Direct arylation of primary and secondary sp3 C-H bonds with diarylhyperiodonium salts via Pd catalysis

Article abstract of DOI:10.1021/ol402116a

Palladium-catalyzed primary and secondary sp³ C-H bond arylation is reported. The method using diarylhyperiodonium salts as arylation reagents shows good functional group tolerance and proceeds under mild reaction conditions. The KIE experiment

Full text of DOI:10.1021/ol402116a

ORGANIC
LETTERS
2013
Vol. 15, No. 18
4758–4761
Direct Arylation of Primary and Secondary
sp3 CÀH Bonds with Diarylhyperiodonium
Salts via Pd Catalysis
Fei Pan,† Peng-Xiang Shen,† Li-Sheng Zhang,† Xin Wang,† and Zhang-Jie Shi*,†,‡
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Education, College of Chemistry
and Green Chemistry Center, Peking University, Beijing 100871, China, and State Key
Laboratory of Organometallic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
zshi@pku.edu.cn
Received July 26, 2013
ABSTRACT
Palladium-catalyzed primary and secondary sp3 CÀH bond arylation is reported. The method using diarylhyperiodonium salts as arylation
reagents shows good functional group tolerance and proceeds under mild reaction conditions. The KIE experiments show that the CÀH bond
activation is the rate-determining step.
Transition-metal-catalyzed direct CÀH arylation has
emerged as an attractive alternative to traditional synthetic
methods.1 In comparison, most achievements in this field
to carry out the formation of CÀC bonds or CÀN bonds
are being focused on the activation of sp2 CÀH bonds of
(hetero)arenes.2 The unreactive sp3 CÀH activation re-
mains challenging, facing problems that approach both
efficiency and selectivity.3 Some achievements have been
made to functionalize the relatively active benzylic and
allylic CÀH bonds directly.4 More recently, many efforts
have also been made to perform direct functionalization of
the “unreactive” sp3 CÀH bonds via Pd catalysis. For
example, work to achieve Pd-catalzyed “unreactive” sp3
CÀH arylation was accomplished by using the N- or
S-contained directing groups with either aryl halides or
organometallic reagents as arylation reagents.5 Daugulis
† Peking University.
‡ Chinese Academy of Sciences.
(1) (a) Yu, J.-Q.; Shi, Z.-J. Topics in Current Chemistry; Springer:
Heidelberg, 2010; Vol. 292. (b) Ackermann, L. Modern Arylation Meth-
ods; Wiley-VCH: Weinheim, 2009.
(4) For selected papers on allylic and benzylic sp3 CÀH functionali-
zation, see: (a) Rakshit, S.; Patureau, F. W.; Glorius, F. J. Am. Chem.
Soc. 2010, 132, 9585. (b) Yin, G.; Wu, Y.; Liu, G. J. Am. Chem. Soc.
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C.; Huang, H. J. Am. Chem. Soc. 2012, 134, 9902. (g) Zhang, Y.; Cui, Z.;
Li, Z.; Liu, Z. Org. Lett. 2012, 14, 1838.
(2) For selected reviews on sp2 CÀH arylation, see: (a) Campeau,
L. C.; Fagnou, K. Chem. Commun. 2006, 1253. (b) Alberico, D.; Scott,
M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (c) Li, B.-J.; Yang, S.-D.;
Shi, Z.-J. Synlett 2008, 949. (d) Chen, X.; Engle, K. M.; Wang, D.-H.;
Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (e) Ackermann, L.;
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Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40,
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(5) For selected papers on “unreactive” CÀH bond functionaliza-
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Chem., Int. Ed. 2012, 51, 2225. (b) Aspin, S.; Goutierre, A.; Larini, P.;
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Gutekunst, W. R.; Gianatassio, R.; Baran, P. S. Angew. Chem., Int. Ed.
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r
10.1021/ol402116a
Published on Web 09/04/2013
2013 American Chemical Society

reported the first example of β-arylation of carboxylic
derivatives and γ-arylation of amine derivatives by using
8-aminoquinolinyl or picolinyl directing groups with aryl
iodides.6 Corey has achieved arylation of sp3 CÀH bonds
in amino acid derivatives with a similar strategy.7 Chen,
Chatani, and other groups made significant contributions
to achieve a number of “unreactive” sp3 CÀH function-
alizations, including arylation/alkenylation/alkynylation/
alkylation with the corresponding organic halides.8
As mentioned above, aryl halides have been broadly
and successfully used as electrophiles to achieve sp3 CÀH
arylation. However, arylhyperiodonium salts, which gen-
erally showed higher reactivity, have never been used to
approach direct arylation of “unreactive” sp3 CÀH bonds
although they exhibited great stability, availability, elec-
trophilicity, and lower toxicity, as well as the application
of sp2 CÀH arylation.9,10 Because of its highly electron-
deficient nature and hyperleaving group ability, this re-
agent might provide the convenient and efficient arylation
of sp3 CÀH bonds, especially for the more challenging
secondary CÀH bonds. Herein, we demonstrate the first
successful example to approach direct arylation of primary
and secondarysp3 CÀH bonds usingdiarylhyperiodonium
salts as arylation reagents.
Table 1. Optimization Studies for Pd-Catalyzed sp3 CÀH Bond
Arylationa
entry
catalyst
Pd(OAc)2
base
solvent
yieldb (%)
1
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
ClCH2CH2Cl
toluene
72
16
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(IPr)Cl2
Pd2(dba)3
Pd(TFA)2
Pd(dba)2
3
DMF
<10
<10
14
4
THF
5
dioxane
6
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
68
7
75
8
17
9
Na2CO3
65
10
11
12
13
14
15
16
17
18
19
Cu(OAc)2 ClCH2CH2Cl
52
KOtBu
K2CO3
K2CO3
K2CO3
K2CO3
ClCH2CH2Cl
ClCH2CH2Cl
C1CH2CH2C1
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
<10
19
18
16
According to previous reports in the field of CÀH
activation via Pd catalysis,5À8,11 we first tested direct ary-
lation of a steric hindered benzylic sp3 CÀH bond of N-3-
phenylpropoyl-8-aminoquinoline with diarylhyperiodo-
nium salts in the presence of Pd catalysts (Table 1). Among
<10
86 (82)c
<10
11
Pd(SIMes)(OAc)2 K2CO3
PdCl2(dppp K2CO3
Pd(MeCN)4(BF4)2 K2CO3
PdCl2 K2CO3
)
<10
a The reactions were conducted with 0.10 mmol of 1a, 0.12 mmol of
2a, 0.005 mmol of catalyst, 0.12 mmol of base, and 1.0 mL of solvent and
stirred for 24 h unless otherwise noted. b Determined by crude 1H NMR
spectroscopy. c Yield of isolated product.
(6) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154. (b) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2010, 132, 3965. (c) Nadres, E. T.; Daugulis, O. J. Am. Chem. Soc. 2012,
134, 7. (d) Tran, L. D.; Popov, I.; Daugulis, O. J. Am. Chem. Soc. 2012,
134, 18237. (e) Tran, L. D.; Daugulis, O. Angew. Chem., Int. Ed. 2012, 51,
5188. (f) Tran, L. D.; Roane, J.; Daugulis, O. Angew. Chem., Int. Ed.
2013, 52, 6043.
various solvents, ClCH2CH2Cl exhibited the best efficacy,
and the desired product 3aa was observed in a good yield
onlyinthe presenceof K2CO3 asthebasewithPd(OAc)2 as
the catalyst (entries 1À5). After screening the different
bases, we found that the carbonates could sharply promote
this transformation (entries 6À11).12 In the absence of
bases, the efficacy of arylation was obviously reduced
(entry 8). Phosphates and acetates could accelerate the
reaction, although they were not comparable with carbo-
nates (entries 7 and 9). Notably, such an arylation is not
sensitive to both moisture and air; thus, they can be
conveniently carried out with commercially available sol-
vents. Notably, the starting material 1a was not completely
consumed in the presence of Pd(OAc)2, and the efficiency
could not be enhanced by simply lengthening the reaction
time and/or raising the temperature. Considering the
possible deactivation of the catalysts, we tested the cata-
lysts with the support of a different ligand set (entries
12À19). To our delight, Pd(SIMes)(OAc)2 (SIMes =1,3-
bis(2,4,6-trimethylphenyl)imidazol-2-ylidane) resultedin a
significant promotion, and the desired product 3aa was
obtained in 82% isolated yield (Table 1, entry 16).12 Under
(7) Reddy, B. V. S.; Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8,
3391.
(8) (a) He, G.; Zhao, Y.; Zhang, S.; Lu, C.; Chen, G. J. Am. Chem.
Soc. 2012, 134, 3. (b) Zhang, S.-Y.; He, G.; Zhao, Y.; Wright, K.; Nack,
W. A.; Chen, G. J. Am. Chem. Soc. 2012, 134, 7313. (c) He, G.; Lu, C.;
Zhao, Y.; Nack, W. A.; Chen, G. Org. Lett. 2012, 14, 2944. (d) Ano, Y.;
Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 12984. (e) Aihara,
Y.; Chatani, N. Chem. Sci 2013, 4, 664. (f) Rit, R. K.; Yadav, M. R.;
Sahoo, A. K. Org. Lett. 2012, 14, 3724. (g) Rodrıguez, N.; Romero-
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Revilla, J. A.; Fernandez-Ibanez, M. A.; Carretero, J. C. Chem. Sci 2013,
4, 175. (h) Zhang, S.-Y.; He, G.; Nack, W. A.; Zhao, Y.-S.; Li, Q.; Chen,
G. J. Am. Chem. Soc. 2013, 135, 2124.
(9) For benzylic C(sp3)ÀH bond arylation using diarylhyperiodo-
nium salts, see: Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S.
J. Am. Chem. Soc. 2005, 127, 7330.
(10) For selected reviews on diarylhyperiodonium salts, see: (a)
Merritt, E. A.; Olofsson, B. Angew. Chem., Int. Ed. 2009, 48, 9052.
For selected Cu-catalyzed arylation with diarylhyperiodonium salts, see:
(b) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008,
130, 8172. (c) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593. (d)
Allen, A. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2011, 133, 4260. (e)
Phipps, R. J.; McMurray, L.; Ritter, S.; Duong, H. A.; Gaunt, M. J.
J. Am. Chem. Soc. 2012, 134, 10773. For selected Pd-catalyzed arylation
with diarylhyperiodonium salts, see: (f) Deprez, N. R.; Sanford, M. S.
J. Am. Chem. Soc. 2009, 131, 11234. (g) Xiao, B.; Fu, Y.; Xu, J.; Gong,
T.-J.; Dai, J.-J.; Yi, J.; Liu, L. J. Am. Chem. Soc. 2010, 132, 468.
(11) (a) Gu, P.; Huang, S.; Xu, J.; Shi, Z.-J.; Su, W.-P. Angew. Chem.,
Int. Ed. 2011, 50, 9926. (b) Li, Y.; Wang, W.-H.; He, K.-H.; Shi, Z.-J.
Organometallics 2012, 31, 4397. (c) Li, H.; Zhu, R.-Y.; Shi, W.-J.; He,
K.-H.; Shi, Z.-J. Org. Lett. 2012, 14, 4850. (d) Zhang, L.-S.; Chen, K.;
Chen, G.-H.; Li, B.-J.; Luo, S.; Guo, Q.-Y.; Wei, J.-B.; Shi, Z.-J. Org.
Lett. 2013, 15, 10. (e) Yang, M.-Y.; Jiang, X.-Y.; Shi, W.-J.; Zhu, Q.-L.;
Shi, Z.-J. Org. Lett. 2013, 15, 690.
(12) For a review on base effects, see: Ouyang, K.-B.; Xi, Z.-F. Acta
Chimica Sinica 2013, 71, 13.
Org. Lett., Vol. 15, No. 18, 2013
4759

such arylation conditions, arylation on either the aromatic
ring or biarylated products was not observed.
Scheme 1. Pd-Catalyzed Direct Arylation of sp3 CÀH Bonds
with Different 8-Aminoquinoline Amidesa
Table 2. Effects of Counteranions.a
entry
X
yieldb (%)
1
2
3
4
5
6
OTf
BF4
PF6
OTs
86
31
30
12
13
37
Br
c
a The reactions were conducted with 0.10 mmol of 1a, 0.12 mmol of
2a, 0.005 mmol of catalyst, 0.12 mmol of base, and 1.0 mL of solvent and
stirred for 24 h unless otherwise noted. b Determined by crude 1H NMR
spectroscopy. c Using iodobenzene as arylation reagent.
Subsequently, we examined the effects of the counter-
anion of diarylhyperiodonium salts (Table 2). We found
that tetrafluoroborates (BF4À), hexafluorophosphates
(PF6À), p-toluenesulfonates (OTsÀ), or bromides (BrÀ)
could be applied as counterions, and 3aa was obtained
with lower efficacy (comparing entry 1 to entries 2À5). The
low yields can be explained by the solubility of each salt in
ClCH2CH2Cl. Alternatively, the anion may be participate
in the rate-limiting proton-abstraction step. To determine
the reactivity of the corresponding ArI from Ar2IOTf,
we also tested PhI as an electrophile. The reaction indeed
took place but the efficiency was much lower. This result
indicated that the reactivity of diarylhyperiodonium tri-
flates is much higher than that of ArI under the same
conditions (entry 6).
With the optimized conditions in hand, we investigated
the scope of amide derivatives (Scheme 1). We found that
(1) various substituents with different electronic features
at the para- position of phenyl showed good to excellent
reactivity (3aaÀae), (2) the steric effect weakly affected this
transformation (3ah), and (3) Other 3-heteroaryl substi-
tuted amides, such as thiophenyl and furanyl, could also be
tolerated and the desired arylation products were obtained
in good to excellent yields (3af and 3ag). Thus, starting
from different amides and diarylhyperiodonium triflates,
there are two alternative routes to approach the same
products, which might be the complementary methods
for each other.
a The reactions were conducted with 0.20 mmol of 1a, 0.24 mmol of
2a, 0.01 mmol of Pd(SIMes)(OAc)2, 0.24 mmol of K2CO3, and 2.0 mL of
ClCH2CH2C1 and stirred for 24 h at 120 °C unless otherwise noted.
smoothly. However, only the double arylations at both
ortho positions were observed (3ajÀal). The primary sp3
CÀH bonds of propionyl derivatives also performed well,
while only mono- and diarylated products were isolated
as a mixture at a nearly 1:1 ratio (3am). To extend the
application of this arylation further, different aliphatic
carboxylic acid derivatives were tested. We found that, in
general, the length of the chain did not affect the efficacy
(3anÀaq), unless a very long chain was involved. The
benzyl and sterically hindered cyclopentyl and isopropyl
groups were compatible, which extended the substrate
scope (3ai, 3ar, and 3as). We further tested the derivatives
of protected amino acids. To our delight, direct arylation
took place, and 3at was isolated in a 69% yield. The
natural oleic acid derivative was also arylated in good
yield, leaving the double bond and allylic CÀH bonds
untouched under these oxidative conditions (3au).13
Considering that different substituents with distinct
electronic and steric features may influence the reactivity
of the diarylhyperiodonium salts, we then surveyed differ-
ent functional groups of diarylhyperiodonium triflates
(Scheme 2). Gratifyingly, a variety of symmetrical or un-
symmetrical diarylhyperiodonium triflates successfully
coupled with 1n. Different functional groups on the aryl
group of diarylhyperiodonium triflates, no matter whether
Since common sp3 CÀH bonds, especially secondary
CÀH bonds other than the benzylic position, exhibit poor
reactivity, we turned to explore the potential reactivity
with aliphatic carboxylic amides (Scheme 1). We first
tested the cyclic substrates and found that 3-membered,
4-membered, and 5-membered ring substrates are arylated
(13) (a) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.;
Baudoin, O. Chem.;Eur. J. 2010, 16, 2654. (b) Li, H.; Li, B.-J.; Shi,
Z.-J. Catal. Sci. Technol. 2011, 1, 191.
4760
Org. Lett., Vol. 15, No. 18, 2013

Scheme 2. Pd-Catalyzed Direct Arylation of sp3 CÀH Bonds
Scheme 3. Proposed Mechanism (L = SIMes)
with Different Diarylhyperiodonium Saltsa
(see the Supporting Information, eq 1). On the basis of
these preliminary results, a proposed mechanism is shown
in Scheme 3. The coordination of the amide 1b with
palladium catalyst formedcomplex 8, which further under-
went the CÀH activation to produce 9. Diarylhyperiodo-
nium salts oxidized the complex 9 to form Pd(IV) complex
10. Following by the reductive elimination, the desired
product 3ab was generated, releasing the Pd(II) catalyst to
fulfill the catalytic cycle.15
In summary, we reported a successful example of Pd-
catalyzed primary and secondary sp3 CÀH arylation by
first using diarylhyperiodonium salts as arylation reagents.
Various acid derivatives and different diarylhyperiodo-
nium reagents were compatible with this arylation. This
method could be applied to direct arylation of naturally
important structural units, such as the derivatives of amino
acids and oleic acid. Preliminary mechanistic studies in-
dicated the possible Pd(II)/Pd(IV) catalytic cycle of this
transformation. These studies provided a new method for
an efficient functionalization of “unreactive” sp3 CÀH
bonds and an alternative way to process direct arylation
of primary and secondary sp3 CÀH bonds under mild
conditions. Further efforts to extend the applications of
this method are underway.
a The reactions were conducted with 0.20 mmol of 1a, 0.24 mmol of
2a, 0.01 mmol of Pd(SIMes)(OAc)2, 0.24 mmol of K2CO3, and 2.0 mL of
ClCH2CH2Cl and stirred for 24 h at 120 °C unless otherwise noted.
electron-withdrawing or electron-donating groups, were
compatiblewiththisarylation. However, theelectron-poor
aryl groups performed better (3na vs 3ne, 3ni vs 3nm).
Notably, the reaction exhibited excellent tolerance of
functional group. For example, fluoro (3na, 3nh, 3nm),
chloro (3nb), bromo (3nc, 3nk), iodo (3no), trifluoromethyl
(3nd, 3nl), and ester (3nn) groups are tolerated, and the
desired products were obtained in moderate to good
yields.14 The ortho-substituted diarylhyperiodonium tri-
flates (3nh) were also suitable with a little decrease of
reactivity, which indicated that the considerable effect of
steric hindrance. It is important to note that the electron-
rich heterocyclic group (3np) could be also transferred in a
good yield, which highly expanded the substrate scope.
To understand the pathway of this arylation better,
we performed KIE experiments. Both intermolecular
KIE (3.8) and intramolecular KIE (3.9) indicated the
involvement of CÀH bond cleavage into the rate deter-
mining step (see the Supporting Information, eqs 2 and 3).
Most importantly, the H/D exchange was examined by
simply heating the substrate 1b in the presence of the
catalyst in the mixed solvent of AcOD/ClCH2CH2Cl.
After 24 h at 120 °C, 46% of deuterium incorporation
was observed at β position, thus implying the CÀH
cleavage in the absence of diarylhyperiodonium triflates
Acknowledgment. We acknowledge financial support
from the National Basic Research Program of China
(973 Program, 2009CB825300) and the national NSF of
China (nos. 20925207 and 21002001).
Supporting Information Available. Experimental pro-
cedures and NMR spectra analysis of the products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
ꢀ
(15) For selected reviews about Pd(IV) chemistry, see: (a) Muniz, K.
Angew. Chem., Int. Ed. 2009, 48, 9412. (b) Xu, L.-M.; Li, B.-J.; Yang, Z.;
Shi, Z.-J. Chem. Soc. Rev. 2010, 39, 712. (c) Hickman, A. J.; Sanford,
M. S. Nature 2012, 484, 177.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 18, 2013
4761