Pd-catalysed intramolecular regioselective arylation of 2-pyrones, pyridones, coumarins and quinolones by C–H bond functionalization

Article abstract of DOI:10.1016/j.tet.2014.04.029

The intramolecular arylation of 2-pyrones, 2-pyridones, coumarins and quinolones is reported using Pd^II precatalyst sources without added phosphine ligands. The excellent yields and convenient reagents enables the formation of various analogues

Full text of DOI:10.1016/j.tet.2014.04.029

Tetrahedron xxx (2014) 1e8
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Tetrahedron
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Pd-catalysed intramolecular regioselective arylation of 2-pyrones,
pyridones, coumarins and quinolones by CeH bond
functionalization
Marie-Therese Nolan a, Joshua T.W. Bray b, Kevin Eccles a, Man Sing Cheung c,
,
Zhenyang Lin c, Simon E. Lawrence a, Adrian C. Whitwood b, Ian J.S. Fairlamb b
*
,
,
Gerard P. McGlacken a
*
a Chemistry Department and Analytical and Biological Chemistry Research Facility, University College Cork, Ireland
b Department of Chemistry, University of York, Heslington, York YO105DD, UK
c Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong
a r t i c l e i n f o
a b s t r a c t
The intramolecular arylation of 2-pyrones, 2-pyridones, coumarins and quinolones is reported using PdII
precatalyst sources without added phosphine ligands. The excellent yields and convenient reagents
enables the formation of various analogues containing these moieties, and access to potential biologically
active candidates. Stoichiometric studies were carried out to provide an insight into the oxidation ad-
dition step. A switch in regioselectivity, together with a hydrodebromination process, was observed in
the case of a 3-bromo-2-pyrone.
Article history:
Received 12 March 2014
Received in revised form 8 April 2014
Accepted 9 April 2014
Available online xxx
Keywords:
Palladium
Ó 2014 Elsevier Ltd. All rights reserved.
Cross-coupling
Direct arylation
Catalysis
Heteroaromatic compounds
1. Introduction
1300 of the closely-related coumarins have been identified from
natural sources.5 These compounds possess useful anti-tumour,
The phenomenal abundance of the 2-pyrone moiety throughout
plant, animal, microbial and insecticidal systems,1 means that there
is an ever-increasing emphasis on their synthesis.2 The structural
diversity of the 2-pyrone compounds can be readily seen in the
wide array of naturally-occurring biologically active compounds.
Examples include pyripyropene A,3 and arisugacin A4 (Fig. 1). Over
anti-HIV and CNS-active properties.6 Potential isosteres of 2-
pyrones and 2-coumarins include 2-pyridones7 and 2-
quinolones.8 Fusaricide, (Fig. 1) a tricyclic 2-pyridinone shows ac-
tivity against Candida albicans and antiviral potential.9 Tricyclic
pyranoquinolones, e.g., Oricine,10 have many applications in drugs,
pharmaceuticals and agrochemicals.11 Given the diverse structural
features of biologically active 2-pyrones, pyridinones and related
compounds, the development of efficient methods for their syn-
thesis and functionalization is critical.
The formation of bicyclic 2-pyrone systems using a catalytic
CeH functionalization strategy has been described by Fairlamb and
Taylor.12 They used systems involving Pd0 precatalysts, additional
phosphine ligands and Cs2CO3 as base in the formation of new five-
membered rings using 4-phenoxypyrones. Regioselective cyclisa-
tion at the 3-position occurred, which mirrored the generally ob-
served regioselectivity in the
6p-electrocyclisation/oxidative
Fig. 1. Biologically-active polycyclic 6-aryl-2-pyrone and 2-pyridone natural products.
aromatisation reactions of related compounds.13 We anticipated
that a similar methodology could be used for the formation of six-
membered rings using 4-benzyloxypyrones. It was anticipated that
C3eH and C5eH functionalization could be possible. Surprisingly,
* Corresponding authors. E-mail addresses: ian.fairlamb@york.ac.uk (I.J.S. Fair-
lamb), g.mcglacken@ucc.ie (G.P. McGlacken).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.04.029
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2
M.-T. Nolan et al. / Tetrahedron xxx (2014) 1e8
employment of the reported conditions12,13 led to only trace
quantities of cyclised product 2 (Scheme 1).
Table 1
Optimisation studiesa
Entry
1b
QAS (1 equiv)
TBAB
TBAI
Yield%c C(3):C(5)c
71:10
2b
14:0d
Base (2.5 equiv)
Na2CO3
Et3N
Yield% C(3):C(5)
58:6
3
4
15:2d
Solvent
NMP
1,4-Dioxane
Toluene
Yield% C(3):C(5)
52:7d
49:5
60:4
Scheme 1. Access to cyclised 2-pyrones 2 and 3.
5
6b
7
In this paper are reported alternative but complementary con-
ditions14 for the regioselective arylation of the 2-pyrone frame-
work, using a simplified catalyst system15 and ‘Jeffrey’s conditions’
for the MizorokieHeck-type reaction.16 Excellent yields were ob-
tained at low Pd catalyst loading. The applicability of these condi-
tions facilitates CeH bond functionalization of 2-pyrones, 2-
coumarins, 2-pyridones and 2-quinolones. The mechanism for
this process has also been investigated (experimentally and theo-
retically). Finally, a remarkable but unusual C5eH regioselective
process, with concomitant hydrodebromination, was discovered as
part of these studies.
Pd cat. (mol %)
Pd(OAc)2 (10)
Pd(OAc)2 (5)
Pd(OAc)2 (2)
Yield% C(3):C(5)
80:12
8b
9
10
60:4d
78:21
a
Reaction conditions: Pd(OAc)2 (10 mol %), TBAB (1 equiv), KOAc (2.5 equiv),
DMF, 100 ꢀC, 16 h (unless otherwise specified within the table).
b
4(2-Iodobenzyloxy)-6-methyl-2-pyrone employed as starting material.
c
Isolated product yield unless otherwise specified within the table.
Yields determined by 1H NMR spectroscopic analysis using an internal standard.
d
for this transformation. The organic base, triethylamine, also
allowed for the formation of both regioisomers but in significantly
reduced yields. Polar solvents gave lower yields compared to tol-
uene, which was therefore used in subsequent reactions. Finally,
evaluation of the catalytic loading was carried out (Table 2). It has
been shown by Reetz and de Vries that reduced catalyst loading can
improve reaction yields due to improved palladium nanoparticle
solubilisation.17 The catalyst loading was reduced to 5 mol %
(w900 ppm Pd) and then 2 mol % (w360 ppm Pd), which led to an
increase in yield along with a decrease in reaction times. Complete
conversion of starting material provided the C-3 and C-5 arylated
2. Results and discussion
Conditions involving traditional MizorokieHeck-type and Jef-
frey’s conditions were evaluated initially (Scheme 1). While both
sets of conditions gave the desired 3-cyclised product 2, higher
yields were obtained using a catalytic system involving added
tetraalkylammonium salts, in the absence of intentionally-added
phosphine. Furthermore, the 5-cyclised product 3 was found ac-
cessible (the X-ray crystallographic structures of 2 and 3 are shown
in Fig. 2), unlike the previous report.12
Fig. 2. Single crystal X-ray structures of regioisomers 2 (left) and 3 (right). Note: arbitrary atom numbering used, thermal ellipsoids shown at 50% (note: hydrogens are shown in
these structures as grey spheres).
Initial conditions using Pd(OAc)2 (10 mol %), TBAB (1 equiv),
KOAc (2.5 equiv) and DMF promoted cyclisation at the 3- and 5-
positions giving 2 and 3 in 45 and 11% yield, respectively. To
probe the regioselectivity and improve upon the product yields,
a series of reactions were performed by varying the anion of the
quaternary ammonium salt (QAS), base, solvent and catalyst/cata-
lytic loading (Table 1).
products in yields of 78% and 21%, respectively, using 2 mol %
Pd(OAc)2. The optimal reaction conditions were then applied to
a
variety of 4-(2-bromobenzyl)oxy substrates including 2-
coumarin, 2-pyridinones and 2-quinolones and other 2-pyrone
substrates. 6-Aryl-2-pyrones are ideal synthetic targets due to
their wide natural occurrence and biological activity.18
To investigate the electronic effects of C-6 substitution, 2-
pyrones 4a and 4b were synthesised using a methodology similar
to that reported by Katritzky and co-workers.19 Successful
It was determined that TBAB is required and that all other halide
anions gave poorer results. KOAc and Na2CO3 proved efficient bases
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M.-T. Nolan et al. / Tetrahedron xxx (2014) 1e8
3
Table 2
work on 1 (Table 2). A methyl blocking-group was then introduced
to give 2-pyrone compound 8. Intramolecular arylation using our
optimal conditions also led to regioselective C5 coupling, affording
compound 9 in 98% yield (Scheme 2; see Fig. 3 for the X-ray crys-
tallographic structure for 9).
Reactions using substituted substrates
3. Mechanistic pathways
To gain an insight into the reaction mechanism of the Pd(OAc)2/
TBAB {reported herein, conditions (a)} and Pd2(dba)3/PPh3 {con-
Entry
Sub.
R1
R2
R3
Prod.
%Yielda
C3:C5
12
ditions (b)} mediated reactions, experiments were conducted to
deduce if oxidative addition to the aryl halide was feasible. We first
attempted to improve the yield of the catalytic cyclization reaction
outlined in Scheme 1, conditions (b), by employing iodide 10
(Scheme 3) in place of bromide 1. However the yield of 2 could only
be improved to 7% (cf. only trace product 2 was seen in Scheme 1
using bromide 1 under otherwise equivalent conditions). Thus we
set out to isolate and test the oxidative addition product formed
during these reactions to determine the susceptibility of this sub-
strate to undergo oxidative addition. It was necessary to use
phosphine for this purpose (phosphine is added to stabilize the
1b
2
3
4
5
6
7
8
9
1
1
O
O
O
O
O
O
CH3
CH3
Ph
H
H
H
H
H
d
H
H
d
2
2
80:12
78:21
99:<1
96:<1
64:<1
62:<1
85:<1
63:<1
65:<1
4a
4b
4c
4d
4e
4f
4g
5a
5b
5c
5d
5e
5f
5g
p-CF3(C6H4)
3,4,5-(OMe)3(C6H2)eOMePh
e(CH)4e
CH3
CH3
NeMe
NeBn
NeMe
e(CH)4e
a
Isolated product yield.
Using 10 mol % Pd(OAc)2.
b
oxidation addition product and allow its characterization using 31
NMR spectroscopy). Reaction of Pd02(dba)3 with 2 equiv of PPh3, in
respect of Pd0, gave Pd0( 2-dba)(PPh3)2 11, as indicated by the
P
intramolecular arylation was found possible, giving 2-pyrones 5a
and 5b (Table 2, entries 3 and 4) in high yields (99% and 96%, re-
spectively). 2-Pyrone 4c allowed for successful intramolecular
arylation to give 5c in good yield (64%). Interestingly, in all of these
substrates, regioselective arylation occurred exclusively at C3eH
with no evidence of the C5 regioisomer, despite the presumed
change in the acidity of the C5 proton. CeH acidity had been pro-
posed as one factor in some CeH bond functionalization/DA re-
actions; with the more acidic sites being favoured for
functionalization.20 Gorelsky et al. have shown that the nucleo-
philicity of the arene (and CeH bond acidity) is a key factor in
controlling the regioselectivity (note: the C3 position is considered
the most nucleophilic site in 2-pyrones).21 2-Coumarin 4d un-
derwent intramolecular arylation in good yield (62%), with com-
plete consumption of starting material noted after 1 h affording 5d.
Substituted tricyclic 2-pyridones are of interest as potential anti-
Alzheimer’s candidates.22 Application of our optimised conditions
to N-substituted pyridinones gave cyclised pyridinones 5e and 5f;
no C-5 product could be isolated. The formation of these analogues
required slightly longer reaction times (12 h), after which Pd0 black
was evident in the reaction vessel. N-methyl-2-quinolone 4g also
gave complete conversion to the C-3 cyclised quinolone 5g in good
yield, within 1 h.
To investigate whether the regioselectivity could be encouraged
to occur solely at the C5 position, ‘blocking’ substituents were in-
troduced at C3. Ideally, the substituent would either be easily re-
moved, or useful in itself as a handle for further synthetic
elaboration. We reasoned that a bromine atom could act as a po-
tential chemical blocking-group with oxidative addition (and thus
subsequent steps) favoured for the CeI bond (i.e., in a chemo-
selective-like process). This would allow for further decoration of
the molecule via traditional cross-couplings, or by an alternative
CeH bond functionalization strategy. Regiospecific bromination at
the C3 position was performed, providing 3-bromo-2-pyrone 6
(Scheme 2). Intramolecular arylation employing our optimised
arylation conditions afforded 2-pyrone 3 with no evidence of any
C3 or C5 regioisomers 2 or 7. Remarkably, C3 hydrodebromination
had occurred to give 3. The lack of any C3-cyclised regioisomer
suggests that oxidative addition to the benzyl iodide occurred first,
followed by CeH bond functionalization at C5. If hydro-
debromination had occurred before intramolecular cyclisation, the
system should have a free site for arylation at the C-3 position. This
would allow for CeH bond functionalization to occur at both sides,
presumably with a bias toward the C-3 position akin to our earlier
h
presence of two 31P NMR signals.23 Addition of 3 equiv of 10 to 11,
under an N2 atmosphere, resulted in 43% conversion to the oxida-
tive addition product 12 trans-[PdIII{(C7H6O-2-(C6H5O2)}(PPh3)2)]
(Scheme 3).24 The oxidative addition product 12 (in a trans-geom-
etry) was isolated and characterised (see Fig. 4 for X-ray structure of
12).
The X-ray data denotes a distorted square planar trans-geometry
with a torsion angle of ꢁ10.6 and þ10.3, indicative of a slight bend
out of the normal square planar orientation.12 A single peak was
observed in the 31P NMR spectrum (22.7 ppm), characteristic of PdII
coordination. We found that 8 equiv of phosphine were necessary
to afford 12. When reduced amounts of PPh3 were employed (less
than 8 equiv), a 1:1 ratio of starting pyrone 10 and 12 precipitated
from solution. This may be due to competing ligation of dba to the
Pd complex. It has been shown that for displacement of dba to
occur, higher phosphine equivalents may be necessary.14a Treat-
ment of 12 with Na2CO3 (mimicking the MizorokieHeck type
conditions (b) as per Scheme 1) in NMP at 130 ꢀC showed near
complete consumption of starting material (>95%). However, the
crude mixture showed a number of side-products and the yield for
2 was determined to be 34% (by 1H NMR spectroscopy using an
internal standard). Thus it appears that 2-pyrone 10 is amenable to
oxidative addition, but the process does not occur efficiently. The
outcome provides an indication that the MizorokieHeck type
conditions, requiring an anti-b
-hydrogen elimination,12 are prob-
lematic. Given the successful systems described above, we postu-
late that catalysis occurs via a more stable 16-electron [Pd0L2X]ꢁ
intermediate25 (where L is most likely solvent) derived from Pd0
colloidal clusters stabilized by the tetraalkylammonium halides.17b
Finally, to gain insight into the origin of the regioselectivity in
the reaction of 1/2þ3, DFT calculations (B3LYP) were conducted
(Scheme 4). Here a Concerted-MetallationeDeprotonation (CMD)/
Ambiphilic Metallation-Ligand Activation-6 (AMLA-6)20b,26 mech-
anism was used as a model for CeH bond abstraction after the
oxidative addition step. From the energy profile, the pathway
leading to the C3 regioselectivity was calculated to be more
favourable by 6.5 kcal/mol (in the free energy barrier). The proton-
abstraction step is also easier at C3 (3.3 kcal/mol) than that a C5
(9.0 kcal/mol). Although the barrier for C5 is higher, it is still an
accessible pathway. Further experimental and theoretical mecha-
nistic studies are necessary, but these preliminary DFT calculations
shed light on the experimentally observed regioselectivity.27
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M.-T. Nolan et al. / Tetrahedron xxx (2014) 1e8
Scheme 2. Introduction of blocking substituents at C-3.
Fig. 3. Single crystal X-ray structure of 9. Note: arbitrary atom numbering used,
thermal ellipsoids shown at 50% and the hydrogens are omitted for clarity (two in-
dependent structures (conformers) are found in the asymmetric unit cell).
Fig. 4. Single crystal X-ray structure of 12. Note: arbitrary atom numbering used,
thermal ellipsoids shown at 50% (the phenyl group carbon atoms are shown as blue
spheres and the hydrogens are omitted for clarity).
4. Conclusion
In conclusion, two sets of catalytic conditions were tested in the
Pd-catalysed cyclization of a number of biologically-relevant het-
erocyclic substrates. Using Pd0 precatalyst sources with added
phosphine ligands, poor conversion was achieved. Utilising Jeffery
conditions at lower Pd catalyst loadings, excellent product yields
were obtained. Optimized conditions using catalytic Pd(OAc)2,
TBAB and KOAc in toluene proved an effective route to substituted
tricyclised 2-pyrones, 2-pyridinones, 2-coumarins and 2-
quinolones. The excellent yields and convenient reagents enables
the formation of analogues containing these moieties, and access to
potential biologically-active candidates. The introduction of a bro-
mine at the C-3 position of the 2-pyrone allowed access to the C5
cyclized productda remarkable switch in regioselectivity. Stoi-
chiometric studies showed that oxidative addition of ‘Pd0(PPh3)2’,
Scheme 3. Stoichiometric studies: isolation of oxidative addition product 12 and its
reaction with Na2CO3 to give 2.
derived from Pd0( 2-dba)(PPh3)2, to 10 is viable (to give 12), but
h
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M.-T. Nolan et al. / Tetrahedron xxx (2014) 1e8
5
Scheme 4. Energy profile involving 2 and 3dthe origin of the regioselectivity, as determined by DFT calculations (B3LYP).
poor yields of the final product 2 and side-reactions were noted.
This suggests that intermediates of the type [Pd0L2X]ꢁ (L¼solvent),
and possibly higher order Pd species, that can be formed under
Jeffrey’s conditions, are key to the success of the reaction
conditions.
d, J¼1.94); dC (DMSO-d6, 75.5 MHz) 170.5, 163.0, 160, 131.02, 130.9,
129, 125.4, 98.4, 89.6; m/z (ESþ): 189 [(MþH)þ].
5.2.2. 4-Hydroxy-6-(4-(trifluoromethyl)phenyl)-2H-pyran-2-one
(19). Yellow solid (0.123 g, 96%), mp 268e269 ꢀC; nmax/cmꢁ1 (KBr):
3096, 2611, 1726, 1679,1658, 1634, 1576, 1479, 1322; dH (Acetone-d6,
500 MHz) 8.12 (2H, d, J¼8.2), 8.03 (2H, d, J¼7.5), 6.84 (1H, d, J¼1.7),
5.53 (1H, d, J¼1.95); dC (Acetone-d6, 75.5 MHz) 170.7, 163.5, 159.8,
136.2, 132.4 (q, J¼33), 127.2, 126.8 (q, J¼3.8), 125 (q, J¼272), 100.5,
91.8; m/z (ESþ): 256 [(MþH)þ]; HRMS (ESI-TOF): Exact mass cal-
culated for C12H8F3O3 [MþHþ], 257.0426. Found 257.0418.
5. Experimental section
5.1. General procedures
Melting point determinations were performed by the open
capillary method and are reported uncorrected. 1H and 13C NMR
spectra were recorded at 25 ꢀC in CDCl3 at 300 and 75 MHz spec-
trometer unless otherwise specified, with TMS as the internal
5.2.3. 4-Hydroxy-6-(3,4,5-trimethoxyphenyl)-2H-pyran-2-one
(20). Orange solid, mp 182e184 ꢀC (lit. 185e188 ꢀC29); dH (DMSO-d6,
300 MHz) 12.0 (1H, br s), 7.12 (2H, s), 6.85 (1H, s), 5.39 (1H, s), 3.86
(6H, s), 3.72 (3H, s); dC (DMSO-d6, 75.5 MHz) 171.2,163.6,160.4,153.6,
126.9, 140.3, 103.5, 98.8, 89.7, 60.6, 56.6; m/z (ESþ): 279 [(MþH)þ].
standard. Chemical Shifts (dH, dC and dP) 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
5.2.4. 4-Hydroxy-1,6-dimethylpyridin-2(1H)-one (21). White solid
(2.02 g, 40%), mp 233e234 ꢀC (lit.30 232 ꢀC); dH (DMSO-d6,
300 MHz) 10.27 (1H, br s), 5.75 (1H, dd, J¼2.6, 0.7), 5.48 (1H, d,
J¼2.6), 3.3 (3H, s), 2.26 (3H, s); dC (DMSO-d6, 75.5 MHz) 165.4,163.9,
147.8, 99.6, 95.5, 29.62, 20.28; m/z (ESþ): 140 [(MþH)þ].
allowed to evaporate (solid samples). Column chromatography was
5.2.5. 1-Benzyl-4-hydroxy-6-methylpyridin-2(1H)-one31
(22). White solid (0.566 g, 33%), mp 212e213 ꢀC (lit.32
208e210 ꢀC); dH (DMSO-d6, 300 MHz) 10.5 (1H, br s), 7.35e7.28
(2H, m), 7.26e7.21 (1H, m), 7.09 (2H, d, J¼7.14), 5.79 (1H, dd, J¼2,5,
0.6), 5.59 (1H, d, J¼2.6), 5.18 (2H, s), 2.16 (3H, s); dC (DMSO-d6,
75.5 MHz) 165.9, 163.4, 147.6, 137.7, 128.5, 126.8, 126.1, 100.4, 95.8,
45.2, 19.9; m/z (ESþ): 216 [(MþH)þ].
ꢀ
carried out using 60 A (35e70
mm) silica.
5.2. General procedure for the preparation of 4-hydroxy-6-
aryl-2H-pyran-2-one19
A round bottomed flask charged with the appropriate 2,2-
dimethyl-6-(2-oxoalkyl)-1,3-dioxin-4-one (3 mmol, 1 equiv) and
toluene (30 mL) was heated under reflux for 20e30 min. The re-
action mixture was concentrated under reduced pressure. The
crude product was purified by column chromatography on silica gel
using ethyl acetate and hexanes mixture as an eluent to afford the
pure title products.
5.3. General procedure for preparation of (4-(2-halobenzyl)
oxy)-substrates14d
To a 3-necked round bottomed flask were added the appropriate
4-hydroxy-6-substituted-2H-substrate (1 equiv), 2-halobenzyl
bromide (1.2 equiv), anhydrous potassium carbonate (7.2 equiv)
and dry acetone. The resulting reaction mixture was then stirred
under reflux at 79 ꢀC for 4 h. The reaction mixture was allowed to
5.2.1. 4-Hydroxy-6-phenyl-2-pyrone19 (18). Yellow solid (0.198 g,
99%), mp 256e258 ꢀC, (lit.28 254e256 ꢀC); dH (DMSO-d6, 300 MHz)
7.86e7.84 (2H, m), 7.54e751 (3H, m), 6.75 (1H, d, J¼1.96), 5.38 (1H,
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6
M.-T. Nolan et al. / Tetrahedron xxx (2014) 1e8
cool and filtered. The solid was washed with acetone (2ꢂ20 mL). The
washes were combined and the solvent was concentrated under
reduced pressure. The residual mass was dissolved in CH2Cl2
(2ꢂ50 mL) and washed with water (1ꢂ20 mL). The combined or-
ganic extracts was dried over MgSO4, filtered and concentrated un-
der reduced pressure. The crude product was purified by column
chromatography on silica gel using ethyl acetate and hexanes mix-
ture as an eluent to afford the pure title products.
(1H, td, J¼7.5, 1.2), 7.2 (1H, td, J¼7.8, 1.7), 5.93 (1H, d, J¼2.7), 5.88
(1H, dd, J¼2.7, 0.8), 5.05 (2H, s), 3.47 (3H, s), 2.32 (3H, s); dC (CDCl3,
75.5 MHz) 165.9, 165.3, 146.4, 134.9, 132.8, 129.6, 128.9, 127.6, 122.6,
100.78, 95.8, 69.7, 30.6, 20.92; m/z (ESþ): 308, Br79 [(MþH)þ], 310,
Br81 [(MþH)þ].
5.3.7. 1-Benzyl-4-((2-bromobenzyl)oxy)-6-methylpyridin-2(1H)-one
(4f). White solid (0.455 g, 51%), mp 116e117 ꢀC; (Found: C, 62.35;
H, 4.26; N, 3.46. C20H18BrNO2 requires C, 62.51; H, 4.72; N, 3.65);
nmax/cmꢁ1 (KBr): 3053, 2916, 1659, 1624, 1597, 1563, 1440, 1354; dH
(300 MHz) 7.59 (1H, dd, J¼8,1.12), 7.47 (1H, dd, J¼7.7,1.5), 7.37e7.29
(3H, m), 7.26e7.19 (3H, m), 7.15 (2H, d, J¼7.2), 6.02 (1H, d, J¼2.7),
5.88 (1H, dd, J¼2.7, 0.7), 5.08 (2H, s), 2.23 (3H, s); dC (CDCl3,
75.5 MHz) 166.2, 165.3, 146.7, 136.8, 134.9, 132.9, 129.7, 129.1, 128.8,
127.6, 127.3, 126.4, 122.7, 101.4, 96, 69.4, 46.6, 20.6; m/z (ESþ): 384,
Br79 [(MþH)þ], 386, Br81 [(MþH)þ]; HRMS (ESI-TOF): Exact mass
calculated for C20H19BrNO2 [MþHþ], 384.0599. Found 384.0570.
5.3.1. 4-((2-Bromobenzyl)oxy)-6-methyl-2H-pyran-2-one
(1). White solid (1.26 g, 63%), mp 99 ꢀC (lit.14d 135e137 ꢀC); nmax
/
cmꢁ1 (KBr): 3435, 1723, 1567, 1379, 1248, 755; dH (300 MHz) 7.61
(1H, dd, J¼7.92, 1.15), 7.43e7.33 (2ꢂ1H, 2ꢂoverlapping dt, J¼7.67,
1.4), 7.27e7.21 (1H, m), 5.87 (1H, m), 5.51 (1H, d, J¼2.19), 5.08 (2H,
s), 2.3 (3H, s); dC (CDCl3, 75.5 MHz) 167.0, 164.8, 162.4, 133.8, 133.0,
130.2, 129.3, 127.8, 123.0, 100.4, 88.7, 70.0, 19.9; m/z (ESþ): 297, Br81
[(MþH)þ], 296, Br79 [(MþH)þ]; HRMS (ESI-TOF): Exact mass cal-
culated for C13H11O3Br [MþHþ], 294.9977. Found 294.9977.
5.3.8. 4-((2-Bromobenzyl)oxy)-2H-chromen-2-one
(4d). White
5.3.2. 4-((2-Iodobenzyl)oxy)-6-methyl-2H-pyran-2-one (10). White
crystals (0.23 g, 65%), mp 101e103 ꢀC; (Found C, 45.60; H, 3.44.
C
1563, 1417, 1356, 1242, 1142, 1004, 758; dH (300 MHz) 7.88 (1H, d,
J¼7.8), 7.4e7.38 (2H, m), 7.1e7.05 (1H, m), 5.88 (1H, m), 5.51 (1H, d,
J¼2.2), 5.01 (2H, s), 2.23 (3H, s); dC (CDCl3, 75.5 MHz) 170, 164.8,
162.4, 136.7, 139.7, 130.4, 129.0, 128.6,100.4, 97.9, 88.8, 74.4, 19.9; m/
z (ESþ): 343 [(MþH)þ 100%]; HRMS (ESI-TOF): Exact mass calcu-
lated for C13H11O3I [MþHþ], 342.9841. Found 342.9828.
crystals (0.281 g, 22%), mp 152e154 ꢀC (lit.33 142 ꢀC); dH (300 MHz)
7.89 (1H, dd, J¼7.8, 1.3), 7.65 (1H, dd, J¼7.9, 1.1), 7.60e7.51 (2H, m),
7.42e7.28 (4H, m), 5.8 (1H, s), 5.28 (2H, s); dC (CDCl3, 75.5 MHz)
165.1, 162.8, 153.4, 133.7, 133.2, 132.6, 130.4, 129.3, 127.7, 124.0,
123.2, 123.1, 116.9, 91.5, 70.5; m/z (ESþ): 332 [(MþH)þ].
13H11O3I requires C, 45.63; H, 3.24%); nmax/cmꢁ1 (KBr): 1722, 1648,
5.3.9. 4-((2-Bromobenzyl)oxy)-1-methylquinolin-2(1H)-one
(4g). White solid (0.234 g, 24%), mp 163e164 ꢀC (lit.33 156e158 ꢀC),
dH (300 MHz) 8.07 (1H, dd, J¼8.01, 1.47), 7.64e7.54 (3H, m),
7.39e7.34 (2H, m), 7.27e7.21 (2H, m), 6.14 (1H, s), 5.24 (2H, s), 3.68
(s, 3H); dC (CDCl3, 75.5 MHz) 163.7, 161.3, 139.8, 134.7, 132.9, 131.4,
129.9, 128.9, 127.7, 123.5, 122.8, 121.8, 116.4, 114.1, 97.9, 69.9, 29.2;
m/z (ESþ): 345, Br79 [(MþH)þ], 347, Br81 [(MþH)þ].
5.3.3. 4-((2-Bromobenzyl)oxy)-6-phenyl-2H-pyran-2-one
(4a). Yellow solid (0.087 g, 31%), mp 134 ꢀC; nmax/cmꢁ1 (KBr): 3431,
3102, 2923, 2854, 1711, 1639, 1571, 1557, 1426; dH (300 MHz)
7.84e7.80 (2H, m), 7.63 (1H, dd, J¼8, 1.08), 7.48e7.44 (4H, m), 7.37
(1H, dd, J¼7.5, 1.1), 7.28e7.24 (1H, m), 6.54 (1H, d, J¼2.16), 5.65 (1H,
d, J¼2.13), 5.16 (2H, s); dC (CDCl3, 125.75 MHz) 170.0, 164.0, 160.5,
133.8, 133.1, 131.1, 130.3, 130, 129.4, 128.9, 127.8, 125.7, 123.03, 97.6,
89.8, 70.3; m/z (ESþ): 359, Br81 [(MþH)þ], 357, Br79 [(MþH)þ];
HRMS (ESI-TOF): Exact mass calculated for C18H14O3Br [MþHþ],
357.0126. Found 357.0109.
5.4. Preparation of 3-substituted-4(2-iodobenzyloxy)-6-
methyl-2H-pyran-2-one
5.4.1. 3-Bromo-4(2-iodobenzyloxy)-6-methyl-2H-pyran-2-one
(6). 4-(2-Iodobenzyloxy)-6-methyl-2-pyrone
10
(0.367
g,
1.07 mmol) was dissolved in dichloromethane (3 mL, 0.33 M), in
a round-bottomed flask wrapped in aluminium foil. The reaction
was stirred at room temperature (17 ꢀC) and a solution of bromine
(0.188 g, 1.18 mmol) in dichloromethane (3 mL, 0.33 M) was added
dropwise over the period of 1 h. The reaction mixture was con-
centrated under reduced pressure and the solid residue recrystal-
lised from ethanol to afford the title product as a white crystalline
solid (0.311 g, 69%), mp 210e215 ꢀC; nmax/cmꢁ1 (CH2Cl2): 2960,
1719, 1641, 1533, 1315, 1063, 1010; dH (400 MHz) 7.87 (1H, dd, J¼8.0,
1.0), 7.51 (1H, dd, J¼8.0, 1.0), 7.43 (1H, td, J¼7.5, 1.0), 7.09 (1H, td,
J¼7.5, 2.0), 6.02 (1H, app. d, J¼1.0), 5.20 (2H, s), 2.28 (3H, d, J¼1.0);
dC (CDCl3, 101 MHz) 165.8, 163.0, 161.0, 139.6, 136.8, 130.4, 129.0,
128.4, 96.3, 96.1, 89.7, 75.5, 20.5; m/z (ESIþ) 421, Br79 [(MþH)þ], 423,
Br81 [(MþH)þ]; HRMS (ESI-TOF): Exact mass calculated for
5.3.4. 4-((2-Bromobenzyl)oxy)-6-(4-(trifluoromethyl)phenyl)-2H-
pyran-2-one (4b). Yellow solid (0.062 g, 30%), mp 172e173 ꢀC; nmax
/
cmꢁ1 (KBr): 3424, 3094, 2924, 2854, 1714, 1647, 1574, 1557, 1451,
1434, 1410, 1329; dH (300 MHz) 7.93 (2H, d, J¼8.2), 7.72 (2H, d,
J¼8.3), 7.6 (1H, dd, J¼7.9, 1.2), 7.47 (1H, dd, J¼7.6, 1.6), 7.38 (1H, td,
J¼7.5, 1.2), 7.29e7.24 (1H, m), 6.59 (1H, d, J¼2), 5.7 (1H, d, J¼2.1),
5.17 (2H, s); dC (CDCl3, 125.75 MHz) 169.6, 163.4, 134.3, 133.6, 133.1,
132.5 (q, J¼32.8), 130.4, 129.5, 127.8, 126.02, 125.9 (q, J¼3.8), 123.7
(q, J¼272), 123.14, 99.5, 90.7, 70.5; m/z (ESþ): 427, Br81 [(MþH)þ],
425, Br79 [(MþH)þ]; HRMS (ESI-TOF): Exact mass calculated for
C
19H13BrF3O3 [MþHþ], 425.0002. Found 424.9995.
C
13H10BrINaO3 [MþHþ], 442.8751. Found 442.8762.
5.3.5. 4-((2-Iodobenzyl)oxy)-6-(3,4,5-trimethoxyphenyl)-2H-pyran-
2-one (4c). Cream solid (0.09 g, 35%), mp 177e179 ꢀC; nmax/cmꢁ1
(NaCl): 3055, 2987, 2686, 2410, 2306, 1719, 1633, 1585, 1503, 1266,
1132, 749; dH (300 MHz) 7.91 (1H, dd, J¼7.8, 0.9), 7.47e7.38 (2H, m),
7.09 (1H, td, J¼7.4, 2.1), 7.03 (2H, s), 6.46 (1H, d, J¼2.1), 5.64 (1H, d,
J¼2.1), 5.09 (2H, s), 3.91 (6H, s), 3.9 (3H, s); dC (CDCl3, 125.75 MHz)
169.9, 164.0, 160.3, 153.5, 140.8, 139.8, 136.7, 130.5, 129.2, 128.6,
126.4, 103.1, 97.9, 97.6, 89.5, 74.7, 61.0, 56.4; m/z (ESþ): 495
[(MþH)þ]; HRMS (ESI-TOF): Exact mass calculated for C21H20O6I
[MþHþ], 495.0305. Found 495.0299.
5.4.2. 3,6-Dimethyl-4(2-iodobenzyloxy)-2H-pyran-2-one
(8). A
mixture of 3,6-dimethyl-4-hydroxy-2-pyrone (0.350 g, 2.5 mmol),
2-iodobenzylbromide (0.825 g, 2.78 mmol) and anhydrous potas-
sium carbonate (0.518 g, 5.94 mmol) were stirred under reflux in
dry acetone (10 mL, 0.25 M) for 16 h. The reaction mixture was
allowed to cool to room temperature, and then quenched with
water (20 mL) and ethyl acetate (20 mL) and the layers separated.
The product formed as a white precipitate formed upon quenching
and was separated by filtration through a sintered glass funnel and
washed with cold EtOAc. The aqueous layer was extracted with
ethyl acetate (3ꢂ20 mL) and the combined organic layers were
dried over Na2SO4, filtered and concentrated under reduced pres-
sure. The solid residue was washed through a sintered glass funnel
5.3.6. 4-((2-Bromobenzyl)oxy)-1,6-dimethylpyridin-2(1H)-one
(4e). White solid (0.421 g, 19%), mp 187e188 ꢀC (lit.26 134e135 ꢀC);
dH (300 MHz) 7.59 (1H, dd, J¼7.92, 1.2), 7.44 (1H, dt, J¼7.7, 0.7), 7.33
Please cite this article in press as: Nolan, M.-T.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.04.029

M.-T. Nolan et al. / Tetrahedron xxx (2014) 1e8
7
using cold EtOAc and water to afford the title product as a white
powder (0.329 g, 37%), mp 185e189 ꢀC; nmax/cmꢁ1 (DMSO): 2903.7,
1691, 1573, 1307, 1245, 1127; dH (400 MHz, DMSO-d6) 7.94 (1H, d,
J¼7.5), 7.54 (1H, dd, J¼7.5, 1.8), 7.46 (1H, t, J¼7.0), 7.16 (1H, t, J¼7.0),
6.62 (1H, s), 5.18 (2H, s), 2.24 (3H, s), 1.78 (3H, s); dC (DMSO-d6,
101 MHz) 165.2, 164.5, 160.9, 139.4, 137.9, 130.6, 130.1, 128.6, 99.5,
99.3, 96.2, 74.2, 19.7, 8.7; m/z (ESIþ) 378.9783 [(MþNa)þ]; HRMS
(ESI-TOF): Exact mass calculated for C14H14IO3 [MþHþ], 356.9982.
Found 356.9982.
7.28 (1H, overlapping td, J¼7.5, 1.2), 7.09 (1H, overlapping m), 7.07
(2H, s), 6.49 (1H, s), 5.30 (2H, s), 3.94 (6H, s), 3.91 (3H, s); dC (CDCl3,
75.5 MHz) 166.1, 160.9, 159.9, 153.6, 140.9, 129.0, 127.8, 127.1, 126.5,
126.3, 124.3, 123.8, 103.1, 100.8, 97.3, 69.5, 61.02, 56.4; m/z (ESþ):
367 [MþHþ]; HRMS (ESI-TOF): Exact mass calculated for C21H19O6
[MþHþ], 367.1182. Found 367.1166.
5.5.6. 2,3-Dimethyl-2,6-dihydro-1H-isochromeno[4,3-c]pyridin-1-
one (5e). White solid (0.031 g, 85%), mp 95e96 ꢀC (lit.18c
100e102 ꢀC); dH (300 MHz) 8.8 (1H, d, J¼8), 7.36 (1H, td, J¼8,
1.3), 7.22 (1H, td, J¼7.44, 1.2), 7.05 (1H, dd, J¼7.44, 0.64), 5.89 (1H, d,
J¼0.6), 5.11 (2H, s), 3.55 (3H, s), 2.35 (3H, s); dC (CDCl3, 75.5 MHz)
162.6, 162.2, 146.2, 128.7, 128.5, 128.1, 126.7, 124.4, 123.6, 105.5,
100.2, 68.9, 29.7, 21.22; m/z (ESþ): 228 [MþHþ]; HRMS (ESI-TOF):
Exact mass calculated for C14H13NO2 [MþHþ], 228.1025. Found
228.1017.
5.5. General procedure for preparation of the intramolecular
coupled products
To
a dried sealed Schlenk tube, the appropriate (4-(2-
halobenzyl)oxy)-substrate (1 equiv), TBAB (1.2 equiv), Pd(OAc)2
(2 mol %), KOAc (2.5 equiv) and 2 mL of toluene were added. Ni-
trogen gas was bubbled through the reaction mass. The reaction
was heated to 127 ꢀC and reaction progress to completion was
monitored by TLC analysis. The reaction mass was cooled to room
temperature and diluted with water (15 mL), and extracted with
EtOAc (3ꢂ15 mL). The combined organic extracts was dried over
MgSO4, filtered and concentrated under reduced pressure. The
crude product was purified by column chromatography on silica gel
using ethyl acetate and hexanes mixture as an eluent to afford the
pure title products.
5.5.7. 2-Benzyl-3-methyl-2,6-dihydro-1H-isochromeno[4,3-c]pyr-
idin-1-one (5f). White solid (0.050 g, 63%), mp 126e127 ꢀC; nmax
/
cmꢁ1 (KBr): 3420, 3075, 2958, 2923, 2854, 1745, 1636, 1602, 1579,
1554, 1487, 1425; dH (300 MHz) 8.83 (1H, d, J¼8), 7.37e7.29 (3H, m),
7.24e7.18 (4H, m), 7.07 (1H, dd, J¼7.44, 0.64), 5.89 (1H, s), 5.38 (2H,
s), 5.15 (2H, s), 2.88 (3H, s); dC (CDCl3, 125.75 MHz) 162.9, 162.2,
146.6, 136.8, 128.82, 128.7, 128.6, 128.1, 127.3, 126.9, 126.4, 124.5,
123.7, 105.8, 100.8, 69, 47, 20.9; m/z (ESþ): 304 [MþHþ]; HRMS (ESI-
TOF): Exact mass calculated for C20H18NO2 [MþHþ], 304.1338.
Found 304.1339.
5.5.1. 3-Methylpyrano[4,3-c]isochromen-1(6H)-one (2). White solid
(0.057 g, 78%), mp 139e141 ꢀC (lit.14d 110e113 ꢀC); dH (300 MHz)
8.46 (1H, dd, J¼7.9, 0.75), 7.39e7.33 (1H, m), 7.24e7.29 (1H, m), 7.04
(1H, dd, J¼7.4, 0.7), 5.91 (1H, d, J¼0.8), 5.23 (2H, s), 2.26 (3H, d,
J¼0.8); dC (CDCl3, 75.5 MHz) 166.3, 162.5, 161.7, 128.9, 127.5, 126.8,
126.5, 124.0, 123.8, 100.3, 99.8, 69.3, 20.1; m/z (ESþ): 215 [(MþH)þ].
5.5.8. 6H, 11H-[2]Benzopyrano[4,3-c][1]benzopyran-11-one
(5d). White powdery solid (0.019 g, 62%), mp 136 ꢀC (lit.19
137 ꢀC); dH (300 MHz) 8.55 (1H, dd, J¼7.9, 0.8), 7.87 (1H, dd,
J¼7.9, 1.4), 7.59e7.4 (1H, m), 7.44e7.38 (1H, m), 7.36e7.27 (3H, m),
7.13 (1H, dd, J¼7.4, 0.7), 5.40 (2H, s); dC (CDCl3, 75.5 MHz) 161.2,
160.2,152.9,132.5,129.1,128.3,127.4,126.7,124.9,124.1,124.0,123.1,
116.5, 115.2, 102.7, 69.8; m/z (ESþ): 251 [(MþH)þ].
5.5.2. 1-Methylpyrano[4,3-c]isochromen-3(6H)-one (3). Off-white
solid (0.015 g, 21%), mp 143 ꢀC; nmax/cmꢁ1 (KBr): 1725, 1557, 1407,
1229, 1196, 1006; dH (300 MHz) 7.51e7.40 (2H, m), 7.34 (1H, td,
J¼7.4, 1.5), 7.23 (1H, dd, J¼7.4, 0.6), 5.76 (1H, s), 5.06 (2H, s), 2.65
(3H, s); dC (CDCl3, 75.5 MHz) 168.9, 163.6, 159.7, 131.4, 128.9, 127.7,
126.1, 125.6, 125.3, 93.5, 77.2, 69.4, 20.5; m/z (ESþ): 215 [(MþH)þ];
HRMS (ESI-TOF): Exact mass calculated for C13H10O3 [MþHþ],
215.0711. Found 215.0708.
5.5.9. 12-Methyl-6H-isochromeno[4,3-c]quinolin-11(12H)-one
(5g). White solid (0.041 g, 65%), mp 131 ꢀC (lit.19 130e132 ꢀC); nmax
/
cmꢁ1 (KBr): 3432, 2925, 2855, 1630, 1589, 1487, 1466; dH (300 MHz)
8.8 (1H, d, J¼7.36), 8.05 (1H, dd, J¼8.01, 1.4), 7.63e7.57 (1H, m),
7.44e7.36 (2H, m), 7.33e7.23 (2H, m), 7.15 (1H, dd, J¼7.4, 0.7), 5.21
(2H, s), 3.78 (3H, s); dC (CDCl3, 75.5 MHz) 161.4, 158.0, 139.2, 131.4,
128.7, 128.7, 127.6, 125.3, 123.8, 123.5, 121.8, 115.6, 107.9, 69.4, 29.4;
m/z (ESþ): 264 [(MþH)þ].
5.5.3. 3-Phenylpyrano[4,3-c]isochromen-1(6H)-one
(5a). Bright
yellow solid (0.023 g, 99%), mp 137 ꢀC; nmax/cmꢁ1 (KBr): 3445,
3060, 2924, 1074, 1627, 1544, 1496, 1417; dH (300 MHz) 8.53 (1H, dd,
J¼7.9, 0.75), 7.89e7.83 (2H, m), 7.49e7.45 (3H, m), 7.43e7.37 (1H,
m), 7.28 (1H, td, J¼7.45, 1.25), 7.07 (1H, dd, J¼7.44, 0.7), 6.56 (1H, s),
5.29 (2H, s); dC (CDCl3, 125.75 MHz) 166.1, 160.9, 160, 131.1, 130.9,
129.5, 128.4, 127.8, 127.1, 126.5, 125.7, 124.3, 123.8, 101.1, 97.6, 69.4;
m/z (ESþ): 277 [(MþH)þ]; HRMS (ESI-TOF): Exact mass calculated
for C18H13O3 [MþHþ], 277.0865. Found 277.0852.
5.5.10. 1,4-Dimethyl-3H,6H-pyrano[4,3-c]isochromen-3-one
(9). Orange crystalline solid (0.049 g, 98%), mp 122e126 ꢀC; nmax
/
cmꢁ1 (CH2Cl2): 2961, 1704, 1648, 1570, 1231, 1215, 1107, 1027; dH
(300 MHz) 7.48 (1H, d, J¼8.0), 7.42 (1H, td, J¼7.5, 1.5), 7.33 (1H, td,
J¼7.5, 1.5), 7.24 (1H, d, J¼8.0), 5.06 (2H, s), 2.62 (3H, s), 2.01 (3H, s);
dC (CDCl3, 101 MHz) 165.0, 163.7, 156.2, 131.9, 128.8, 127.6, 127.0,
125.3, 107.7, 102.6, 69.5, 20.2, 8.9; HRMS (ESI-TOF) calcd for
5.5.4. 3-(4-(Trifluoromethyl)phenyl)pyrano[4,3-c]isochromen-1(6H)-
one (5b). Yellow solid (0.0396 g, 96%), mp 172e173 ꢀC; nmax/cmꢁ1
(KBr): 3431, 2925, 2855, 1684, 1634, 1543, 1409, 1328; dH (300 MHz)
8.45 (1H, d, J¼7.26), 7.9 (2H, d, J¼8.2), 7.66 (2H, d, J¼8.4), 7.34 (1H,
td, J¼7.7, 1.2), 7.23 (1H, td, J¼7.5, 1.2), 7.02 (1H, d, J¼7.11), 6.57 (1H,
s), 5.25 (2H, s); dC (CDCl3, 150 MHz) 165.6, 160.5, 158, 134.2,132.6 (q,
J¼33),129.1,128.2,127.1,126.1,126 (q, J¼3),125.9,124.4,123.9,123.7
(q, J¼270), 102.1, 99.1, 69.5; HRMS (ESI-TOF): Exact mass calculated
for C19H12F3O3 [MþHþ], 345.0739. Found 345.0753.
C
14H13O3 [MþHþ], 229.0859. Found 229.0858.
5.6. trans-[Pd{(C7H6O-2-(C6H5O2))}I(PPh3)2] (12)
To a dried sealed Schlenk tube, Pd2dba3 (26.8 mg, 29.31 mmol)
and PPh3 (61.5 mg, 234.5 mmol) and 8 mL of THF were added. Ni-
trogen gas was bubbled through the reaction mass and the reaction
was stirred at ambient temperature for 15 min followed by the
addition of 10 (30 mg, 87.94 mmol). The solution was then allowed
to stir for 1 h at 70 ꢀC. The THF was then concentrated under re-
duced pressure to afford a yellow resin, which was subsequently
dissolved in Et2O (5 mL) and stored between 8 and 5 ꢀC for 12 h,
affording yellow crystals. The solution was then filtered and the
crystals washed with Et2O (2 mL), and dried under high vacuum to
5.5.5. 3-(3,4,5-Trimethoxyphenyl)pyrano[4,3-c]isochromen-1(6H)-
one (5c). Yellow solid (0.014 g, 64%), mp 154e156 ꢀC; nmax/cmꢁ1
(NaCl): 3055, 2987, 2686, 2306, 1712, 1549, 1504, 1422, 1265, 1133,
896, 743; dH (300 MHz) 8.52 (1H, dd, J¼7.9, 0.7), 7.43e7.37 (1H, m),
Please cite this article in press as: Nolan, M.-T.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.04.029

8
M.-T. Nolan et al. / Tetrahedron xxx (2014) 1e8
9, 6265e6270; (c) Chaladaj, W.; Corbet, M.; Fuerstner, A. Angew. Chem., Int. Ed.
2012, 51, 6929e6933.
afford the pure title produced as a yellow crystalline solid (0.0368 g,
43%), dH (300 MHz) 7.47e7.43 (13H, m), 7.33 (7H, t, J¼7.4), 7.25e7.21
(10H, m), 6.82 (1H, dd, J¼7.7, 0.9), 6.52 (1H, t, J¼7.2), 6.44 (1H, dd,
J¼7.1, 0.6), 6.28 (1H, t, J¼7.6), 5.37 (1H, d, J¼2.1), 5.08 (1H, q, J¼2.04,
0.9), 4.61 (2H, s), 2.1 (3H, s); dC (CDCl3, 75.5 MHz): 170.4, 165, 162,
161.4, 136.9, 136.5, 134.8 (t, 2JPeC¼6), 131.7 (t, 1JPeC¼23, CeP), 130.0,
3. (a) Omura, S.; Tomoda, H.; Kim, Y. K.; Nishida, H. J. Antibiot. 1993, 46,
1168e1169; (b) Nagamitsu, T.; Sunazuka, T.; Obata, R.; Tomoda, H.; Tanaka, H.;
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3
129.3, 127.9 (t, JPeC¼5), 127.3, 123.0, 100.6, 87.6, 74.3, 19.8; dP
(121.5 MHz): 22.77; FTMS: Exact mass calculated for C49H41O3P2Pd
972.08 Found C49H41O3P2Pd, 846.1588. (The parent peak was not
observed.) Crystals suitable for single crystal analysis were pre-
pared by dissolution of 12 in hot Et2O and subsequent slow cooling
between 5 and 8 ꢀC to produce single crystals.
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5.7. Computational details
Molecular geometries were optimized at the Becke3LYP (B3LYP)
level of density functional theory (DFT). The effective core poten-
tials (ECPs) of Hay and Wadt with the double-z valence basis sets
(LanL2DZ) were used to describe the Pd atom. The 6-311G* Pople
basis set was used for those C, H and O atoms involved in the bond
breaking and making processes. The standard 6-31G basis set was
used for all other atoms. Polarization functions were added for Pd
(zf¼1.472). Frequency calculations were carried out to confirm the
characteristics of all of the optimized structures as minima (zero
imaginary frequency) or transition-states (one imaginary fre-
quency) and to provide free energies at 298.15 K, which include
entropy contributions. Calculations of intrinsic reaction coordinates
(IRC) were also performed to confirm that the transition-states
connect two relevant minima. All of the calculations were per-
formed with the Gaussian 03 software package.
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DFT calculations (B3LYP) reveal the energy profile of C3/C5
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under the reaction conditions (with DMF used as the ligand, O-
bound). From the energy profile (see overleaf), the pathway leading
to C3 regioselectivity was calculated to be more favourable by
6.5 kcal/mol in the free energy barrier. The proton-abstraction step
is also easier at C3 (3.3 kcal/mol) than that at C5 (9.0 kcal/mol).
Although the barrier for C5 regioselectivity is higher it is still
accessible.
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Acknowledgements
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[24]. Formation of oxidative addition product containing bromide was attempted.
However, no evidence of the desired product was observed by 31P and 1H
NMR spectroscopic analysis of the crude reaction mixture.
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[27]. Other mechanistic possibilities exist for the reactions detailed in this paper,
including, but not limited to, a Heck-like mechanism involving either neutral
or anionic Pd species. See also Ref. 12b.
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1329e1331.
This publication has emanated from research conducted with
the financial support of Science Foundation Ireland under Grant
Numbers SFI/12/IP/1315, SFI/12/RC/2275 and SFI/09/RFP/CHS2353
and 05/PICA/B802/EC07. The Irish Research Council and Pfizer
Process Development Centre, Cork are gratefully acknowledged.
This project is underpinned by work previously conducted in York
and funded by the Engineering and Physical Sciences Research
Council (EP/D078776/1), Royal Society and University of York.
Johnson-Matthey is thanked for loans of palladium salts (G.P.M.).
References and notes
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Please cite this article in press as: Nolan, M.-T.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.04.029