Cyclization of 4-Phenoxy-2-coumarins and 2-Pyrones via a Double C-H Activation

Article abstract of DOI:10.1021/acs.orglett.6b00751

Aryl-heteroaryl coupling via double C-H activation is a powerful transformation that avoids the installation of activating groups. A double C-H activation of privileged biological scaffolds, 2-coumarins and 2-pyrones, is reported. Despite the rich chemistry of these molecular frameworks, the yields are very good. Excellent regioselectivity was achieved on the pyrones. This methodology was applied to the synthesis of flemichapparin C in three steps. Isotope effect experiments were carried out, and a mechanism is proposed.

Full text of DOI:10.1021/acs.orglett.6b00751

Letter
pubs.acs.org/OrgLett
Cyclization of 4‑Phenoxy-2-coumarins and 2‑Pyrones via a Double
C−H Activation
Katrina Mackey, Leticia M. Pardo, Aisling M. Prendergast, Marie-T. Nolan, Lorraine M. Bateman,
and Gerard P. McGlacken*
Department of Chemistry and Analytical & Biological Chemistry Research Facility, University College Cork, College Road, Cork,
Ireland
S
* Supporting Information
ABSTRACT: Aryl−heteroaryl coupling via double C−H
activation is a powerful transformation that avoids the
installation of activating groups. A double C−H activation of
privileged biological scaffolds, 2-coumarins and 2-pyrones, is
reported. Despite the rich chemistry of these molecular
frameworks, the yields are very good. Excellent regioselectivity
was achieved on the pyrones. This methodology was applied to
the synthesis of flemichapparin C in three steps. Isotope effect experiments were carried out, and a mechanism is proposed.
and related ring systems,10a,c,11 including the oxygen-containing
he formation of aryl−heteroaryl (Ar−HetAr) bonds is an
Timportant transformation in organic synthesis due to the six-membered variant.12
1
The cyclization of such substrates currently requires the
installation of a halogen on one coupling partner.11c,13 Instead,
we sought to gain access to tricyclic pyrones and coumarins by
the coupling of phenoxy-substituted substrates via two C−H
activation events. This is a far more challenging approach as
outlined (vide supra). We initially prepared the 4-phenoxy-2-
coumarin by reacting 4-bromocoumarin and phenol (not shown;
see Supporting Information (SI)).
abundance of Ar−HetAr moieties in natural products and
pharmaceuticals.2 Direct arylation involving the coupling of a C−
H and C−X bond that avoids one of the preactivating groups is
certainly progressive;3 however, the ideal approach would
involve the coupling of two C−H bonds.4 As a green route to
biaryls and heteroaryls, this reaction is on the “wanted list” of top
pharmaceutical companies.5 This is challenging for two main
reasons: (1) aromatic C−H bonds are highly stable and (2) most
molecules possess a number of potential C−H coupling sites,
which often poses prohibitive regioselectivity problems.
The 2-pyrone substrate, specifically, 4-hydroxy- and 4-alkoxy-
based 2-pyrones (Figure 1),6 represents a privileged biological
scaffold with broad spectrum biological activity spanning
cytotoxic, antibiotic, and antifungal activity.6,7
Additionally, 2-pyrones are a promising class of biorenewable
platform chemicals that provide access to an array of chemical
products and intermediates.8 Finally, the 2-pyrone moiety
displays similar reactivity to aromatics, dienes, and enones and
is thus bestowed with both challenging and rewarding properties.
The related 2-coumarins display a similarly remarkable biological
profile.9 The coumestan subgroup (Figure 1) exhibits impressive
biological activities,10 and thus a number of novel synthetic
methods have been developed for constructing the coumestan
Our optimization studies started with two seminal reports by
Fagnou14 and Shi.15 In summary, Pd(OAc)2 was the best
palladium source, PivOH the preferred solvent, and NaOtBu the
preferred base. The reaction failed to progress satisfactorily
without added oxidant (Table 1, entry 1). Using Ag2O as oxidant,
the coupling proceeded with excellent yield (Table 1, entry 2).
The reaction also worked well in TFA, this time with K2CO3 as
base (Table 1, entry 3). Only 5 mol % of palladium was required
here, and the cyclized product was isolated in an impressive 86%
yield. Other solvents, such as DME, gave no reaction (Table 1,
entry 4), and other oxidants, such as K2S2O8, were ineffective
(Table 1, entry 5). A substrate scope was then investigated
(Scheme 1). Electron-donating groups at the para-position of the
phenoxy group provided the corresponding products 15 and 16
in good yields (72−77%). Electron-withdrawing groups gave the
highest yields, affording 17−19 in 80−99%. The meta-
substituted starting materials gave excellent regioselectivity in
some cases (92:8 for 8)16 but was lower when fluorine was
present at the meta-position (67:33 for 9). Interestingly, when a
methyl group was located at the meta-position, only one
1
regioisomer, 22, was observed in the H NMR of the crude
product mixture, and this was isolated in moderate yield. An
Received: March 15, 2016
Figure 1. Biologically active 4-alkoxy-2-pyrone and 2-coumarin.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00751
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization for 2-Coumarin
a
entry
[Pd] (mol %)
[O] (1.5 equiv)
base (equiv)
solvent
yield (%)
1
2
3
4
5
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (5)
Pd(TFA)2 (5)
Pd(OAc)2 (5)
NaOtBu (0.2)
NaOtBu (0.2)
K2CO3 (2.5)
K2CO3 (2.5)
PivOH
PivOH
TFA
0
92
86
0
Ag2O
Ag2O
Ag2O
K2S2O8
DME
TFA
0
a
Isolated yields.
Scheme 1. 2-Coumarin Scaffold Scope
a
Table 2. Optimization for 2-Pyrone
b
entry
[Pd] (mol %)
[O] (1.5 equiv)
base (equiv)
solvent
t (°C)
yield (%)
1
2
3
4
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (5)
Pd(TFA)2 (5)
Ag2O
Ag2O
Ag2O
Ag2O
NaOtBu (0.2)
NaOtBu (0.2)
K2CO3 (2.5)
K2CO3 (2.5)
THF
70
140
140
100
3
52
56
0
PivOH
TFA
DMF
a
b
For full optimization studies, see the SI. Isolated yields.
ortho-substituent did not overly affect the reaction progress, and
corresponding product 23 was isolated in 72% yield. When the
phenoxy group was substituted with two methoxy groups
(common in many natural products), the reaction worked well
(98% of 24 and 76% of 25). Finally, 2-quinolone did not work as
well; however, product 26 could be isolated in 30% yield. We
B
DOI: 10.1021/acs.orglett.6b00751
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. 2-Pyrone Scaffold Scope
Scheme 5. Plausible Reaction Mechanism
in place of Pd(OAc)2/TFA gave no conversion to product
(Table 2, entry 4).
A substrate scope for the 2-pyrone was investigated (Scheme
2). Electron-donating groups at the para-position of 4-phenoxy-
2-pyrones (29 and 30) gave the cyclized products in moderate to
good yields. However, an electron-withdrawing group at the
para-position did not work well, with the presence of a fluoro
group (31) completely inhibiting the reaction. The meta-
substituted phenoxy groups (32−34) gave the products again
in moderate yield.16 Some good regioselectivity toward the least
sterically hindered position was observed. For example, the
reaction of 32 gave 39a/39b in a 93:7 ratio.
Scheme 3. Synthesis of Flemichapparin C in Three Steps
Good yields and regioselectivity observed with coumarin 13
prompted us to attempt to access the coumestan group of natural
products.10 Commercially available 4-hydroxy-2-coumarin 43
(Scheme 3) was brominated at the 4-position in good yield (44,
72%) and coupled with sesamol (45, 96%). Application of our
reactions conditions gave flemichapparin C 46a and a minor
regioisomer, 46b, in 82% combined yield. Under certain
conditions, complete regioselectivity could be observed.18
The focus of our study then turned toward mechanistic
investigations. Incorporating the deuterium on the coumarin
(47) allowed us to measure the involvement of the C-3−H bond
in the mechanism. The kinetic isotope effect (KIE) was
determined to be 1.08 using the initial rates method19 (Scheme
4; see SI for further details), indicating that C-3−H cleavage is
not rate-limiting. In the reaction of 47, the abstraction of
Scheme 4. Kinetic Isotope Effects
1
deuterium at C-3 was observed to be reversible, with the H
NMR integral of the C-3 proton increasing with reaction time.20
Efforts to elucidate the corresponding KIE values for C−H/D
cleavage on the phenoxy group were hampered by scrambling
effects (see SI).
Based on these preliminary mechanistic studies, an initial
palladation−protodepalladation of the C-3−H bond to give IM1
as the first step is proposed,21 accounting for the nonsignificant
KIE (Scheme 4). An SEAr-type step22 is envisaged next to give
IM2.23 Irreversible deprotonation (to give IM3) and reductive
elimination give the product. Finally, the appearance of an
induction period (see Scheme 5 and SI) suggests a key
precatalyst → catalyst event. Further mechanistic studies are
underway and will be reported in due course.
next targeted the 2-pyrone moiety. Here, we expected some
added problems given that two sites were now available on the
pyrone for C−H activation, and the pyrone unit itself is
susceptible to ring opening.17
A direct transfer of the optimized conditions which worked for
the coumarins, using PivOH as solvent (Table 2, entry 2), gave
product 28 in 52% isolated yield, while using TFA as solvent
(Table 2, entry 3) gave 28 in 56% yield. Use of Pd(TFA)2/DMF
C
DOI: 10.1021/acs.orglett.6b00751
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
́
(12) (a) Pardo, L. M.; Prendergast, A. M.; Nolan, M.-T.; O
Muimhneachain, E.; McGlacken, G. P. Eur. J. Org. Chem. 2015, 2015,
In conclusion, a double C−H activation protocol applied to 2-
coumarins and 2-pyrones gives quick access to the cyclized
products. This is certainly one of the most delicate molecular
frameworks to have been reported for this type of trans-
formation. Substitution patterns (on the phenoxy), which would
be difficult to access via other routes, are available with this
methodology. This approach facilitated a short, three-step
synthesis to flemichapparin C. Deuterium isotope effects were
examined, and a preliminary mechanism has been suggested
based on these studies.
́
3540−3550. (b) Nolan, M.-T.; Bray, J. T. W.; Eccles, K.; Cheung, M. S.;
Lin, Z.; Lawrence, S. E.; Whitwood, A. C.; Fairlamb, I. J. S.; McGlacken,
G. P. Tetrahedron 2014, 70, 7120−7127.
(13) (a) Laschober, R.; Kappe, T. Synthesis 1990, 1990, 387−388.
(b) Jin, Y. L.; Kim, S.; Kim, Y. S.; Kim, S.-A.; Kim, H. S. Tetrahedron Lett.
2008, 49, 6835−6837.
́
(14) Liegault, B.; Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou, K. J.
Org. Chem. 2008, 73, 5022−5028.
(15) Li, H.; Zhu, R.-Y.; Shi, W.-J.; He, K.-H.; Shi, Z.-J. Org. Lett. 2012,
14, 4850−4853.
(16) Difficulties with the purification prevented complete isolation of
the minor regioisomer in the reactions of 8, 33, and 34. The structure is
assigned based on the data available for the minor regioisomer
contaminated with some of the major isomer.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00751.
■
S
(17) Sun, C. L.; Furstner, A. Angew. Chem., Int. Ed. 2013, 52, 13071−
̈
13075.
General experimental procedures, characterization data,
and copies of 1H and 13C NMR spectra of all key
compounds (PDF)
(18) We were able to achieve complete regioselectivity in favor of
flemichapparin C with 77% isolated yield when the conditions described
in Table 1, entry 3, at 120 °C were employed. However, we found this
result was highly dependent upon the quality of the TFA employed in
the reaction.
(19) (a) Zhao, J.; Zhang, Q.; Liu, L.; He, Y.; Li, J.; Li, J.; Zhu, Q. Org.
Lett. 2012, 14, 5362−5365. (b) Tang, D.-T. D.; Collins, K. D.; Ernst, J.
B.; Glorius, F. Angew. Chem., Int. Ed. 2014, 53, 1809−1813.
(20) Alternatively, performing the reaction with 1 in PivOD showed
deuterium incorporation exclusively at C-3, confirming a reversible C−
H activation event (see SI).
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: g.mcglacken@ucc.ie.
Notes
The authors declare no competing financial interest.
(21) Fagnou proposed a reversible palladation−proto(deuterio)
depalladation step for the intramolecular coupling of arenes and
ACKNOWLEDGMENTS
■
́
alkanes: Liegault, B.; Fagnou, K. Organometallics 2008, 27, 4841−4843.
The research was supported by Science Foundation Ireland
(SFI/12/IP/1315, SFI/12/RC/2275, and 14/ADV/RC2751)
and the Irish Research Council/Pfizer.
Also, C-3−H has been shown to be labile in similar systems: Burns, M. J.;
Thatcher, R. J.; Taylor, R. J. K.; Fairlamb, I. J. S. F. Dalton Trans. 2010,
39, 10391−10400.
(22) For two examples of a proposed SEAr, see: (a) Tunge, J. A.;
Foresee, L. N. Organometallics 2005, 24, 6440−6444. (b) Shi, S.-L.;
REFERENCES
■
Buchwald, S. L. Angew. Chem., Int. Ed. 2015, 54, 1646−1650.
A
(1) Hassan, J.; Sev
Rev. 2002, 102, 1359−1470.
́
ignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
concerted metalation deprotonation (CMD)/ambiphilic metal ligand
activation (AMLA)-type mechanism should lead to a large positive KIE,
which we have yet to determine. For CMD, see: (c) Lapointe, D.;
Fagnou, K. Chem. Lett. 2010, 39, 1118−1126. (d) Campeau, L.-C.;
Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581−590.
For AMLA, see: (e) García-Cuadrado, D.; de Mendoza, P.; Braga, A. A.;
Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2007, 129, 6880−6886.
(f) García-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M.
J. Am. Chem. Soc. 2006, 128, 1066−1067.
(2) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103,
893−930.
(3) (a) McGlacken, G. P.; Bateman, L. M. Chem. Soc. Rev. 2009, 38,
2447−2464. (b) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem.,
Int. Ed. 2009, 48, 9792−9826.
(4) (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335−344. (b) Liu, C.; Yuan,
J.; Gao, M.; Tang, S.; Li, W.; Shi, R.; Lei, A. Chem. Rev. 2015, 115,
12138−12204.
(23) Based on the mechanistic studies carried out to date, we cannot be
certain which C−H bond is activated first. An initial, irreversible C−H
activation of the phenoxy group followed by reversible C−H activation
of the coumarin C-3−H could give similar results. We thank one
reviewer for this point.
(5) Constable, D. J.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.;
Leazer, J. L., Jr; Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B. A.;
Wells, A. Green Chem. 2007, 9, 411−420.
(6) McGlacken, G. P.; Fairlamb, I. J. Nat. Prod. Rep. 2005, 22, 369−
385.
(7) (a) Dickinson, J. Nat. Prod. Rep. 1993, 10, 71−98. (b) Fairlamb, I. J.
S.; Marrison, L. R.; Dickinson, J. M.; Lu, F.-J.; Schmidt, J. P. Bioorg. Med.
Chem. 2004, 12, 4285−4299.
(8) Chia, M.; Haider, M. A.; Pollock, G., III; Kraus, G. A.; Neurock, M.;
Dumesic, J. A. J. Am. Chem. Soc. 2013, 135, 5699−5708.
(9) Murray, R. D. H. Nat. Prod. Rep. 1989, 6, 591−624.
(10) (a) Tuskaev, V. Pharm. Chem. J. 2013, 47, 1−11. (b) Xu, M.-Y.;
Kim, Y. S. Food Chem. Toxicol. 2014, 74, 311−319. (c) Kowalski, K.;
Szczupak, Ł.; Oehninger, L.; Ott, I.; Hikisz, P.; Koceva-Chyła, A.;
Therrien, B. J. Organomet. Chem. 2014, 772−773, 49−59. (d) Nehybova,
T.; Smarda, J.; Daniel, L.; Brezovsky, J.; Benes, P. J. Steroid Biochem. Mol.
Biol. 2015, 152, 76−83.
(11) (a) Liu, J.; Liu, Y.; Du, W.; Dong, Y.; Liu, J.; Wang, M. J. Org.
Chem. 2013, 78, 7293−7297. (b) Ghosh, R.; Stridfeldt, E.; Olofsson, B.
Chem. - Eur. J. 2014, 20, 8888−8892. (c) Nolan, M.-T.; Pardo, L. M.;
Prendergast, A. M.; McGlacken, G. P. J. Org. Chem. 2015, 80, 10904−
10913.
D
DOI: 10.1021/acs.orglett.6b00751
Org. Lett. XXXX, XXX, XXX−XXX