Pd-Catalyzed/Iodide-Promoted α-Arylation of Ketones for the Regioselective Synthesis of Isocoumarins

Article abstract of DOI:10.1021/acs.joc.7b01355

A variety of isocoumarins have been synthesized directly from 2-halobenzoates and ketones through a palladium-catalyzed α-arylation step followed by an intramolecular cyclization process. The addition of iodide anions to the reaction mixture increased yields and selectivities especially when 2-bromobenzoates were employed. This phosphine-free one-pot synthesis features a high functional group tolerance and gives access to richly decorated isocoumarins. This general methodology was successful in the total synthesis of Xyridin A, an important natural product with antibacterial and antifungal activity.

Full text of DOI:10.1021/acs.joc.7b01355

Note
pubs.acs.org/joc
Pd-Catalyzed/Iodide-Promoted α‑Arylation of Ketones for the
Regioselective Synthesis of Isocoumarins
Alessandra Casnati, Raimondo Maggi, Giovanni Maestri, Nicola Della Ca’,* and Elena Motti*
Dipartimento di Scienze Chimiche, della Vita e della Sostenibilita
Scienze, 17/A, 43124 Parma, Italy
̀ ̀
Ambientale (SCVSA), Universita di Parma, Parco Area delle
S
* Supporting Information
ABSTRACT: A variety of isocoumarins have been synthe-
sized directly from 2-halobenzoates and ketones through a
palladium-catalyzed α-arylation step followed by an intra-
molecular cyclization process. The addition of iodide anions to
the reaction mixture increased yields and selectivities especially
when 2-bromobenzoates were employed. This phosphine-free
one-pot synthesis features a high functional group tolerance
and gives access to richly decorated isocoumarins. This general
methodology was successful in the total synthesis of Xyridin A, an important natural product with antibacterial and antifungal
activity.
socoumarins are one of the most important classes of
organic compounds thanks to their widespread biological
Scheme 1. Pd-Catalyzed Syntheses of Isocoumarins from 2-
Halobenzoates and Ketone Derivatives
I
activities1 and usefulness to build several pharmaceutical and
natural products.2 Traditional and, more recently, transition
metal-catalyzed methods have been developed for the
construction of isocoumarin scaffold.3 The metal-catalyzed
intramolecular annulation of benzoic acid derivatives bearing an
alkyne in suitable position is probably the most popular
approach.3,4 The intermolecular version has been extensively
investigated and several metals can be active in this trans-
formation.3,5 The atom economy is particularly high in the Rh
or Ru/Cu-catalyzed oxidative annulation of alkynes by
nonhalogenated carboxylic acids via a direct C−H bond
activation.6 However, this approach requires the use of
expensive alkynes and manifests regioselectivity issues. Over
the years, the use of diketones or vinyl acetates as coupling
partners of benzoic acid has also received considerable
attention.7 Very recently, Zhang et al. have reported the
synthesis of isocoumarins by Pd-catalyzed reaction of β-hydroxy
carbonyl compounds with ortho-halobenzoates.8 A palladium-
catalyzed retro-aldol/α-arylation reaction provides the α-
arylated carbonyl intermediates, which undergo intramolecular
condensation with the ester moiety to obtain isocoumarin
derivatives. Unfortunately this methodology suffers from some
limitations, including low atom economy, the use of phosphine,
high catalyst loading, and a limited substrate scope (Scheme 1,
previous work). Taking advantage of our experience,9 we now
report a new and practical palladium-catalyzed synthesis of
isocoumarins from 2-halobenzoates and ketones. This method
features the α-arylation of the ketone and the intramolecular
condensation with the ester group. We discuss for the first time
the role of iodide anions in the synthesis of isocoumarins. The
high accessibility of ketone derivatives together with other
evident advantages (Scheme 1, this work) make this method-
ology a valuable alternative compared to existing ones. A direct
and general route from ketones to isocoumarins is, up to now,
unprecedented.10
At first, our investigations were focused in exploring the Pd-
catalyzed annulation reaction of methyl 2-bromobenzoate 1a
with acetophenone 2a (Table 1). In an initial experiment, 1a
(0.4 mmol) reacted with 5 equiv of acetophenone in dry DMF
with 2.5 mol% of palladium acetate as catalyst and a mixture of
K2CO3 and PhOK as bases (1.1 and 0.3 equiv. respectively).
Mixtures were heated and samples periodically taken for
analyses. The model reaction gave an encouraging 34% isolated
yield of 3a upon 24 h, mostly accompanied by unreacted
starting material (Table 1, entry 1). Increasing the temperature
proved beneficial for conversion and marginal for yield (entry 2,
Received: June 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b01355
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 1. Optimization of KI Amount and Reaction
Conditions
Scheme 2. Catalytic Synthesis of Isocoumarins from 2-
a,b
a
Bromobenzoates and Ketones
b
b
entry
KI (equiv)
T (°C)
t (h)
conv 1a (%)
yield 2a (%)
1
2
3
4
5
6
7
8
9
10
105
130
130
130
130
130
130
105
80
24
24
24
24
24
24
4
45
34
50
61
66
70
73
77
96
0.1
0.2
0.5
1.0
2.0
2.0
2.0
4.0
2.0
98
100
100
100
100
100
37
c
4
84
24
4
31
39
105
105
62
d
11
24
a
Reaction conditions: 1a (0.4 mmol, 1 equiv), 2a (5 equiv), Pd(OAc)2
(2.5 mol%, 0.002 M), K2CO3 (1.1 equiv), PhOK (0.3 equiv) in DMF
b
c
d
(4 mL) under N2. By GC. Isolated yield. No palladium source was
used.
50%), reduction of 1a to methyl benzoate and Ullmann-type
coupling being undesired side reactions (25% and 20%,
respectively).
An ample mix of tertiary phosphines proved ineffective to
steer the outcome of this coupling. Similarly, various
combinations of carbonates, phosphates, and alcoholates did
not improve the yield of 3a. We then resorted to test the effect
of a source of iodide anions. The latter often serves indeed as
reagent for metal-catalyzed halogen exchange reactions.11
Iodide anions have been proposed as source of electrons,12
which can serve to generate aryl radicals that add then on
enolized ketones,13 and might thus enable open-shell
mechanisms.14
a
b
Reaction conditions: as Table 1, entry 8. Isolated yield.
Addition of KI proved decisive in our case. Furthermore, our
preliminary results strongly suggest that its actual role in these
reactions differs from those named above. Substoichiometric
amounts of KI showed an impact on the yield 3a (entries 3−5,
up to 70%). A further increase is observed increasing its
concentration up to 2 equiv (entry 7, 77%). Reactions became
significantly faster too, complete conversion requiring only 4 h.
This enabled us to reduce back the temperature to 105 °C,
delivering 3a in 84% isolated yield (entry 8). Further
modifications proved marginal (details in Table S1). No
reaction took place without palladium (entry 11).
Once best conditions were secured, we studied scope and
limitations of the reaction. Results are summarized in Scheme
2. Acetophenone could be decorated with various donating or
withdrawing groups without hampering the outcome of the
reactions (3b−d, 71−79%). Less acidic aliphatic ketones could
be similarly employed, albeit at the expense of yield (3e−j, 38−
73%). Noteworthy, ketones that have two different enolization
sites provided a single regioisomer (3f, 3g). The cyclopropyl
ring remained untouched (3h). This result rules out
mechanisms involving addition of aryl radicals on enolized
ketones.13 Methylene groups of cyclic ketones could be
similarly arylated, enabling one to access fused tricycles (3j,
45%). Although the arylation of a furan could easily take place
under similar conditions,15 we managed to exclude this side-
reaction to selectively obtain 3k (62%). Switching to
substituents on the bromide partner, electron-rich ones
performed better (3l−n, 56−82%). Free amino groups are
indeed tolerated, offering a valuable handle for further
functionalization. Halo-coumarins could be prepared too
(3o−p, 48−57%).
Wondering whether KI triggers a halogen-exchange reac-
tion,11 we tested methyl 2-iodobenzoates. They can be
successfully employed as coupling partners in place of the
corresponding bromides without KI (Scheme 3, values in
parentheses show the relative difference with their bromide
peers). In general, slightly lower yields were observed (by 5−
9% for 3a-j). This combines with shortened reaction times,
usually within one to a few hours. Pinacolone and 2-
acetylfurane provided 3i and 3k with +3% and +7%,
respectively. Only traces of products were obtained with
butyrophenone (3q, 10%).
The aryl iodide could be decorated with methyl groups (3r−
t, 75−83%) and chloride ones (3u, 52%). A methoxy
substituent para to iodide gave the worst outcome compared
with its bromide peer (3m, Δ = −12%). Interestingly,
heterocyclic iodides, such as thiophenes, also worked in this
chemistry (3v, 64%).
B
DOI: 10.1021/acs.joc.7b01355
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
concentrations, as witnessed by retrieving 79% of 3a with 0.1
equiv of TEMPO. We were however unable to identify any
radical recombination product.13,14 Moreover, the isolation of
3h using both aryl-bromides and iodides together with the
absence of products arising from cyclopropane ring-opening
reduce the odds that phenoxide anions act as single electron
donor13 to trigger a radical ketone arylation mediated by DMF.
More likely, TEMPO is able to oxidize the in situ formed Pd(0),
decreasing the concentration of the active catalyst.
Scheme 3. Catalytic Synthesis of Isocoumarins from 2-
Iodobenzoates and Ketones
a,b
Addition of KI to a reaction involving an aryl iodide (Scheme
4b) has a negligible impact on yield (44% against 47% without
KI), in sharp contrast to observation with aryl bromides. On
the contrary, the time required to consume the substrate did
change significantly from 24 to 8 h. Since in this case no
halogen exchange can be at work, the present result strongly
supports that the role of iodide anions is crucial in the
coordination of the metal providing anionic species able to
increase the apparent reaction rate.16 In addition when a further
excess of KI was employed (Table 1, entry 10) the rate
decreased drastically, suggesting that a too high concentration
of iodides makes more difficult the coordination of the ketone,
allowing side-reactions to take place.
Taken together all these results seem to exclude that KI
serves as source of electrons.12 Although the possibility that I−
anions operate as reagent for a halogen-exchange reaction11
prior to ketone arylation cannot be ruled out, the observed
acceleration in reactions involving aryl iodides suggests that
iodide anions can act as ligands in this palladium-catalyzed
phosphine-free synthesis of isocoumarins. According to these
considerations we propose the pathway in Scheme 5.
Scheme 5. Proposed Pathway for the Pd-Catalyzed Synthesis
of Isocoumarins from 2-Halobenzoates and Ketones
a
b
Reaction conditions: as Table 1, entry 1. Isolated yield.
Additional experiments were carried out in order to gain
insights on the role of KI in this sequence and the reaction
mechanism as well (Scheme 4). Reactivity is quenched by
radical traps, as hindered phenols and TEMPO.14 The yield of
3a shrinks down to 17% performing the reaction with 1 equiv
of TEMPO (Scheme 4a). This effect blurs at lower
Scheme 4. Experimental Findings
Oxidative addition of the Pd0Ln with 2-halobenzoates 1a or
4a affords the PdII organometallic intermediate I. The ketone
enters into the coordination sphere of palladium (II) and its
subsequent deprotonation/enolization by the bases provides
the PdII organometallic intermediate III, which is in equilibrium
with IV.17 Then, reductive elimination from intermediate IV
gives the α-arylated ketone and regenerates the Pd0Ln catalyst.
As we have demonstrated (Scheme 4c) and in agreement with
literature,18 compound 5 yields isocoumarin 3a and methanol
as coproduct.
C
DOI: 10.1021/acs.joc.7b01355
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
To further demonstrate the synthetic usefulness of our
approach, Xyridin A19 was synthesized in two steps from the
corresponding commercial acid in 71% overall yield (Scheme
6). Quantitative esterification with iodomethane provided the
10% Pd/C (0.20 g) was added to a solution of methyl 2-bromo-5-
nitro benzoate (1.5 g, 5.7 mmol) in EtOAc (40 mL) and the resulting
mixture was stirred for 2.5 h at room temperature under 2.5 bar
hydrogen pressure. After filtration through a Celite pad and removal of
the solvent methyl 2-bromo-5-amino benzoate 1n (1.3 g, 99%) was
obtained as pale yellow oil. Spectroscopic data were consistent with
those reported in the literature.22
Scheme 6. Synthesis of Xyridin A
General Procedure A. Catalyzed synthesis of isocoumarins 3 from
methyl 2-bromo benzoates 1 (Scheme 2). A Schlenk-type flask,
equipped with a magnetic stirring bar, was charged, under nitrogen,
with methyl 2-bromo benzoate (1, 0.4 mmol), ketone (2, 2 mmol),
K2CO3 (0.45 mmol, 62 mg), PhOK (0.15 mmol, 20 mg), KI (0.8
mmol, 143 mg), Pd(OAc)2 (2.5 mol%, 2.2 mg) in DMF (4 mL). The
resulting mixture was stirred in an oil bath at 105 °C for 5−24 h. After
cooling to room temperature, the reaction crude was filtered through a
sand core funnel and washed with ethyl acetate (20 mL). Solvent was
removed under reduced pressure and the residue was purified by flash
column chromatography on silica gel using mixtures of hexane-EtOAc
as eluent.
General Procedure B. Catalyzed synthesis of isocoumarins 3 from
methyl 2-iodo benzoates 4 (Scheme 3). A Schlenk-type flask, equipped
with a magnetic stirring bar, was charged, under nitrogen, with methyl
2-iodo benzoate (4, 0.4 mmol), ketone (2, 2 mmol), K2CO3 (0.45
mmol, 62 mg), PhOK (0.15 mmol, 20 mg), Pd(OAc)2 (2.5 mol%, 2.2
mg) in DMF (4 mL). The resulting mixture was stirred in an oil bath
at 105 °C for 1−24 h. After cooling to room temperature, the reaction
crude was filtered through a sand core funnel and washed with ethyl
acetate (20 mL). Solvent was removed under reduced pressure and the
residue was purified by flash column chromatography on silica gel
using mixtures of hexane-EtOAc as eluent.
3-Phenylisocoumarin (3a). Following general procedure A,
product 3a was synthesized starting from methyl 2-bromo benzoate
(1a, 86 mg) and acetophenone (240 mg). The crude product was
purified by flash column chromatography using hexane/ethyl acetate
(from 10:0 to 8:2) as eluent to give 3a (75 mg, 84% yield) as white
solid. Spectroscopic data of 3a were consistent with literature values.7b
Compound 3a was also obtained from methyl 2-iodo benzoate (106
mg) and acetophenone (240 mg) following general procedure B. The
crude product was purified by flash column chromatography using
hexane/ethyl acetate (from 10:0 to 8:2) as eluent to give 3a (69 mg,
77% yield) as white solid. 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J =
8.2 Hz, 1H), 7.88−7.83 (m, 2H), 7.71−7.66 (m, 1H), 7.49−7.39 (m,
5H), 6.89 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 162.3, 153.5,
137.5, 134.9, 131.9, 129.9, 129.6, 128.8, 128.1, 126.0, 125.2, 120.5,
101.8; IR (neat) 1716 cm−1; MS (ESI) calcd for C15H11O2 [M+H]+
m/z 223.08, found m/z 223.11.
bromoester used for the coupling, which eventually delivered
the desired natural product. This result shows that acetals are
compatible with present methodology and further witness its
generality.
In summary, we have described the first general methodology
for the regioselective Pd-catalyzed synthesis of isocoumarins
from 2-halobenzoates and ketones. The reaction makes direct
use of simple and abundant ketones without the requirement of
phosphine ligands or preformed diketones to generate richly
decorated isocoumarins. The addition of iodide anions to the
reaction mixture was crucial when 2-bromobenzoates were
employed as starting materials. In view of the excellent
regioselectivity, functional group tolerance, and simple protocol
without expensive ligands, we expect widespread diffusion
within the organic chemistry community.
EXPERIMENTAL SECTION
■
General Remarks. All chemicals were purchased from commercial
sources and used as received, unless otherwise indicated. Acetone,
DMF, and all other solvents were dried and stored over molecular
sieves previously activated in oven at 300 °C overnight. Catalytic
reactions were carried out under nitrogen using standard Schlenk
technique. GC analyses were performed with an Agilent Tenchnol-
ogies 7820A equipped with a FID detector and a 30 m capillary
column. GC-MS analyses (m/z, relative intensity %) were performed
with an Agilent Technologies 6890N gas chromatograph coupled to an
5973N mass selective detector (Agilent Technologies) working at 70
eV ionizing voltage. Flash chromatography was carried out on an
automated system (Combiflash Rf+ Lumen) using prepacked
cartridges of silica (12 g RediSep Rf Columns). NMR spectra were
recorded at 298 K, in CDCl3 on a Bruker 400 MHz using the solvent
1
as internal standard (7.26 ppm for H NMR and 77.00 ppm for 13C
NMR). The terms m, s, d, t, q, and quint represent multiplet, singlet,
doublet, triplet, quadruplet, and quintuplet, respectively, and the term
br means a broad signal. MS-ESI analyses were recorded on an
Infusion Water Acquity Ultra Performance LC HO6UPS-823 M
instrument (electrospray source, quadrupole analyzer). IR spectra were
run on a Nicolet FT-IR 5700 spectrophotometer paired with a
Diamond Smart Orbit accessory. Melting points were measured with
an Electrothermal apparatus and are uncorrected. Elemental analyses
were performed with a Carlo Erba EA 1108-Elemental Analyzer.
Preparation of Starting Materials. Methyl 2-bromobenzoate
(1a),20 methyl 2-bromo-4-methyl benzoate (1l),21 methyl 2-bromo-5-
methoxy benzoate (1m),21 methyl 5-chloro-2-bromo benzoate (1o),21
methyl 2-bromo-4-fluoro benzoate (1p),21 methyl 2-iodo-5-methoxy
benzoate (4m),20 methyl 2-iodo-4,5-dimethyl benzoate (4t),21 methyl
4-chloro-2-iodo-6-methyl benzoate (4u),21 and 6-bromobenzo[d]-
[1,3]dioxole-5-carboxylate21 were prepared from the corresponding
benzoic acids according to standard methods. Methyl 2-bromo-5-
amino benzoate (1n) was obtained from methyl 2-bromo-5-nitro
benzoate by hydrogenation as described below.
3-(4′-Methylphenyl)isocoumarin (3b). Following general proce-
dure A, product 3b was synthesized from methyl 2-bromo benzoate
(1a, 86 mg) and 4-methyl acetophenone (268 mg). The crude product
was purified by flash column chromatography using hexane/ethyl
acetate (from 10:0 to 8:2) as eluent to give 3b (61 mg, 71% yield) as
white solid. Spectroscopic data of 3b were consistent with literature
values.23 Compound 3b was also obtained from methyl 2-iodo
benzoate (106 mg) and 4-methyl acetophenone (268 mg) following
general procedure B. The crude product was purified by flash column
chromatography using hexane/ethyl acetate (from 10:0 to 8:2) as
1
eluent to give 3b (61 mg, 64% yield) as white solid. H NMR (400
MHz, CDCl3) δ 8.29 (d, J = 8.2 Hz, 1H), 7.80−7.74 (m, 2H), 7.70
(td, J = 7.5, 1.3 Hz, 1H), 7.49−7.44 (m, 2H), 7.29−7.23 (m, 2H), 6.89
(s, 1H), 2.40 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.4, 153.8,
140.3, 137.7, 134.8, 129.6, 129.5, 129.2, 127.9, 125.9, 125.2, 120.4,
101.1, 21.4; IR (neat) 1714 cm−1; MS (ESI) calcd for C16H13O2 [M
+H]+ m/z 237.09, found 237.12.
3-(4′-Methoxyphenyl)isocoumarin (3c). Following general proce-
dure A, product 3c was synthesized from methyl 2-bromo benzoate
D
DOI: 10.1021/acs.joc.7b01355
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(1a, 86 mg) and 4-methoxy acetophenone (300 mg). The crude
product was purified by flash column chromatography using hexane/
ethyl acetate (from 10:0 to 8:2) as eluent to give 3c (76 mg, 75%
yield) as white solid. Spectroscopic data of 3c were consistent with
literature values.7b Compound 3c was also obtained from methyl 2-
iodo benzoate (106 mg) and 4-methoxy acetophenone (300 mg)
following general procedure B. The crude product was purified by flash
column chromatography using hexane/ethyl acetate (from 10:0 to
eluent to give 3g (39 mg, 47% yield) as pale yellow oil. 1H NMR (400
MHz, CDCl3) δ 8.25 (d, J = 8.0 Hz, 1H), 7.68 (t, J = 8.1 Hz, 1H), 7.45
(t, J = 7.8 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 6.25 (s, 1H), 2.38 (d, J =
7.2 Hz, 2H), 2.20−2.10 (m, 1H), 0.99 (s, 3H), 0.97 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 163.1, 157.4, 137.6, 134.7, 129.5, 127.6, 125.0,
120.1, 104.0, 42.8, 26.6, 22.2; IR (neat) 1718 cm−1; MS (ESI) calcd for
C13H15O2 [M+H]+ m/z 203.11, found m/z 203.17; Anal. Calcd for
C13H14O2: C, 77.20; H, 6.98; O, 15.82. Found: C, 77.06; H, 7.03.
3-Cyclopropylisocoumarin (3h). Following general procedure A,
product 3h was synthesized from methyl 2-bromo benzoate (1a, 86
mg) and methyl cyclopropyl ketone (170 mg). The crude product was
purified by flash column chromatography using hexane/ethyl acetate
(from 10:0 to 8:2) as eluent to give 3h (34 mg, 45% yield) as pale
yellow oil. The spectroscopic data of 3h were consistent with literature
values.26 Compound 3h was also obtained from methyl 2-iodo
benzoate (106 mg) and methyl cyclopropyl ketone (170 mg)
following general procedure B. The crude product was purified by
flash column chromatography using hexane/ethyl acetate (from 10:0
1
8:2) as eluent to give 3c (67 mg, 66% yield) as white solid. H NMR
(400 MHz, CDCl3) δ 8.24 (d, J = 8.2 Hz, 1H), 7.79−7.73 (m, 2H),
7.65 (td, J = 7.5, 1.3 Hz, 1H), 7.45−7.38 (m, 2H), 6.96−6.89 (m, 2H),
6.77 (s, 1H), 3.83 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.4,
161.0, 153.6, 137.9, 134.8, 129.5, 127.6, 126.7, 125.7, 124.4, 120.1,
114.2, 100.2, 55.4; IR (neat) 1736 cm−1; MS (ESI) calcd for C16H13O3
[M+H]+ m/z 253.10, found m/z 253.15.
3-(4′-Chlorophenyl)isocoumarin (3d). Following general proce-
dure A, product 3d was synthesized from methyl 2-bromo benzoate
(1a, 86 mg) and 4-chloro acetophenone (308 mg). The crude product
was purified by flash column chromatography using hexane/ethyl
acetate (from 10:0 to 8:2) as eluent to give 3d (77 mg, 79% yield) as
pale yellow solid. Spectroscopic data of 3d were consistent with
literature values.24 Compound 3d was also obtained from methyl 2-
iodo benzoate (106 mg) and 4-chloro acetophenone (308 mg)
following general procedure B. The crude product was purified by flash
column chromatography using hexane/ethyl acetate (from 10:0 to
1
to 8:2) as eluent to give 3h (28 mg, 37% yield) as pale yellow oil. H
NMR (400 MHz, CDCl3) δ 8.20 (d, J = 7.6 Hz, 1H), 7.67−7.61 (m,
1H), 7.39 (t, J = 7.3 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 6.29 (s, 1H),
1.84−1.76 (m, 1H), 1.09−1.03 (m, 2H), 0.95−0.87 (m, 2H); 13C
NMR (101 MHz, CDCl3) δ 162.8, 158.4, 137.9, 134.8, 129.5, 127.1,
124.6, 119.9, 101.4, 13.8, 7.0; IR (neat) 1715 cm−1; MS (ESI) calcd for
C12H11O2 [M+H]+ m/z 187.08, found m/z 187.17.
1
8:2) as eluent to give 3d (72 mg, 70% yield) as pale yellow solid. H
3-tert-Butylisocoumarin (3i). Following general procedure A,
product 3i was synthesized from methyl 2-bromo benzoate (1a, 86
mg) and pinacolone (200 mg). The crude product was purified by
flash column chromatography using hexane/ethyl acetate (from 10:0
to 8:2) as eluent to give 3i (31 mg, 38% yield) as pale yellow oil.
Spectroscopic data of 3i were consistent with literature values.27
Compound 3i was also obtained from methyl 2-iodo benzoate (106
mg) and pinacolone (200 mg) following general procedure B. The
crude product was purified by flash column chromatography using
hexane/ethyl acetate (from 10:0 to 8:2) as eluent to give 3i (34 mg,
41% yield) as pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J
= 8.0 Hz, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.39
(d, J = 7.8 Hz, 1H), 6.32 (s, 1H), 1.34 (s, 9H); 13C NMR (101 MHz,
CDCl3) δ 165.2, 163.0, 137.7, 134.6, 129.4, 127.6, 125.5, 120.1, 99.7,
35.6, 28.0; IR (neat) 1718 cm−1; MS (ESI) calcd for C13H15O2 [M
+H]+ m/z 203.11, found m/z 203.18.
NMR (400 MHz, CDCl3) δ 8.25 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 8.0
Hz, 2H), 7.69 (t, J = 7.3 Hz, 1H), 7.47 (t, J = 8.3 Hz, 2H), 7.38 (d, J =
7.9 Hz, 2H), 6.87 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 161.9,
152.4 137.2, 135.9, 134.9, 130.4, 129.6, 129.1, 128.4, 126.4, 126.0,
120.5, 102.0; IR (neat) 1722 cm−1; MS (ESI) calcd for C15H10O2Cl
[M+H]+ m/z 257.04, found m/z 257.12.
3-Methylisocoumarin (3e). Following general procedure A,
product 3e was synthesized from methyl 2-bromo benzoate (1a, 86
mg) and acetone (116 mg). The crude product was purified by flash
column chromatography using hexane/ethyl acetate (from 10:0 to
8:2) as eluent to give 3e (47 mg, 73% yield) as white solid.
Spectroscopic data of 3e were consistent with literature values.7b
Compound 3e was also obtained from methyl 2-iodo benzoate (106
mg) and acetone (116 mg) following general procedure B. The crude
product was purified by flash column chromatography using hexane/
ethyl acetate (from 10:0 to 8:2) as eluent to give 3e (45 mg, 70%
2,3-Dihydro-1H-cyclopenta[c]isochromen-5-one (3j). Following
general procedure A, product 3j was synthesized from methyl 2-
bromo benzoate (1a, 86 mg) and cyclopentanone (168 mg). The
crude product was purified by flash column chromatography using
hexane/ethyl acetate (from 10:0 to 8:2) as eluent to give 3j (34 mg,
45% yield) as white solid. Spectroscopic data of 3j were consistent
with literature values.28 Compound 3j was also obtained from methyl
2-iodo benzoate (106 mg) and cyclopentanone (168 mg) following
general procedure B. The crude product was purified by flash column
chromatography using hexane/ethyl acetate (from 10:0 to 8:2) as
1
yield) as white solid. H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 7.9
Hz, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.33 (d, J =
7.8 Hz, 1H), 6.25 (s, 1H), 2.28 (s, 3H); 13C NMR (101 MHz,
CDCl3): δ 163.0, 154.5, 137.6, 134.7, 129.7, 127.5, 124.9, 119.9, 103.5,
19.6; IR (neat) 1714 cm−1; MS (ESI) calcd for C10H9O2 [M+H]+ m/z
161.06, found m/z 161.12.
3-Propylisocoumarin (3f). Following general procedure A, product
3f was synthesized from methyl 2-bromo benzoate (1a, 86 mg) and
pentan-2-one (170 mg). The crude product was purified by flash
column chromatography using hexane/ethyl acetate (from 10:0 to
8:2) as eluent to give 3f (42 mg, 56% yield) as pale colorless oil.
Spectroscopic data of 3f were consistent with literature values.25 1H
NMR (400 MHz, CDCl3) δ 8.25 (dd, J = 8.0, 0.6 Hz, 1H), 7.67 (td, J
= 7.8, 1.3 Hz, 1H), 7.45 (td, J = 7.9, 1.3 Hz, 1H), 7.36 (d, J = 7.9 Hz,
1H), 6.26 (s, 1H), 2.51 (t, J = 7.5 Hz, 2H), 1.80−1.71 (m, 2H), 1.00
(t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 163.0, 158.1,
137.6, 134.7, 129.5, 127.5, 125.0, 120.2, 103.0, 35.4, 20.2, 13.5; IR
(neat) 1721 cm−1; MS (ESI) calcd for C12H13O2 [M+H]+ 189.09,
found m/z 189.20.
3-(2-Methylpropyl)isocoumarin (3g). Following general procedure
A, product 3g was synthesized from methyl 2-bromo benzoate (1a, 86
mg) and 4-methylpentan-2-one (200 mg). The crude product was
purified by flash column chromatography using hexane/ethyl acetate
(from 10:0 to 8:2) as eluent to give 3g (39 mg, 48% yield) as pale
yellow oil. Compound 3g was also obtained from methyl 2-iodo
benzoate (106 mg) and 4-methylpentan-2-one (200 mg) following
general procedure B. The crude product was purified by flash column
chromatography using hexane/ethyl acetate (from 10:0 to 8:2) as
1
eluent to give 3j (30 mg, 40% yield) as white solid. H NMR (400
MHz, CDCl3) δ 8.26 (further split d, J = 8.0 Hz, 1H), 7.69 (td, J = 7.9,
1.1 Hz, 1H), 7.42 (td, J = 8.1, 1.1 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H),
2.87−2.78 (m, 4H), 2.22−2.12 (m, 2H); 13C NMR (101 MHz,
CDCl3) δ 163.8, 156.0, 136.4, 134.8, 130.4, 127.0, 122.5, 119.6, 113.3,
31.0, 26.5, 19.8; IR (neat) 1716 cm−1; MS (ESI) calcd for C12H11O2
[M+H]+ 187.08, found m/z 187.15.
3-(2-Furanyl)isocoumarin (3k). Following general procedure A,
product 3k was synthesized from methyl 2-bromo benzoate (1a, 86
mg) and 2-acetylfuran (220 mg). The crude product was purified by
flash column chromatography using hexane/ethyl acetate (from 10:0
to 8:2) as eluent to give 3k (52 mg, 62% yield) as orange solid.
Spectroscopic data of 3k were consistent with literature values.27
Compound 3k was also synthesized from methyl 2-iodo benzoate (106
mg) and 2-acetylfuran (220 mg) following general procedure B. The
crude product was purified by flash column chromatography using
hexane/ethyl acetate (from 10:0 to 8:2) as eluent to give 3k (59 mg,
69% yield) as orange solid. 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J =
8.2 Hz, 1H), 7.68 (td, J = 7.8, 1.3 Hz, 1H), 7.50 (d, J = 1.7 Hz, 1H),
E
DOI: 10.1021/acs.joc.7b01355
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
7.47−7.42 (m, 2H), 6.93 (d, J = 3.4 Hz, 1H), 6.83 (s, 1H), 6.52 (dd, J
= 3.4, 1.8 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 161.5, 146.9,
146.1, 144.0, 137.3, 135.0, 129.8, 128.0, 126.0, 120.4, 112.1, 110.1,
100.0; IR (neat) 1731 cm−1; MS (ESI) calcd for C13H9O3 [M+H]+ m/
z 213.06, found m/z 213.14.
6-Methyl-3-phenylisocoumarin (3l). Following general procedure
A, product 3l was synthesized from methyl 2-bromo-4-methyl
benzoate (1l, 92 mg) and acetophenone (240 mg). The crude
product was purified by flash column chromatography using hexane/
ethyl acetate (from 10:0 to 8:2) as eluent to give 3l (78 mg, 82% yield)
as white solid. Spectroscopic data of 3l were consistent with literature
values.24 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.1 Hz, 1H), 7.83
(dd, J = 8.0, 1.6 Hz, 2H), 7.47−7.36 (m, 3H), 7.27−7.20 (m, 2H),
6.82 (s, 1H), 2.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.2,
153.5, 145.9, 137.6, 132.0, 129.8, 129.51, 129.49, 128.8, 126.0, 125.2,
118.1, 101.5, 21.9; IR (neat) 1712 cm−1; MS (ESI) calcd for C16H13O2
[M+H]+ m/z 237.09, found m/z 237.17.
10.4 Hz), 131.6, 130.4, 128.9, 125.4, 117.0, 116.46 (d, JC,F = 23.4 Hz),
111.52 (d, JC,F = 22.6 Hz), 101.22 (d, JC,F = 2.9 Hz); IR (neat) 1723
cm−1; MS (ESI) calcd for C15H10FO2 [M+H]+ m/z 241.07, found m/z
241.15.
3-Phenyl-4-ethylisocoumarin (3q). Following general procedure B,
product 3q was synthesized from methyl 2-iodo benzoate (106 mg)
and 1-phenylbutanone (296 mg). The crude product was purified by
flash column chromatography using hexane/ethyl acetate (from 10:0
to 8:2) as eluent to give 3q (10 mg, 10% yield) as pale yellow solid.
Mp 109−111 °C. 1H NMR (400 MHz, CDCl3) δ 8.42 (dd, J = 7.9, 0.9
Hz, 1H), 7.83 (td, J = 8.6, 1.4 Hz, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.62−
7.45 (m, 6H), 2.75 (q, J = 7.5 Hz, 2H), 1.32 (t, J = 7.5 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ 162.4, 151.3, 137.7, 134.7, 133.5, 130.1,
129.4, 129.0, 128.4, 127.8, 123.4, 121.4, 115.2, 20.1, 14.7; IR (neat)
1721 cm−1; MS (ESI) calcd for C17H15O2 [M+H]+ m/z 251.11, found
m/z 251.21; Anal. Calcd for C17H14O2: C, 81.58; H, 5.64; O, 12.78.
Found: C, 81.43; H, 5.70.
7-Methyl-3-methylisocoumarin (3r). Following general procedure
B, product 3r was synthesized from methyl 2-iodo-5-methyl benzoate
(110 mg) and acetone (116 mg). The crude product was purified by
flash column chromatography using hexane/ethyl acetate (from 10:0
to 8:2) as eluent to give 3r (52 mg, 75% yield) as white solid.
Spectroscopic data of 3r were consistent with literature values.29 1H
NMR (400 MHz, CDCl3) δ 8.05 (further split s, 1H), 7.48 (dd, J =
8.0, 1.5 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 6.22 (s, 1H), 2.44 (s, 3H),
2.26 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 163.2, 153.6, 137.7,
136.0, 135.2, 129.1, 124.8, 119.8, 103.4, 21.3, 19.5; IR (neat) 1712
cm−1; MS (ESI) calcd for C11H11O2 [M+H]+ 175.08, found m/z
175.18.
7-Methyl-3-phenylisocoumarin (3s). Following general procedure
B, product 3s was synthesized from methyl 2-iodo-5-methyl benzoate
(110 mg) and acetophenone (240 mg). The crude product was
purified by flash column chromatography using hexane/ethyl acetate
(from 10:0 to 8:2) as eluent to give 3s (76 mg, 81% yield) as white
solid. Spectroscopic data of 3s were consistent with literature values.30
1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.83 (d, J = 7.6 Hz, 2H),
7.51−7.33 (m, 5H), 6.88 (s, 1H), 2.43 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 162.4, 152.7, 138.5, 136.1, 135.0, 132.0, 129.7, 129.3, 128.8,
125.9, 125.1, 120.4, 101.7, 21.4; IR (neat) 1712 cm−1; MS (ESI) calcd
for C16H13O2 [M+H]+ 237.09, found m/z 237.18.
7-Methoxy-3-phenylisocoumarin (3m). Following general proce-
dure A, product 3m was synthesized from methyl 2-bromo-5-methoxy
benzoate (1m, 98 mg) and acetophenone (240 mg). The crude
product was purified by flash column chromatography using hexane/
ethyl acetate (from 10:0 to 8:2) as eluent to give 3m (76 mg, 75%
yield) as pale yellow solid. Spectroscopic data of 3m were consistent
with literature values.27 Compound 3m was also synthesized from
methyl 2-iodo-5-methoxy benzoate (4m, 117 mg) and acetophenone
(240 mg) following general procedure B. The crude product was
purified by flash column chromatography using hexane/ethyl acetate
(from 10:0 to 8:2) as eluent to give 3m (64 mg, 63% yield) as pale
yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.88−7.83 (m, 2H), 7.72
(d, J = 2.7 Hz, 1H), 7.48−7.37 (m, 4H), 7.31 (dd, J = 8.6, 2.7 Hz, 1H),
6.92 (s, 1H), 3.92 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.5,
159.6, 151.7, 132.1, 131.2, 129.6, 128.8, 127.6, 124.9, 124.7, 121.7,
110.0, 101.6, 55.8; IR (neat) 1733 cm−1; MS (ESI) calcd for C16H13O3
[M+H]+ m/z 253.09, found m/z 253.17.
7-Amino-3-phenylisocoumarin (3n). Following general procedure
A, product 3n was synthesized from methyl 2-bromo-5-amino
benzoate (1n, 92 mg) and acetophenone (240 mg). The crude
product was purified by flash column chromatography using hexane/
ethyl acetate (from 10:0 to 8:2) as eluent to give 3n (53 mg, 56%
1
yield) as pale yellow solid. Mp 171−173 °C. H NMR (400 MHz,
CDCl3) δ 7.87−7.82 (m, 2H), 7.56 (d, J = 2.4 Hz, 1H), 7.47−7.42 (m,
2H), 7.42−7.36 (m, 1H), 7.34 (d, J = 8.3 Hz, 1H), 7.08 (dd, J = 8.3,
2.5 Hz, 1H), 6.89 (s, 1H), 4.05 (br s, 2H); 13C NMR (101 MHz,
CDCl3) δ 162.7, 150.4, 146.9, 132.4, 129.2, 128.8, 127.4, 124.7, 122.9,
121.9, 112.7, 102.0; IR (neat) 1728 cm−1; MS (ESI) calcd for
C15H11NO2 [M]+ m/z 237.08, found m/z 237.14; Anal. Calcd for
C15H11NO2: C, 75.94; H, 4.67; N, 5.90; O, 13.49. Found: C, 76.11; H,
4.61; N, 5.84.
7-Chloro-3-phenylisocoumarin (3o). Following general procedure
A, product 3o was synthesized from methyl 5-chloro-2-bromo
benzoate (1o, 100 mg) and acetophenone (240 mg). The crude
product was purified by flash column chromatography using hexane/
ethyl acetate (from 10:0 to 8:2) as eluent to give 3o (59 mg, 57%
yield) as pale yellow solid. Spectroscopic data of 3o were consistent
with literature values.27 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 1.8
Hz, 1H), 7.93−7.86 (m, 2H), 7.69 (dd, J = 8.3, 2.0 Hz, 1H), 7.53−
7.44 (m, 4H), 6.96 (s, 1H); 13C NMR (101 MHz, CDCl3): δ 161.2,
154.0, 135.9, 135.3, 133.9, 131.6, 130.3, 129.2, 128.9, 127.5, 125.3,
121.7, 101.0; IR (neat) 1722 cm−1; MS (ESI) calcd for C15H10ClO2
[M+H]+ m/z 257.04, found m/z 257.15.
6,7-Dimethyl-3-phenylisocoumarin (3t). Following general proce-
dure B, product 3t was synthesized from methyl 2-iodo-4,5-dimethyl
benzoate (4t, 116 mg) and acetophenone (240 mg). The crude
product was purified by flash column chromatography using hexane/
ethyl acetate (from 10:0 to 8:2) as eluent to give 3t (87 mg, 83%
yield) as white solid. Spectroscopic data of 3t were consistent with
literature values.24 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.87
(d, J = 7.7 Hz, 2H), 7.48−7.40 (m, 3H), 7.25 (s, 1H), 6.87 (s, 1H),
2.38 (d, J = 6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 162.5, 152.9,
145.2, 137.8, 135.6, 132.2, 129.7, 129.6, 128.8, 126.6, 125.1, 118.4,
101.6, 20.4, 19.8; IR (neat) 1712 cm−1; MS (ESI) calcd for C17H15O2
[M+H]+ 251.11, found m/z 251.20.
6-Chloro-8-methyl-3-phenylisocoumarin (3u). Following general
procedure B, product 3u was synthesized from methyl 4-chloro-2-
iodo-6-methyl benzoate (4u, 124 mg) and acetophenone (240 mg).
The crude product was purified by flash column chromatography using
hexane/ethyl acetate (from 10:0 to 8:2) as eluent to give 3u (57 mg,
1
52% yield) as white solid. Mp 158−160 °C. H NMR (400 MHz,
CDCl3) δ 7.89−7.86 (m, 2H), 7.52−7.44 (m, 3H), 7.32 (d, J = 1.9 Hz,
1H), 7.26 (further split s, 1H), 6.82 (s, 1H), 2.84 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 160.8, 154.4, 145.7, 140.5, 140.2, 131.6, 130.9,
130.2, 128.9, 125.3, 123.5, 117.3, 101.3, 23.0; IR (neat) 1716 cm−1;
MS (ESI) calcd for C16H12ClO2 [M+H]+ 271.05, found m/z 271.15;
Anal. Calcd for C16H11ClO2: C, 70.99; H, 4.10; Cl, 13.10; O, 11.82.
Found: C, 71.13; H, 4.15.
6-Fluoro-3-phenylisocoumarin (3p). Following general procedure
A, product 3p was synthesized from methyl 2-bromo-4-fluoro
benzoate (1p, 94 mg) and acetophenone (240 mg). The crude
product was purified by flash column chromatography using hexane/
ethyl acetate (from 10:0 to 8:2) as eluent to give 3p (46 mg, 48%
yield) as white solid. Spectroscopic data of 3p were consistent with
literature values.7b 1H NMR (400 MHz, CDCl3) δ 8.35 (dd, J = 8.7,
5.6 Hz, 1H), 7.93−7.86 (m, 2H), 7.52−7.45 (m, 3H), 7.24−7.13 (m,
3-Methyl-5-phenyl-7H-thieno[2,3-c]pyran-7-one (3v). Following
general procedure B, product 3v was synthesized from methyl 3-iodo-
4-methylthiophene-2-carboxylate (113 mg) and acetophenone (240
mg). The crude product was purified by flash column chromatography
using hexane/ethyl acetate (from 10:0 to 8:2) as eluent to give 3v (72
2H), 6.93 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 166.8 (d, JC,F
256.5 Hz), 161.4, 154.9, 140.24 (d, JC,F = 10.8 Hz), 133.03 (d, JC,F
=
=
F
DOI: 10.1021/acs.joc.7b01355
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
mg, 64% yield) as pale orange solid. Mp 136−138 °C. 1H NMR (400
MHz, CDCl3) δ 7.89 (dd, J = 7.2, 1.2 Hz, 2H), 7.49−7.41 (m, 4H),
7.00 (s, 1H), 2.40 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 158.5,
156.3, 147.2, 134.0, 132.4, 132.0, 130.1, 128.9, 125.4, 122.9, 97.6, 13.7;
IR (neat) 1704 cm−1; MS (ESI) calcd for C14H11O2S [M+H]+ 243.05,
found m/z 243.15; Anal. Calcd for C14H10O2S: C, 69.40; H, 4.16; O,
13.21; S, 13.23. Found: C, 69.28; H, 4.09.
(3) (a) Saeed, A.; Haroon, M.; Muhammad, F.; Larik, F. A.; Hesham,
E.-S.; Channar, P. A. J. Organomet. Chem. 2017, 834, 88. (b) Pal, S.;
Chatare, V.; Pal, M. Curr. Org. Chem. 2011, 15, 782. (c) Napolitano, E.
Org. Prep. Proced. Int. 1997, 29, 631. (d) Yao, T.; Larock, R. C. J. Org.
Chem. 2003, 68, 5936. (e) Ashraf, Z. Chem. Heterocycl. Compd. 2016,
52, 149.
(4) (a) Zheng, M.; Huang, L.; Tong, Q.; Wu, W.; Jiang, H. Eur. J.
Org. Chem. 2016, 47, 667. (b) Wang, H.; Han, X.; Lu, X. Tetrahedron
2013, 69, 8626. (c) Li, X.; Chianese, A. R.; Vogel, T.; Crabtree, R. H.
Org. Lett. 2005, 7, 5437. (d) Bellina, F.; Ciucci, D.; Vergamini, P.;
Rossi, R. Tetrahedron 2000, 56, 2533.
(5) (a) Yoo, W. J.; Nguyen, T. V.; Kobayashi, S. Angew. Chem., Int.
Ed. 2014, 53, 10213. (b) Lessi, M.; Masini, T.; Nucara, L.; Bellina, F.;
Rossi, R. Adv. Synth. Catal. 2011, 353, 501. (c) Subramanian, V.;
Batchu, V. R.; Barange, D.; Pal, M. J. Org. Chem. 2005, 70, 4778.
(d) Larock, R. C.; Yum, E. K.; Doty, M. J.; Sham, K. K. C. J. Org.
Chem. 1995, 60, 3270.
(6) (a) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9, 1407.
(b) Shimizu, M.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009,
74, 3478. (c) Chinnagolla, R. K.; Jeganmohan, M. Chem. Commun.
2012, 48, 2030. (d) Deponti, M.; Kozhushkov, S. I.; Yufit, D. S.;
Ackermann, L. Org. Biomol. Chem. 2013, 11, 142. (e) Ackermann, L.;
Pospech, J.; Graczyk, K.; Rauch, K. Org. Lett. 2012, 14, 930.
(7) (a) Hurtley, W. R. H. J. Chem. Soc. 1929, 0, 1870. (b) Cai, S.;
Wang, F.; Xi, C. J. Org. Chem. 2012, 77, 2331. (c) Kavala, V.; Wang,
C.-C.; Barange, D. K.; Kuo, C.-W.; Lei, P.-M.; Yao, C.-F. J. Org. Chem.
2012, 77, 5022. (d) Zhang, M.; Zhang, H. J.; Han, T.; Ruan, W.; Wen,
T. B. J. Org. Chem. 2015, 80, 620.
Synthesis of Xyridine A (Scheme 6). (i) 6-Bromobenzo[d][1,3]-
dioxole-5-carboxylate was synthesized from the corresponding benzoic
acids according to literature.21 (ii) A Schlenk-type flask, equipped with
a magnetic stirring bar was charged, under nitrogen, with methyl 6-
bromobenzo[d][1,3]dioxole-5-carboxylate (122 mg, 0.4 mmol),
pentan-2-one (170 mg, 2 mmol), K2CO3 (0.45 mmol, 62 mg),
PhOK (0.15 mmol, 20 mg), KI (0.8 mmol, 142.8 mg), Pd(OAc)2 (2.5
mol%, 2.2 mg) in DMF (4 mL). The resulting mixture was stirred in
an oil bath at 105 °C for 5 h. After cooling to room temperature, the
reaction crude was filtered through a sand core funnel and washed
with ethyl acetate (20 mL). Solvent was removed under reduced
pressure and the residue was purified by flash column chromatography
on silica gel using hexane-EtOAc as eluent to afford Xyridine A as
white solid (66 mg, 71%). Spectroscopic data were consistent with
reported values.19b 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 6.72
(s, 1H), 6.15 (s, 1H), 6.08 (s, 2H), 2.48 (t, J = 7.5 Hz, 2H), 1.79−1.66
(m, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
162.7, 157.1, 153.6, 147.8, 135.3, 114.6, 107.3, 103.6, 103.0, 102.1,
35.3, 20.3, 13.5; IR (neat) 1739 cm−1; MS (ESI) calcd for C13H13O4
[M+H]+ 233.08, found m/z 233.18.
ASSOCIATED CONTENT
* Supporting Information
■
(8) (a) Zhang, S.-L.; Yu, Z.-L. J. Org. Chem. 2016, 81, 57. (b) Zhang,
S.-L.; Yu, Z.-L. Org. Biomol. Chem. 2016, 14, 10511.
(9) Maestri, G.; Della Ca’, N.; Catellani, M. Chem. Commun. 2009,
4892.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b01355.
(10) There is a single example of Pd-catalyzed coupling of alkyl 6-
bromo-2,3-dimethoxybenzoate with 6,7-methylenedioxy-1-tetralone
for the total synthesis of Arnottin I and II in: Konno, F.; Ishikawa,
T.; Kawahata, M.; Yamaguchi, K. J. Org. Chem. 2006, 71, 9818.
(11) (a) Petrone, D. A.; Ye, J.; Lautens, M. Chem. Rev. 2016, 116,
8003. (b) Li, L.; Liu, W.; Zeng, H.; Mu, X.; Cosa, G.; Mi, Z.; Li, C.-J. J.
Am. Chem. Soc. 2015, 137, 8328. (c) Lei, Y.; Zhang, R.; Wu, L.; Ou,
Q.; Mei, H.; Li, G. J. Mol. Catal. A: Chem. 2014, 392, 105.
(d) Sheppard, T. D. Org. Biomol. Chem. 2009, 7, 1043.
Optimization study and copy of NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: nicola.dellaca@unipr.it
*E-mail: elena.motti@unipr.it
ORCID
■
(12) (a) Hartmann, M.; Studer, A. Angew. Chem., Int. Ed. 2014, 53,
8180. (b) Manolikakes, G.; Knochel, P. Angew. Chem., Int. Ed. 2009,
48, 205.
(13) Pichette Drapeau, M.; Fabre, I.; Grimaud, L.; Ciofini, I.;
Ollevier, T.; Taillefer, M. Angew. Chem., Int. Ed. 2015, 54, 10587.
(14) Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2016, 55, 58.
(15) Della Ca’, N.; Maestri, G.; Catellani, M. Chem. - Eur. J. 2009, 15,
7850.
(16) (a) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314.
(b) Amatore, C.; Jutand, A.; Suarez, A. J. Am. Chem. Soc. 1993, 115,
9531. (c) Amatore, C.; Jutand, A.; Lemaître, F.; Ricard, J. L.; Kozuch,
S.; Shaik, S. J. Organomet. Chem. 2004, 689, 3728.
(17) For α-arylation of ketones see: (a) Bellina, F.; Rossi, R. Chem.
Rev. 2010, 110, 1082. (b) Johansson, C. C.; Colacot, T. J. Angew.
Chem., Int. Ed. 2010, 49, 676. (c) Hesp, K. D.; Lundgren, R. J.;
Stradiotto, M. J. Am. Chem. Soc. 2011, 133, 5194. (d) Ackermann, L.;
Spatz, J. H.; Gschrei, C. J.; Born, R.; Althammer, A. Angew. Chem., Int.
Ed. 2006, 45, 7627. (e) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res.
2003, 36, 234. (f) Ehrentraut, A.; Zapf, A.; Beller, M. Adv. Synth. Catal.
2002, 344, 209. (g) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M.
Angew. Chem., Int. Ed. Engl. 1997, 36, 1740. (h) Palucki, M.; Buchwald,
S. L. J. Am. Chem. Soc. 1997, 119, 11108.
Giovanni Maestri: 0000-0002-0244-8605
Nicola Della Ca’: 0000-0002-7853-7954
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We warmly give thanks for support from SIR project AROMA-
TriP (Grant No.: RBSI14NKFL, GM), University of Parma and
MIUR. We also acknowledge COST action CA15106
(“CHAOS”, CH-Activation in Organic Synthesis) for support
and CIM (Centro Interdipartimentale “Giuseppe Casnati”) for
facilities.
REFERENCES
■
(1) (a) Saeed, A. Eur. J. Med. Chem. 2016, 116, 290. (b) Engelmeier,
D.; Hadacek, F.; Hofer, O.; Lutz-Kutschera, G.; Nagl, M.; Wurz, G.;
Greger, H. J. Nat. Prod. 2004, 67, 19. (c) Hussain, M. T.; Rama, N. H.;
Malik, A. Indian J. Chem. Sect. B 2001, 40, 372. (d) Sakurai, M.; Nishio,
M.; Yamamoto, K.; Okuda, T.; Kawano, K.; Ohnuki, T. Org. Lett.
2003, 5, 1083. (e) Saeed, A.; Ehsan, S. Chem. Heterocycl. Compd. 2005,
41, 1381.
(18) Sudarshan, K.; Manna, M. K.; Aidhen, I. S. Eur. J. Org. Chem.
2015, 2015, 1797.
(19) Isolated from Xyris indica, Xyridin A displays antifungal and
antimicrobial activity. For properties and synthesis (23% overall yield
from the same starting bromide) see: (a) Ruangrungsi, N.; Sekine, T.;
(2) (a) Woon, E. C. Y.; Sunderland, P. T.; Paine, H. A.; Lloyd, M. D.;
Thompson, A. S.; Threadgill, M. D. Bioorg. Med. Chem. 2013, 21,
5218. (b) Rudyanto, M.; Tomizawa, Y.; Morita, H.; Honda, T. Org.
Lett. 2008, 10, 1921.
G
DOI: 10.1021/acs.joc.7b01355
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Phadungcharoen, T.; Suriyagan, S.; Murakoshi, I. Phytochemistry 1995,
38, 481. (b) Saeed, A. J. Heterocycl. Chem. 2003, 40, 337.
(20) Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R.
Vogel’s Textbook of Practical Organic Chemistry; Longmann Scientific &
Technical: New York, 1989.
(21) Powers, D. C.; Lee, E.; Ariafard, A.; Sanford, M. S.; Yates, B. F.;
Canty, A. J.; Ritter, T. J. Am. Chem. Soc. 2012, 134, 12002.
(22) Carlson, E. J.; Riel, A. M. S.; Dahl, B. J. Tetrahedron Lett. 2012,
53, 6245.
(23) Shahzad, S. A.; Venin, C.; Wirth, T. Eur. J. Org. Chem. 2010,
2010, 3465.
(24) Yoo, W.-J.; Nguyen, T. V. Q.; Kobayashi, S. Angew. Chem., Int.
Ed. 2014, 53, 10213.
(25) Peuchmaur, M.; Lisowski, V.; Gandreuil, C.; Maillard, L. T.;
Martinez, J.; Hernandez, J.-F. J. Org. Chem. 2009, 74, 4158.
(26) Kumar, M. R.; Irudayanathan, F. M.; Moon, J. H.; Lee, S. Adv.
Synth. Catal. 2013, 355, 3221.
(27) Ge, Z.-Y.; Fei, X.-D.; Tang, T.; Zhu, Y.-M.; Shen, J.-K. J. Org.
Chem. 2012, 77, 5736.
(28) Tadd, A. C.; Fielding, M. R.; Willis, M. C. Chem. Commun.
2009, 44, 6744.
(29) Liu, L.; Hu, J.; Wang, X. C.; Zhong, M. J.; Liu, X. Y.; Yang, S. D.;
Liang, Y. M. Tetrahedron 2012, 68, 5391.
(30) Zhang, M.; Zhang, H.-J.; Han, T.; Ruan, W.; Wen, T.-B. J. Org.
Chem. 2015, 80, 620.
H
DOI: 10.1021/acs.joc.7b01355
J. Org. Chem. XXXX, XXX, XXX−XXX