N-Heterocyclic Carbene Ligand-Enabled C(sp3)-H Arylation of Piperidine and Tetrahydropyran Derivatives

Article abstract of DOI:10.1002/chem.201600191

Pd^II-catalyzed C(sp³)-H arylation of saturated heterocycles with a wide range of aryl iodides is enabled by an N-heterocyclic carbene (NHC) ligand. A C(sp³)-H insertion step by the Pd^II/NHC complex in the absence of ArI is demonstrated experimentally for the first time. Experimental data suggests that the previously established NHC-mediated Pd⁰/Pd^II catalytic manifold does not operate in this reaction. This transformation provides a new approach for diversifying pharmaceutically relevant piperidine and tetrahydropyran ring systems. Pd^II-catalyzed C(sp³)-H arylation of saturated heterocycles with a wide range of aryl iodides is enabled by an N-heterocyclic carbene (NHC) ligand. A C-H insertion step by the Pd^II/NHC complex in the absence of ArI is demonstrated experimentally for the first time. This arylation method provides a new approach for diversifying pharmaceutically relevant piperidine and tetrahydropyran ring systems (see scheme).

Full text of DOI:10.1002/chem.201600191

DOI: 10.1002/chem.201600191
Communication
&
CÀH Activation
N-Heterocyclic Carbene Ligand-Enabled C(sp3)ÀH Arylation of
Piperidine and Tetrahydropyran Derivatives
Shengqing Ye,[a] Weibo Yang,[a] Timothy Coon,[b] Dewey Fanning,[b] Tim Neubert,[b]
Dean Stamos,*[b] and Jin-Quan Yu*[a]
medicinally important piperidines and tetrahydropyrans that
Abstract: PdII-catalyzed C(sp3)ÀH arylation of saturated
are unreactive when using the quinoline ligands.
heterocycles with a wide range of aryl iodides is enabled
Piperidine and tetrahydropyran motifs are widespread
by an N-heterocyclic carbene (NHC) ligand. A C(sp3)ÀH in-
among drug molecules.[7] An analysis of all launched drugs
sertion step by the PdII/NHC complex in the absence of
within the Integrity database shows approximately 320 regis-
ArI is demonstrated experimentally for the first time. Ex-
tered drugs containing saturated piperidines and approximate-
perimental data suggests that the previously established
ly 130 containing saturated tetrahydropyrans (THPs).[8] When
NHC-mediated Pd0/PdII catalytic manifold does not oper-
one eliminates natural product-based drugs from the analysis
ate in this reaction. This transformation provides a new
(where the piperidine moiety is derived from biosynthetic pro-
approach for diversifying pharmaceutically relevant piperi-
cesses and carbohydrate-based THP derivatives) the remaining
dine and tetrahydropyran ring systems.
approximately 260 piperidines are mostly derived from simple
commodity chemicals: unsubstituted piperidine itself and all
regioisomers of piperidone and piperidine carboxylic acids. A
In the past decade, a wide range of PdII-catalyzed b-CÀH func-
similar conclusion can be drawn for the approximately 10 non-
carbohydrate derived THP-based drugs.[8] We envisage that di-
tionalizations of aliphatic acids have been developed by using
directed CÀH activation.[1] Our early studies demonstrated ex-
cellent stereocontrol in b-CÀH functionalizations by using
a chiral oxazoline as the auxiliary.[2] The use of aminoquinoline
bidentate directing groups proved to be exceptionally effective
for methylene CÀH arylation.[3] Towards the ultimate goal of
achieving simple and practical b-CÀH functionalization reac-
tions, we have developed a number of weakly coordinating di-
recting groups.[4] Although these directing groups are highly
efficient for the activation of C(sp2)ÀH[4a,c] and primary C(sp3)À
H[4a,b] bonds, poor reactivity in methylene CÀH activation has
been observed.
rected CÀH arylation of readily available piperidine or tetrahy-
dropyran building blocks with a wide range of aryl iodides
could rapidly expand the diversity of these molecules. Despite
significant progress in sp3 CÀH arylation, arylation of piperi-
dines and tetrahydropyrans at the C3 and C4 positions remains
a significant challenge.[9–13] Our recent finding that pyridine-
and quinoline-type monodentate s-donor ligands can signifi-
cantly accelerate sp3 CÀH functionalization of amide sub-
strates[5] prompted us to investigate whether the readily avail-
able NHC ligands could be harnessed to promote CÀH aryla-
tion through PdII/PdIV catalysis. Although a Pd0/NHC-catalyzed
intramolecular enantioselective C(sp3)ÀH arylation through
Pd0/PdII redox has been demonstrated in pioneering stud-
ies,[14,15] the feasibility of NHC ligands to promote intermolecu-
lar C(sp3)ÀH arylation remains to be demonstrated.[16] Thus, the
development of NHC-promoted C(sp3)ÀH arylation reactions of
piperidines and tetrahydropyrans is of fundamental importance
to catalysis, in addition to being useful in medicinal chemistry.
Our recent success in developing a number of PdII-catalyzed
CÀH arylations of amides enabled by mono-dentate s-donor li-
gands led us to focus on the use of PdII catalysts. Guided by
the need for diverse piperidines in medicinal chemistry, we
began to develop b-arylation of amide 1a derived from 2-pi-
peridinecarboxylic acid (Table 1). We found that the reaction of
0.1 mmol of amide 1a with 2.0 equivalents of aryl iodide 2a in
the presence of 10 mol% of Pd(TFA)2, 20 mol% of commercial-
ly available NHC ligand L1, and 3.0 equivalents of AgOAc (in
0.5 mL of hexafluorobenzene at 1008C under air for 24 h) gave
exclusively the cis diastereoisomer of the desired product in
53% yield (Table 1). In the absence of ligand, only a trace
amount of product was detected, thus confirming the signifi-
Recently, the discovery of a series of pyridine and quinoline
ligands has enabled methylene CÀH activation using these
simple weakly coordinating directing groups.[5] However, the
scope and efficiency of this ligand scaffold remain limited.
Herein we demonstrate that N-heterocyclic carbenes, as anoth-
er class of s-donor ligands,[6] can promote PdII-catalyzed meth-
ylene CÀH arylation, thus offering another opportunity for
ligand development. Notably, this protocol is compatible with
[a] Dr. S. Ye, Dr. W. Yang, Prof. Dr. J.-Q. Yu
Department of Chemistry, The Scripps Research Institute (TSRI)
10550 North Torrey Pines Road
La Jolla, CA 92037 (USA)
E-mail: yu200@scripps.edu
[b] T. Coon, D. Fanning, T. Neubert, D. Stamos
Medicinal Chemistry, Vertex Pharmaceuticals
11010 Torreyana Rd, San Diego, CA 92121 (USA)
E-mail: Dean_Stamos@vrtx.com
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201600191.
Chem. Eur. J. 2016, 22, 4748 – 4752
4748
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Table 1. Ligand screening.[a,b,c]
Table 2. C(sp3)ÀH Arylation.[a,b,c]
Entry
Ligand
Yield of 3a1 [%]
Entry
Ligand
Yield of
3a1 [%]
1
2
3
4
5
6
7
8
no ligand <5
9
L8
L9
64
trace
12
42
6
L1
L2
L3
L4
L5
L6
L7
53
66
70
98
72
96
97
10
11
12
13
14
15
L10
L11
L12
L13
L14
84
88
[a] Conditions: 1a (0.1 mmol), 2a (2.0 equiv), Pd(TFA)2 (10 mol%), ligand
(20 mol%), AgOAc (3.0 equiv), hexafluorobenzene (0.5 mL), 1008C, under
air, 24 h; [b] yields determined by 1H NMR analysis of the crude product
with CH2Br2 as an internal standard; [c] single cis-diastereoisomer was ob-
tained.
cant impact of NHC ligands on the b-C(sp3)ÀH arylation reac-
tion of piperidine amide 1a. We next performed a systematic
screening of 4,5-dihydroimidazolium ligands under these stan-
dard conditions. Increasing the steric hindrance on the N-aryl
ring improved the yield to 66% (L2). Replacement of the N-
aryl group with sterically bulky alkyl groups consistently im-
proved the reaction and afforded excellent yields (L4, L6 and
L7). The significantly lower yield obtained with L8 suggests
that the tertiary carbon attached to the nitrogen is required.
We also examined imidazolium ligands with similar steric envi-
ronments. The results with L9–L14 showed that imidazolium li-
gands are inferior to 4,5-dihydroimidazolium ligands for this re-
action.
[a] Conditions (unless otherwise stated): 1a (0.1 mmol), 2 (2.0 equiv),
Pd(TFA)2 (10 mol%), L4 (20 mol%), AgOAc (3.0 equiv), hexafluorobenzene
(0.5 mL), 1008C, under air, 24 h; [b] yields of isolated product; [c] single
cis-diastereoisomer was obtained; [d] 2 (3.0 equiv), L7 (20 mol%), and
Ag2CO3 (2.0 equiv) were used.
and 3,4-methylenedioxyiodobenzene were also effective cou-
pling partners, affording 3a5 and 3a6 in 98 and 88% yield, re-
spectively. However, other aryl iodides, especially the ortho, or
meta-substituted aryl iodides, gave moderate yields (ca. 40%)
under these initially optimized conditions. We were pleased to
With these optimized reaction conditions in hand, we exam-
ined the scope of aryl iodides (Table 2). Arylation of 1a with
a few simple aryl iodides and ligand L4 gave the expected
products 3a1–4 in excellent yields. Para-methoxylphenyl iodide
Chem. Eur. J. 2016, 22, 4748 – 4752
www.chemeurj.org
4749
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
find that the use of the less hindered ligand L7 significantly
improved the yields in these cases (3a7, 3a8). Aryl iodides with
different protecting groups [tributylsilyl (TBS), Ac, tert-butoxy-
carbonyl (Boc)] are also compatible with this arylation reaction,
using ligand L7 (3a9–12). Notably, aryl iodides containing ortho-
OMe (3a8), and ortho-NHAc (3a12) are especially challenging
coupling partners in previous studies.[3,4] These results indicate
that a better match between substrates and ligands can be
achieved by tuning the ligand structures. Para-fluoro-, chloro-,
and bromophenyliodides were effective coupling partners
(3a13, 3a15, 3a16), whereas ortho-fluorophenyl iodide gave the
desired product 3a14 in 40% yield. Other strongly electron-
withdrawing groups such as CF3, Ac, COOMe, and CHO were
also tolerated (3a17–21).
known be equally reactive due to the conformation.[3] The ex-
clusive regioselectivity observed in 3b appears to indicate that
Pd insertion into the
CÀH bonds adjacent to the nitrogen atoms is less favored,
which could be due to the known a-effect as the carbon
center will be negatively charged during the CÀH cleavage
step. The use of 2,2,2-trichloroethyl carbonate (Troc) instead of
the trifluoroacetyl protecting group did not affect the yield sig-
nificantly (3d). Interestingly, 2-methyl-3-piperidinecarboxamide
gave the arylated trans isomer 3e selectively in higher yield.
The high trans selectivity can be explained by the 1,3-interac-
tion that significantly increases the steric hindrance if the Pd
were to insert into the cis-axial CÀH bond (Figure 1). Arylation
of 2-pyrrolidinecarboxamide gave the cis isomer 3 f selectively,
Importantly, functionalities such as bromo and CHO are
uniquely compatible with these conditions and are more effi-
ciently installed by using this methodology in comparison to
more traditional routes that rely on pyridine saturation to gen-
erate the piperidine cores. Aryl iodides containing potentially
coordinating groups, such as phosphate and thioether, also
gave synthetically useful yields (3a22, 3a23). A limited number
of heteroaryl iodides were also successfully coupled with 1a
(3a24À28) to give heterocycles that are potentially medicinally
important.
Figure 1. Possible explanation for diastereoselectivity.
albeit in low yield. This arylation protocol was also extended to
the functionalization of tetrahydropyrans. In this case, although
arylation of 3-tetrahydropyrancarboxamide 2g afforded a mix-
ture of the cis and trans products in 72% yield, 4-tetrahydro-
pyrancarboxamide 2h was not as reactive, affording the prod-
uct 3h in low yield. The lower reactivity of 2h was most likely
due to bidentate coordination from the directing group and
the 4-oxygen atom, which was not possible in 2g due to geo-
metric constraints. Interestingly, arylation of 1,1-dioxohexahy-
drothiopyran-4-carboxamide 1i also proceeded to give the de-
sired product 3i in 62% yield, with the cis isomer being the
major product. The preference for inserting at the cis-axial CÀH
bonds indicates a strong impact of the large sulfonyl group on
the conformation of the six-membered ring (Figure 1).
However, the strongly coordinating pyridinyl, quinolinyl, and
pyrazolyl iodides were not compatible with these conditions.
Having established the scope of aryl iodides, we subjected
3- and 4-piperidinecarboxamides 1b and 1c to the standard
arylation conditions (Table 3). The reactions of these substrates
Table 3. C(sp3)ÀH Arylation.[a,b]
To demonstrate the scalability of this b-C(sp3)ÀH arylation
reaction, we performed the arylation with 4.4 g of 1a to form
3a1 in 84% yield (Scheme 1). Since this reaction is compatible
[a] Conditions: 1 (), 3.0 equiv of 2a (0.1 mmol), Pd(TFA)2 (10 mol%), L7
(20 mol%), Ag2CO3 (2.0 equiv), hexafluorobenzene (0.5 mL), 1008C, under
air, 24 h; [b] yields of isolated product.
Scheme 1. Gram-scale synthesis.
were slower and homocoupling of aryl iodides was observed.
Hence, 3 equivalents of aryl iodide was used to improve the
yield. The arylated products were obtained in 66 and 57%
yields respectively as mixtures of cis and trans isomers (3b,
3c). Although the directed CÀH activation typically favors the
cis-CÀH bond, the trans-axial CÀH bond in cyclohexane is
with a wide range of solvents including dichloroethane (DCE),
toluene, EtOAc (see the Supporting Information), we chose
DCE to perform the gram-scale reaction. Two different proto-
cols were also developed to convert the amide into ester and
thioester, respectively, in one-pot reactions (Scheme 2). Treat-
ment with lithium hexamethyl disilazide (LiHMDS) during the
Chem. Eur. J. 2016, 22, 4748 – 4752
www.chemeurj.org
4750
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Firstly, AgI salts are incompatible with Pd0/PdII catalysis, as
Pd0 would be oxidized by AgI prior to the oxidative addition
with ArI in the absence of an efficient phosphine ligand.[14–16]
Secondly, we have performed a stepwise stoichiometric aryla-
tion reaction of 1a, which demonstrates that the PdII/NHC
complex inserts into CÀH in the absence of ArI to form the
alkyl–PdII intermediate. Although we have not been able to
obtain the X-ray structure of the intermediate 6a,
1H NMR,13C NMR, and mass spectra provided definitive evi-
dence for carbon–Pd bond formation (Scheme 4). Since one of
Scheme 2. Deprotection of 3a1.
deprotection was carried out for no longer than 10 min to
ensure that no epimerization would occur under these condi-
tions.
Although NHC ligands have been employed to promote
CÀH arylation and alkynylation through Pd0/PdII catalysis,[14–16]
a number of experimental observations have provided strong
evidence against the involvement of oxidative addition of ArI
with Pd0/NHC complex in this case. Although whether the re-
action of the CÀH insertion intermediate with ArI involves PdIV
has not been fully established in previous studies and is not
the subject of this study, we have experimentally shown that
the PdII/NHC complex cleaves the C(sp3)ÀH bond in the ab-
sence of ArI and the intermediate reacts with ArI subsequently
to give the arylated product. Based on these experiments,
a PdII/PdIV catalytic cycle (Scheme 3) is proposed, as discussed
below.
Scheme 4. Mechanistic investigations.
the most notable differences between Pd0/PdII and PdII/PdIV
catalysis is the order of the CÀH insertion step and the reaction
with ArI (Scheme 3), the observed CÀH insertion in the ab-
sence of ArI is consistent with the PdII/PdIV pathway. While
direct evidence for the involvement of PdII/PdIV redox chemis-
try in CÀH arylation reactions is generally lacking in the litera-
ture,[18] the Vicente group recently reported the synthesis of
a rare PdIV complex through the stoichiometric reaction of an
alkylpalladium(II) species with 2-iodobenzoic acid,[19] support-
ing the formation of PdIV by reaction of 6a with aryl iodide
(Scheme 4). Thirdly, a stoichiometric amount of AgOAc is es-
sential for the second step to proceed, in accordance with the
previous observation in PdIV chemistry.[18] Although it is possi-
ble that the role of the AgI salt might be to abstract the Cl
anion from the intermediate 6a, the lack of reactivity with the
preformed complex of PdII with ligand L12 bearing BF4 in the
absence of AgOAc suggests that AgI is required for the oxida-
tion of PdII to PdIV by ArI, as previously documented.[18] Finally,
considering that ArBr was used by Kündig and co-workers as
the coupling partner in Pd0/NHC-catalyzed CÀH arylation,[14]
the lack of reactivity with ArBr in this reaction is also inconsis-
tent with a Pd0/PdII catalytic cycle.
In summary, NHC ligands have been found to promote b-
C(sp3)ÀH insertion by PdII catalysts for the first time. Experi-
mental data are consistent with a PdII/NHC complex insertion
into C(sp3)ÀH bonds followed by subsequent reaction with ArI,
which is distinct from the Pd0/NHC/ArI catalysis. Both C3 and
C4 CÀH arylation of piperidines and tetrahydropyrans were en-
abled by NHC ligands. Further optimization of the ligand struc-
ture to broaden the scope of heterocycles is underway in our
laboratory.
Scheme 3. Comparison of Pd0/PdII (top) and PdII/PdIV (bottom) catalytic
cycles.
Chem. Eur. J. 2016, 22, 4748 – 4752
www.chemeurj.org
4751
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Liang, J. Org. Chem. 2010, 75, 2893; b) B. Sundararaju, M. Achard,
G. V. M. Sharma, C. Bruneau, J. Am. Chem. Soc. 2011, 133, 10340; c) T.
Boudiar, Z. Sahli, B. Sundararaju, M. Achard, Z. Kabouche, H. Doucet, C.
Bruneau, J. Org. Chem. 2012, 77, 3674; d) K. Yuan, F. Jiang, Z. Sahli, M.
Achard, T. Roisnel, C. Bruneau, Angew. Chem. Int. Ed. 2012, 51, 8876;
Angew. Chem. 2012, 124, 9006; e) N. Takasu, K. Oisaki, M. Kanai, Org.
Lett. 2013, 15, 1918; f) A. Millet, P. Larini, E. Clot, O. Baudoin, Chem. Sci.
2013, 4, 2241; g) W. Chen, Y. Kang, R. G. Wilde, D. Seidel, Angew. Chem.
Int. Ed. 2014, 53, 5179; Angew. Chem. 2014, 126, 5279.
Acknowledgements
We gratefully acknowledge The Scripps Research Institute, the
NIH (NIGMS, 2R01M084019), and Vertex Pharmaceuticals for fi-
nancial support.
Keywords: arylation · CÀH activation · heterocycles · N-
heterocyclic carbenes · palladium
[13] Selected C2ÀH arylation: a) P. Beak, S. T. Kerrick, S. Wu, J. Chu, J. Am.
Chem. Soc. 1994, 116, 3231; b) R. K. Dieter, S. Li, Tetrahedron Lett. 1995,
36, 3613; c) R. K. Dieter, S. Li, J. Org. Chem. 1997, 62, 7726; d) Z. Li, C.-J.
Li, J. Am. Chem. Soc. 2005, 127, 6968; e) K. R. Campos, A. Klapars, J. H.
Waldman, P. G. Dormer, C.-Y. Chen, J. Am. Chem. Soc. 2006, 128, 3538;
f) S. J. Pastine, D. V. Gribkov, D. Sames, J. Am. Chem. Soc. 2006, 128,
14220; g) A. Klapars, K. R. Campos, J. H. Waldman, D. Zewge, P. G.
Dormer, C. Chen, J. Org. Chem. 2008, 73, 4986; h) M. Ohta, M. P. Quick,
J. Yamaguchi, B. Wünsch, K. Itami, Chem. Asian J. 2009, 4, 1416; i) N.
Yoshikai, A. Mieczkowski, A. Matsumoto, L. Ilies, E. Nakamura, J. Am.
Chem. Soc. 2010, 132, 5568; j) A. McNally, C. K. Prier, D. W. C. MacMillan,
Science 2011, 334, 1114; k) J. Jin, D. W. C. MacMillan, Angew. Chem. Int.
Ed. 2015, 54 1565; Angew. Chem. 2015, 127, 1591.
[14] a) M. Nakanishi, D. Katayev, C. Besnard, E. P. Kündig, Angew. Chem. Int.
Ed. 2011, 50, 7438; Angew. Chem. 2011, 123, 7576; b) D. Katayev, M. Na-
kanishi, T. Buergi, E. P. Kündig, Chem. Sci. 2012, 3, 1422; c) E. Larionov,
M. Nakanishi, D. Katayev, C. Besnard, E. P. Kündig, Chem. Sci. 2013, 4,
1995; d) D. Katayev, E. Larionov, M. Nakanishi, C. Besnard, E. P. Kündig,
Chem. Eur. J. 2014, 20, 15021.
[15] For selected examples of Pd0/NHC catalyzed sp2 CÀH arylation: a) N.
Gürbüz, I. Özdemir, B. Cetinkaya, Tetrahedron Lett. 2005, 46, 2273; b) L.-
C. Campeau, P. Thansandote, K. Fagnou, Org. Lett. 2005, 7, 1857; c) D.
Ghosh, H. M. Lee, Org. Lett. 2012, 14, 5534; d) J. D. Dooley, S. R. Chidipu-
di, H. W. Lam, J. Am. Chem. Soc. 2013, 135, 10829; e) Z.-S. Gu, W.-X.
Chen, L.-X. Shao, J. Org. Chem. 2014, 79, 5806; f) X.-B. Shen, Y. Zhang,
W.-X. Chen, Z.-K. Xiao, T.-T. Hu, L.-X. Shao, Org. Lett. 2014, 16, 1984.
[16] For Pd0/NHC-catalyzed C(sp3)ÀH alkynylation: J. He, M. Wasa, K. S. L.
Chan, J.-Q. Yu, J. Am. Chem. Soc. 2013, 135, 3387.
[1] For selected reviews: a) O. Daugulis, H.-Q. Do, D. Shabashov, Acc. Chem.
Res. 2009, 42, 1074; b) R. Jazzar, J. Hitce, A. Renaudat, J. Sofack-Kreutzer,
O. Baudoin, Chem. Eur. J. 2010, 16, 2654; c) T. W. Lyons, M. S. Sanford,
Chem. Rev. 2010, 110, 1147; d) M. Wasa, K. M. Engle, J.-Q. Yu, Isr. J. Chem.
2010, 50, 605; e) O. Baudoin, Chem. Soc. Rev. 2011, 40, 4902; f) G. Rou-
quet, N. Chatani, Angew. Chem. Int. Ed. 2013, 52, 11726; Angew. Chem.
2013, 125, 11942.
[2] R. Giri, X. Chen, J.-Q. Yu, Angew. Chem. Int. Ed. 2005, 44, 2112; Angew.
Chem. 2005, 117, 2150.
[3] a) V. G. Zaitsev, D. Shabashov, O. Daugulis, J. Am. Chem. Soc. 2005, 127,
13154; b) Y. Feng, G. Chen, Angew. Chem. Int. Ed. 2010, 49, 958; Angew.
Chem. 2010, 122, 970; c) W. R. Gutekunst, P. S. Baran, J. Am. Chem. Soc.
2011, 133, 19076; d) L. D. Tran, O. Daugulis, Angew. Chem. Int. Ed. 2012,
51, 5188; Angew. Chem. 2012, 124, 5278.
[4] a) R. Giri, N. Maugel, J.-J. Li, D.-H. Wang, S. P. Breazzano, L. B. Saunders,
J.-Q. Yu, J. Am. Chem. Soc. 2007, 129, 3510; b) D.-H. Wang, M. Wasa, R.
Giri, J.-Q. Yu, J. Am. Chem. Soc. 2008, 130, 7190; c) D.-H. Wang, T.-S. Mei,
J.-Q. Yu, J. Am. Chem. Soc. 2008, 130, 17676; d) M. Wasa, K. M. Engle, J.-
Q. Yu, J. Am. Chem. Soc. 2009, 131, 9886.
[5] a) M. Wasa, K. S. L. Chan, X.-G. Zhang, J. He, M. Miura, J. Q. Yu, J. Am.
Chem. Soc. 2012, 134, 18570; b) J. He, S. Li, Y. Deng, H. Fu, B. N. Laforte-
za, J. E. Spangler, A. Homs, J.-Q. Yu, Science 2014, 343, 1216; c) R.-Y. Zhu,
J. He, J.-Q. Yu, J. Am. Chem. Soc. 2014, 136, 13194.
[6] For selected reviews: a) N. Marion, S. P. Nolan, Acc. Chem. Res. 2008, 41,
1440; b) M. N. Hopkinson, C. Richter, M. Schedler, F. Glorius, Nature
2014, 510, 485.
[17] For the use of cis-chelated palladium(II)-bis(NHC) complex in alkane oxi-
dation see: a) M. Muehlhofer, T. Strassner, W. A. Herrmann, Angew.
Chem. Int. Ed. 2002, 41, 1745; Angew. Chem. 2002, 114, 1817; b) X.-F.
Hou, Y.-N. Wang, I. GÅttker-Schnetmann, Organometallics 2011, 30, 6053.
[18] a) For related mechanistic studies on arylation via PdIV intermediates: D.
Shabashov, O. Daugulis, J. Am. Chem. Soc. 2010, 132, 3965; b) For the
synthesis of a carbene-bound PdIV complex using PhICl2: P. L. Arnold,
M. S. Sanford, S. M. Pearson, J. Am. Chem. Soc. 2009, 131, 13912.
[19] a) J. Vicente, A. Arcas, F. Juliµ-Hernµndez, D. Bautista, Angew. Chem. Int.
Ed. 2011, 50, 6896; Angew. Chem. 2011, 123, 7028; b) F. Juliµ-Hernµndez,
A. Arcas, J. Vicente, Chem. Eur. J. 2012, 18, 7780.
[7] a) N. A. McGrath, M. Brichacek, J. T. Njardarson, J. Chem. Educ. 2010, 87,
1348; b) Njardarson group website: http:/cbc.arizona.edu/njardarson/
group; c) N. A. Meanwell, Chem. Res. Toxicol. 2011, 24, 1420; d) F. Lover-
ing, J. Bikker, C. Humblet, J. Med. Chem. 2009, 52, 6752.
[8] http://thomsonreuters.com/en/products-services/pharma-life-sciences/
pharmaceutical-research/integrity.html.
[9] Arylation of proline: a) D. P. Affron, O. A. Davis, J. A. Bull, Org. Lett. 2014,
16, 4956; b) R. Feng, B. Wang, Y. Liu, Z. Liu, Y. Zhang, Eur. J. Org. Chem.
2015, 142.
[10] Arylation of tetrahydrofuran: R. Parella, S. A. Babu, J. Org. Chem. 2015,
80, 2339.
[11] For a single example of alkylation of 2-piperidinecarboxamide sub-
strate: S.-Y. Zhang, Q. Li, G. He, W. A. Nack, G. Chen, J. Am. Chem. Soc.
2013, 135, 12135.
Received: January 15, 2016
[12] Selected C3ÀH functionalization of piperidines through dehydrogena-
tion: a) X.-F. Xia, X.-Z. Shu, K.-G. Ji, Y.-F. Yang, A. Shaukat, X.-Y. Liu, Y.-M.
Published online on February 24, 2016
Chem. Eur. J. 2016, 22, 4748 – 4752
www.chemeurj.org
4752
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim