Heteroatom-Guided, Palladium-Catalyzed, Site-Selective C-H Arylation of 4H-Chromenes: Diastereoselective Assembly of the Core Structure of Myristinin B through Dual C-H Functionalization

Article abstract of DOI:10.1002/chem.201500755

A highly site-selective, heteroatom-guided, palladium-catalyzed direct arylation of 4H-chromenes is reported. The C-H functionalization is driven not only by the substituents and structure of the substrate but also by the coupling partner being used. The diastereoselective assembly of the core structure of Myristinin B has been achieved by using a dual C-H functionalization strategy for regioselective direct arylation.

Full text of DOI:10.1002/chem.201500755

DOI: 10.1002/chem.201500755
Full Paper
&
CÀH Functionalization
Heteroatom-Guided, Palladium-Catalyzed, Site-Selective CÀH
Arylation of 4H-Chromenes: Diastereoselective Assembly of the
Core Structure of Myristinin B through Dual CÀH
Functionalization
Govind Goroba Pawar, Virendra Kumar Tiwari, Himanshu Sekhar Jena, and
Manmohan Kapur*[a]
Abstract:
A
highly site-selective, heteroatom-guided,
coupling partner being used. The diastereoselective
assembly of the core structure of Myristinin B has been
achieved by using a dual CÀH functionalization strategy
for regioselective direct arylation.
palladium-catalyzed direct arylation of 4H-chromenes is re-
ported. The CÀH functionalization is driven not only by the
substituents and structure of the substrate but also by the
Introduction
Over recent decades, carbon–carbon bond-formation reactions
that take place through CÀH functionalization have become
one of the most popular research topics for synthetic chemists
worldwide.[1] Transition-metal catalyzed and, in particular, palla-
dium-mediate, CÀH activation reactions offer a good alterna-
tive to organic transformations of unfunctionalized substrates
without having to go through cumbersome prefunctionaliza-
tion processes. In this regard, transformations proceeding
through electrophilic palladation mechanisms have been em-
ployed in regioselective CÀH functionalization of electron-rich
arenes as well as many heterocyclic substrates.[2] This mode of
CÀH activation involves precoordination of the metal to the
electron-rich p system, followed by formation of a Wheland-
like intermediate or a s complex, which then looses a proton
to a bound nucleophilic ligand (Scheme 1).[3,4] The regioselec-
tivity is usually determined by the most nucleophilic carbon
center, and this is particularly true for electron-rich (hetero)ar-
enes. Similarly, for alkenes over which a pair of electrons can
be delocalized (electron-rich olefins), the oxidative-Heck reac-
tion (also called the Fujiwara–Moritani reaction)[5] of arenes
also follows a similar mechanism. This palladium-catalyzed
transformation usually involves a PdII–Pd0 catalytic cycle in
which CÀH activation at the arene is often the first step.[6]
After the first report by Hallberg and co-workers, several
groups have succeeded in inverting the regioselectivity of mi-
gratory insertion for electron-rich olefins in the Mizoroki–Heck
Scheme 1. Selected modes of CÀH activation.
reaction, by using suitable heteroatom-based directing groups
tethered to the olefin.[7] These transformations usually involve
a Pd0–PdII mechanism. There are a limited number of reports
involving the PdII–Pd0 pathway in which the site-selectivity has
been switched for such reactions.[8]
We have been interested in regioselective CÀH functionaliza-
tion reactions that proceed through electrophilic palladation
mechanisms[9] in which it is possible to differentiate the elec-
trophilic CÀH activation of arenes from that of nonaromatic,
electron-rich olefins with the term “heteroatom-guided CÀH
activation”. This term has also been introduced to differentiate
the “heteroatom-directed CÀH activation” in which the
Lewis-basicity of the heteroatom directing groups is utilized in
“directing” the metal to a particular CÀH bond.[2]
[a] G. G. Pawar, V. K. Tiwari, Dr. H. S. Jena, Dr. M. Kapur
Department of Chemistry
Indian Institute of Science Education and Research Bhopal
Indore Bypass Road, Bhauri, Bhopal 462066, MP (India)
E-mail: mk@iiserb.ac.in
In the present study, we put forth our results on the direct
arylation reactions of 4H-chromenes through CÀH functional-
izations and propose alternative mechanisms that explain our
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500755.
Chem. Eur. J. 2015, 21, 9905 – 9911
9905
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
observations. These mechanisms differ from the regular
carbopalladation mechanisms put forward to explain similar
transformations.
Table 1. Substrate scope of the reaction with arenes and aryl halides and
monosubstituted chromenes.[16]
The benzopyran (or chromane) framework is present in
several natural products of biological importance such as
flavonoids, and many of these exhibit unique pharmacological
activities. Myristinins,[10] sarcandrones,[11] ephedrannin,[12] and
procyanidins[13] are a few of the notable examples in which the
chromane has a 2,4-diaryl substitution (Figure 1). Myristinins
[a] Conditions A: Ar-H, Pd(OAc)2 (10 mol%), AgOAc (2.0 equiv), PivOH
(3.0 equiv), 80–1008C (yield of isolated product); [b] Conditions B: Ar-I
(2.0 equiv), Pd(OAc)2 (10 mol%), AgOAc (2.0 equiv), dioxane (0.2m), 808C.
Yields given refer to isolated products.
formed, which were characterized by a double bond in a
position that differed from that of substrates 1a–e. Product 2r
was obtained from 2,4-disubstituted 4H-chromene.
In both cases (arenes as well the aryl halides), one could
postulate a simple Heck-type carbopalladation mechanism on
the monosubstituted chromene, and syn b-hydrogen elimina-
tion to generate the C3–C4 endocyclic olefin. However, this
pathway seems quite unlikely when aryl halides are employed
because the PdII catalyst would not undergo a favorable oxida-
tive insertion with the ArX so as to generate a PdIV species,
which then would have to undergo a migratory insertion with
the chromene. Such migratory insertions involving PdIV are
rather difficult and uncommon.[17] Furthermore, reductive elimi-
nation from PdIV is expected to be faster than carbopalladation.
Another argument that could be put forth is the generation of
Pd0 by sacrificing some of the chromene through the mecha-
nism reported by Heck.[18] This could then undergo an oxida-
tive insertion to generate ArPdX and the further catalytic cycle
would follow. During the optimization of the reaction condi-
tions, reactions with Pd0 catalysts and phosphine ligands re-
sulted in quite sluggish conversions.[15] Given that we were not
convinced that the regular carbopalladation pathway was
being followed in this transformation, we attempted to carry
out a deuterodemetalation on the substrate 1a (Scheme 2). No
deuterodemetalation was observed when the reaction was
carried out in D2O. In case of substrate 1a, the major product
obtained under a dioxane/D2O mixture was undeuterated
Figure 1. 2,4-Diarylchromane-containing natural products.
A–F have been isolated from a variety of natural sources and
some of them possess very impressive biological activities
such as being DNA damaging agents and DNA polymerase b-
inhibitors.[10]
Results and Discussion
To derive a general approach towards the synthesis of these
natural products, which incorporate a 2,4-diaryl chromane
framework, we were required to devise a strategy for the in-
stallation of both aryl groups through CÀH functionalization.
To our knowledge, such an approach has not been reported
for this class of compounds. Whereas most reports of aryla-
tions of chromenes with aryl halides usually follow a Pd0–PdII
pathway, we were more interested in developing a PdII–Pd0
pathway.[8a,14] In this context, we first took up the direct aryla-
tion reactions of 4H-chromenes monosubstituted at the C4-po-
sition. The substrate scope of the reaction with arenes, as well
as aryl halides worked out quite well under different optimized
conditions, as depicted in Table 1.[15] In all cases, the regioselec-
tivity was the same; the C2-arylated compounds 2a–r were
Chem. Eur. J. 2015, 21, 9905 – 9911
www.chemeurj.org
9906
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
ingly, substrate 1g, showed a secondary kinetic isotope effect
(kH/kD) of 0.4. The reaction of 1b with deuterated benzene
showed a primary kinetic isotope effect of 4.81, which indicat-
ed that CÀH activation through a concerted metalation–depro-
tonation (CMD) process[4] on the arene occurred either before
or during the rate-limiting step. Based on these observations,
a mechanism was proposed (Scheme 3) in which the initially
formed C3-palladated species could then undergo a 1,2-migra-
tion so as to generate the C2-palladated species, with the
C3ÀC4 olefin being generated by removal of the C4 hydrogen.
Such 1,2-migrations of palladium have been documented
earlier.[19] The pathway depicted in Scheme 3 would also
necessitate the involvement of PdIV species of type 14 being
generated in the case of oxidative addition with aryl halides.
The C2-palladated species would undergo a CÀH activation
with the arene (ArÀH) followed by reductive elimination to
yield the observed C2-arylated chromene. Given that the deu-
terium labeling studies showed that neither C2-H nor C3-H are
lost in the reaction, a CMD-type metalation on the chromene
can be ruled out. These studies however, do not yet rule out
the possibility of a Heck-type pathway in this substrate.
Scheme 2. Attempts at deuterodemetalation.
coumarin 6a. The reaction resulted in the same products
even without the oxygen atmosphere.
The fact that the double bond rearranged to the benzylic
position indicated that the product did not arise from a simple
hydration of the benzopyran and subsequent oxidation of the
lactol. The C3-deuterated substrate 1 f, when reacted under
the same conditions, resulted in coumarin 4, in which the deu-
terium remained. In the case of C2-deuterated chromene 1g,
intermediate lactol 6 was clearly detected by GC–MS analysis.
In our opinion, this result gives a strong indication of the
first palladation occurring at C3. In another observation, the ar-
ylation reactions with C2- or C3-deuterated substrates resulted
in products in which the deuterium label remained intact
(Scheme 3), with almost no loss of deuterium content. Interest-
Table 2. Substrate scope of the reaction with arenes and aryl halides and
4,4-disubstituted chromenes.[20]
[a] Conditions A: Ar-H, Pd(OAc)2 (10 mol%), AgOAc (2.5 equiv), PivOH
(3.0 equiv), 80–1008C (yield of isolated product); [b] Conditions B: Ar-I
(2.0 equiv), Pd(OAc)2 (10 mol%), AgOAc (2.0 equiv), dioxane (0.2m), 808C.
Yields given refer to isolated products.
Scheme 3. Studies with the deuterated substrates and postulated
mechanism involving 1,2-palladium migration.
Chem. Eur. J. 2015, 21, 9905 – 9911
www.chemeurj.org
9907
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
To probe the above conclusions further, we envisaged that
preventing b-hydrogen elimination would give further insights
into the mechanism. For this purpose, 4,4-dimethylchromenes
were chosen as substrate. The arylation reactions were per-
formed under the same conditions as that for chromene 1a–e.
As expected, the results were different. The reactions with
arenes and aryl iodides resulted exclusively in ring contraction
and concomitant arylation (Table 2).[15] The products obtained
were deduced to possess Z stereochemistry. In the case of the
reaction with arenes, traces of C3-arylation products were ob-
tained in which the ring contraction had not taken place. Nota-
bly, benzofuran substrates 16a–u were excellent starting mate-
rials for the synthesis of chroman spiroketals, and this method
constitutes a unique approach to this class of compounds.[21]
Initially, it seemed that the ring may have opened up so as to
generate an alkyne species. However, the formation of the
products with Z stereochemistry negated this possibility of a
5-exo-dig type cyclization.
Table 3. Substrate scope of the reaction with 4,4-disubstituted
chromenes and arylboronic acids.[a,22]
As shown in Scheme 4, the product of C2-deuterated start-
ing material 15d was found to be missing the deuterium,
whereas the deuterium was present in the product arising
from the C3-deuterated starting material 15c. Here too, a pri-
mary kinetic isotope effect of 5.0 was observed with deuterat-
ed benzene. This led us to propose a different mechanism in
which we postulated a migration of the C3ÀC4 carbon–carbon
bond to explain the ring contraction (Scheme 4). This mecha-
nism probably also explains why the products are exclusively
formed with Z stereochemistry; the relative orientation of the
[a] Yields given refer to isolated products.
groups on the carbocation is such that the palladium is away
from the gem-dimethyl groups.
In the direct arylation with pentafluorobenzene and 1,3-
bis(trifluoromethyl)benzene, the C3 aryl products were ob-
tained (16w, 16x), without any ring contraction (Table 2). This
observation gives a strong indication that the palladation
would occur on the C3-position and that the mechanism may
not follow a simple Heck-type pathway. After the arylations
using arenes and aryl iodides, we then attempted the reaction
with boronic acids.[15] The reactions proceeded very well and
gave, as expected, the C3-arylated product without any trace
of the ring contraction product (Table 3). The substrate scope
was very good and the site-selectivity was excellent. In fact, to
our knowledge, direct C3 arylation of 4H-chromenes has not
been reported.
The reaction with C2-deuterated substrate resulted in the
deuterium remaining in the product (Scheme 5). The C3 deute-
Scheme 4. Studies with deuterated substrates and postulated pathway
involving CÀC bond migration.
Scheme 5. Plausible pathway for the direct C3 arylation with arylboronic
acids.
Chem. Eur. J. 2015, 21, 9905 – 9911
www.chemeurj.org
9908
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
rium did not survive the reaction conditions because, under
protic conditions, the deuterium at C3 is very labile and
exchanges very fast. The pathway seems to follow an electro-
philic palladation route that is heteroatom-guided at C3
(Scheme 5). In the case of arylboronic acids, it may also be
possible that the transmetalation is the first step followed by
a heteroatom-guided CÀH activation at C3. A fast reductive
elimination is proposed so as to negate the possibility of a
competing ring contraction process.
It is quite possible that the formation of 16w and 16x (both
electron-deficient arenes with more acidic CÀH than normal
arenes), may follow a pathway similar to that shown in
Scheme 5, with the CÀH activation through CMD being the
first step.
Finally, a more convincing indication of C3 palladation was
obtained when arylboronic acids were used in the direct aryla-
tion of C4-monosubstituted 4H-chromenes (Table 4). In some
Table 4. Substrate scope of the reaction with arylboronic acids and 4-
monosubstituted 4H-chromenes.[a]
Scheme 6. Synthesis of the core structure of Myristinin B.[24] [a] Prepared
from ArB(OH)2. [b] Prepared from ArH; yield is for the hydrogenation step.
29, worked well.[23] The reaction was carried out in acidic
medium, which meant that the protodemetalation was a faster
process than b-hydride elimination and resulted in the
formation of lactone 30 as the major product. Coumarin 31
was obtained as a minor product and was easily converted
into 30 by simple hydrogenation. Diisobutylaluminum hydride
(DIBAL-H)-mediated reduction of the lactone and subsequent
dehydration of the resulting lactol provided dihydropyran 32
for the arylation reaction. As depicted in Table 4, this reaction
proceeded reasonably with aryl boronic acid to result in 2p.
The hydrogenation of the endocyclic olefin proceeded in
a highly diastereoselective fashion to give 33a. Thus, the dia-
stereoselective synthesis of the core structure for Myristinin B
was achieved by using a dual CÀH functionalization strategy.
Substrates 33b–d were also achieved in a similar fashion, and
the relative stereochemistry was easily established based on
the crystal structure of 33d.
[a] Yields given refer to isolated products.
cases, we were able to isolate a good amount of C3-arylated
products (27a–c), without rearrangement of the double bond.
The products were obtained together with the corresponding
C2-arylated substrates (2h, 2 f, and 2l, respectively). This result
also gives an indication that, unlike the case of arenes or aryl
iodides, the pathway proposed in Scheme 5 for arylboronic
acids may involve the generation of arylpalladium species in
the first step, followed by palladation at C3.
Conclusion
We have presented herein, the site-selective direct arylation of
4H-chromenes, in which we propose a heteroatom-guided or
electrophilic metalation followed by a migration of the metal
to the neighboring carbon, so as to explain the regioselectivity
of the arylation. In the case of the 4,4-disubstituted chro-
menes, we propose a CÀC bond migration to explain the for-
mation of the observed benzopyrans. In both cases, we feel
the reaction may not proceed through the usually postulated
Heck-type carbopalladation pathway of the chromene with the
arylpalladium species; rather, it is quite possible that electro-
philic metalation may be the predominant pathway. We have
also demonstrated a rare direct C3 arylation of chromenes. The
Furthermore, to devise a general strategy for the synthesis
of natural products possessing the 2,4-diarylbenzopyran core,
we attempted the synthesis of the racemic form of the core
structure of Myristinin B (Scheme 6).
Starting with phenol 28, the annulation reaction through an
oxidative-Heck reaction using the substituted ethyl cinnamate
Chem. Eur. J. 2015, 21, 9905 – 9911
www.chemeurj.org
9909
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Boissarie, I. Gillaizeau, Org. Lett. 2013, 15, 816–819; u) K. C. Pereira, A. L.
Porter, S. Potavathri, A. P. LeBris, B. DeBoef, Tetrahedron 2013, 69, 4429–
4435; see also: v) S. R. Neufeldt, M. S. Sanford, Acc. Chem. Res. 2012, 45,
936–946; w) M. K. Manna, A. Hossian, R. Jana, Org. Lett. 2015, 17, 672–
675; x) N. A. B. Juwaini, J. K. P. Ng, J. Seayad, ACS Catal. 2012, 2, 1787–
1791; y) H. Zhang, D. Liu, C. Chen, C. Liu, A. Lei, Chem. Eur. J. 2011, 17,
9581–9585; z) H. S. Lee, S. H. Kim, J. N. Kim, Bull. Korean Chem. Soc.
2010, 31, 238–241; aa) L. L. Joyce, R. A. Batey, Org. Lett. 2009, 11, 2792–
2795; ab) J.-J. Li, R. Giri, J.-Q. Yu, Tetrahedron 2008, 64, 6979–6987; for
heteroatom-directed CÀH functionalizations, see ac) D. A. Colby, R. G.
Bergman, J. A. Ellman, Chem. Rev. 2010, 110, 624–655; ad) T. W. Lyons,
M. S. Sanford, Chem. Rev. 2010, 110, 1147–1169; ae) K. M. Engle, T.-S.
Mei, J.-Q. Yu, Acc. Chem. Res. 2012, 45, 788–802; af) C. Wang, Y. Huang,
Synlett 2013, 145–149; ag) Y.-J. Liu, H. Xu, W.-J. Kong, M. Shang, H.-X.
Dai, J.-Q. Yu, Nature 2014, 515, 389–393.
reactions depicted herein proceed with high regioselectivity
and with good to moderate yields. We also feel that the
method is general and shall be of good synthetic utility. The
utility of this arylation methodology has been demonstrated in
the diastereoselective synthesis of the core structure of
Myristinin B.
Acknowledgements
Financial support from DST-India (SR/S1/OC-60/2010), is
gratefully acknowledged. G.G.P and V.K.T thank CSIR-India for
a doctoral fellowship. We thank Dr. Sanjit Konar (IISERB) for as-
sistance in X-ray analysis and CIF, IISERB, for the analytical data.
We also thank the Director, IISERB for funding and infra-
structure. We thank the Reviewers for useful suggestions.
[3] a) A. D. Ryabov, Chem. Rev. 1990, 90, 403–424; b) A. D. Ryabov, Synthesis
1985, 233–252.
[4] a) S. I. Gorelsky, D. Lapointe, K. Fagnou, J. Am. Chem. Soc. 2008, 130,
10848–10849; b) D. Lapointe, K. Fagnou, Chem. Lett. 2010, 39, 1118–
1126, and references therein; for the role of pivalic acid in CÀH func-
tionalization, see c) M. Lafrance, K. Fagnou, J. Am. Chem. Soc. 2006, 128,
16496–16497.
[5] a) I. Moritanl, Y. Fujiwara, Tetrahedron Lett. 1967, 8, 1119–1122; b) Y. Fuji-
wara, I. Moritani, S. Danno, R. Asano, S. Teranishi, J. Am. Chem. Soc.
1969, 91, 7166–7169; c) C. Jia, T. Kitamura, Y. Fujiwara, Acc. Chem. Res.
2001, 34, 633–639; d) E. M. Ferreira, H. Zhang, B. M. Stoltz in The Mizor-
oki-Heck Reaction (Ed.: M. Oestreich), Wiley, Chichester, 2009, pp. 345–
382; e) L. Zhou, W. Lu, Chem. Eur. J. 2014, 20, 634–642.
[6] For reviews related to this topic see a) J. Le Bras, J. Muzart, Chem. Rev.
2011, 111, 1170–1214; b) C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111,
1215–1292; see also: c) S. Kozhushkov, L. Ackermann, Chem. Sci. 2013,
4, 886–896; d) X. Shang, Z.-Q. Liu, Chem. Soc. Rev. 2013, 42, 3253–
3260; e) T. Kitamura, Y. Fujiwara in From CÀH to CÀC bonds: Cross-Dehy-
drogenative-Coupling (Ed.: C.-J. Li), Royal Society of Chemistry, Cam-
bridge (UK), 2015, pp. 33–54; f) J. Le Bras, J. Muzart, Synthesis 2014, 46,
1555–1572; g) W. Rauf, J. M. Brown, Chem. Commun. 2013, 49, 8430–
8440.
[7] a) C.-M. Andersson, J. Larsson, A. Hallberg, J. Org. Chem. 1990, 55,
5757–5761; b) K. Nilsson, A. Hallberg, J. Org. Chem. 1990, 55, 2464–
2470; c) M. Larhed, C.-M. Andersson, A. Hallberg, Acta. Chem. Scand.
1993, 47, 212–7; d) M. Larhed, C.-M. Andersson, A. Hallberg, Tetrahe-
dron 1994, 50, 285–304; e) G. D. Daves, Jr., A. Hallberg, Chem. Rev.
1989, 89, 1433–1445; for some other selected works, see ref. [2c] and:
f) D. Badone, U. Guzzi, Tetrahedron Lett. 1993, 34, 3603–3606; g) K.
Itami, K. Mitsudo, K. T. Kamei, J. Am. Chem. Soc. 2000, 122, 12013–
12014; h) A. F. Littke, G. C. Fu, J. Am. Chem. Soc. 2001, 123, 6989–7000;
i) I. Alonso, J. C. Carretero, J. Org. Chem. 2001, 66, 4453–4456; j) K.
Itami, M. Mineno, N. Maruoka, J. Yoshida, J. Am. Chem. Soc. 2004, 126,
11778–11779.
[8] a) L. Meng, C. Liu, W. Zhang, C. Zhou, A. Lei, Chem. Commun. 2014, 50,
1110–1112, and references therein; for an example with acrylates, see:
b) P. Wucher, L. Caporaso, P. Roesle, F. Ragone, L. Cavallo, S. Mecking, I.
Gottker-Schnetmann, Proc. Natl. Acad. Sci. USA 2011, 108, 8955–8959.
[9] a) V. K. Tiwari, G. G. Pawar, R. Das, A. Adhikary, M. Kapur, Org. Lett. 2013,
15, 3310–3313; b) G. G. Pawar, G. Singh, V. K. Tiwari, M. Kapur, Adv.
Synth. Catal. 2013, 355, 2185–2190; c) V. K. Tiwari, G. G. Pawar, H. K.
Jena, M. Kapur, Chem. Commun. 2014, 50, 7322–7325; d) V. K. Tiwari, N.
Kamal, M. Kapur, Org. Lett. 2015, 17, 1766–1769.
[10] a) S. Sawadjoon, P. Kittakoop, K. Kirtikara, V. Vichai, M. Tanticharoen, Y.
Thebtaranonth, J. Org. Chem. 2002, 67, 5470–5475, and references
therein; b) J.-Z. Deng, S. R. Starck, S. Li, S. M. Hecht, J. Nat. Prod. 2005,
68, 1625–1628; c) D. J. Maloney, J.-Z. Deng, S. R. Starck, Z. Gao, S. M.
Hecht, J. Am. Chem. Soc. 2005, 127, 4140–4141; d) D. J. Maloney, S.
Chen, S. M. Hecht, Org. Lett. 2006, 8, 1925–1927; e) K. Li, V. Kumar,
W. H. Thompson, J. A. Tunge, Org. Lett. 2006, 8, 4711–4714; f) S. J. Ghar-
pure, A. M. Sathiyanarayanana, P. K. Vurama, RSC Adv. 2013, 3, 18279–
18282.
Keywords: arylation
diastereoselectivity · oxygen heterocycles · palladium
·
CÀH activation
·
chromenes
·
[1] For some recent reviews, see: a) A. E. Shilov, G. B. Shul’pin, Chem. Rev.
1997, 97, 2879–2932; b) J. A. Labinger, J. E. Bercaw, Nature 2002, 417,
507; c) V. Ritleng, C. Sirlin, M. Pfeffer, Chem. Rev. 2002, 102, 1731–1770;
d) Activation and Functionalization of CÀH Bonds, ACS Symposium Series,
Vol. 885 (Eds.: K. I. Goldberg, A. S. Goldman), American Chemical Society,
Washington, 2004; e) F. Kakiuchi, T. Kochi, Synthesis 2008, 3013–3039;
f) X. Chen, K. M. Engle, D.-H. Wang, J.-Q. Yu, Angew. Chem. Int. Ed. 2009,
48, 5094–5115; Angew. Chem. 2009, 121, 5196–5217; g) L. Ackermann,
R. Vicente, A. R. Kapdi, Angew. Chem. Int. Ed. 2009, 48, 9792–9826;
Angew. Chem. 2009, 121, 9976–10011; h) Topics in Current Chemistry,
Vol. 292: CÀH Activation (Eds.: J.-Q. Yu, Z. Shi), Springer, Berlin, 2010; i) J.
Wencel-Delord, T. Drçge, F. Liu, F. Glorius, Chem. Soc. Rev. 2011, 40,
4740–4761; j) Y. Yamaguchi, A. D. Yamaguchi, K. Itami, Angew. Chem.
Int. Ed. 2012, 51, 8960–9009; Angew. Chem. 2012, 124, 9092–9142;
k) M. P. Doyle, K. I. Goldberg, Acc. Chem. Res. 2012, 45, 777 (special
issue); l) Y. Wu, J. Wang, F. Mao, F. Y. Kwong, Chem. Asian J. 2014, 9, 26–
47; m) F. Zhang, D. R. Spring, Chem. Soc. Rev. 2014, 43, 6906–6919; n) F.
Juliµ-Hernµndez, M. Simonetti, I. Larrosa, Angew. Chem. Int. Ed. 2013, 52,
11458–11460; Angew. Chem. 2013, 125, 11670–11672; o) M. Corbet, F.
De Campo, Angew. Chem. Int. Ed. 2013, 52, 9896–9898; Angew. Chem.
2013, 125, 10080–10082; p) J. Yang, Org. Biomol. Chem. 2015, 13,
1930–1941.
[2] a) T. Itahara, M. Ikeda, T. Sakakibara, J. Chem. Soc. Perkin Trans. 1 1983,
1361–1363; b) E. A. Severino, E. R. Costenaro, A. L. L. Garcia, C. R. D. Cor-
reia, Org. Lett. 2003, 5, 305–308; c) A. Stadler, H. von Schenck, K. S. A.
Vallin, M. Larhed, A. Hallberg, Adv. Synth. Catal. 2004, 346, 1773–1781;
d) Y. Hatamoto, S. Sakaguchi, Y. Ishii, Org. Lett. 2004, 6, 4623–4625;
e) B. S. Lane, M. A. Brown, D. Sames, J. Am. Chem. Soc. 2005, 127, 8050–
8057; f) D. R. Stuart, K. Fagnou, Science 2007, 316, 1172–1175; g) D. R.
Stuart, E. Villemure, K. Fagnou, J. Am. Chem. Soc. 2007, 129, 12072–
12073; h) H. Zhou, W.-J. Chung, Y.-H. Xu, T.-P. Loh, Chem. Commun.
2009, 3472–3474; i) H. Zhou, Y.-H. Xu, W.-J. Chung, T.-P. Loh, Angew.
Chem. Int. Ed. 2009, 48, 5355–5357; Angew. Chem. 2009, 121, 5459–
5461; j) L. Bi, G. I. Georg, Org. Lett. 2011, 13, 5413–5415; k) M. Min, S.
Hong, Chem. Commun. 2012, 48, 9613–9615; l) S. Pankajakshan, Y.-H.
Xu, J. K. Cheng, M. T. Low, T.-P. Loh, Angew. Chem. Int. Ed. 2012, 51,
5701–5705; Angew. Chem. 2012, 124, 5799–5803; m) Y. Moon, D.
Kwon, S. Hong, Angew. Chem. Int. Ed. 2012, 51, 11333–11336; Angew.
Chem. 2012, 124, 11495–11498; n) A. Petit, J. Flygare, A. T. Miller, G.
Winkel, D. H. Ess, Org. Lett. 2012, 14, 3680–3683; o) H. Wang, L.-N. Guo,
X.-H. Duan, Org. Lett. 2012, 14, 4358–4361; p) K. H. Kim, H. S. Lee, S. H.
Kim, J. N. Kim, Tetrahedron Lett. 2012, 53, 2761–2764; q) F. Chen, Z.
Feng, C.-Y. He, Y.-I. Guo, X. Zhang, Org. Lett. 2012, 14, 1176–11179; r) N.
Gigant, L. Chausset-Boissarie, M.-C. Belhomme, T. Poisson, X. Panne-
coucke, I. Gillaizeau, Org. Lett. 2013, 15, 278–281; s) Y.-Y. Yu, L. Bi, G. I.
Georg, J. Org. Chem. 2013, 78, 6163–6169; t) N. Gigant, L. Chausset-
[11] a) C. M. Cao, Y. Peng, L. J. Xu, Y. J. Wang, J. S. Yang, P. G. Xiao, Chem.
Pharm. Bull. 2009, 57, 743–746; b) C.-M. Cao, L.-J. Xu, Y. Peng, Q.-W. Shi,
P.-G. Xiao, Chem. Pharm. Bull. 2010, 58, 1395–1398.
Chem. Eur. J. 2015, 21, 9905 – 9911
www.chemeurj.org
9910
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[12] a) H. Hikino, M. Takahashi, C. Konno, Tetrahedron Lett. 1982, 23, 673–
676; b) F. Perron, K. F. Albizati, Chem. Rev. 1989, 89, 1617–1661; c) I.-S.
Kim, Y.-J. Park, S.-J. Yoon, H.-B. Lee, Int. Immunopharmacol. 2010, 10,
1616–1625; d) F. Wang, F. Chen, M. Qu, T. Li, Y. Liua, M. Shi, Chem.
Commun. 2013, 49, 3360–3362; e) X. Zang, M. Shang, F. Xu, J. Liang, X.
Wang, M. Mikage, S. Cai, Molecules 2013, 18, 5172–5189.
Angew. Chem. Int. Ed. 2008, 47, 9462–9465; Angew. Chem. 2008, 120,
9604–9607; b) K. MuÇiz, Angew. Chem. Int. Ed. 2009, 48, 9412–9423;
Angew. Chem. 2009, 121, 9576–9588; c) P. Sehnal, R. J. K. Taylor, I. J. S.
Fairlamb, Chem. Rev. 2010, 110, 824–889; d) F. Juliµ-Hernµndez, A.
Arcas, J. Vicente, Chem. Eur, J. 2012, 18, 7780–7786; e) A. J. Hickman,
M. S. Sanford, Nature 2012, 484, 177–185; f) L. Huang, Q. Li, C. Wang, C.
Qi, J. Org. Chem. 2013, 78, 3030–3038; g) J. J. Topczewski, M. S. Sanford,
Chem. Sci. 2015, 6, 70–76; see also reference [2ad].
[13] a) K. Kondo, M. Kurihara, K. Fukuhara, T. Tanaka, T. Suzuki, N. Miyata, M.
Toyoda, Tetrahedron Lett. 2000, 41, 485–488; b) L.-C. Lin, Y.-C. Kuo, C.-J.
Chou, J. Nat. Prod. 2002, 65, 505–508; c) W.-S. Jeong, A.-N. T. Kong,
Pharm. Biol. 2004, 42, 84–93; d) H. Makabe, Heterocycles 2013, 87,
2225–2248; e) J. Afonso, C. P. Passos, M. A. Coimbra, P. Soares-da-Silva,
C. M. Silva in Grapes: Production, Phenolic Composition and Potential Bio-
medical Effects (Ed.: J. S. Câmara), Nova Science Publishers, New York,
NY, 2014, pp. 339–363; f) N. Gonzalez-Abuin, M. Pinent, A. Casanova-
Marti, L. Arola, M. Blay, A. Ardevol, Curr. Med. Chem. 2015, 22, 39–50.
[14] For some selected reviews, see: ref. [6a–b]; for selected examples, see:
a) V. Bellosta, S. Czernecki, D. Avenel, S. El Bahij, H. Gillier-Pandraud,
Can. J. Chem. 1990, 68, 1364–1368; b) R. Benhaddou, S. Czernecki, G.
J. Ville, J. Org. Chem. 1992, 57, 4612–4616; c) S. Czernecki, V. Decha-
vanne, Can. J. Chem. 1983, 61, 533–543; d) R. C. Larock, W. H. Gong,
G. B. Baker, Tetrahedron Lett. 1989, 30, 2603–2606; e) J. Ramnauth, O.
Poulin, S. Rakhit, S. P. Maddaford, Org. Lett. 2001, 3, 2013–2015; f) N. de
La Figuera, P. Forns, J.-C. Fernµndez, S. Fiol, D. Fernµndez-Fornerb, F. Al-
bericio, Tetrahedron Lett. 2005, 46, 7271–7274; g) A-H. L. Machado,
M. A. De Sousa, D.-C. S. Patto, l.-F. S. Azevedo, F. I. Bombonato, C-R. D.
Correia, Tetrahedron Lett. 2009, 50, 1222–1225; h) H.-H. Li, X.-S. Ye, Org.
Biomol. Chem. 2009, 7, 3855–3861; i) S. Xiang, S. Cai, J. Zeng, X.-W. Liu,
Org. Lett. 2011, 13, 4608–4611; j) Y. Bai, M. Leow, J. Zeng, X.-W. Liu, Org.
Lett. 2011, 13, 5648–5651; k) I. Cobo, M. I. Matheu, S. Castillon, O. Bou-
tureira, B. G. Davis, Org. Lett. 2012, 14, 1728–1731; l) Y. Bai, L. Mai, H.
Kim, H. Liao, X.-W. Liu, J. Org. Chem. 2013, 78, 8821–8825; m) C.-F. Liu,
D.-C. Xiong, X.-S. Ye, J. Org. Chem. 2014, 79, 4676–4686; n) B.-S. Zeng,
X. Yu, P. W. Siu, K. A. Scheidt, Chem. Sci. 2014, 5, 2277–2281; o) A. K. Ku-
sunuru, S. K. Yousuf, M. Tatina, D. Mukherjee, Eur. J. Org. Chem. 2015,
459–462.
[18] a) R. F. Heck, J. Am. Chem. Soc. 1969, 91, 6707–6714; See also b) W.
Kitching, Z. Rappoport, S. Winstein, W. G. Young, J. Am. Chem. Soc.
1966, 88, 2054–2055.
[19] N. P. Grimster, C. Gauntlett, C. R. A. Godfrey, M. J. Gaunt, Angew. Chem.
Int. Ed. 2005, 44, 3125–3129; Angew. Chem. 2005, 117, 3185–3189; N. P.
Grimster, C. Gauntlett, C. R. A. Godfrey, M. J. Gaunt, Angew. Chem. 2005,
117, 3185–3189; see also reference [2e].
[20] CCDC-995284 (16a), -995286 (16b), and -995283 (16w) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[21] a) M. A. Marsini, Y. Huang, C. C. Lindsey, K.-L. Wu, T. R. R. Pettus, Org.
Lett. 2008, 10, 1477–1480; b) J. C. Green, G. L. Burnett IV, T. R. R. Pettus,
Pure Appl. Chem. 2012, 84, 1621–1631; c) N. Wongsa, U. Sommart, T.
Ritthiwigrom, A. Yazici, S. Kanokmedhakul, K. Kanokmedhakul, A. C.
Willis, S. G. Pyne, J. Org. Chem. 2013, 78, 1138–1148; d) R. Quach, D. P.
Furkert, M. A. Brimble, Tetrahedron Lett. 2013, 54, 5865–5868.
[22] CCDC-995282 (22b) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[23] a) C. Jia, D. Piao, J. Oyamada, W. Lu, T. Kitamura, Y. Fujiwara, Science
2000, 287, 1992–1995; b) B. M. Trost, F. D. Toste, K. Greenman, J. Am.
Chem. Soc. 2003, 125, 4518–4526; c) S. Ito, M. Mabuchi, N. Sato, H.
Aoki, Bull. Chem. Soc. Jpn. 2005, 78, 371; d) D. Kim, M. Min, S. Hong,
Chem. Commun. 2013, 49, 4021–4023.
[24] CCDC-995285 (33d) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[15] See the Supporting Information for details on the optimization of the
reaction conditions.
[16] CCDC-995287 (2a) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from the Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
Received: February 24, 2015
[17] For some selected reviews and reports on higher valent palladium
chemistry, see: a) V. S. Thirunavukkarasu, K. Parthasarathy, C.-H. Cheng,
Published online on May 26, 2015
Chem. Eur. J. 2015, 21, 9905 – 9911
www.chemeurj.org
9911
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim