Enantioselective Intermolecular Pd-Catalyzed Hydroalkylation of Acyclic 1,3-Dienes with Activated Pronucleophiles

Article abstract of DOI:10.1021/jacs.7b13300

We report a highly enantioselective Pd-PHOX-catalyzed intermolecular hydroalkylation of acyclic 1,3-dienes. Meldrum's acid derivatives and other activated C-pronucleophiles, such as β-diketones and malononitriles, react with a variety of aryl- and alkyl-substituted dienes in ≤20 h at room temperature. The coupled products, obtained in up to 96% yield and 97.5:2.5 er, are easily transformed into useful chemical building blocks for downstream synthesis.

Full text of DOI:10.1021/jacs.7b13300

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Communication
Enantioselective Intermolecular Pd-Catalyzed Hydroalkylation
of Acyclic 1,3-Dienes with Activated Pronucleophiles
Nathan J. Adamson, Katherine C. E. Wilbur, and Steven J. Malcolmson
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b13300 • Publication Date (Web): 15 Feb 2018
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Enantioselective Intermolecular Pd-Catalyzed Hydroalkylation of
Acyclic 1,3-Dienes with Activated Pronucleophiles
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Nathan J. Adamson, Katherine C. E. Wilbur, and Steven J. Malcolmson*
Department of Chemistry, Duke University, Durham, NC 27708, United States
Supporting Information Placeholder
substituted acyclic dienes (Scheme 1). Reactions take place
ABSTRACT: We report a highly enantioselective Pd–PHOX-
within 20 h at room temperature to generate products bearing
internal olefins with allylic stereogenic centers by the formal
addition of an enol across the diene’s terminal olefin. Several
transformations of the carbonyls and/or the olefins within the
coupled products highlight the synthetic utility of the process.
catalyzed intermolecular hydroalkylation of acyclic 1,3-dienes.
Meldrum’s acid derivatives and other activated C-pronucleo-
philes, such as -diketones and malononitriles, react with a
variety of aryl- and alkyl-substituted dienes in ≤20 h at room
temperature. The coupled products, obtained in up to 96%
yield and 97.5:2.5 er, are easily transformed into useful chem-
ical building blocks for downstream synthesis.
Scheme 1. Previous and Present Work in Intermolecu-
lar Enantioselective Hydroalkylation
The discovery of new methods for the enantioselective con-
struction of C–C bonds is a critical objective in chemical syn-
thesis, especially if novel transformations additionally offer
access to new or expanded chemical space. Catalytic protocols
are particularly desirable. A steadfast approach in C–C bond
formation involves the enantioselective addition of polarized
electrophiles to preformed enolates or their analogs. Alterna-
tively, the direct addition of enolate precursors (pronucleo-
philes) to polarized reaction partners have also been devel-
oped. Aldol and Mannich reactions,1 conjugate additions,1a,b,e,2
allylic substitutions,3 and alkylation with alkyl halides4 com-
prise several examples.
Far less common are catalytic enantioselective additions of
enols/enolates to simple unsaturated hydrocarbons. The
Trost5 and Luo6 laboratories have reported Pd-catalyzed
transformations involving terminal allenes. The Breit group
has illustrated Rh-catalyzed reactions with 1,1-disubstituted
allenes7,8 and Dong and coworkers have described Rh-cata-
lyzed reactions of methyl-substituted alkynes (Scheme 1).9,10
These transformations involve the intermediacy of a terminal
metal–-allyl complex. The resulting products contain a ter-
minal olefin with an allylic stereogenic center or internal ole-
fins with a homoallylic stereogenic center. Additionally, the
Hartwig group has demonstrated Pd-catalyzed additions of
two -diketones to cyclohexadiene and 2,3-dimethylbutadi-
ene.11–14
We began by examining the coupling of Meldrum’s acid 1a
and phenylbutadiene 2a under previously established condi-
tions for hydroamination (Table 1); however, none of the de-
sired addition product 3a was observed with Pd-1 (entry 1).
Reasoning that an ammonium salt might be needed as the
acid source for Pd–H formation within the catalytic cycle, we
explored the addition of amine base additives, which upon
deprotonating 1a would generate the corresponding ammo-
nium enolate. Pleasingly, with Et3N (2.0 equiv), 3a is formed
as the sole site isomer in 72% yield and 96.5:3.5 er (entry 2).
Hünig’s base (entry 3) offers identical enantioselectivity but
higher yield of 3a than Et3N. DABCO also shows improved
product yield and similar selectivity (entry 4). However, both
bases consistently lead to lower product yields with other nu-
cleophile classes.16 DBU is ineffective (entry 5). We therefore
chose to pursue Et3N as the base of choice due to its generality.
As little as 5 mol % Et3N generates 3a, but increasing the quan-
tity of the base raises the reaction yield and enantioselectivity
(entries 6–8). By introducing 1.5 equivalents 1a with 3.0 equiv-
alents Et3N and increasing the reaction time to 15 h, 3a was
isolated in 81% yield and 97.5:2.5 er (entry 9). Neither lower
Our lab has recently disclosed highly enantioselective and
efficient intermolecular additions of aliphatic amines to 1,3-
dienes.15 The reactions, promoted by an electron deficient Pd–
PHOX catalyst, proceed via a 1,3-disubstituted Pd–-allyl in-
termediate to generate myriad allylic amines. Herein, we
demonstrate that Pd–PHOX catalysts permit the addition of a
variety of activated C-pronucleophiles to several aryl- or alkyl-
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temperature nor electronically-modified phosphines (Pd-2–3)
Page 2 of 5
With conditions determined for enantioselective hydroal-
kylation of 2a, we next sought to discover the range of pronu-
cleophiles that were amenable to the coupling (Table 2). Cy-
clic -diketones5b efficiently undergo addition to phenylbuta-
diene to afford adducts 3b–d in up to 95% yield and 96.5:3.5
er. Acyclic diketones5b,7 also participate, delivering diones 3e–
h in 66–96% yield and 90.5:9.5 to 92:8 er and illustrating that
both alkyl and aryl ketones are competent partners. Bis(sul-
fones) (3i), malononitrile (3j), and -nitroesters (3k) all take
part in diene hydroalkylation reactions. Dimethylmalonate
(pKa in DMSO = 15.9),18a however, fails to add to phenylbuta-
diene with the present catalytic system, suggesting an upper
limit in pronucleophile acidity to between 14.2 (ben-
zoylacetone 2h)18b and 15.9. It should also be noted that prod-
ucts 3h and 3k, formed by the addition of prochiral nucleo-
philes to 2a, are generated as a 1:1 mixture of diastereomers at
the nucleophilic carbon; however, both stereoisomers are ob-
tained with identical enantioselectivity in each case. In all
cases, addition occurs across the diene’s terminal olefin to
form the illustrated product exclusively; the site selectivity is
likely at least somewhat attributable to the PHOX ligand.12b
were able to improve upon this result (entries 10–13).17
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Table 1. Reaction Optimization for Meldrum’s Acid
Addition to Phenylbutadienea
Me
O
Me
O
5 mol % Pd-1 3
Me
O
base
+
Ph
O
Ph
O
CH2Cl2
O
O
Me
Me
2a
3a
O
O
1a
22 °C, 3 h
9
Ar = 3,5-(CF3)2C6H3
Ar = 4-CF3C6H4
Ar = Ph
Pd-1
Pd-2
Pd-3
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N
PAr2
Pd
t-Bu
BF4
1a (equiv)
entry
catalyst
base (equiv)
yield (%)b
erc
1
Pd-1
Pd-1
Pd-1
Pd-1
Pd-1
Pd-1
Pd-1
Pd-1
Pd-1
Pd-1
Pd-2
Pd-2
Pd-3
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.5
1.5
1.5
1.5
1.5
none
<2
72
82
88
<2
46
51
72
81
84
95
89
80
2
Et3N (2.0)
i-Pr2NEt (2.0)
DABCO (2.0)
DBU (2.0)
Et3N (0.05)
Et3N (0.50)
Et3N (3.0)
Et3N (3.0)
Et3N (3.0)
Et3N (3.0)
Et3N (3.0)
Et3N (3.0)
96.5:3.5
96.5:3.5
95:5
3
4
5
Substituted Meldrum’s acid derivatives5a,b and malono-
nitriles also participate in coupling with phenylbutadiene to
deliver products that contain quaternary centers adjacent to
the allylic stereogenic center (Table 3). The former’s products
3l–o are generated with modest efficiency but good enantiose-
lectivity. These sterically congested pronucleophiles afford
ca. 5% 1,4-addition product16 with C–C bond formation occur-
ring at the terminus of the diene. The enantioselectivity de-
pendence on Et3N equivalents is magnified in several cases
with the Meldrum’s acids 1l–o compared to unsubstituted 1a:
with fewer equivalents of Et3N, lower enantioselectivity is ob-
tained, becoming even lower with longer reaction times.16 In
contrast, enantioselectivity is largely constant over the course
of the reaction with 3.0 equivalents Et3N, suggesting less reac-
tion reversibility under the optimized conditions.
6
94:6
95:5
7
8
98:2
9d
10d,e
11
12e,f
13d
97.5:2.5
97.5:2.5
93:7
96:4
94:6
aReactions run with 0.2 mmol 2a in 0.25 mL CH2Cl2. bIsolated yield of
3a. cEnantiomeric ratio determined by HPLC analysis of purified prod-
ucts. d15 h reaction. e0 C reaction. f16 h reaction.
Table 2. Addition of Unsubstituted Pronucleophiles
to Phenylbutadienea–c
Table 3. Quaternary Center Formation by Addition of
Substituted Pronucleophiles to Phenylbutadienea–c
5 mol % Pd-1
EWG1 EWG2
Me
R
Ph
EWG1
2a
Ph
R
1l t
EWG2
3.0 equiv Et3N
3l t
(1.5 equiv)
CH2Cl2, 22 °C, time
3ld,e
R = Me:
48% yield, 94:6 er
37% yield, 91:9 er
33% yield, 91:9 er
29% yield, 88:12 er
90% yield, 95:5 er
Me
O
R
3md,e R = Et:
Ph
O
3nd,e
3od,e
3pf
R = -Bu:
n
Me
Me
O
O
R = i-Pr:
R = Me:
Me
R
3qf
R = n-Bu:
79% yield, 96:4 er
CN
Ph
3rf
R = Bn: >98% yield, 94.5:5.5 er
CN
3sf
81% yield, 97.5:2.5 er
:
Ph
R =
3tf 80% yield, 1.5:1 dr, 10% 1,4-addition
major: 94.5:5.5 er
Me
Me
CO2t-Bu
Ph
minor: 86:14 er
CN
aSee the Supporting Information for experimental details. bIsolated
c
yield of 3. Enantiomeric ratio determined by HPLC analysis of puri-
a–cSee Table 2. dCa. 5% 1,4-addition observed. e6 h reaction. f2 h reac-
tion.
fied products. dBArF4 counterion used in place of BF4 for Pd-1. e1:1 dr at
carbonyls’ -position; both diastereomers have the same er. f2.0 mmol
scale reaction. g2 h reaction; ca. 20% double alkylation product.
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Conversely, the less hindered substituted malononitriles
The Meldrum’s acid addition products provide a useful plat-
form for accessing a number of -methyl-,-unsaturated car-
bonyls. Ethanol addition to 3a, prepared on 4.0 mmol scale,
generates carboxylic ester 5a in 96% yield (Scheme 2A).20 Sim-
ilarly, N-hydroxyphthalimide ester21 5b (91% yield), carboxylic
acid 5c (79% yield), and Weinreb amide 5d (74% yield) may
be obtained. Products resulting from the addition of the un-
substituted malononitrile (e.g., 3j, Scheme 2B) may undergo
oxidation with MMPP and conversion to the methyl ester to
furnish 6 in 63% yield,22 which now bears a stereogenic center
at the carbonyl’s -position. The transformation takes place
with minimal erosion of enantiopurity. Additionally, the -
diketone scaffold may be utilized to generate heterocycles
with -stereogenic centers.7,10c For example, hydroxylamine
condensation with diketone 3h affords isoxazole 7 in
84% yield (Scheme 2C). The transformation significantly fa-
vors initial amine attack upon the alkyl ketone (13:1 regioselec-
tivity)16 and ameliorates the lack of stereochemical control at
the carbonyl’s -position in the hydroalkylation reaction by
erasing the stereochemistry at the offending center.
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3
4
5
6
7
8
couple with 2a to deliver products 3p–s in 77 to >98% yield
within 2 h. In general, enantioselectivity is enhanced and the
reactions show perfect site selectivity. Notably, unlike with
Pd–bis(phosphine) catalysts, deallylation of malononitrile 1s,
which ultimately yields a statistical distribution of allylation
products, does not occur with Pd-1. Prochiral pronucleo-
philes, such as tert-butyl cyanopropionate 1t, also effectively
add to diene 1a but with little stereocontrol at the nucleo-
phile’s carbon (1.5:1 dr in forming 3t); enantioselectivity of
each diastereomer is substantial but unequal. Approximately
10% 1,4-addition accompanies the major product.
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Several dienes have been examined for additions of Mel-
drum’s acid (Table 4). Aryl-substituted dienes lead to styrenyl
products 4a–d in good yields (66–78%) within 15 h with Pd-1
(96:4–97:3 er); however, an o-methyl group significantly slows
the reaction (28% yield of 4e; 97:3 er).19 A furyl-substituted
diene affords 4f in 54% yield and 93:7 er. Just as in Pd–PHOX-
catalyzed hydroaminations of these dienes,15 the reaction is
fastest with electron rich substrates, but unlike in amine–
diene couplings, electron deficient or sterically hindered aro-
matic rings do not lead to 1,4-addition.
Scheme 2. Carbonyl Functionalization within Coupled
Products
Alkyl-substituted dienes react sluggishly with Meldrum’s
acid when Pd-1 is employed (ca. 50% yield in 15 h). Con-
trastingly, with the sterically less hindered Pd-2, reactions are
complete within 6 h, affording unsaturated Meldrum’s acids
4g–m in 68–89% yield (Table 4). Unlike in reactions of aryl-
substituted dienes, Pd-2 is equally as enantioselective as Pd-1
(93:7 to 95:5 er). Several functional groups are tolerated, in-
cluding ethers (4i), imides (4k), and even free alcohols (4j,l).
A) Meldrum's acid derivatization:
Me
O
Me
O
EtOH, Et3N
Ph
O
Ph
OEt
toluene, reflux, 2 h
5a
96% yield
3a
Me
Me
O
O
86% yield (4.0 mmol)
97:3 er
Me
O
Me
O
Me
O
Table 4. Meldrum’s Acid Addition to Various Aryl- and
Alkyl-Substituted Dienesa–c
Me
Ph
O
Ph
OH Ph
N
5ba
5c
5d
NPhth
OMe
91% yield
79% yield
74% yield
B) Malononitrile oxidation:
Me
Me
MMPP, Li2CO3
CN
OMe
Ph
Ph
CN
O
3j
MeOH, 0 °C, 3 h
6
66% yield (4.0 mmol)
97:3 er
63% yield
94:6 er
C) Isoxazole formation:
Me
O
Me
Ph
HONH2•HCl
Ph
Ph
Ph
O
N
3h
EtOH, 80 °C, 16 h
Me
O
Me
7
1:1 dr
84% yield, 90.5:9.5 er
13:1 regioselectivity
90.5:9.5 er each
aReaction at 80 C.
The presence of both carbonyl and olefin functionality
within the products may be leveraged to build molecular com-
plexity quickly. The allylic hydroxyl group of 4l may be selec-
tively acylated and subjected to Pd-catalyzed allylic substitu-
tion in the presence of ethanol,23 yielding -lactone 8 in 66%
yield as a 7:1:1 mixture of diastereomers with the major isomer
shown (Scheme 3A).16 Additionally, Sharpless dihydroxylation
of unsaturated ester 5a with AD-mix  leads to spontaneous
lactonization to afford -lactone 9 as the sole product of the
reaction (70% yield, 19:1 dr, Scheme 3B).16
a–cSee Table 2. d1.0 equiv Meldrum’s acid and 1.1 equiv diene 2l.
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(3) For reviews, see: (a) Helmchen, G.; Pfaltz, A. Acc. Chem. Res.
2000, 33, 336. (b) Trost, B. M.; Machacek, M. R.; Aponick, A. Acc.
Chem. Res. 2006, 39, 747.
Scheme 3. Simultaneous Carbonyl and Olefin Derivat-
ization within Hydroalkylation Products
1
2
(4) For select examples, see: (a) Ooi, T.; Miki, T.; Taniguchi, M.; Shi-
raishi, M.; Takeuchi, M.; Maruoka, K. Angew. Chem., Int. Ed. 2003, 42,
3796. (b) Hong, S.; Lee, J.; Kim, M.; Park, Y.; Park, C.; Kim, M-h.; Jew,
S-s.; Park, H-g. J. Am. Chem. Soc. 2011, 133, 4924. (c) Kanemitsu, T.;
Koga, S.; Nagano, D.; Miyazaki, M.; Nagata, K.; Itoh, T. ACS Catal.
2011, 1, 1331. (d) Kano, T.; Hayashi, Y.; Maruoka, K. J. Am. Chem. Soc.
2013, 135, 7134. (e) Teng, B.; Chen. W.; Dong, S.; Kee, C. W.; Ganda-
mana, D. A.; Zong, L.; Tan, C-H. J. Am. Chem. Soc. 2016, 138, 9935.
3
4
5
6
7
8
9
(5) (a) Trost, B. M.; Jäkel, C.; Plietker, B. J. Am. Chem. Soc. 2003, 125,
4438. (b) Trost, B. M.; Simas, A. B. C.; Plietker, B.; Jäkel, C.; Xie, J.
Chem. Eur. J. 2005, 11, 7075. (c) Trost, B. M.; Xie, J.; Sieber, J. D. J. Am.
Chem. Soc. 2011, 133, 20611.
10
11
12
13
14
15
16
17
18
19
20
21
22
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(6) Zhou, H.; Wang, Y.; Zhang, L.; Cai, M.; Luo, S. J. Am. Chem. Soc.
2017, 139, 3631.
Highly efficient and enantioselective intermolecular addi-
tion of activated C-pronucleophiles to acyclic dienes is ena-
bled by Pd catalysts bearing electron deficient phosphines
within a PHOX ligand scaffold. A range of aryl- and alkyl-sub-
stituted dienes may be coupled with a number of -dicar-
bonyl-like nucleophiles to generate allylic stereogenic centers
at the carbonyl’s -position. The olefin and carbonyl func-
tional groups provide handles for subsequent complexity-
building product elaboration and access to useful synthetic
motifs. Application of Pd–PHOX catalysts to other enantiose-
lective hydrofunctionalizations is underway.
(7) Beck, T. M.; Breit, B. Angew. Chem., Int. Ed. 2017, 56, 1903.
(8) For non-enantioselective intermolecular hydroalkylation of al-
lenes, see: (a) Yamamoto, Y.; Al-Masum, M.; Asao, N. J. Am. Chem.
Soc. 1994, 116, 6019. (b) Trost, B. M.; Gerusz, V. J. J. Am. Chem. Soc.
1995, 117, 5156. (c) Li, C.; Breit, B. J. Am. Chem. Soc. 2014, 136, 862.
(9) Cruz, F. A.; Dong, V. M. J. Am. Chem. Soc. 2017, 139, 1029.
(10) For non-enantioselective intermolecular hydroalkylation of al-
kynes, see: (a) Cruz, F. A.; Chen, Z.; Kurtoic, S. I.; Dong, V. M. Chem.
Commun. 2016, 52, 5836. (b) Li, C.; Grugel, C.; Breit, B. Chem. Com-
mun. 2016, 52, 5840. (c) Beck, T.; Breit, B. Org. Lett. 2016, 18, 124.
(11) Leitner, A.; Larsen, J.; Steffens, C.; Hartwig, J. F. J. Org. Chem.
2004, 69, 7552.
ASSOCIATED CONTENT
Supporting Information
(12) For non-enantioselective intermolecular hydroalkylation of
dienes, see: (a) Takahashi, K.; Miyake, A.; Hata, G. Bull. Chem. Soc.
Jpn. 1972, 45, 1183. (b) Trost, B. M.; Zhi, L. Tetrahedron Lett. 1992, 33,
1831.
Experimental procedures and analytical data for new com-
pounds. This material is available free of charge via the Inter-
net at http://pubs.acs.org.
(13) For enantioselective intermolecular hydroarylation reactions,
see: (a) Bexrud, J.; Lautens, M. Org. Lett. 2010, 12, 3160. (b) Pattison,
G.; Piraux, G.; Lam, H. W. J. Am. Chem. Soc. 2010, 132, 14373. (c) Po-
dhajsky, S. M.; Iwai, Y.; Cook-Sneathen, A.; Sigman, M. S. Tetrahedron
2011, 67, 4435. (d) Saxena, A.; Lam, H. W. Chem. Sci. 2011, 2, 2326. (e)
So, C. M.; Kume, S.; Hayashi, T. J. Am. Chem. Soc. 2013, 135, 10990. (f)
Friis, S. D.; Pirnot, M. T.; Buchwald, S. L. J. Am. Chem. Soc. 2016, 138,
8372. (g) Cruz, F. A.; Zhu, Y.; Tercenio, Q. D.; Shen, Z.; Dong, V. M. J.
Am. Chem. Soc. 2017, 139, 10641. (h) Marcum, J. S.; Roberts, C. C.;
Manan, R. S.; Cervarich, T. N.; Meek, S. J. J. Am. Chem. Soc. 2017, 15580.
AUTHOR INFORMATION
Corresponding Author
*steven.malcolmson@duke.edu
Notes
The authors declare no competing financial interests.
(14) For a related transformation, see: Wu, X.; Lin, H-C.; Li, M-L.; Li,
L-L.; Han, Z-Y.; Gong, L-Z. J. Am. Chem. Soc. 2015, 137, 13476.
(15) Adamson, N. J.; Hull, E.; Malcolmson, S. J. J. Am. Chem. Soc. 2017,
139, 7180.
ACKNOWLEDGMENT
(16) For details, see the Supporting Information.
We are grateful to Duke University for sponsoring this re-
search. N.J.A. was supported by NIGMS (T32GM007105–42).
K.C.E.W. thanks the Duke Chemistry Department for a sum-
mer research fellowship. NMR spectroscopic assistance was
provided by Dr. Benjamin Bobay and the Duke NMR center.
We thank Prof. Alex Grenning (University of Florida) for sug-
gesting the malononitrile oxidation to methyl ester 6.
(17) Dienes with other substitution patterns, such as isoprene and
2,3-dimethylbutadiene, fail to undergo reaction with Meldrum’s acid.
(18) (a) Arnett, E. M.; Maroldo, S. G.; Schilling, S. L.; Harrelson, J. A.
J. Am. Chem. Soc. 1984, 106, 6759. (b) Bordwell, F. G.; Harrelson, Jr., J.
A. Can. J. Chem. 1990, 68, 1714.
(19) Product 4e is generated in 82% yield and 82.5:17.5 er with Pd-2.
(20) Adapted from Sato, M.; Ban, H.; Kaneko, C. Tetrahedron Lett.
1997, 38, 6689.
REFERENCES
(21) For potential applications, see: (a) Toriyama, F.; Cornella, J.;
Wimmer, L.; Chen, T-G.; Dixon, D. D.; Creech, G.; Baran, P. S. J. Am.
Chem. Soc. 2016, 138, 11132. (b) Li, C.; Wang, J.; Barton, L. M.; Yu, S.;
Tian, M.; Peters, D. S.; Kumar, M.; Yu, A. W.; Johnson, K. A.; Chatter-
jee, A. K.; Yan, M.; Baran, P. S. Science 2017, 356, eaam7355.
(1) For reviews, see: (a) Johnson, J. S.; Evans, D. A. Acc. Chem. Res.
2000, 33, 325. (b) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B.
Chem. Rev. 2007, 107, 5471. (c) Kobayashi, S.; Mori, Y.; Fossey, J. S.;
Salter, M. M. Chem. Rev. 2011, 111, 2626. (d) Beutner, G. L.; Denmark,
S. E. Angew. Chem., Int. Ed. 2013, 52, 9086. (e) Pellissier, H. Chem. Rev.
2016, 116, 14868.
(22) Adapted from Förster, S.; Tverskoy, O.; Helmchen, G. Synlett
2008, 2803.
(23) Adapted from Fillion, E. Carret, S.; Mercier, L. G.; Trépanier, V.
É. Org. Lett. 2008, 10, 437.
(2) For reviews, see: (a) Cohen, D. T.; Scheidt, K. A. Chem. Sci. 2012,
3, 53. (b) Hui, C.; Pu, F.; Xu, J. Chem. Eur. J. 2017, 23, 4023.
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