Pd(OAc)2
(0.18 g, 0.007 mmol), and PCy3·HBF4 (0.008 g, 0.022 mmol) were
then added. The reagents were then stirred under vacuum, and the
Schlenk tube was refilled with N2. This procedure was repeated twice
more. Xylenes (1 mL/0.25 mmol) was then added. The reaction
mixture was heated to 130 °C and stirred for 14 h. Upon cooling, the
reaction mixture was diluted with water (15 mL) and EtOAc (15 mL).
The mixture was extracted with EtOAc (2 × 15 mL). The organic
layer was then dried over MgSO4, filtered, and concentrated under
reduced pressure. The residues were purified by silica gel
chromatography using 3% EtOAc in hexane as eluent. The product,
6H-benzofuro[3,2-c]chromen-6-one, was isolated as a white solid
(0.03 g, 90%): mp 177−180 °C (lit. mp 179−180 °C); νmax/cm−1
(NaCl) 1742, 1736, 1675, 1486, 1373; δH (CDCl3, 300 MHz) 7.39−
7.52 (m, 4H), 7.59−7.70 (m, 2H), 8.03 (dd, J = 7.8, 1.3, 1H), 8.13−
8.18 (m, 1H); δC (CDCl3, 75.5 MHz) 105.9, 111.8, 112.6, 117.5,
121.9, 123.4, 124.7, 125.2, 126.8, 132.0, 153.7, 155.5, 158.1, 160.0; m/z
JC−F = 4), 107.7 (d, JC−F = 4), 111.6 (d, JC−F = 20), 112.0 (d, JC−F
=
22), 127.0 (d, JC−F = 7), 156.0 (JC−F = 255), 156.4 (d, JC−F = 9),
158.1, 164.0, 164.6 (d, JC−F = 1); δF (CDCl3, 282 MHz) −113.7; m/z
(ES+) 218 (100); HRMS (ESI) exact mass calculated for C12H8O3F
[M + H+] 219.0457, found 219.0453.
7-Fluoro-3-methyl-1H-pyrano[4,3-b]benzofuran-1-one (23b):
(conditions A) white solid (0.04 g, 40%), mp 201−202 °C; νmax
/
cm−1 (NaCl) 1731, 1643, 1575, 1498, 1416, 1324, 1279; δH (CDCl3,
300 MHz) 2.42 (s, 3H), 6.53 (s, 1H), 7.17 (td, J = 9.0, 2.2, 1H), 7.27
(d, J = 2.2, 1H), 7.95 (d, J = 8.6, 1H); δC (CDCl3, 75.5 MHz) 20.6,
95.8, 99.8 (d, JC−F = 27), 103.5, 113.1 (d, JC−F = 24), 119.2 (d, JC−F
2), 121.8 (d, JC−F = 10), 155.0 (d, JC−F = 13), 159.2, 162.5 (d, JC−F
=
=
246), 162.8, 165.1; δF (CDCl3, 282 MHz) −112.2; m/z (ES+) 218
(100); HRMS (ESI) exact mass calculated for C12H8O3F [M + H+]
219.0457, found 219.0449.
3-Methyl-8-trifluoromethyl-1H-pyrano[4,3-b]benzofuran-1-one
(24):21a yellow solid (from 13a, conditions A, 0.03 g, 90%; from 13b,
conditions B, 0.03 g, 60%), mp 139−142 °C; νmax/cm−1 (NaCl) 1747,
1321, 1116; δH (CDCl3, 300 MHz) 2.46 (d, J = 0.8, 3H), 6.58 (d, J =
0.9, 1H), 7.43−7.82 (m, 2H), 8.17−8.45 (m, 1H); δC (CDCl3, 75.5
MHz) 20.7, 95.7, 103.4, 111.9, 119.0 (d, J 4.0), 123.3, 123.5, 125.9,
G
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Article
(ES+) 236 (48); HRMS (ESI) exact mass calculated for C15H9O3 [M
+ H+] 237.0552, found 237.0547.
1H), 6.99 (d, J = 2.5, 1H), 7.12 (s, 1H), 7.47 (s, 1H), 7.85 (d, J = 9.2,
1H); δC (CDCl3, 150 MHz) 55.8, 94.0, 100.2, 101.5, 102.0, 104.0,
106.2, 113.0, 117.1, 122.3, 146.1, 147.4, 150.6, 154.9, 158.5, 160.0,
162.5; m/z (ES+) 310 (20); HRMS (ESI) exact mass calculated for
C17H11O6 [M + H+] 311.0556, found 311.0551.
9-Methoxy-12H-[1,3]dioxolo[4′,5′:4,5]benzofuro[3,2-c]chromen-
12-one (32). white solid (0.18 g, 67%), mp >230 °C; νmax/cm−1
(NaCl) 1732, 1639, 1449, 1254; δH (CDCl3, 300 MHz) 3.91 (s, 3H),
6.19 (s, 2H), 6.83−7.03 (m, 3H), 7.10 (d, J = 8.6, 1H,), 7.87 (dd, J =
8.6, 1.6, 1H); δC (CDCl3, 150 MHz) 55.9, 101.4, 101.7, 102.5, 103.5,
105.5, 106.4, 108.1, 113.3, 123.0, 139.8, 145.1, 152.0, 155.9, 157.8,
161.7, 163.3; m/z (ES+) 310 (10); HRMS (ESI) exact mass calculated
for C17H11O6 [M + H+] 311.0556, found 311.0550.
4-Bromo-7-methoxy-2-coumarin (29). A solution of 4-hydroxy-
7-methoxy-2-coumarin (3.00 g, 15.6 mmol), TBAB (7.50 g, 23.4
mmol), and P2O5 (5.32 g. 37.5 mmol) in toluene (4.0 mL/mmol
starting material) was stirred at 94 °C for 1.5 h. Upon cooling, the
reaction mixture was washed with toluene (2 × 30 mL). The
combined organic extracts were then washed with saturated aqueous
NaHCO3 (2 × 20 mL) and H2O (2 × 20 mL). The organic layer was
then dried over MgSO4, filtered, and concentrated under reduced
pressure. The product, 4-bromo-7-methoxy-2-coumarin, was isolated
as a brown solid (2.70 g, 72%): mp 114−117 °C; νmax/cm−1 (NaCl)
1732, 1719, 1609, 1592; δH (CDCl3, 300 MHz) 3.90 (s, 3H), 6.67 (s,
1H), 6.79 (d, J = 2.5, 1H), 6.90 (dd, J = 8.9, 2.5, 1H), 7.71 (d, J = 8.9,
1H); δC (CDCl3, 75.5 MHz) 56.0, 100.6, 112.6, 113.1, 116.0, 129.1,
141.5, 154.3, 159.2, 163.8; m/z (ES+) 255 (20); HRMS (ESI) exact
mass calculated for C10H8O3Br [M + H+] 254.9657, found 254.9653.
4-(Benzo[d][1,3]dioxol-5-yloxy)-7-methoxy-2H-chromen-2-
one. A solution of 4-bromo-7-methoxy-2-coumarin (1 equiv),
substituted phenol (1.5 equiv), and K2CO3 (1.8 equiv) in acetone
(4.0 mL/mmol starting material) was heated to 65 °C and stirred for
16 h. Upon cooling, the reaction mixture was diluted with water (10
mL) and EtOAc (20 mL). The mixture was extracted with EtOAc (2 ×
20 mL), and the combined organic layers were washed with aqueous
NaOH (10% w/v, 2 × 20 mL). The organic layer was then dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residues were purified by recrystallization from EtOH. The product
was isolated as a pale yellow solid (3.20 g, 96%): mp 174−177 °C;
νmax/cm−1 (NaCl) 1717, 1617, 1389; δH (CDCl3, 300 MHz) 3.90 (s,
3H), 5.33 (s, 1H), 6.02 (s, 2H), 6.64 (dd, J = 9.0, 5.2, 2H), 6.74−7.06
(m, 3H), 7.87 (d, J = 9.0, 1H); δC (CDCl3, 75.5 MHz) 55.8, 90.9,
100.6, 102.1, 103.3, 108.6, 112.4, 113.8, 124.1, 146.0, 146.7, 148.7,
155.5, 163.1, 163.6, 167.0; m/z (ES+) 312 (79); HRMS (ESI) exact
mass calculated for C17H13O6 [M + H+], 313.0712, found 313.0707.
4-(Benzo[d][1,3]dioxol-5-yloxy)-3-chloro-7-methoxy-2H-
chromen-2-one (30). A solution of 4-phenoxy-2-coumarin (0.15 g,
0.48 mmol), N-chlorosuccinimide (0.06 g, 0.48 mmol), and TFA
(0.033 mL, 0.4 mmol) in CHCl3 (5.0 mL/mmol starting material) was
stirred in darkness at 55 °C for 72 h. The reaction mixture was then
washed with aqueous saturated NaHCO3 (2 × 5 mL), and H2O (2 × 5
mL). The organic layer was then dried over MgSO4, filtered, and
concentrated under reduced pressure. The residues were purified by
silica gel chromatography using DCM as eluent. The product was
o-Deuteriophenol.43 A solution of o-bromophenol (0.50 g, 2.89
mmol) in THF (14.0 mL/mmol of starting material) at 0 °C was
stirred for 30 min. n-BuLi (2.5 M in hexanes, 3.3 mL, 6.36 mmol) was
then added dropwise to the solution at 0 °C over 15 min. The reaction
mixture was stirred at 0 °C for 3 h and quenched with D2O. The
reaction mixture was then concentrated under reduced pressure. The
residue was then dissolved in ether (10 mL) and washed with
saturated aqueous NH4Cl (2 × 5 mL). The organic layer was then
dried over MgSO4, filtered, and concentrated under reduced pressure.
The product, o-deuteriophenol, synthesized twice (80% deuterium
incorporated), was obtained as a yellow oil and used without further
purification (0.33 g): δH (CDCl3, 300 MHz) 6.83 (d, J = 8.3, 1.2H),
6.92 (td, J = 7.4, 1.0, 1H), 7.16−7.31 (m, 2H); m/z (ES−) mass
calculated for C6H4D2O 95 (<10).
4-(2-Deuteriophenoxy)-6-methyl-2-pyrone. A solution of 4-
bromo-6-methyl-2-pyrone (0.53 g, 2.8 mmol), o-deuteriophenol (0.40
g, 4.21 mmol), and K2CO3 (0.69 g, 5.05 mmol) in acetone (4.0 mL/
mmol starting material) was heated to 65 °C and stirred for 16 h.
Upon cooling, the reaction mixture was diluted with water (10 mL)
and EtOAc (20 mL). The mixture was extracted with EtOAc (2 × 20
mL), and the combined organic layers were washed with aqueous
NaOH (10% w/v, 2 × 20 mL). The organic layer was then dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residues were purified by recrystallization from EtOH. The product, 4-
(2-deuterio)phenoxy-6-methyl-2-pyrone, was isolated as a cream solid
(0.35 g, 62%): mp 72−73 °C; νmax/cm−1 (NaCl) 3091, 1732, 1645,
1570, 1445, 1320, 1261; δH (CDCl3, 300 MHz) 2.26 (s, 3H), 5.21 (d, J
= 2.1, 1H), 5.97 (dd, J = 2.1, 0.9, 1H), 6.94−7.18 (m, 1.2H), 7.18−
7.35 (m, 1H), 7.43 (ddd, J = 7.1, 6.6, 2.0, 2H); δC (CDCl3, 75.5 MHz)
20.0, 91.0, 99.9, 120.2 (t, JC‑D = 25), 121.1, 126.5, 130.1, 130.2, 152.3,
163.3, 164.6, 170.7; HRMS (ESI) exact mass calculated for
C12H10DO3 [M + H+] 204.0771, found 204.0770.
isolated as a pale white solid (0.09 g, 56%): mp 129−132 °C; νmax
/
cm−1 (NaCl) 1732, 1616, 1482, 1365, 1172; δH (CDCl3, 300 MHz)
3.89 (s, 3H), 5.98 (s, 2H), 6.38 (dd, J = 8.5, 2.5, 1H), 6.58 (d, J = 2.5,
1H), 6.71 (d, J = 8.5, 1H), 6.86 (dt, J = 8.6, 2.2, 2H), 7.55 (dd, J = 8.6,
0.5, 1H); δC (CDCl3, 75.5 MHz) 55.9, 99.3, 100.8, 101.8, 108.2, 108.5,
110.0, 113.2, 124.9, 144.1, 148.7, 150.7, 153.6, 159.0, 159.3, 163.5; m/z
(ES+) 346 (60); HRMS (ESI) exact mass calculated for C17H12O6Cl
[M + H+] 347.0322, found 347.0320.
3-Bromo-4-(2-deuteriophenoxy)-6-methyl-2-pyrone (33). A
solution of 4-(2-deuterio)phenoxy-6-methyl-2-pyrone (0.20, 0.99
mmol) and bromine (0.17 g, 1.08 mmol) in DCM (5.0 mL/mmol
starting material) was stirred in darkness at room temperature (ca. 17
°C) for 2 h. The reaction mixture was concentrated under reduced
pressure. The residues were purified by recrystallization from EtOH.
The product, 3-bromo-4-(2-deuterio)phenoxy-6-methyl-2-pyrone, was
Coupling of 3-Chlorocoumarin (30): Synthesis of Com-
pounds 31 and 32. K2CO3 (3.0 equiv) was placed in a Schlenk tube.
The Schlenk tube was then heated under vacuum using a heat gun and
refilled with N2. This procedure was repeated twice more, and the
Schlenk tube was cooled. Pyrone (1.0 equiv), Pd(OAc)2 (5 mol %),
and PCy3·HBF4 (15 mol %) were then added. The reagents were then
stirred under vacuum, and the Schlenk tube was refilled with N2. This
procedure was repeated twice more. Xylenes (1 mL/0.25 mmol) was
then added. The reaction mixture was heated to 130 °C and stirred for
14 h. Upon cooling, the reaction mixture was diluted with water (15
mL) and EtOAc (15 mL). The mixture was extracted with EtOAc (2 ×
15 mL). The organic layer was then dried over MgSO4, filtered, and
concentrated under reduced pressure. The residues were purified by
silica gel chromatography using 3% EtOAc in hexane as eluent to
afford the title products.
isolated as a pale orange solid (0.21 g, 78%): mp 113−114 °C; νmax
/
cm−1 (NaCl) 1727, 1643, 1544, 1442, 1313, 1262; δH (CDCl3, 300
MHz) 2.17 (s, 3H), 5.62 (d, J = 0.7, 1H), 7.10 (dd, J = 8.5, 1.0, 1.2H),
7.28−7.36 (m, 1H), 7.44−7.49 (m, 2H); δC (CDCl3, 75.5 MHz) 20.1,
90.8, 97.7, 120.4 (t, JC‑D = 25), 120.9, 126.6, 130.3, 130.4, 152.9, 161.0,
162.4, 165.7; m/z (ES+) 282 (8); HRMS (ESI) exact mass calculated
for C12H9DO3Br [M + H+] 281.9876, found 281.9879.
4-(2-Deuteriophenoxy)-2-coumarin. A solution of 4-bromo-2-
coumarin (0.87 g, 3.85 mmol), o-deuteriophenol (0.44 g, 4.63 mmol),
and K2CO3 (0.96 g, 6.93 mmol) in acetone (4.0 mL/mmol of starting
material) was heated to 65 °C and stirred for 16 h. Upon cooling, the
reaction mixture was diluted with water (10 mL) and EtOAc (20 mL).
The mixture was extracted with EtOAc (2 × 20 mL), and the
combined organic layers were washed with aqueous NaOH (10% w/v,
2 × 20 mL). The organic layer was then dried over MgSO4, filtered,
and concentrated under reduced pressure. The residues were purified
by recrystallization from EtOH. The product, 4-(2-deuteriophenoxy)-
2-coumarin, was isolated as a cream solid (0.35 g, 38%): mp 128−130
3-Methoxy-6H-[1,3]dioxolo[4′,5′:5,6]benzofuro[3,2-c]chromen-6-
one (flemichapparin C, 31):42 white solid (0.08 g, 31%), mp >230 °C
(lit. mp 270−273 °C); νmax/cm−1 (NaCl) 1739, 1628, 1472, 1362; δH
(CDCl3, 300 MHz) 3.91 (s, 3H), 6.08 (s, 2H), 6.96 (dd, J = 9.2, 2.5,
H
DOI: 10.1021/acs.joc.5b02027
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The Journal of Organic Chemistry
Article
°C; νmax/cm−1 (NaCl) 1713, 1625, 1389, 1225; δH (CDCl3, 300 MHz)
5.42 (s, 1H), 7.18 (dd, J = 8.5, 1.1, 1.2H), 7.29−7.43 (m, 3H), 7.43−
7.56 (m, 2H), 7.62 (ddd, J = 8.5, 7.2, 1.2, 1H), 8.04 (dd, J = 7.9, 1.2,
1H); δC (CDCl3, 75.5 MHz) 93.6, 115.4, 116.9, 121.3, 123.1, 124.1,
126.8, 130.3, 130.4, 132.8, 152.4, 153.7, 162.6, 166.4; m/z (ES+) 203
(12); HRMS (ESI) exact mass calculated for C12H10DO3 [M + H+],
204.0771, found 204.0769.
3-Chloro-4-(2-deuteriophenoxy)-2-coumarin (35). A solution
of 4-(2-deuteriophenoxy)-2-coumarin (0.20 g, 0.84 mmol), N-
chlorosuccinimide (0.13 g, 1.0 mmol), and TFA (0.08 mL, 1.0
mmol) in CHCl3 (5.0 mL/mmol starting material) was stirred in
darkness at 55 °C for 72 h. The reaction mixture was then washed with
aqueous saturated NaHCO3 (2 × 5 mL) and H2O (2 × 5 mL). The
organic layer was then dried over MgSO4, filtered, and concentrated
under reduced pressure. The residues were purified by recrystallization
from EtOH. The product was isolated as a yellow solid (0.12 g, 52%):
mp 80−85 °C; νmax/cm−1 (NaCl) 1737, 1609, 1468, 1350, 1175; δH
(CDCl3, 300 MHz) 6.94−7.06 (m, 1.2H), 7.15 (td, J = 7.6, 1.0, 1H),
7.22−7.49 (m, 4H), 7.52−7.75 (m, 2H); δC (CDCl3, 75.5 MHz)
112.0, 116.1, 116.7, 117.0, 123.8, 124.1, 124.9, 130.0, 130.1, 132.7,
151.7, 155.6, 158.3, 158.8; m/z (ES+) 273 (30); HRMS (ESI) exact
mass calculated for C15H9DO3Cl [M + H+] 274.0381, found 274.0379.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02027.
Experimental procedure and data for mechanistic
1
experiments and H, 13C, and 19F NMR spectra for all
novel compounds, key intermediates, and final products.
(PDF)
(20) (a) Liu, J.; Liu, Y.; Du, W.; Dong, Y.; Liu, J.; Wang, M. J. Org.
Chem. 2013, 78, 7293−7297. (b) Ghosh, R.; Stridfeldt, E.; Olofsson, B.
Chem. - Eur. J. 2014, 20, 8888−8892.
(21) (a) Burns, M. J.; Thatcher, R. J.; Taylor, R. J.; Fairlamb, I. J. S.
Dalton Trans. 2010, 39, 10391−10400. (b) Shah, P.; Santana, M. D.;
Garcia, J.; Serrano, J. L.; Naik, M.; Pednekar, S.; Kapdi, A. R.
Tetrahedron 2013, 69, 1446−1453. (c) Kapdi, A. R.; Karbelkar, A.;
Naik, M.; Pednekar, S.; Fischer, C.; Schulzke, C.; Tromp, M. RSC Adv.
2013, 3, 20905−20912.
AUTHOR INFORMATION
Corresponding Author
*E-mail for G.P.M.: g.mcglacken@ucc.ie.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(22) (a) Majumdar, K. C.; Debnath, P.; Taher, A.; Pal, A. K. Can. J.
Chem. 2008, 86, 325−332. (b) Majumdar, K.; Pal, A.; Taher, A.;
Debnath, P. Synthesis 2007, 2007, 1707−1711. (c) Nolan, M.-T.; Bray,
J. T. W.; Eccles, K.; Cheung, M. S.; Lin, Z.; Lawrence, S. E.;
Whitwood, A. C.; Fairlamb, I. J. S.; McGlacken, G. P. Tetrahedron
2014, 70, 7120−7127. (d) Pardo, L. M.; Prendergast, A. M.; Nolan, M.
The research was supported by Science Foundation Ireland
(SFI/12/IP/1315 and SFI/12/RC/2275) and the Irish
Research Council.
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