FOCUS REVIEW

DOI: 10.1002/ajoc.201200035

Carbon–Halogen Bond Formation by the Reductive Elimination of PdII

Species

Xuefeng Jiang,*[a] Hui Liu,[a] and Zhenhua Gu*[b]

16  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Asian J. Org. Chem. 2012, 1, 16 – 24
 Abstract: It is well known that Pd0 undergoes oxidative addition to organic halides, especially
aryl or vinyl halides. In the contrast, the formation of organic halides by reductive elimination of
RPdIIX (X = halogen) has been mostly ignored until very recently. This Focus Review discusses
recent developments in palladium-catalyzed carbon–halogen bond formation by the reductive
elimination of RPdIIX. These new developments have enriched the scope of palladium-catalyzed
reactions, and provide a new way to construct carbon–halogen bonds.

Keywords: alkyl halides · carbohalogenation · ligand effect · palladium · reductive elimination

1. Introduction

The last 40 years has witnessed great developments in tran-

sition metal catalyzed reactions. Among all these transition
metals, palladium has attracted much more attention as it
has a wide functional group tolerance and the ability to cat-
alyze a wide variety of reactions.[1] To explain and predict
these reactions, four fundamental reactions of the transi-
tion-metal complexes, that is, ligand substitution, oxidative
addition/reductive elimination, insertion/retro-insertion,
and nucleophilic/electrophilic attacks on coordinated li-
gands, have been proposed.[1] Among carbon–heteroatom
bond-forming reactions (C N, C O, C S and so on), palla-
dium-catalyzed carbon–halogen bond-forming reactions
have gained much less attention than others, probably be-
cause of the slow reductive elimination. Recently, efforts
from several research groups achieved great advances in Scheme 1. a) sp2-Carbon–halogen bond formation by the reductive elimi-
sp2-carbon–halogen bond formation from PdII or PdIV spe- nation of PdII. b) Alkyl–halogen bond formation by the reductive elimi-
cies by reductive elimination (Scheme 1 a).[2] In contrast to nation of PdIV. c) Alkyl–halogen bond formation by the reductive elimi-
the well-studied sp3-carbon–halogen bond formation nation of PdII.
through the reductive elimination of PdIV species under oxi-
dative conditions, as reported by Sanford and co-workers as
well as Yu and co-workers (Scheme 1 b),[3, 4] the formation a 100 % atom-economic transformation. Usually, this kind
of alkyl–halogen bonds by reductive elimination of PdII spe- of reaction is thought as an atom transfer radical cyclization
cies was only reported very recently (see below and process.[6] Newman and Lautens developed this transforma-
Scheme 1 c). tion with palladium catalysis. They found that bulky phos-
phine ligands QPhos and PACHTUNGRE(tBu)3, could force the reductive
elimination of PdII species 2 to form 3.[7] Less bulky ligands,
2. sp3-Carbon–Halogen Bond Formation such as PCy3 and PACHTUNGRE(o-tol)3, gave no detectable product.
Various oxygen- and nitrogen-containing heterocycles, as
Atom-economic transformations have gained much atten- well as carbocycles were obtained in high yields. The corre-
tion from organic chemists.[5] The construction of alkyl sponding reaction with an aryl bromide or aryl chloride
halide 3 from iodide 1 (Scheme 2), in which one C I bond does not give the desired carbohalogenation product. The
was cleaved and new C C and C I bonds were formed, is reaction does not work if b-hydrogen atoms are present in
the cyclized alkyl PdII halide intermediate, and olefin iso-
merization or Heck-type products were obtained instead.
[a] Prof. X. Jiang, Dr. H. Liu Tong and co-workers studied the carboiodination of vinyl
Shanghai Key Laboratory of Green Chemistry and
iodide 4 a (Scheme 3), and no Grigg-type cyclopropanyl
Chemical Processes
Department of Chemistry, East China Normal University product was obtained.[8] A significant ligand-loading effect
3663 North Zhongshan Road, Shanghai 200062 (P. R. China) was reported. In the presence of PdACHTUNGRE(OAc)2 (10 mol %) and
Fax: (+ 86) 21-52133654 1,1’-bis(diphenylphosphino)ferrocene (dppf, 20 mol %) the
E-mail: xfjiang@chem.ecnu.edu.cn reaction gave a trace amount of product 5 a. However, the
[b] Prof. Z. Gu yield was dramatically increased to 43 % when 25 mol % of
Department of Chemistry
University of Science and Technology of China
dppf was used. The best yield was obtained with 30 mol %
Hefei, 230026 (P. R. China) of dppf. Interestingly, only a 71 % yield of 5 a was obtained
E-mail: zhgu@ustc.edu.cn by increasing the loading of dppf to 40 mol %. This reaction

Asian J. Org. Chem. 2012, 1, 16 – 24  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.AsianJOC.org 17
 Xuefeng Jiang, Zhenhua Gu et al.
FOCUS REVIEW
catalyzed carboiodination reaction is a stereospecific pro-
cess, which was confirmed by studies with deuterium-la-
beled alkenes in the presence of two equivalents of
TEMPO. Interestingly, 4 b-D and 5 b-D gave 5 c after pro-
longed reaction times under the standard conditions in the
absence of TEMPO (Scheme 4). This is probably a result
of a Pd/dppf-initiated radical process after the formation of
5 b.
To increase the usefulness of this method, Lautens and
co-workers explored carbohalogenation with aryl bro-
mides.[10] However, no useful quantity of carbobromination
product was obtained under the previous standard condi-
tions. The reaction afforded a 95 % yield of iodide 3 when
two equivalents of KI were added (Scheme 5). This result
suggests that reductive elimination of C Pd Br is much

Xuefeng Jiang was born in Gansu,

China. After he received his B.Sc. degree
from Northwest University (China) in
2003, he pursued his Ph.D. studies with
Professor Shengming Ma at the Shanghai
Institute of Organic Chemistry, Chinese
Scheme 2. Carboiodonation of aryl iodides. Bn = benzyl; Ts = 4-toluene- Academy of Sciences. From 2008 to 2011
sulfonyl. he was a postdoctoral researcher under
the guidance of Professor K. C. Nicolaou
at the Scripps Research Institute in the
afforded excellent yields (80–97 %), and QPhos, at a loading field of total synthesis of natural prod-
ucts. He is currently a professor at East
of between 2.5–10 mol %, played a much more efficient
China Normal University and his re-
role. The addition of the free-radical scavenger (2,2,6,6-tet- search interests are in methodology-ori-
ramethyl-piperidin-1-yl)oxyl (TEMPO) did not inhibit the ented total synthesis.
reaction, which indicates that it was not a radical process
and that it is greatly different from the palladium-catalyzed Hui Liu was born in Shandong, China.
He received his B.S degree in Chemical
alkyl halide/alkene Heck-type reaction disclosed by Alexa-
Engineering and Technology at Qufu
nian and co-workers recently.[9] As expected, the palladium- Normal University (China) in 2006. In
2012, he received his Ph.D. degree in Ap-
plied Chemistry from East China Univer-
sity of Science and Technology under the
supervision of Prof. Xiaofeng Tong,
where he studied the palladium-catalyzed
carboiodination of alkenes. He is now
pursuing his postdoctoral studies at East
China Normal University with Prof.
Xuefeng Jiang.

Zhenhua Gu was born in Jiangsu,

China. He studied chemistry at Nanjing
University (China). In 2002 he pursued
Scheme 3. Carboiodonation of vinyl iodide 4 a. his Ph.D. studies with Professor Shengm-
ing Ma at the Shanghai Institute of Or-
ganic Chemistry, Chinese Academy of
Sciences. After postdoctoral research
with Professor K. Peter C. Vollhardt at
Abstract in Chinese: the University of California Berkeley,
and with Professor Armen Zakarian at
the University of California Santa Bar-
bara in the field of natural total synthesis,
he joined the University of Science and
Technology of China in 2012. His re-
search interests are in the development
new transformations and their applica-
tions in total synthesis.

18 www.AsianJOC.org  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Asian J. Org. Chem. 2012, 1, 16 – 24
Carbon–Halogen Bond Formation with PdII

Scheme 4. Studies with deuterium-labeled vinyl iodides.

Scheme 6. Syntheses of polycycles.

Scheme 5. Carboiodination of aryl bromides

slower than C I bond formation under these conditions.

An enantioselective version was also tested, and treatment
of 6 with Pd2ACHTUNGRE(dba)3/Josiphos in the presence of KI gave 3 in
14 % yield and 94 %ee.
The domino synthesis of polycycles 8 a–c was achieved
with moderate to excellent yields (Scheme 6). The rates of
carbopalladation and reductive elimination of the PdII spe-
cies in the domino synthesis of polycyclic alkyl halides
could be controlled by the substrate or the ligand. Thus,
ether 7 d, which is not subject to the Thorpe–Ingold
effect,[11] gave the monocyclized product in 60 % yield.
When the second carbopalladation was slowed down, the
reductive elimination to the monounsaturated product
could proceed. Thus, it was shown that subtly tuning the
properties of substrates as well as ligands can control the
selectivity of mono- or multiple cyclizations in the synthesis
of complex molecules.
The intermolecular version of the carboiodination reac-
tion was tested by using norbornene as the alkene partner,
which avoids the b-hydride elimination (Scheme 7). In this
case, Pd[PACHTUNGRE(tBu)3]2 is the most active catalyst. By using a dif-
ferent method, the reaction of alkynyl halides with norbor- Scheme 7. Intermolecular carboiodination with norbornene
nenes to afford an alkynlated halide was achieved by Jiang
et al. and Tong and co-workers independently
(Scheme 7).[12] Both 1,7-iodoalkylation product 12 and 1,2-
iodoalkylation product 13 were isolated, and a significant product when a nonpolar solvent was used, that is, a selec-
solvent effect was detected. Compound 13 was the major tivity of 96:4 favoring 13 was obtained when CCl4 was used

Asian J. Org. Chem. 2012, 1, 16 – 24  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.AsianJOC.org 19

FOCUS REVIEW
as solvent. Only 3 % of 13 was formed when the reaction
was conducted in MeCN.
Though more investigation is needed to explore this cata-
lytic mechanism, a nonclassical cation process likely ac-
counts for the formation of abnormal 1,7-iodoalkylation
product 12 (Scheme 8). Thus, cationic species 15 is more fa-
Scheme 8. Plausible pathways for alkynylhalogenation with norbornene.
vored in MeCN than in CCl4. It is reasonable to believe
that in 15, the alkynyl group would coordinate with the cat-
ionic palladium atom, though no experimental or computa-
tional results support this hypothesis. This mechanism is
probably different with an aryl iodide as the substrate
(Scheme 7). The positive charge on the palladium atom of
15 could be delocalized by forming nonclassical carbocation
16, which would rearrange to the less sterically congested
palladium intermediate 17. The coordination of the alkyne
and palladium may be the reason for the stereochemistry of
the final alkynyl halide 12. Interestingly, no product of b-
hydride elimination from the possible intermediate 18 was
detected. Notably, bromoalkyne also underwent the same
reaction as the iodoalkyne.
Recently, Houk and co-workers reported a theoretical
DFT study on the mechanism of Pd0-catalyzed carbohalo-
genation of alkenes.[13] It was the first time that the full cat-
alytic cycle, the effect of ligands, and the factors that con-
trol the rate of C X reductive elimination was established
by theoretical studies. The calculated catalytic cycle in-
cludes three elementary reactions: oxidative addition of the
aryl halide, alkene insertion, and CACHTUNGRE(sp3) I reductive elimi-
nation. The reductive elimination is the rate-determining
step. Several mechanisms for the reductive elimination step
20 www.AsianJOC.org  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Xuefeng Jiang, Zhenhua Gu et al.
were proposed, and the calculated data indicates that the
dissociative mechanism is favored for reductive elimination
of alkyl halides (Scheme 9). The dissociative mechanism in-
volves dissociation of the alkyl halide product 21 from com-
plex 20 to free monoligated Pd0 complex 22, which then as-
sociates with one PACHTUNGRE(tBu)3 ligand to regenerate the catalyst
Pd[PACHTUNGRE(tBu)3]2.
Scheme 9. Possible pathway for reductive elimination and ligand ex-
change with alkyl halides.
Alkyl bromides and chlorides are predicted to be less re-
active in reductive eliminations because of high activation-
energy barriers, which can be attributed to the different
bond dissociation energies of the Pd X bond. The calculat-
ed bond dissociation energies of the Pd X, Pd C, and C
X bonds are shown in Scheme 10. The Pd Br and Pd Cl
bonds are much stronger than the Pd I bond, and thus C
Br and C Cl reductive eliminations are required to over-
come higher activation-energy barriers.
Scheme 10. The bond dissociation energies of alkyl PdII halides and
alkyl halide products. The values are given in kcal mol 1.
The steric and electronic properties of the ligands have
significant effects on the mechanism of alkyl-halogen reduc-
tive elimination. Bulky ligands, such as PACHTUNGRE(tBu)3 and QPhos
facilitate the CACHTUNGRE(sp3) I reductive elimination by favoring the
formation of tricoordinated intermediates 19 a and 19 d
(Scheme 11). In contrast, smaller ligands, such as PMe3,
Asian J. Org. Chem. 2012, 1, 16 – 24
Carbon–Halogen Bond Formation with PdII
Scheme 11. Tricoordinated and tetracoordinated PdII halide complexes.
could form stable tetracoordinated PdII halide complexes
favorably, which prohibits the reductive elimination. Elec-
tron-withdrawing groups on the ligands facilitate the reduc-
tive elimination by promoting electron transfer from the
substrates to the palladium atom.[14]
Tong and co-workers reported an example of carboiodo-
nation of non-activated alkyl iodides (Scheme 12).[15] Alkyl
iodides, especially those with b-hydrogen atoms, are a class
Scheme 12. Carboiodonation of alkyl iodides.
of challenging substrates for palladium-catalyzed transfor-
mations, as these compounds undergo b-hydride elimina-
tion easily. This reaction was realized by performing it in
a sealed vessel with PdACHTUNGRE(OAc)2 (10 mol %) and dppf
(30 mol %) at 130 8C for 24 h, and afforded moderate to
good yields. Control experiments were designed to investi-
gate the mechanism. Two deuterium-labeled substrates
were tested under the optimized conditions. The two sub-
strates (Z)-23 i-D and (E)-23 i-D give the same product 24 i-
D in similar yields (Scheme 13). These results strongly indi-
cate that the mechanism might involve a radical intermedi-
ate, which results in the dispersion of the deuterium label.
Testing was then carried out with TEMPO to probe the po-
Scheme 13. Investigation into the mechanism of carboiodonation of
alkyl iodides with deuterated substrates.
Asian J. Org. Chem. 2012, 1, 16 – 24  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
tential intermediacy of carbon-centered radicals. Indeed,
two intermediate adducts 25 a and 26 a were trapped by
TEMPO in 8 % and 3 % yields, respectively (Scheme 13).
Based on these results, a mechanism that involves a radical
process was proposed, but the detailed mechanism for this
process still remains uncertain.
3. sp2-Carbon–Halogen Bond Formation
It is well known that Pd0 can undergo oxidative addition to
sp2-carbon–halogen bonds easily (Path a, Scheme 14). In
Scheme 14. Interactions of sp2-carbon–halogen bonds with Pd0.
contrast, the reverse process, reductive elimination of C
PdII X, is thermodynamically unfavorable.[2a] In 2003, Hart-
wig and co-workers obtained aryl halides by reductive elim-
ination from PdII–phosphine complexes (Scheme 15).[16, 2b,c]
Scheme 15. Reductive elimination of Ar-X from sterically hindered PdII
complexes.
Sterically hindered phosphine ligands were used in this re-
action to form three-coordinate complex 29, which could
squeeze the aryl and halide groups from the metal coordi-
nation sphere into undergoing reductive elimination. Al-
though the reductive elimination of ArPdCl is thermody-
namically favored, kinetic factors play a more important
role and result in the reactivity trend I > Br > Cl for the re-
ductive elimination. Also, the reverse process of oxidative
addition and reductive elimination exists in this the Pd0/
PdII system.
During studies of CACHTUNGRE(sp2) F bond formation based on
DFT calculations, Yandulov and co-workers proposed the
possible intermediate p-NO2C6H4 PdII F (31, Scheme 16).
Reductive elimination product 32 was obtained in 10 %
yield when the sterically hindered XPhos was used.[17] Fur-
ther investigation indicated that the strongly electron-with-
drawing group (NO2) was necessary for reductive elimina-
tion.
In the same year, Grushin and Marshall investigated the
mechanism of CACHTUNGRE(sp2) F bond formation, and proposed that
www.AsianJOC.org 21

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Scheme 16. Ar F bond formation from PdII complexes.
Scheme 17. Proposed mechanism for Ar F bond formation.
a cationic Meisenheimer-type intermediate 35 could be
formed during the reaction (Scheme 17).[18]
In 2009, Buchwald and co-workers reported the first ex-
ample of PdII-catalyzed fluorination of aryl triflates with
the extremely bulky ligand BrettPhos (Scheme 18).[2g] The
three-coordinate (BrettPhos)Pd(Ar)F intermediate was iso-
lated and underwent the reductive elimination to form the
C F bond easily upon heating in toluene.
Scheme 18. Fluorination of Ar-OTf catalyzed by Pd0 phosphine com-
plexes.
22 www.AsianJOC.org  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Xuefeng Jiang, Zhenhua Gu et al.
Recently, Buchwald and co-workers also made a break-
through with reductive elimination to form C halogen
bonds (Ar-Br and Ar-Cl, Scheme 19).[2i] By using sterically
hindered ligand tBuBrettPhos, aryl triflates 38 were
smoothly converted to aryl chlorides and aryl bromides 39.
By using the same method, alkenyl bromides and chlorides
41 were prepared efficiently in the presence of KF
(0.5 equivalents, Scheme 19).[21]
Scheme 19. PdII-catalyzed conversion of aryl triflates to aryl bromides or
aryl chlorides.
During the synthesis of indoles from gem-dibromoolefins,
such as 42 (Scheme 20), Newman and Lautens found that
oxidative addition of 43 was reversible if tBu3P was used as
ligand.[22]
Scheme 20. Reversible oxidative addition of Pd0 to a CACHTUNGRE(sp2) Br bond.
Jiang and co-workers reported a palladium-catalyzed
cross-coupling reaction between bromoalkynes 45 and
other disubstituted alkynes 46 (Scheme 21).[4j] This bro-
moalkynylation process is a method for the regio and ste-
reoselective synthesis of conjugated cis-bromoalkenynes 47.
In this study, a PdII/PdIV catalytic cycle was proposed.
Asian J. Org. Chem. 2012, 1, 16 – 24
Carbon–Halogen Bond Formation with PdII
Scheme 21. PdII-catalyzed bromoalkynylation of bromoalkynes with al-
kynes.
In 1991, Ma and Lu realized a cyclization of 1-halo-2-bu-
tenyl-2-alkynoates 48 to form a CACHTUNGRE(sp2) X bond with PdX2
ACHTUNGRE(PhCN)2 (10 mol %) in HOAc (Scheme 22).[21] The cycliza-
tion process was initiated by trans-halopalladation to form
intermediate 49, then a subsequent intramolecular carbo-
pallidation of the trans-C=C bond afforded 50, and b-halide
elimination yielded 51. This method is a way to construct
a-methylene lactone rings.
Scheme 22. Cyclization of 1-halo-2-butenyl-2-alkynoates.
Later Lu and co-workers found treatment of 52 with
a PdII species provided 53 in the presence of CuX2 and LiX
(Scheme 23).[22] .
Scheme 23. Cyclization of 2-alkenyl 2-alkylnoates.
4. Conclusions
The results summarized in this review highlight the impor-
tant advances that have been made in C X bond formation
by the reductive elimination of PdII species. This technique
provides chemists with new methods to construct carbon–
halogen bonds, which is important in synthetic chemistry.
sp3-Carbon–halogen bond formation by the reductive elimi-
nation PdII species is being pursued because of new percep-
Asian J. Org. Chem. 2012, 1, 16 – 24  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
tions of the typical properties of PdII catalysts and of atom
economy in these types of reactions. This rare process is ef-
ficiently driven by ligand selection, which again shows the
power of palladium in synthetic chemistry, and opens
a door for new coupling reactions. However, to uncover the
reaction mechanisms, especially in reactions with norbor-
nene, more experimental and computational efforts are still
needed. Future aims must consist of synthesis of alkyl hal-
ides with b-hydrogen atoms and C Cl or C F formation as-
sisted by ligands and additives. Aryl and alkenyl halides are
important synthetic materials. By the use of sterically hin-
dered ligands, lots of methods have been developed to con-
struct CACHTUNGRE(sp2) I, CACHTUNGRE(sp2) Br, and CACHTUNGRE(sp2) Cl bonds. Most im-
portantly, this strategy is successfully used in constructing
aryl fluorides, which is a huge challenge in synthetic
chemistry. It can be predicted that more palladium-cata-
lyzed carbon–halogen bond-forming reactions will be dis-
covered in the near future.
Acknowledgements
We thank Prof. X. Tong for helpful discussions.
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Received: May 17, 2012
Published online: July 2, 2012
Asian J. Org. Chem. 2012, 1, 16 – 24