Pd/pivalic acid mediated direct arylation of 2-pyrones and related heterocycles

Article abstract of DOI:10.1002/ejoc.201500262

Abstract Direct arylation represents a favourable alternative to traditional cross-coupling reactions and has found widespread use with simple aryls and robust heterocycles. Herein a direct arylation protocol has been optimised and applied to more delicat

Full text of DOI:10.1002/ejoc.201500262

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FULL PAPER
DOI: 10.1002/ejoc.201500262
Pd/Pivalic Acid Mediated Direct Arylation of 2-Pyrones and Related
Heterocycles
Leticia M. Pardo,[a] Aisling M. Prendergast,[a] Marie-T. Nolan,[a] Eoin Ó Muimhneacháin,[a]
and Gerard P. McGlacken*[a]
Keywords: Synthetic methods / Homogeneous catalysis / Palladium / C–C bond formation / Arylation / Oxygen
heterocycles
Direct arylation represents a favourable alternative to tradi-
tional cross-coupling reactions and has found widespread
use with simple aryls and robust heterocycles. Herein a direct
arylation protocol has been optimised and applied to more
delicate, privileged biological motifs. The intramolecular di-
rect arylation of 2-pyrones, 2-coumarins, 2-pyridones and 2-
quinolones occurs in very good to excellent yields using a
Pd0 source and pivalic acid as a crucial additive. Preliminary
mechanistic investigations were also carried out.
erate strong bases such as Cs2CO3, CsOAc and KOtBu in
direct arylation reactions at temperatures exceeding 100 °C.
It seems to us that development of direct arylation meth-
odology [Pd, base and pivalic acid (PivOH)] would be well
served by the optimisation of reaction conditions for less
robust heterocyclic systems,[20] more specifically those
prominent in natural products and mimetics.
We chose the 2-pyrone substrate, specifically 4-hydroxy-
2-pyrones[21] due to their status as a privileged biological
scaffold with broad spectrum biological activity,[22] span-
ning cytotoxic,[21] antibiotic,[23] and antifungal activity.[24]
For example, the bufadienolide class of compounds has
been shown to have diverse biological effects, including
causing cardiac poisoning in animals and inhibitory activity
towards leukaemia cell lines.[21] Radicinin (Figure 1) dem-
Introduction
The formation of aryl–heteroaryl (Ar–HetAr) bonds is a
very important transformation in organic synthesis[1] 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,[3–5] Stille,[6–8] Negi-
shi,[9,10] and similar reactions.[11] More recently the develop-
ment 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.[12–14] For ex-
ample, the need for installation of activating groups is not
required and the production of waste (e.g. B, Sn or Zn
based) is eliminated. One impediment to the widespread ap-
plication of direct arylation methodology is the develop-
ment of regioselective methods. In many cases a number of
C–H bonds are available as coupling sites. Thus it can be
troublesome to control and predict regioselectivity, and di-
recting groups are needed to guide the transition metal into
position and facilitate smooth reactivity.[15]
Direct arylation protocols have been applied to a number
of Ar–HetAr bond forming reactions.[16] In most of these
cases, harsh conditions are utilised including very high tem-
peratures, strong bases and long reaction times. This is not
necessarily a problem in many cases due to the stability of
many simple aryls and prominent heterocyclic systems. For
example, indoles,[17] purines[18] and (benz)imidazoles[19] tol-
[a] Department of Chemistry and the Analytical and Biological
Chemistry Research Facility (ABCRF), University College
Cork,
Cork, Ireland
E-mail: g.mcglacken@ucc.ie
http://publish.ucc.ie/researchprofiles/D004/gmcglacken
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500262.
Figure 1. Biologically active examples of a 4-alkoxy-2-pyrone, 2-
coumarin, 2-pyridone and 2-quinolone.
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onstrates inhibitory activity towards the growth of some (AdmOH) being the most useful, affording 2 in 62% yield
Gram-positive bacteria, such as Staphylococcus aureus and (Table 1, entry 2). In the absence of PivOH or AdmOH un-
Clostridium species.[23] The 2-pyrone would also prove suit- der otherwise identical conditions, only 11% of pyrone 2
able to probe the regioselectivity of an optimised direct was detected (Table 1, entry 3). The use of Cs2CO3 and
arylation methodology as it bears two potential sites for C- KOtBu, which had previously proved successful in the di-
H activation. Finally the 2-pyrone moiety displays reactivity rect arylation of purines[18] and (benz)imidazoles[19] respec-
reminiscent of aromatic compounds,[25] dienes,[26,27] and en- tively, caused degradation of the 2-pyrone motif, verifying
ones[28] and thus represents both a challenging and re- our hypothesis that conditions must be sought which better
warding synthon.
tolerate sensitive functional groups and the privileged mo-
The related 2-coumarins also display a wide and varied tifs found in natural products. The use of K2CO3 gave a
biological profile.[29] 4-Hydroxycoumarins represent an im- reduced yield of 38% (Table 1, entry 4) as did NaOAc
portant and common subgroup, as well as intermediates in (70%) (Table 1, entry 5). Of the palladium sources screened,
the production of dye stuffs, herbicides and anticancer Pd(OAc)2 (Table 1, entry 6) and Pd2(dba)3 (Table 1, entry
agents.[30] Ferprenin (Figure 1), from Ferula communis, 1) facilitated complete consumption of starting material,
shows antithrombotic activity.[31] While 2-coumarins have whereas Pd(dba)2 (Table 1, entry 7) and Pd(PPh3)4 (Table 1,
only one obvious site for C-H activation under the condi- entry 8) did not. None of the other phosphine ligands per-
tions described here, the added aromaticity, presumably be- formed as well as PPh3 (Table 1, entries 9–11). Polar aprotic
stowed on the entire system by an additional ring, could solvents are generally the solvents of choice for direct aryl-
hinder cleavage of the key C–H bond. 2-Pyridones (isosteres ation reactions involving palladium catalysts, so it is unsur-
of 2-pyrones) possess numerous biological effects, including prising that toluene gave a very poor yield of 7% (Table 1,
antifungal, antibacterial, insecticidal and cytotoxic ac- entry 12). DMA (Table 1, entry 13) as solvent allowed com-
tivity.[32] Leporin A (Figure 1) shows activity against the plete consumption of starting material, however, the re-
corn earworm Helicoverpa zea and antibacterial activity duced isolated yield led us to favour NMP for future reac-
against Bacillus subtilis.[32] 2-Quinolones also have a promi- tions. Finally, the Pd loading could be reduced to 2 mol-%
nent biological profile,[33] such as the antihistamine Repirin- with a concomitant reduction of PPh3 to 4 mol-% with no
ast (Figure 1).[34,35] 2-Pyridones and 2-quinolones bear a ni- erosion of the product yield (Table 1, entry 14). In all cases,
trogen and thus a potentially problematic Pd-ligation site.
Development to include to these substrates would greatly
improve the widespread usability of any protocol. The Pd-
cyclisation of pyrones to form a five-membered ring has
been reported by Taylor and Fairlamb.[36] Importantly, no
conditions were reported to form the 6-membered analogues
and the conditions reported,[36] failed to form six-mem-
bered rings in our hands. Previous cyclisations by Majum-
bar[37,38] and us,[39] using so-called Jeffrey’s conditions, re-
quire the use of stoichiometric or superstoichiometric
amounts of TBAB and thus suffer from poor atom and cost
economy, falter from an environmental viewpoint (halide
waste) and would be avoided by the pharmaceutical indus-
try. Finally, a direct mechanistic probe was unavailable to
us under Jeffrey’s conditions due the requirement of P-li-
gands for the isolation of oxidative addition products.
Scheme 1. General procedure for direct arylation reaction of
pyrone 1 to 2.
Table 1. Optimisation of direct arylation reaction of pyrone 1 to 2.
Entry Pd source, phosphine, carboxylic acid, base,
solvent
% Yield
of 2[a]
1
2
3
4
5
6
7
8
9
Pd2(dba)3, PPh3, PivOH, Na2CO3, NMP
Pd2(dba)3, PPh3, AdmOH, Na2CO3, NMP
Pd2(dba)3, PPh3, –, Na2CO3, NMP
Pd2(dba)3, PPh3, PivOH, K2CO3, NMP
Pd2(dba)3, PPh3, PivOH, NaOAc NMP
Pd(OAc)2, PPh3, PivOH, Na2CO3, NMP
Pd(dba)2, PPh3 PivOH, Na2CO3, NMP
Pd(PPh3)4, PPh3, PivOH, Na2CO3, NMP
Pd2(dba)3, DavePhos, PivOH, Na2CO3, NMP
Pd2(dba)3, cataCXium®A, PivOH, Na2CO3,
NMP
77
62
(11)
38
(70)
54
(51)
(66)
(48)
(52)
Results and Discussion
Thus we turned our attention to concerted metalation-
deprotonation (CMD) conditions which would facilitate the
turnover under a different mechanism. Fagnou[40] and
Echavarren[41,42] demonstrated that pivalic acid (PivOH) is
a key additive in direct arylation reactions and facilitates
high yields when used with a Pd source [usually Pd-
(OAc)2], added phosphine and an inorganic base. Our ini-
tial test involved an intramolecular direct arylation reac-
tion, and we chose a catalytic system of Pd2(dba)3, PPh3,
Na2CO3 and PivOH using pyrone 1 (Scheme 1). A promis-
ing yield (77%) was obtained (Table 1, entry 1) after 2 h.
A number of other acid co-catalysts were investigated (not
10
11
Pd2(dba)3, P(Cy)3·HBF4, PivOH, Na2CO3,
NMP
(60)
12
13
14
Pd2(dba)3, PPh3, PivOH, Na2CO3, toluene
Pd2(dba)3, PPh3, PivOH, Na2CO3, DMA
Pd2(dba)3 (2 mol-%), PPh3 (4 mol-%),
PivOH, Na2CO3, NMP
(7)
30
78
15
Pd2(dba)3 (2 mol-%), PPh3 (4 mol-%), PivOH,
Na2CO3, NMP, 100 °C for 5 h
46
[a] Isolated yields. NMR yields are given in parentheses using 1,3,5-
trimethoxybenzene as the internal standard and were consistent
included here), with 1-adamantanecarboxylic acid with isolated yields in test cases.
2
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Direct Arylation of 2-Pyrones and Related Heterocycles
very good regioselectivity was observed favouring the 3-po- which are found in natural products.[23] In the case of 6-
sition.[43]
(hetero)aryl substrates, the presence of either electron-do-
The reaction also occurs at 100 °C (Table 1, entry 15). nating or withdrawing groups resulted in excellent yields
While complete conversion was achieved at the lower tem- (Scheme 2, compounds 14–17). However, the o-tolyl- and
perature, an erosion of yield and regioselectivity was ob- trimethoxy-substituted 2-pyrones gave reduced yields
served. With our optimised conditions in hand, we sought (Scheme 2, compounds 18 and 20), presumably due to a
to test the broader applicability of our system to a range of steric and reduced acidity[44] effect respectively. Pyrone 10
novel 2-pyrones in terms of yield and regioselectivity. As with a benzyl group at the 6-position failed to cyclise per-
can be seen from Scheme 2, the procedure proved to be ge- haps due to the acidic benzylic hydrogens. A methylene
neral for most substrates tested, giving moderate to excel- group was tolerated at C-6 however, and isobutyl-substi-
lent yields under the optimised reaction conditions. Despite tuted pyrone 11[45] gave the corresponding cyclised pyrone
the relative difficulty in accessing 6-aryl- and 6-alkyl-4-hy- 22 in a very good yield of 84%. A favourable alternative
droxy-2-pyrones, we were keen to ensure that our optimised site for oxidative addition inhibited turnover of the cyclis-
conditions tolerated a wide range of C-6 substitutions ation, and no cyclised pyrone was observed using 12. How-
ever, chloro analogue 13 was cyclised successfully in 90%
yield, leaving the chloride bond unaffected and available for
further cross-coupling. It is noteworthy that in all these
cases complete regioselectivity was observed and none of
the 5-cyclised product could be isolated. Furthermore, no
significant amounts of hydrodehalogenation products were
detected.
We next probed the electronics of the benzyl group (Fig-
ure 2, pyrones 25 and 26). The positioning of an electron-
donating substituent on the benzyl group para to the oxi-
dative addition site, proved a significant hindrance to cou-
pling (Figure 2, pyrone 42). Conversely, introduction of an
electron-withdrawing group para to the oxidative addition
site gave an excellent yield of pyrones 43 and 44.[46] Re-
markably, the regioselectivity previously observed, declined
significantly and substantial amounts of the C-5 cyclised
analogue was isolated.[47]
The wide range of tolerated substituents on our 2-py-
rones encouraged us to test our procedure on related het-
erocycles. Thus a range of substituted 2-coumarins, 2-pyrid-
inones and a 2-quinolone was synthesised and subjected to
the optimised protocol (Figure 2). (Bromobenzyloxy)cou-
marin 27 gave moderate yields, but returning to the iodo
analogue 28 facilitated smooth coupling and furnished 45
in excellent yield. A short substrate scope was investigated
and good yields were maintained affording 46–49. It is
pleasing that our protocol is widely applicable across a
range of substituted 2-pyridone heterocycles 33–40 (Fig-
ure 2).
A range of N-substituents are tolerated by this protocol
and the successful coupling of pyridone 33 containing a free
NH is particularly gratifying, as N-functionalization proto-
cols can be subsequently applied. 2-Quinolone 41 was also
cyclised to 56 in a 60% yield. The broad applicability of the
catalytic system prompted us to carry out some preliminary
mechanistic investigations. Firstly, we used coumarin sub-
strate 28 as a model to isolate and test the potential oxidat-
ive addition (OA) product formed. Pd2(dba)3 and 8 equiv.
of PPh3 were mixed to give precatalyst Pd0(η2-dba)(PPh3)2
in THF, which is the optimal solvent for the isolation of
oxidative addition products. Addition of coumarin 28 and
heating allowed formation of oxidation product [I-Pd-
R(L)2] 57 in 90% yield. The nature of 57 as a catalytically
Scheme 2. Substrate scope of optimised direct arylation reaction.
relevant intermediate was then established. Thus coumarin
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Scheme 3. Isolated oxidative addition product as a catalytically rel-
evant intermediate.
stirring at 70 °C for 1 h. Subsequent addition of Na2CO3
(10 equiv.) and PivOH (3 equiv.) and stirring at 129 °C for a
further 3 h, resulted in cyclised product 45 in 47% yield.[48]
Given the proficiency of oxidative addition compound
57 to facilitate coupling, we postulate oxidative addition as
the first critical mechanistic step.[49] However, an alternative
initial step could involve a C-H activation. Given the appar-
ent acidity of the C3–H bond,[50] the potential for an initial
reversible C–H bond activation was considered. This was
assessed using three tests with PivOD. The experiments
consisted of (1) Exposing 28 to the optimised reaction con-
ditions in the presence of PivOD and halting the reaction
before completion. (2) Using an unhalogenated variant of
28 under the standard conditions with PivOD. (3) Using an
unhalogenated variant of 28 with PivOD but with a stoi-
chiometric amount of the Pd and phosphine sources. All
three failed to give any deuterium incorporation. This rules
out an initial step involving a pivalate assisted reversible C–
H activation.[51]
Based on our preliminary mechanistic studies, we envis-
age an initial oxidative addition (OA) step resulting in PdII
complex 57. It is tempting to consider OA as the rate-limit-
ing step given the improvement in yields on changing from
an aryl bromide to aryl iodide in a number of cases (to
form 45, 51 and 53), and the favourable result when elec-
tron-poor aryl halide 26 (87% yield of 2 regioisomers) is
used vs. electron-rich 25 (8%). However the OA step should
be facile, occurring at room temperature, and we consider
it unlikely to be the rate-limiting step. In any case, we postu-
Figure 2. Extension of methodology to further 2-pyrones, 2-couma-
rins, 2-pyridones and 2-quinolones.
28 was subjected to the optimised reaction conditions, re- late a mechanism involving an initial OA, followed by a
placing Pd2(dba)3 (2 mol-%) and PPh3 (4 mol-%) with 57 ligand exchange and a concerted metallation-deprotonation
(2 mol-%). The cyclisation product 45, was obtained in 55% promoted by PivOH.[52] Finally, ligand dissociation and re-
yield, comparable to results under the standard reaction ductive elimination restores the catalyst and expels arylated
conditions (Scheme 3).
product 45 (Scheme 4). The importance of PivOH to the
This reaction was also performed in the absence of success of our system could be interpreted as evidence that
PivOH, resulting in only 3% yield of product 45 by NMR these arylation reactions proceed via CMD, based on work
spectroscopy. Isolated oxidative addition product 57 (in the by the Fagnou and Echavarren groups which demonstrates
absence of substrate 28) also gave cyclised product 45 in the importance of PivOH as a promoter of phosphine
36% yield in the presence of PivOH and Na2CO3 in NMP. dissociation from the PdII intermediate, enabling the CMD
In the absence of PivOH under otherwise identical condi- transition state,[52] and as a catalytic proton shuttle[40] in
tions, only 5% of 45 was identified. Finally, stoichiometric the CMD mechanism.[53] It should be noted that an SEAr
amounts of oxidative addition product 57 were also clearly mechanism[54] would also account for the deleterious effect
identified in NMP (our optimised reaction solvent) after on yield when an electron-donating group is present on aryl
4
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Direct Arylation of 2-Pyrones and Related Heterocycles
halide 25 and the corresponding excellent yield using an regioselectivity is observed and conditions and mechanistic
electron poor aryl halide 26. A Heck-type mechanism studies suggest an initial oxidative addition followed by a
would require an anti-hydride elimination (or an isomeris- pivalate assisted CMD-type mechanism, although a SEAr
ation) and is thus deemed unlikely. Further studies are on- route cannot be ruled out at this time.
going to delineate the likely modes of action.
Experimental Section
General: Melting point determinations were performed by the open
1
capillary method and are reported uncorrected. H and 13C NMR
spectra were recorded at 25 °C in CDCl3 at 300 and 75 MHz spec-
trometer unless otherwise specified, with TMS as the internal stan-
dard. Chemical shifts (δH, δC and δP) were expressed as parts per
million (ppm) positive shift 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 ESI
source. High-resolution mass spectra were recorded only for new
compounds. Literature citations are provided for known com-
pounds and representative characterisation 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.
General Procedure for Starting Materials 1, 3–13 and 25–41: Start-
ing materials 1, 3–13 and 25–41 were prepared as follows: a solu-
tion of pyrone,[57] coumarin,[30,58] pyridone[59] or quinolone[60]
(1.0 equiv.), 2-bromobenzyl bromide or 2-iodobenzyl bromide
(1.2 equiv.) and K2CO3 (3.0 equiv.) in acetone (4.0 mL/mmol start-
ing material) was refluxed (79 °C) for 4 h. The mixture was
quenched with water (20 mL), extracted with EtOAc (3ϫ 10 mL),
dried and the solvents evaporated. The crude obtained was purified
by column chromatography (SiO2, DCM/MeOH, 99.5:0.5).
4-[(2-Iodobenzyl)oxy]-6-methyl-2H-pyran-2-one (1): See ref.[39]
4-[(2-Bromobenzyl)oxy]-6-phenyl-2H-pyran-2-one (3): See ref.[39]
Scheme 4. Suggested mechanism.
4-[(2-Bromobenzyl)oxy]-6-(thiophen-2-yl)-2H-pyran-2-one (4): Yel-
Initial application of our optimised conditions to the
more challenging intermolecular variant (58 to 59) did not
allow coupling.[55] However, when precatalyst 60[56] (de-
signed to produce active Pd0 quickly) was used, an encour-
aging yield was obtained. Further optimisation is ongoing
and will be reported in due course (Scheme 5).
low solid (0.1458 g, 42%), m.p. 124–125 °C (hexanes). 1H NMR
(300 MHz, CDCl3): δ = 7.62–7.58 (m, 2 H), 7.47–7.43 (m, 2 H),
7.39–7.34 (m, 1 H), 7.27–7.21 (m, 1 H), 7.11–7.08 (m, 1 H), 6.35
(d, J = 2.3 Hz, 1 H), 5.57 (d, J = 2.3 Hz, 1 H), 5.13 (s, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 169.8 (C), 163.3 (C), 156.0 (C),
134.7 (C), 133.7 (C), 133.0 (CH), 130.3 (CH), 129.4 (CH), 129.1
(CH), 128.3 (CH), 127.8 (CH), 127.7 (CH), 123.0 (C), 96.7 (CH),
89.3 (CH), 70.3 (CH ) ppm. IR (film): ν = 1724 cm–1. HRMS (ESI,
˜
2
[M + H]+) m/z calcd. for C16H12O3SBr 362.9691, found 362.9675.
4-Hydroxy-6-(thiophen-2-yl)-2H-pyran-2-one: See ref.[57]
4-[(2-Bromobenzyl)oxy]-6-(furan-2-yl)-2H-pyran-2-one (5): Yellow-
ish solid (0.0630 g, 36%), m.p. 132–133 °C (hexanes). 1H NMR
(300 MHz, CDCl3): δ = 7.63–7.60 (m, 1 H), 7.51–7.44 (m, 2 H),
7.39–7.34 (m, 1 H), 7.28–7.24 (m, 1 H) 7.01 (d, J = 3.2 Hz, 1 H),
6.54–6.52 (m, 1 H), 6.55 (d, J = 2.4 Hz, 1 H), 5.57 (d, J = 2.4 Hz,
1 H), 5.15 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.9
(C), 163.2 (C), 152.4 (C), 146.2 (C), 144.9 (CH), 133.7 (C), 133.0
(CH), 130.2 (CH), 129.2 (CH), 127.7 (CH), 122.9 (C), 112.4 (CH),
Scheme 5. Preliminary intermolecular variant.
112.3 (CH), 96.1 (CH), 89.5 (CH), 70.2 (CH ) ppm. IR (film): ν =
˜
2
1732 cm–1. MS (M+, ES+) m/z (%) 347 (44), 291 (60), 42 (100).
HRMS (ESI, [M + H]+) m/z calcd. for C16H12O4Br 346.9919,
found 346.9910.
Conclusions
In conclusion, we report the intramolecular cyclisation
of the privileged 2-pyrone, 2-coumarin, 2-pyridone and 2-
quinolone motifs under direact arylation conditions condi-
6-(Furan-2-yl)-4-hydroxy-2H-pyran-2-one: See ref.[57]
4-[(2-Bromobenzyl)oxy]-6-[4-(trifluoromethyl)phenyl]-2H-pyran-2-
tions using pivalic acid as a necessary additive. Excellent one (6): See ref.[39]
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4-[(2-Bromobenzyl)oxy]-6-(o-tolyl)-2H-pyran-2-one (7): White solid ES-) m/z (%) 202 (12), 201 (100), 157 (33). HRMS (ESI,
(0.2210 g, 60%), m.p. 133–135 °C (MeOH). 1H NMR (300 MHz,
CDCl3): δ = 7.62 (dd, J = 9.9, 0.9 Hz, 1 H), 7.54–7.44 (m, 2 H),
7.37–7.31 (m, 2 H), 7.27–7.23 (m, 3 H), 6.20 (d, J = 2.2 Hz, 1 H),
5.64 (d, J = 2.2 Hz, 1 H), 5.15 (s, 2 H), 2.48 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 169.8 (C), 164.2 (C), 162.6 (C), 136.7
(C), 133.8 (C), 133.1 (CH), 131.9 (C), 131.3 (CH), 130.4 (CH),
130.3 (CH), 129.4 (CH), 128.9 (CH), 127.8 (CH), 126.1 (CH), 123.0
(C), 102.0 (CH), 89.5 (CH), 70.2 (CH2), 20.8 (CH3) ppm. IR (film):
[M + H]+) m/z calcd. for C12H11O3 203.0708, found 203.0708.
4-[(2-Iodobenzyl)oxy]-6-isobutyl-2H-pyran-2-one (11): Yellow oil
(0.0733 g, 36%). 1H NMR (300 MHz, CDCl3): δ = 7.54 (d, J =
7.6 Hz, 1 H), 7.33–7.30 (m, 2 H), 7.02–6.96 (m, 1 H), 5.77 (d, J =
2.2 Hz, 1 H), 5.43 (d, J = 2.2 Hz, 1 H), 4.93 (s, 2 H), 2.24 (d, J =
7.2 Hz, 2 H), 2.06–1.97 (m, 1 H), 0.88 (d, J = 6.6 Hz, 6 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 169.8 (C), 165.2 (C), 164.9 (C),
139.6 (CH), 136.8 (C), 130.3 (CH), 129.0 (CH), 128.5 (CH), 100.6
(CH), 97.7 (C), 88.9 (CH), 74.3 (CH2), 42.9 (CH2), 26.7 (CH), 22.2
ν = 1715 cm–1. MS (M+, ES+) m/z (%) 371 (10), 323 (100), 150
˜
(700). HRMS (ESI, [M + H]+) m/z calcd. for C19H16O3Br 371.0283,
(CH ) ppm. IR (film): ν = 1720 cm–1. MS (M+, ES+) m/z (%) 384
˜
3
found 371.0284.
(100). HRMS (ESI, [M + H]+) m/z calcd. for C16H18O3I 385.0302,
4-Hydroxy-6-(o-tolyl)-2H-pyran-2-one: White solid, m.p. 191–
192 °C (MeOH). H NMR (300 MHz, [D6]DMSO): δ = 11.88 (br.
found 385.0301.
1
4-Hydroxy-6-isobutyl-2H-pyran-2-one: White solid, m.p. 106–
108 °C (MeOH). H NMR (300 MHz, CDCl3): δ = 10.82 (br. s, 1
s, 1 H), 7.48–7.29 (m, 4 H), 6.28 (d, J = 2.0 Hz, 1 H), 5.40 (d, J =
2.0 Hz, 1 H), 2.39 (s, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO):
δ = 170.7 (C), 163.9 (C), 162.7 (C), 136.5 (C), 132.5 (C), 131.6
(CH), 130.7 (CH), 129.2 (CH), 126.7 (CH), 102.7 (CH), 89.7 (CH),
1
H), 5.97 (d, J = 1.1 Hz, 1 H), 5.59 (d, J = 1.4 Hz, 1 H), 2.34 (d, J
= 7.2 Hz, 2 H), 2.11–2.04 (m, 1 H), 0.95 (d, J = 6.6 Hz, 6 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 172.4 (C), 168.3 (C), 166.5 (C),
102.3 (CH), 89.9 (CH), 42.8 (CH2), 26.1 (CH), 22.2 (CH3) ppm.
20.6 (CH ) ppm. IR (film): ν = 1636 cm–1. MS (M+, ES+) m/z (%)
˜
3
202 (100), 64 (30), 42 (30). HRMS (ESI, [M + H]+) m/z calcd. for
IR (film): ν = 1678 cm–1. MS (M+, ES+) m/z (%) 168 (100), 102
˜
C12H11O3 203.0708, found 203.0700.
(10), 42 (10). HRMS (ESI, [M + H]+) m/z calcd. for C9H13O3
4-[(2-Bromobenzyl)oxy]-6-(4-methoxyphenyl)-2H-pyran-2-one (8): 169.0865, found 169.0857.
White solid (0.0389 g, 15%), m.p. 82–86 °C (hexanes). 1H NMR
4-[(2-Bromobenzyl)oxy]-6-(4-iodophenyl)-2H-pyran-2-one (12): Yel-
(300 MHz, CDCl3): δ = 7.76 (d, J = 9.0 Hz, 2 H), 7.62 (dd, J =
7.9, 1.1 Hz, 1 H), 7.47 (dd, J = 7.9, 1.6 Hz, 1 H), 7.40 (dtd, J =
8.8, 7.6, 1.4 Hz, 1 H), 7.24 (dt, J = 7.7, 2.0 Hz, 1 H), 6.95 (d, J =
9.0 Hz, 2 H), 6.41 (d, J = 2.1 Hz, 1 H), 5.58 (d, J = 2.1 Hz, 1 H),
5.14 (s, 2 H), 3.85 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
170.3 (C), 164.2 (C), 160.6 (C), 160.6 (C), 133.9 (C), 133.0 (CH),
130.2 (CH), 129.3 (CH), 127.8 (CH), 127.4 (CH), 123.5 (C), 123.0
(C), 114.3 (CH), 96.3 (CH), 88.9 (CH), 70.1 (CH2), 55.4 (CH3)
low solid (0.1076 g, 37%), m.p. 188–192 °C (hexanes). 1H NMR
(300 MHz, CDCl3): δ = 7.80 (d, J = 8.6 Hz, 2 H), 7.67–7.58 (m, 1
H), 7.53 (d, J = 8.6 Hz, 2 H), 7.46 (dd, J = 7.6, 1.5 Hz, 1 H), 7.41–
7.33 (m, 1 H), 7.30–7.17 (m, 1 H), 6.51 (d, J = 2.0 Hz, 1 H), 5.65 (d,
J = 2.0 Hz, 1 H), 5.15 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 169.8 (C), 163.6 (C), 159.5 (C), 138.2 (CH), 133.7 (C), 133.1
(CH), 130.5 (C), 130.3 (CH), 129.4 (CH), 127.8 (CH), 127.1 (CH),
123.1 (C), 98.2 (CH), 97.7 (C), 90.1 (CH), 70.4 (CH2) ppm. IR
ppm. IR (film): ν = 1715 cm–1. MS (M+, ES+) m/z (%) 387 (74),
˜
(film): ν = 1720 cm–1. MS (M+, ES+) m/z (%) 483 (30), 389 (100).
˜
46 (35). HRMS (ESI, [M + H]+) m/z calcd. for C19H16O4Br
HRMS (ESI, [M + H]+) m/z calcd. for C18H13O3BrI 482.9093,
387.0232, found 387.0232.
found 482.9096.
4-Hydroxy-6-(4-methoxyphenyl)-2H-pyran-2-one: Yellow solid, m.p.
193–195 °C (hexanes). 1H NMR (300 MHz, [D6]DMSO): δ = 11.75
(br. s, 1 H), 7.80 (d, J = 9.0 Hz, 2 H), 7.07 (d, J = 9.0 Hz, 2 H),
6.63 (d, J = 1.9 Hz, 1 H), 5.33 (d, J = 1.9 Hz, 1 H), 3.83 (s, 3 H)
ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 171.3 (C), 163.6 (C),
161.9 (C), 160.7 (C), 127.7 (CH), 123.9 (C), 114.9 (CH), 97.1 (CH),
4-Hydroxy-6-(4-iodophenyl)-2H-pyran-2-one: Orange solid, m.p.
Ͼ230 °C (hexanes). 1H NMR (300 MHz, [D6]DMSO): δ = 11.89
(br. s, 1 H), 7.89 (d, J = 8.3 Hz, 2 H), 7.63 (d, J = 8.3 Hz, 2 H),
6.79 (d, J = 1.3 Hz, 1 H), 5.42 (d, J = 1.3 Hz, 1 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 170.9 (C), 163.3 (C), 159.6 (C), 138.4
(CH), 131.0 (C), 127.7 (CH), 99.2 (CH), 98.7 (C), 90.4 (CH) ppm.
89.1 (CH), 55.9 (CH ) ppm. IR (film): ν = 1634 cm–1. MS (M+,
˜
3
IR (film): ν = 1601 cm–1. MS (M+, ES+) m/z (%) 314 (52), 242
˜
ES+) m/z (%) 218 (100), 64 (42). HRMS (ESI, [M + H]+) m/z calcd.
(100), 64 (49). HRMS (ESI, [M + H]+) m/z calcd. for C11H8O3I
for C12H11O4 219.0657, found 219.0650.
314.9518, found 314.9519.
4-[(2-Bromobenzyl)oxy]-6-(3,4,5-trimethoxyphenyl)-2H-pyran-2-one
(9): See ref.[39]
4-[(2-Bromobenzyl)oxy]-6-(4-chlorophenyl)-2H-pyran-2-one
(13):
Yellow solid (0.1020 g, 30%), m.p. 146–148 °C (hexanes). 1H NMR
6-Benzyl-4-[(2-bromobenzyl)oxy]-2H-pyran-2-one (10): Yellow oil (300 MHz, CDCl3): δ = 7.81–7.67 (m, 2 H), 7.63 (dd, J = 7.0,
(0.1008 g, 54%). 1H NMR (300 MHz, CDCl3): δ = 7.60 (d, J =
8.1 Hz, 1 H), 7.57–7.19 (m, 8 H), 5.72 (d, J = 2.2 Hz, 1 H), 5.50
1.0 Hz, 1 H), 7.59–7.12 (m, 5 H), 6.49 (d, J = 2.1 Hz, 1 H), 5.65 (d,
J = 2.1 Hz, 1 H), 5.15 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ
(d, J = 2.2 Hz, 1 H), 5.05 (s, 2 H), 3.77 (s, 2 H) ppm. 13C NMR = 169.8 (C), 163.6 (C), 159.3 (C), 137.2 (C), 133.7 (C), 133.1 (CH),
(75 MHz, CDCl3): δ = 169.9 (C), 164.9 (C), 164.5 (C), 134.6 (C),
130.3 (CH), 129.5 (C), 129.4 (CH), 129.2 (CH), 127.8 (CH), 127.0
(CH), 123.1 (C), 98.2 (CH), 90.0 (CH), 70.4 (CH2) ppm. IR (film):
˜
133.7 (C), 133.0 (C), 133.0 (CH), 130.2 (CH), 129.4 (CH), 129.3
(CH), 128.9 (CH), 127.7 (CH), 127.4 (CH), 100.5 (CH), 88.9 (CH), ν = 1729 cm–1. MS (M+, ES+) m/z (%) 391 (90), 373 (60), 235 (57),
70.1 (CH ), 39.9 (CH ) ppm. IR (film): ν = 1720 cm–1. MS (M+, 102 (50), 64 (79). HRMS (ESI, [M + H]+) m/z calcd. for
˜
2
2
ES+) m/z (%) 371 (68), 323 (32), 42 (100). HRMS (ESI, [M + H]+) C18H13O3ClBr 390.9737, found 390.9744.
m/z calcd. for C19H16O3Br 371.0283, found 371.0265.
6-(4-Chlorophenyl)-4-hydroxy-2H-pyran-2-one: Yellow solid, m.p.
215–216 °C (MeOH). H NMR (300 MHz, [D6]DMSO): δ = 11.91
1
6-Benzyl-4-hydroxy-2H-pyran-2-one: Cream solid, m.p. 134–135 °C
1
(MeOH). H NMR (300 MHz, [D6]DMSO): δ = 11.70 (br. s, 1 H), (br. s, 1 H), 7.87 (d, J = 8.6 Hz, 2 H), 7.58 (d, J = 8.6 Hz, 2 H),
7.35–7.28 (m, 5 H), 5.94 (s, 1 H), 5.23 (s, 1 H), 3.80 (s, 2 H) ppm.
6.80 (d, J = 1.9 Hz, 1 H), 5.41 (d, J = 1.9 Hz, 1 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 170.9 (C), 163.2 (C), 159.3 (C), 136.1
13C NMR (75 MHz, [D6]DMSO): δ = 170.8 (C), 165.6 (C), 164.2
(C), 136.4 (C), 129.6 (CH), 129.1 (CH), 127.4 (CH), 100.9 (CH), (C), 130.4 (C), 129.6 (CH), 127.7 (CH), 99.3 (CH), 90.3 (CH) ppm.
88.9 (CH), 39.3 (CH ) ppm. IR (film): ν = 1663 cm–1. MS (M–, IR (film): ν = 1657 cm–1. MS (M+, ES+) m/z (%) 222 (100), 83 (30),
˜
˜
2
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50262
/KAP1
Date: 27-04-15 11:55:33
Pages: 12
Direct Arylation of 2-Pyrones and Related Heterocycles
42 (52). HRMS (ESI, [M + H]+) m/z calcd. for C11H8O3Cl
223.0162, found 223.0167.
105.5 (CH), 97.9 (C), 91.8 (CH), 74.8 (CH2), 55.9 (CH3) ppm. IR
(film): ν = 1715 cm–1. MS (M+, ES+) m/z (%) 408 (100), 102 (7),
˜
64 (15). HRMS (ESI, [M + H]+) m/z calcd. for C17H14O4I
4-[(2-Bromo-5-methoxybenzyl)oxy]-6-methyl-2H-pyran-2-one (25):
408.9937, found 408.9929.
See ref.[37]
4-Hydroxy-6-methoxy-2H-chromen-2-one: See ref.[30]
4-[(2-Bromo-5-fluorobenzyl)oxy]-6-methyl-2H-pyran-2-one
(26):
1
White solid (0.1370 g, 57%), m.p. 111–113 °C (hexanes). H NMR
(300 MHz, CDCl3): δ = 7.55 (dd, J = 8.8, 5.2 Hz, 1 H), 7.17 (dd,
J = 9.1, 3.0 Hz, 1 H), 7.03–6.89 (m, 1 H), 5.90 (d, J = 2.2 Hz, 1
H), 5.48 (d, J = 2.2 Hz, 1 H), 5.05 (s, 2 H), 2.24 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 169.6 (C), 164.5 (C), 162.6 (C), 162.3
(d, J = 124.0 Hz, F-C), 136.0 (d, J = 7.6 Hz, F-C), 134.2 (d, J =
8.0 Hz, F-CH), 117.1 (d, J = 22.5 Hz, F-CH), 116.1 (d, J = 3.4 Hz,
F-C), 115.9 (d, J = 24.4 Hz, F-CH), 100.2 (CH), 88.8 (CH), 69.3
7-Fluoro-4-[(2-iodobenzyl)oxy]-2H-chromen-2-one (32): White solid
(0.0760 g, 35%), m.p. 166–167 °C (DCM). 1H NMR (300 MHz,
CDCl3): δ = 7.95–7.85 (m, 2 H), 7.50–7.39 (m, 2 H), 7.15–6.93 (m,
3 H), 5.76 (s, 1 H), 5.20 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 166.7 (C), 164.1 (d, J = 209.3 Hz, C-F), 162.4 (C), 154.6 (d, J
= 13.2 Hz, C-F), 139.8 (CH), 136.5 (C), 130.6 (CH), 129.3 (CH),
128.6 (CH), 125.1 (d, J = 10.3 Hz, F-CH), 112.2 (C), 112.1 (d, J =
22.7 Hz, F-CH), 104.2 (d, J = 25.6 Hz, F-CH), 98.1 (C), 90.5 (CH),
(CH ), 19.8 (CH ) ppm. IR (film): ν = 1729 cm–1. MS (M–, ES+)
74.9 (CH ) ppm. IR (film): ν = 1703 cm–1. MS (M+, ES+) m/z (%)
˜
2
3
˜
2
m/z (%) 311(33), 81 (100), 79 (79). HRMS (ESI, [M + H]–) m/z
396 (20), 393 (100), 64 (24), 42 (16). HRMS (ESI, [M + H]+) m/z
calcd. for C13H11O3FBr 312.9876, found 312.9872.
calcd. for C16H11O3FI 396.9737, found 396.9733.
4-[(2-Bromobenzyl)oxy]-2H-chromen-2-one (27): See ref.[39]
7-Fluoro-4-hydroxy-2H-chromen-2-one: White solid (0.1220 g,
15%).[58]
4-[(2-Iodobenzyl)oxy]-2H-chromen-2-one
(28):
White
solid
1
(0.3390 g, 73%), m.p. 158–159 °C (hexanes). H NMR (300 MHz,
CDCl3): δ = 7.98–7.78 (m, 2 H), 7.66–7.23 (m, 5 H), 7.18–7.05 (m,
1 H), 5.80 (s, 1 H), 5.21 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 165.0 (C), 162.7 (C), 153.4 (C), 139.8 (CH), 136.7 (C), 132.5
(CH), 130.5 (CH), 129.1 (CH), 128.6 (CH), 124.0 (CH), 123.2
(CH), 116.8 (CH), 115.6 (C), 97.9 (C), 91.5 (CH), 74.8 (CH2) ppm.
4-[(2-Bromobenzyl)oxy]-6-methylpyridin-2(1H)-one (33): White so-
lid (0.1480 g, 23%), m.p. 191 °C (hexanes). 1H NMR (300 MHz,
CDCl3): δ = 12.89 (br. s, 1 H), 7.58 (d, J = 7.9 Hz, 1 H), 7.45 (d,
J = 7.4 Hz, 1 H), 7.33 (t, J = 7.4 Hz, 1 H), 7.20 (t, J = 7.7 Hz, 1
H), 5.85 (d, J = 4.0 Hz, 2 H), 5.08 (s, 2 H), 2.31 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 168.8 (C), 167.6 (C), 146.0 (C), 134.8
(C), 132.8 (CH), 129.6 (CH), 128.8 (CH), 127.6 (CH), 122.5 (C),
IR (film): ν = 1717 cm–1. MS (M+, ES+) m/z (%) 378 (82), 235 (52),
˜
64 (58). HRMS (ESI, [M + H]+) m/z calcd. for C16H12O3I
99.9 (CH), 95.3 (CH), 69.4 (CH ), 18.9 (CH ) ppm. IR (film): ν =
˜
2
3
378.9831, found 378.9827.
1646 cm–1. MS (M+, ES+) m/z (%) 294 (10). HRMS (ESI,
4-[(2-Iodobenzyl)oxy]-6-methyl-2H-chromen-2-one (29): White solid [M + H]+) m/z calcd. for C13H13NO2Br 294.0130, found 294.0121.
(0.0880 g, 20%), m.p. 168–169 °C (DCM). 1H NMR (300 MHz,
4-Hydroxy-6-methylpyridin-2(1H)-one: White solid (0.4920 g,
CDCl3): δ = 7.93 (d, J = 8.2 Hz, 1 H), 7.65 (s, 1 H), 7.56–7.31 (m,
50%).[62]
3 H), 7.24 (t, J = 8.2 Hz, 1 H), 7.11 (t, J = 7.6 Hz, 1 H), 5.77 (s, 1
H), 5.18 (s, 2 H), 2.41 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
4-[(2-Bromobenzyl)oxy]-1,6-dimethylpyridin-2(1H)-one (34): See
ref.[39]
δ = 165.0 (C), 162.9 (C), 151.6 (C), 139.8 (CH), 136.8 (C), 136.8
(C), 133.5 (CH), 130.5 (CH), 129.1 (CH), 128.6 (CH), 122.8 (CH),
116.6 (CH), 115.2 (C), 97.9 (C), 91.5 (CH), 74.8 (CH2), 20.9 (CH3)
4-Hydroxy-1,6-dimethylpyridin-2(1H)-one: See ref.[39]
ppm. IR (film): ν = 1715 cm–1. MS (M+, ES+) m/z (%) 392 (100),
˜
4-[(2-Iodobenzyl)oxy]-1,6-dimethylpyridin-2(1H)-one (35): White so-
lid (0.4210 g, 29%), m.p. 134–136 °C (hexanes). 1H NMR
(300 MHz, CDCl3): δ = 7.86 (d, J = 7.9 Hz, 1 H), 7.44–7.31 (m, 2
H), 7.03 (td, J = 7.5, 1.8 Hz, 1 H), 5.93 (d, J = 2.6 Hz, 1 H), 5.88
(d, J = 2.4 Hz, 1 H), 4.96 (s, 2 H), 3.47 (s, 3 H), 2.31 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 165.9 (C), 165.3 (C), 146.4 (C),
139.5 (CH), 137.8 (C), 129.8 (CH), 128.7 (CH), 128.4 (CH), 100.8
(CH), 97.5 (C), 95.9 (CH), 73.7 (CH2), 30.6 (CH3), 20.9 (CH3)
64 (24). HRMS (ESI, [M + H]+) m/z calcd. for C17H14O3I
392.9988, found 392.9983.
4-Hydroxy-6-methyl-2H-chromen-2-one: See ref.[30]
6-Ethyl-4-[(2-iodobenzyl)oxy]-2H-chromen-2-one (30): White solid
1
(0.4500 g, 42%), m.p. 156–161 °C (hexanes). H NMR (300 MHz,
CDCl3): δ = 7.92 (d, J = 8.3 Hz, 1 H), 7.67 (d, J = 2.0 Hz, 1 H),
7.54–7.35 (m, 3 H), 7.30–7.21 (m, 1 H), 7.11 (td, J = 1.7, 7.6 Hz,
1 H), 5.77 (s, 1 H), 5.19 (s, 2 H), 2.71 (q, J = 7.5 Hz, 2 H), 1.26 (t,
J = 7.6 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.1 (C),
162.9 (C), 151.7 (C), 140.2 (C), 139.8 (CH), 136.8 (C), 132.4 (CH),
130.5 (CH), 129.1 (CH), 128.6 (CH), 121.7 (CH), 116.7 (CH), 115.3
(C), 97.9 (C), 91.5 (CH), 74.8 (CH2), 28.4 (CH2), 15.8 (CH3) ppm.
ppm. IR (film): ν = 1644 cm–1. MS (M+, ES+) m/z (%) 356 (18).
˜
HRMS (ESI, [M + H]+) m/z calcd. for C14H15NO2I 356.0147,
found 356.0144.
4-Hydroxy-1,6-dimethylpyridin-2(1H)-one: See ref.[39]
4-[(2-Bromobenzyl)oxy]-6-methyl-1-phenylpyridin-2(1H)-one (36):
White solid (0.1101 g, 20%), m.p. 143 °C (hexanes). 1H NMR
(300 MHz, CDCl3): δ = 7.60 (dd, J = 8.0, 1.2 Hz, 1 H), 7.53–7.40
(m, 4 H), 7.38–7.33 (td, J = 7.5, 1.2 Hz, 1 H); 7.24–7.18 (m, 3 H)
5.99 (d, J = 2.6 Hz, 1 H), 5.96 (dd, J = 2.6, 0.8 Hz, 1 H), 5.09 (s,
2 H), 1.92 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.7
(C), 165.4 (C), 146.4 (C), 138.6 (C), 134.9 (C), 132.9 (CH), 129.7
(CH), 129.6 (CH), 129.1 (CH), 128.7 (CH), 128.3 (CH), 127.6
(CH), 122.7 (CH), 100.8 (CH), 96.3 (CH), 69.5 (CH2), 21.5 (CH3)
IR (film): ν = 1716 cm–1. MS (M+, ES+) m/z (%) 407 (18). HRMS
˜
(ESI, [M + H]+) m/z calcd. for C18H16O3I 407.0144, found
407.0146.
6-Ethyl-4-hydroxy-2H-chromen-2-one:
Brown
solid
(1.16 g,
76%).[61]
4-[(2-Iodobenzyl)oxy]-6-methoxy-2H-chromen-2-one (31): Yellow
solid (0.2340 g, 55%), m.p. 132–133 °C (DCM). 1H NMR
(300 MHz, CDCl3): δ = 7.92 (d, J = 7.9 Hz, 1 H), 7.52–7.38 (m, 2
H), 7.33–7.20 (m, 2 H), 7.19–7.04 (m, 2 H), 5.78 (s, 1 H), 5.19 (s,
2 H), 3.84 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 164.7
(C), 162.9 (C), 155.9 (C), 147.8 (C), 139.8 (CH), 136.7 (C), 130.5
ppm. IR (film): ν = 1661 cm–1. HRMS (ESI, [M + H]+) m/z calcd.
˜
for C19H17NO2Br 370.0443, found 370.0427.
4-Hydroxy-6-methyl-1-phenylpyridin-2(1H)-one:
White
solid
7
(CH), 129.2 (CH), 128.6 (CH), 120.2 (CH), 117.9 (CH), 115.9 (C), (0.3400 g, 21%).[63]
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org

Job/Unit: O50262
/KAP1
Date: 27-04-15 11:55:33
Pages: 12
G. P. McGlacken et al.
FULL PAPER
1-Benzyl-4-[(2-bromobenzyl)oxy]-6-methylpyridin-2(1H)-one (37):
131.3 (CH), 130.0 (CH), 128.8 (CH), 128.5 (CH), 123.6 (CH), 121.7
(CH), 116.4 (C), 114.1 (CH), 98.0 (CH), 74.2 (CH2), 29.1 (CH3)
See ref.[39]
ppm. IR (film): ν = 1630 cm–1. MS (M+, ES+) m/z (%) 391 (10).
˜
1-Benzyl-4-hydroxy-6-methylpyridin-2(1H)-one: See ref.[39]
HRMS (ESI, [M + H]+) m/z calcd. for C17H15INO2 392.0141,
1-Benzyl-4-[(2-iodobenzyl)oxy]-6-methylpyridin-2(1H)-one
(38):
found 392.0148.
1
White solid (0.2200 g, 55%), m.p. 129–134 °C (hexanes). H NMR
(300 MHz, CDCl3): δ = 7.87 (dd, J = 7.9, 0.7 Hz, 1 H), 7.47–7.10
(m, 7 H), 7.04 (td, J = 7.6, 1.8 Hz, 1 H), 6.01 (d, J = 2.7 Hz, 1 H),
5.88 (d, J = 2.3 Hz, 1 H), 5.29 (s, 2 H), 5.00 (s, 2 H), 2.23 (s, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 166.2 (C), 165.3 (C), 146.7
(C), 139.5 (CH), 137.8 (C), 136.8 (C), 129.9 (CH), 128.8 (CH),
128.4 (CH), 127.3 (CH), 126.4 (CH), 101.4 (CH), 97.5 (C), 96.1
4-Hydroxy-1-methylquinolin-2(1H)-one: See ref.[60]
General Procedure for the Coupling Reaction. Compounds 2, 14–24
and 42–56: A solution of pyrone, coumarin, pyridone or quinolone
(1.0 equiv.), Pd2(dba)3 (2 mol-%), pivalic acid (30 mol-%), tri-
phenylphosphine (4 mol-%) and Na2CO3 (3.0 equiv.) in N-methyl-
2-pyrrolidone (3.0 mL/mmol starting material) was stirred in a
Schlenk tube under N2 at 129 °C. After 3 h, water (10 mL) and
EtOAc (10 mL) were added. The mixture was extracted with
EtOAc (2ϫ 10 mL) and the combined organic layers were washed
with 1 m HCl (1ϫ 20 mL), water (3ϫ 10 mL), brine (1ϫ 20 mL),
dried and the solvents evaporated. The crude obtained was purified
by column chromatography (SiO2, DCM).
(CH), 73.8 (CH ), 46.6 (CH ), 20.6 (CH ) ppm. IR (film): ν = 1653
˜
2
2
3
cm–1. MS (M+, ES+) m/z (%) 432(28). HRMS (ESI, [M + H]+) m/z
calcd. for C20H19INO2 432.0460, found 432.0444.
1-Benzyl-4-hydroxy-6-methylpyridin-2(1H)-one: See ref.[39]
4-[(2-Bromobenzyl)oxy]-1-(4-methoxyphenyl)-6-methylpyridin-2-
(1H)-one (39): White solid (0.1250 g, 24%), m.p. 189–190 °C (hex-
anes). H NMR (300 MHz, CDCl3): δ = 7.59 (dd, J = 7.9, 1.0 Hz,
3-Methylpyrano[4,3-c]isochromen-1(6H)-one (2): White solid
1
(0.0480 g, 78%).[39]
1 H), 7.48 (dd, J = 7.6, 1.4 Hz, 1 H), 7.35 (td, J = 7.5, 1.0 Hz, 1
H), 7.21 (td, J = 7.7, 1.6 Hz, 1 H), 7.08 (m, 2 H), 7.02–6.97 (m, 2
H), 5.99 (d, J = 2.6 Hz, 1 H), 5.94 (d, J = 2.4 Hz, 1 H), 5.09 (s, 2
H), 3.84 (s, 3 H), 1.94 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 166.6 (C), 165.7 (C), 159.5 (C), 146.8 (C), 134.9 (C), 132.9
(CH), 131.2 (C), 129.7 (CH), 129.2 (CH), 129.0 (CH), 127.6 (CH),
122.7 (C), 115.0 (CH), 100.1 (CH), 96.3 (CH), 69.5 (CH2), 55.5
3-Phenylpyrano[4,3-c]isochromen-1(6H)-one (14): Yellow solid
(0.0368 g, 99%).[39]
3-(Thiophen-2-yl)pyrano[4,3-c]isochromen-1(6H)-one (15): Orange
solid (0.0711 g, 93%), m.p. 165–167 °C (MeOH). 1H NMR
(300 MHz, CDCl3): δ = 8.50 (d, J = 7.9 Hz, 1 H), 7.64 (d, J =
3.1 Hz, 1 H), 7.48 (d, J = 4.7 Hz, 1 H), 7.39 (t, J = 7.5 Hz, 1 H),
7.30–7.25 (m, 1 H), 7.14–7.06 (m, 2 H), 6.40 (s, 1 H), 5.28 (s, 2 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 166.0 (C), 160.3 (C), 155.7
(C), 134.8 (C), 129.3 (CH), 129.0 (CH), 128.4 (CH), 127.8 (CH),
127.7 (CH), 127.0 (C), 126.6 (C),124.2 (CH), 123.8 (CH), 100.7 (C),
(CH ), 21.6 (CH ) ppm. IR (film): ν = 1660 cm–1. MS (M+, ES+)
˜
3
3
m/z (%) 432 (28). HRMS (ESI, [M + H]+) m/z calcd. for
C20H19NO3Br 400.0563, found 400.0548.
4-Hydroxy-1-(4-methoxyphenyl)-6-methylpyridin-2(1H)-one: White
96.5 (CH), 69.4 (CH ) ppm. IR (film): ν = 1711 cm–1. MS (M+,
solid (0.534 g, 29%).[64]
˜
2
ES+) m/z (%) 282 (10), 42 (100). HRMS (ESI, [M + H]+) m/z calcd.
4-[(2-Bromobenzyl)oxy]-1-(4-fluorophenyl)-6-methylpyridin-2(1H)-
one (40): White solid (0.1280 g, 23%), m.p. 172 °C (hexanes). 1H
NMR (300 MHz, CDCl3): δ = 7.48 (dd, J = 7.6, 1.6 Hz, 1 H), 7.60
(dd, J = 7.9, 1.2 Hz, 1 H), 7.35 (td, J = 7.5, 1.2 Hz, 1 H), 7.23 (dd,
J = 7.7, 1.8 Hz, 1 H), 7.19 (d, J = 0.4 Hz, 2 H), 7.17 (s, 2 H), 5.98–
5.95 (m, 2 H), 5.09 (s, 2 H), 1.93 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 166.8 (C), 165.4 (C), 162.4 (d, J = 249 Hz, F-C), 146.3
(C), 134.8 (C), 134.4 (d, J = 3.5 Hz, F-C), 132.9 (CH), 130.1 (d, J
= 8.76 Hz, F-CH), 129.8 (CH), 129.1 (CH), 127.6 (CH), 122.8 (C),
116.8 (d, J = 23 Hz, F-CH), 101.1 (CH), 96.3 (CH), 69.5 (CH2),
for C16H11O3S 283.0429, found 283.0415.
3-(Furan-2-yl)pyrano[4,3-c]isochromen-1(6H)-one (16): Yellow solid
(0.0342 g, 98%), m.p. 153–155 °C (MeOH). 1H NMR (300 MHz,
CDCl3): δ = 8.51 (d, J = 8.3 Hz, 1 H) 7.50 (d, J = 1.1 Hz, 1 H),
7.42–7.37 (m, 1 H), 7.30–7.25 (m, 1 H), 7.08–7.05 (m, 2 H), 6.57–
6.55 (m, 1 H), 6.48 (s, 1 H), 5.28 (s, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 166.0 (C), 160.2 (C), 151.9 (C), 146.3 (C), 127.7 (C),
127.0 (C), 145.1 (CH), 129.0 (CH), 127.7 (CH), 124.2 (CH), 123.8
(CH), 112.6 (CH), 112.5 (CH), 100.9 (C), 95.9 (CH), 69.4 (CH2)
ppm. IR (film): ν = 1712 cm–1. MS (M+, ES+) m/z (%) 266 (12),
˜
21.5 (CH ) ppm. IR (film): ν = 1663 cm–1. MS (M+, ES+) m/z (%)
˜
3
42 (100). HRMS (ESI, [M + H]+) m/z calcd. for C16H11O4
388 (22). HRMS (ESI, [M + H]+) m/z calcd. for C19H16NO2FBr
267.0657, found 267.0652.
388.0348, found 388.0347.
3-[4-(Trifluoromethyl)phenyl]pyrano[4,3-c]isochromen-1(6H)-one (17):
1-(4-Fluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one: White so-
lid (0.4190 g, 24%), m.p. 258–260 °C (hexanes). 1H NMR
(300 MHz, [D6]DMSO): δ = 10.61 (br. s, 1 H), 7.35–7.20 (m, 4 H),
5.89 (dd, J = 2.5, 0.8 Hz, 1 H), 5.55 (d, J = 2.5 Hz, 1 H), 3.35 (s,
3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 166.9 (C), 164.6
(C), 163.5 (d, J = 245.1 Hz, F-C), 147.5 (C), 135.5 (d, J = 3.19 Hz,
F-C), 131.3 (d, J = 8.8 Hz, F-CH), 116.4 (d, J = 22.8 Hz, F-CH),
Yellow solid (0.0208 g, 96%).[39]
3-(o-Tolyl)pyrano[4,3-c]isochromen-1(6H)-one (18): White solid
(0.0220 g, 58%), m.p. 124–126 °C (MeOH). 1H NMR (300 MHz,
CDCl3): δ = 8.54 (d, J = 7.7 Hz, 1 H), 7.58–7.49 (m, 1 H), 7.49–
7.11 (m, 5 H), 7.07 (d, J = 7.7 Hz, 1 H), 6.25 (s, 1 H), 5.30 (s, 2
H), 2.52 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.8 (C),
162.3 (C), 161.2 (C), 136.8 (C), 131.8 (C), 131.4 (CH), 130.5 (CH),
129.0 (CH), 128.9 (CH), 128.4 (CH), 127.8 (CH), 127.1 (C), 126.5
(C), 124.3 (CH), 123.8 (CH), 101.7 (CH), 100.7 (C), 69.4 (CH2),
100.6 (CH), 96.5 (CH), 21.5 (CH ) ppm. IR (film): ν = 1649 cm–1.
˜
3
MS (M+, ES+) m/z (%) 220(30). HRMS (ESI, [M + H]+) m/z calcd.
for C12H11NO2F 220.0774, found 220.0764.
20.9 (CH ) ppm. IR (film): ν = 1712 cm–1. HRMS (ESI, [M + H]
˜
3
4-[(2-Iodobenzyl)oxy]-1-methylquinolin-2(1H)-one (41): White solid
+) m/z calcd. for C19H15O3 291.1017, found 291.1021.
1
(0.1660 g, 42%), m.p. 162–163 °C (hexanes). H NMR (300 MHz,
CDCl3): δ = 8.07 (d, J = 8.1 Hz, 1 H), 7.91 (d, J = 8.1 Hz, 1 H),
3-(4-Methoxyphenyl)pyrano[4,3-c]isochromen-1(6H)-one (19): Yel-
7.61 (t, J = 8.0 Hz, 1 H), 7.53 (dd, J = 7.6, 1.5 Hz, 1 H), 7.45–7.32 low solid (0.0250 g, 81%), m.p. Ͼ230 °C (MeOH). 1H NMR
(m, 2 H), 7.25 (t, J = 7.6 Hz, 1 H), 7.08 (t, J = 7.6 Hz, 1 H), 6.15
(300 MHz, CDCl3): δ = 8.52 (d, J = 7.6 Hz, 1 H), 7.81 (d, J =
(s, 1 H), 5.16 (s, 2 H), 3.69 (s, 3 H) ppm. 13C NMR (75 MHz, 10.0 Hz, 2 H), 7.39 (t, J = 7.9 Hz, 1 H), 7.26 (t, J = 7.9 Hz, 1 H),
CDCl3): δ = 163.1 (C), 161.3 (C), 139.9 (C), 139.6 (CH), 137.7 (C), 7.07 (d, J = 7.6 Hz, 1 H), 6.97 (d, J = 10.0 Hz, 2 H), 6.45 (s, 1 H),
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50262
/KAP1
Date: 27-04-15 11:55:33
Pages: 12
Direct Arylation of 2-Pyrones and Related Heterocycles
5.28 (s, 2 H), 3.87 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 3-Ethyl-6H,11H-isochromeno[4,3-c]chromen-11-one (47): Orange
166.4 (C), 162.0 (C), 161.1 (C), 160.3 (C), 129.0 (CH), 127.5 (CH), solid (0.0500 g, 71%), m.p. 72–75 °C (hexanes). 1H NMR
127.4 (CH), 127.0 (C), 126.7 (C), 124.1 (CH), 123.8 (CH), 123.5
(300 MHz, CDCl3): δ = 8.54 (dd, J = 7.9, 0.8 Hz, 1 H), 7.64 (d, J
(C), 114.4 (CH), 100.2 (C), 95.9 (CH), 69.4 (CH2), 55.5 (CH3) ppm. = 2.0 Hz, 1 H), 7.43–7.18 (m, 4 H), 7.14–7.06 (m, 1 H), 5.36 (s, 2
IR (film): ν = 1706 cm–1. MS (M+, ES+) m/z (%) 306 (64), 262 H), 2.70 (q, J = 7.6 Hz, 2 H), 1.27 (t, J = 7.6 Hz, 3 H) ppm. 13C
˜
(100), 206 (38). HRMS (ESI, [M + H]+) m/z calcd. for C19H15O4 NMR (75 MHz, CDCl3): δ = 161.3 (C), 160.3 (C), 151.2 (C), 140.2
307.0970, found 307.0973.
(C), 132.5 (CH), 129.0 (CH), 128.1 (CH), 127.4 (C), 126.8 (CH),
124.9 (C), 123.9 (CH), 121.5 (CH), 116.3 (CH), 114.9 (C), 102.4
3-(3,4,5-Trimethoxyphenyl)pyrano[4,3-c]isochromen-1(6H)-one (20):
(C), 69.7 (CH ), 28.4 (CH ), 15.6 (CH ) ppm. IR (film): ν = 1710
˜
(0.0179 g, 54%).[39]
2
2
3
cm–1. MS (M+, ES+) m/z (%) 279 (2). HRMS (ESI, [M + H]+) m/z
3-Isobutylpyrano[4,3-c]isochromen-1(6H)-one (22): Yellow oil
(0.0144 g, 84%). 1H NMR (300 MHz, CDCl3): δ = 8.47 (d, J =
7.9 Hz, 1 H), 7.36 (t, J = 7.4 Hz, 1 H), 7.25 (t, J = 7.4 Hz, 1 H),
7.04 (d, J = 7.4 Hz, 1 H), 5.89 (s, 1 H), 5.24 (s, 2 H), 2.35 (d, J =
7.2 Hz, 2 H), 2.18–2.09 (m, 1 H), 0.97 (d, J = 6.6 Hz, 6 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 166.0 (C), 165.4 (C), 161.7 (C),
128.8 (CH), 127.5 (CH), 126.8 (C), 126.6 (C), 124.0 (CH), 123.7
(CH), 100.4 (CH), 100.0 (C), 69.3 (CH2), 43.0 (CH2), 26.8 (CH),
calcd. for C18H15O3 279.1021, found 279.1019.
3-Methoxyisochromeno[4,3-c]chromen-11(6H)-one (48): Yellow so-
lid (0.0282 g, 82%), m.p. 178–179 °C (hexanes). 1H NMR
(300 MHz, CDCl3): δ = 8.57 (d, J = 7.8 Hz, 1 H), 7.48–7.22 (m, 4
H), 7.19–7.07 (m, 2 H), 5.40 (s, 2 H) 3.87 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 160.9 (C), 160.3 (C), 156.0 (C), 147.5 (C),
129.0 (CH), 128.2 (CH), 127.4 (C), 126.7 (C), 125.0 (CH), 123.9
(CH), 121.0 (CH), 117.7 (CH), 115.5 (C), 104.5 (CH), 102.8 (C),
22.2 (CH ) ppm. IR (film): ν = 1708 cm–1. MS (M+, ES+) m/z (%)
˜
3
69.7 (CH ), 55.9 (CH ) ppm. IR (film): ν = 1713 cm–1. MS (M+,
˜
2
3
256 (8). HRMS (ESI, [M + H]+) m/z calcd. for C16H17O3 257.1174,
ES+) m/z (%) 280 (100), 42 (10). HRMS (ESI, [M + H]+) m/z calcd.
found 257.1178.
for C17H13O4 281.0814, found 281.0810.
3-(4-Chlorophenyl)pyrano[4,3-c]isochromen-1(6H)-one (24): Yellow
solid (0.0280 g, 90%), m.p. 182–184 °C (MeOH). 1H NMR
(300 MHz, CDCl3): δ = 8.51 (d, J = 7.8 Hz, 1 H), 7.79 (d, J =
7.8 Hz, 2 H), 7.53–7.22 (m, 4 H), 7.07 (d, J = 7.2 Hz, 1 H), 6.31
(s, 1 H), 5.29 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.8
(C), 160.6 (C), 158.8 (C), 137.3 (C), 129.4 (C), 129.3 (CH), 129.0
(CH), 128.4 (C), 127.9 (CH), 127.1 (C), 126.9 (CH), 124.3 (CH),
2-Fluoroisochromeno[4,3-c]chromen-11(6H)-one (49): White solid
(0.0190 g, 71%), m.p. 178–179 °C (hexanes). H NMR (300 MHz,
1
CDCl3): δ = 8.52 (dd, J = 7.9, 0.8 Hz, 1 H), 7.86 (ddd, J = 8.4,
6.1, 0.7 Hz, 1 H), 7.45–7.38 (m, 1 H), 7.32 (td, J = 7.5, 1.3 Hz, 1
H), 7.21–6.97 (m, 3 H), 5.41 (s, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 166.8 (C), 163.4 (d, J = 279.9 Hz, C-F), 160.8 (C),
159.8 (C), 154.5 (d, J = 13.2 Hz, C-F), 129.0 (CH), 128.3 (CH),
127.2 (C), 126.8 (C), 125.1 (d, J = 10.4 Hz, F-CH), 124.8 (CH),
123.9 (CH), 112.3 (d, J = 23.0 Hz, F-CH), 111.8 (C), 104.0 (d, J =
123.8 (CH), 101.4 (C), 97.8 (CH), 69.5 (CH ) ppm. IR (film): ν =
˜
2
1694 cm–1. HRMS (ESI, [M + H]+) m/z calcd. for C18H12O3Cl
311.0475, found 311.0471.
25.6 Hz, F-CH), 69.8 (CH ) ppm. IR (film): ν = 1704 cm–1. MS
˜
2
(M+, ES+) m/z (%) 268 (50), 235 (100), 102 (44), 64 (50), 42 (38).
HRMS (ESI, [M + H]+) m/z calcd. for C16H10O3F 269.0614, found
269.0611.
8-Methoxy-3-methylpyrano[4,3-c]isochromen-1(6H)-one (42): White
solid (0.0023 g, 8%).[37] This compound could not be fully sepa-
rated from the residual starting material by chromatographic meth-
ods.
3-Methyl-2,6-dihydro-1H-isochromeno[4,3-c]pyridin-1-one
(50):
1
8-Fluoro-3-methylpyrano[4,3-c]isochromen-1(6H)-one (43): White
solid (0.0200 g, 54%), m.p. 150–154 °C (MeOH). 1H NMR
(300 MHz, CDCl3): δ = 8.48 (dd, J = 8.8, 5.6 Hz, 1 H), 7.05 (td, J
= 8.8, 2.7 Hz, 1 H), 6.77 (dd, J = 8.3, 2.7 Hz, 1 H), 5.92 (d, J =
0.9 Hz, 1 H), 5.22 (s, 2 H), 2.27 (d, J = 0.8 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 165.6 (C), 163.6 (C), 161.6 (d, J =
156.0 Hz, C-F), 160.4 (C), 129.0 (d, J = 7.4 Hz, F-C), 126.2 (d, J
= 8.0 Hz, F-CH), 122.5 (C), 115.5 (d, J = 20.9 Hz, F-CH), 111.1
(d, J = 23.2 Hz, F-CH), 100.1 (CH), 99.4 (C), 68.8 (CH2), 20.1
White solid (0.0250 g, 66%), m.p. 187–188 °C (hexanes). H NMR
(300 MHz, CDCl3): δ = 12.03 (br. s, 1 H), 8.79 (d, J = 7.9 Hz, 1
H), 7.38 (t, J = 7.5 Hz, 1 H), 7.25 (t, J = 7.3 Hz, 1 H), 7.09 (d, J
= 7.4 Hz, 1 H), 5.90 (s, 1 H), 5.17 (s, 2 H), 2.39 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 165.3 (C), 163.8 (C), 145.3 (C), 128.6
(CH), 128.5 (C), 128.3 (C), 126.9 (CH), 124.3 (CH), 123.7 (CH),
105.4 (C), 99.8 (CH), 68.9 (CH ), 19.1 (CH ) ppm. IR (film): ν =
˜
2
3
1728 cm–1. MS (M+, ES+) m/z (%) 213 (6). HRMS (ESI,
[M + H]+) m/z calcd. for C13H12NO2 214.0868, found 214.0869.
This product was subject to some degradation over time.
(CH ) ppm. IR (film): ν = 1703 cm–1. MS (M+, ES+) m/z (%) 233
˜
3
(80), 102 (35), 64 (48). HRMS (ESI, [M + H]+) m/z calcd. for
2,3-Dimethyl-2,6-dihydro-1H-isochromeno[4,3-c]pyridin-1-one
(51):[66] White solid (0.0300 g, 74%).[39]
C13H10O3F 233.0614, found 233.0619.
8-Fluoro-1-methylpyrano[4,3-c]isochromen-3(6H)-one (44): White
solid (0.0131 g, 35%). 178–180 °C (MeOH). H NMR (300 MHz,
3-Methyl-2-phenyl-2,6-dihydro-1H-isochromeno[4,3-c]pyridin-1-one
(52): White solid (0.0320 g, 82%), m.p. 172–174 °C (hexanes). 1H
NMR (300 MHz, CDCl3): δ = 8.76 (dd, J = 7.9, 0.9 Hz, 1 H), 7.56–
7.43 (m, 3 H), 7.33–7.18 (m, 4 H), 7.06 (dd, J = 7.3, 0.8 Hz, 1 H),
5.98 (d, J = 0.8 Hz, 1 H), 5.18 (s, 2 H), 1.97 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 163.4 (C), 162.6 (C), 146.2 (C), 138.9
(C), 129.7 (CH), 128.7 (CH), 128.5 (CH), 128.4 (C), 128.3 (CH),
126.9 (CH), 124.5 (CH), 123.5 (CH), 121.8 (C), 105.9 (C), 100.3
1
CDCl3): δ = 7.47 (dd, J = 8.7, 5.1 Hz, 1 H), 7.14 (td, J = 8.6,
2.7 Hz, 1 H), 6.97 (dd, J = 8.1, 2.6 Hz, 1 H), 5.77 (s, 1 H), 5.02 (s,
2 H), 2.62 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 168.4
(C), 163.3 (C), 162.7 (C), 160.7 (C), 159.2 (C), 133.7 (d, J = 7.5 Hz,
F-C), 127.6 (d, J = 8.2 Hz, F-CH), 122.3 (C), 115.9 (d, J = 21.8 Hz,
F-CH), 112.6 (d, J = 22.6 Hz, F-CH), 93.7 (CH), 68.9 (CH2), 20.5
(CH ) ppm. IR (film): ν = 1722 cm–1. MS (M+, ES+) m/z (%) 232
(CH), 69.0 (CH ), 21.7 (CH ) ppm. IR (film): ν = 1651 cm–1. MS
˜
3
˜
2
3
(100), 102 (69), 64 (34), 42 (14). HRMS (ESI, [M + H]+) m/z calcd.
(M+, ES+) m/z (%) 289 (100). HRMS (ESI, [M + H]+) m/z calcd.
for C13H10O3F 233.0614, found 233.0609.
for C19H16NO2 290.1181, found 290.1171.
Isochromeno[4,3-c]chromen-11(6H)-one (45): White solid (0.0281 g,
2-Benzyl-3-methyl-2,6-dihydro-1H-isochromeno[4,3-c]pyridin-1-one
(53):[66] Yellow solid (0.0500 g, 77%).[39]
86%).[39]
3-Methylisochromeno[4,3-c]chromen-11(6H)-one (46): Yellow solid 2-(4-Methoxyphenyl)-3-methyl-2,6-dihydro-1H-isochromeno[4,3-c]-
(0.0198 g, 76%).[65]
pyridin-1-one (54): Orange solid (0.0254 g, 64%), m.p. 172–174 °C
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O50262
/KAP1
Date: 27-04-15 11:55:33
Pages: 12
G. P. McGlacken et al.
FULL PAPER
(hexanes). 1H NMR (300 MHz, CDCl3): δ = 8.76 (dd, J = 7.9, Procedure for the Intermolecular Coupling Reaction. Compound 59:
0.9 Hz, 1 H), 7.30 (td, J = 7.7, 1.4 Hz, 1 H), 7.21 (td, J = 7.4, A solution of the coumarin 58 (2.0 equiv.), 2Ј-(PdPCy3Cl)-2-amino-
1.3 Hz, 1 H), 7.17–7.12 (m, 2 H), 7.08–7.00 (m, 3 H), 5.96 (d, J = biphenyl (60) (5 mol-%), pivalic acid (30 mol-%), K2CO3
0.8 Hz, 1 H), 5.17 (s, 2 H), 3.86 (s, 3 H), 1.98 (d, J = 0.7 Hz, 3 H) (1.5 equiv.) and bromobenzene (1.0 equiv.) in toluene (3.0 mL/
ppm. 13C NMR (75 MHz, CDCl3): δ = 163.3 (C), 162.8 (C), 159.6 mmol starting material) was stirred in a Schlenk tube under N2 at
(C), 146.7 (C), 131.5 (C), 129.2 (CH), 128.5 (CH), 127.8 (C), 126.8 140 °C. After 2.5 d, water (20 mL) and EtOAc (10 mL) were added.
(CH), 124.5 (CH), 123.5 (CH), 115.0 (CH), 105.9 (C), 100.2 (CH), The mixture was extracted with EtOAc (2ϫ 10 mL) and the com-
69.0 (CH ), 55.5 (CH ), 21.8 (CH ) ppm. IR (film): ν = 1651 cm–1.
bined organic layers were dried and the solvents evaporated. The
crude obtained was purified by column chromatography (SiO2,
Hex/EtOAc, 99.5:0.5).
˜
2
3
3
MS (M+, ES+) m/z (%) 319 (100). HRMS (ESI, [M + H]+) m/z
calcd. for C20H18NO3 320.1287, found 320.1286.
4-Methoxy-2H-chromen-2-one (58): See ref.[67]
2-(4-Fluorophenyl)-3-methyl-2,6-dihydro-1H-isochromeno[4,3-c]-
pyridin-1-one (55): Yellow solid (0.0290 g, 80%), m.p. 187–188 °C
(hexanes). H NMR (300 MHz, CDCl3): δ = 8.72 (d, J = 7.8 Hz,
4-Methoxy-3-phenyl-2H-chromen-2-one (59): White solid (0.050 g,
1
1
33%), m.p. 117–119 °C (hexanes). H NMR (300 MHz, CDCl3): δ
1 H), 7.30 (t, J = 7.6 Hz, 1 H), 7.24–7.18 (m, 5 H), 7.06 (d, J =
7.3 Hz, 1 H), 5.98 (s, 1 H), 5.18 (s, 2 H), 1.97 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 163.4 (C), 162.6 (C), 162.4 (d, J =
248.3 Hz, F-C), 146.1 (C), 134.8 (d, J = 3.02 Hz, F-C), 130.1 (d, J
= 8.3 Hz, F-CH), 128.6 (CH), 128.3 (C), 127.8 (C), 126.9 (CH),
124.5 (CH), 123.6 (CH), 116.8 (d, J = 23.4 Hz, F-CH), 105.9 (C),
= 7.88 (dd, J = 7.9, 1.2 Hz, 1 H), 7.59–7.53 (td, J = 7.2, 1.5 Hz, 1
H), 7.49–7.43 (m, 4 H), 7.42–7.39 (m, 1 H), 7.36 (dd, J = 8.4,
0.8 Hz, 1 H), 7.33–7.28 (m, 1 H), 3.56 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 162.4 (C), 161.8 (C), 151.4 (C), 131.4 (C),
131.0 (CH), 130.0 (CH), 127.4 (CH), 127.3 (CH), 123.0 (CH), 122.9
(CH), 116.7 (C), 115.5 (CH), 110.0 (C), 60.2 (CH3) ppm. MS (M+,
ES+) m/z (%) 253 (100). HRMS (ESI, [M + H]+) m/z calcd. for
C16H13O3 253.0865, found 253.0869.
100.6 (CH), 69.1 (CH ), 21.7 (CH ) ppm. IR (film): ν = 1651 cm–1.
˜
2
3
MS (M+, ES+) m/z (%) 307 (100). HRMS (ESI, [M + H]+) m/z
calcd. for for C19H15FNO2 308.1087, found 308.1081.
12-Methyl-6H-isochromeno[4,3-c]quinolin-11(12H)-one (56): Yellow
solid (0.0400 g, 60%).[38]
Acknowledgments
Mechanistic Studies
The research was supported by the Science Foundation Ireland
(grant numbers SFI/12/IP/1315 and SFI/12/RC/2275), the Irish Re-
search Council and the UCC Strategic Research Fund. The authors
are indebted to Prof. Ian Fairlamb (University of York) for useful
discussion throughout this project and his initial contribution to
this area is acknowledged.
(Pd{[C7H6O-2-(C9H5O2)]}I(PPh3)2) (57).
A Schlenk tube was
heated under vacuum and refilled with N2 three times. Pd2(dba)3
(1.0 equiv.) and PPh3 (8.0 equiv.) were then added. The Schlenk
was then evacuated and refilled with N2 three times. The vessel was
then left under vacuum overnight. The Schlenk tube was refilled
with N2. 10 mL freshly distilled THF was added giving a brown
solution. The reaction was stirred at ambient temperature for
15 min, resulting in a dark green solution. 4-[(2-iodobenzyl)oxy]-2
coumarin 28 (1 equiv.) was added to the THF solution. The couma-
rin dissolved and the solution remained dark green. The reaction
mixture was heated to 70 °C and stirred at this temperature for 1 h.
The vessel was cooled to room temperature and the reaction mix-
ture concentrated under reduced pressure yielding a green residue.
5 mL Et2O was added to the residue which dissolved. The solution
was stored at 5–8 °C for 2 h. The resulting grey precipitate was
isolated by suction filtration and dried under vacuum overnight to
yield a grey powder 57 in 90% yield (0.0679 g). 1H NMR
(300 MHz, CDCl3): δ = 7.52–7.41 (m, 13 H), 7.35–7.14 (m, 20 H),
7.08–7.00 (m, 1 H), 6.87–6.81 (m, 1 H), 6.64–6.57 (m, 2 H), 6.37–
6.30 (m, 1 H), 5.64 (s, 1 H), 4.85 (s, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 165.5 (C), 162.9 (C), 161.3 (C), 153.3 (C), 137.1 (C),
136.3 (t, JP-C = 5 Hz, CH), 134.7 (t, JP-C = 6 Hz, CH), 132.1 (CH),
131.9 (C), 131.6 (C), 131.3 (C), 130.0 (CH), 128.7 (CH), 127.9 (t,
JP-C = 5 Hz, CH), 127.4 (CH), 123.5 (CH), 123.2 (CH), 123.0 (CH),
116.6 (CH), 115.7 (C), 90.4 (CH), 74.3 (CH2) ppm. 31P{1H} NMR
(121.5 MHz, CDCl3): δ = 22.8 ppm.
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CDCl3): δ = 165.3 (C), 162.8 (C), 153.4 (C), 134.4 (C), 132.5 (CH),
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˜
2
cm–1. MS (M+, ES+) m/z (%) 253 (94). HRMS (ESI, [M + H]+)
m/z calcd. for C16H13O3 253.0857, found 253.0865.
10
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Direct Arylation of 2-Pyrones and Related Heterocycles
ˇ
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Received: April 10, 2015
Published Online: ᭿
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11

Job/Unit: O50262
/KAP1
Date: 27-04-15 11:55:33
Pages: 12
G. P. McGlacken et al.
FULL PAPER
Catalysis
L. M. Pardo, A. M. Prendergast,
M.-T. Nolan, E. Ó Muimhneacháin,
G. P. McGlacken* ........................... 1–12
Pd/Pivalic Acid Mediated Direct Arylation
of 2-Pyrones and Related Heterocycles
Keywords: Synthetic methods
/ Homo-
Direct Arylation represents a favourable
alternative to traditional cross-coupling re-
actions. However there are limited reports
on application to more delicate, privileged
biological motifs. Herein the intramolec-
ular Pd/PivOH promoted direct arylation
of 2-pyrones, 2-coumarins, 2-pyridones and
2-quinolones is reported. One intermolecu-
lar example is included along with prelimi-
nary mechanistic investigations.
geneous catalysis / Palladium / C–C bond
formation / Arylation / Oxygen
heterocycles
12
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