Cu-Catalyzed Three-Component Carboamination of Alkenes

Article abstract of DOI:10.1021/jacs.7b10529

Copper-catalyzed intermolecular carboamination of alkenes with α-halocarbonyls and amines is presented with 42 examples. Electron rich, electron poor, and internal styrenes, as well as α-olefins, are functionalized with α-halocarbonyls and aryl or aliphat

Full text of DOI:10.1021/jacs.7b10529

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Communication
Cu-Catalyzed Three-Component Carboamination of Alkenes
Samuel N. Gockel, Travis L. Buchanan, and Kami L. Hull
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 02 Nov 2017
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Cu-Catalyzed Three-Component Carboamination of Alkenes
Samuel N. Gockel,‡ Travis L. Buchanan,‡ Kami L. Hull*
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Department of Chemistry, University of Illinois at Urbana–Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, United
States
Supporting Information Placeholder
Scheme 1. Three-component carboamination reactions
ABSTRACT: The copper-catalyzed intermolecular carboamination
of alkenes with α-halocarbonyls and amines is presented with 42
examples. Electron rich, electron poor, and internal styrenes, as well
a. This work: radical carboamination via oxocarbenium intermediates
O
R1
R1
R4 R6
N
R6 R7
N
O
R2
R3
R2
R3
Br
as α-olefins, are readily functionalized with
a variety of α-
cat. [Cu]
R1
R1
R7
H
O
O
+
R2R3
R4
halocarbonyls and aryl or aliphatic amines. Preliminary mechanistic
investigations suggest that the reaction is proceeding through the
addition of a carbon-centered radical across an olefin followed by
oxidation to form a 5-membered oxocarbenium intermediate and
subsequent nucleophilic ring opening to forge the C–N bond.
•
R2R3
R5
R5
R4 R5
R4 R5
II
I
b. Radical carboamination via carbocation intermediates
R3R4NH
cat. [Fe]
Ag2CO3
R3 R4
N
R1 R2
CN
R1 R2
CN
EDG
Ph
R1R2CHCN (solvent)
EDG
Ph
EDG
(R1CO2)2
cat. [Fe]
Ac
Ph
O
NH O
O
The invention of new methods for the streamlined construction of
small organic molecules is essential to the advancement of organic
chemistry. Given the ubiquity of C–N bonds in biologically active
molecules, devising improved methods for the synthesis of amines is a
particularly important challenge.1 The difunctionalization of olefins
provides direct access to complex molecular frameworks that otherwise
require multiple synthetic operations to assemble. The carboamination
of alkenes is an important subset of such reactions, resulting in the
concurrent introduction of carbon and nitrogen functionalities into
readily accessible alkene frameworks.2
OMe
OMe
OMe
MeCN (solvent)
H2O/H2SO4
R1
R1
of the other coupling partners and of strong oxidants. An alternative
approach to the three-component carboamination of alkenes via Pd-
catalysis was also recently reported.2k A pre-installed bidentate direct-
ing group is utilized to avoid β-hydride elimination and promote oxida-
tion, thereby enabling the difunctionalization.
In the context of our mechanistic hypothesis, the oxidation of a radi-
I
cal addition intermediate ( ) would afford a cationic species. Typically
To date, most carboamination methodologies have exploited a two-
component approach, delivering cyclic products from preassembled
starting materials.2a-g As a consequence of their two-component na-
tures, these methods are innately limited in their modularities. To
address this, we envisioned that a three-component alkene carboami-
nation could be realized by harnessing the reactivities and selectivities
of radical intermediates.3 Toward this end, we became interested in the
proclivity of copper salts to generate electrophilic alkyl radicals from
functionalized tertiary alkyl halides, such as α-halocarbonyl com-
pounds.4 We reasoned that the combination of such electrophiles with
nucleophilic amines in the presence of an olefin could deliver the car-
boamination product in a regio- and chemo- selective fashion (Scheme
1a). These electrophiles are resistant to undesirable SN1/SN2 reactivity,
therefore reducing the tendency to couple this electrophilic compo-
nent directly with the amine nucleophile. Furthermore, the addition of
these radicals to olefins is well-documented in related methodologies
and in the field of atom transfer radical polymerization (ATRP).5, 6
such oxidations require electronically activated alkenes, which facilitate
the oxidation of the resultant radical addition intermediate.2h-j Alt-
hough this tactic enables the desired transformation, it imposes signifi-
cant limitations on the substrate scope. We reasoned that the use of an
α-halocarbonyl compound as the electrophilic source of carbon would
reveal access to a particular geometric relationship between the inci-
dent carbonyl group with the newly formed alkyl radical that could
assist with the oxidation of this intermediate.8 Such an oxidation event
would afford an oxocarbenium ion intermediate (II), which could
undergo opening via nucleophilic attack by the amine to furnish the
carboamination product.9 Through this assisted oxidation, we envi-
sioned a general platform for olefin carboamination. Indeed, we report
herein a carboamination reaction of unprecedented generality.
Experimentation began by exploring the reactivity of ethyl α-bromo
1
isobutyrate ( ), styrene, and N-methylaniline as model reaction com-
ponents in the presence of various Cu catalysts. Gratifyingly, it was
found that product 2a could be formed under a variety of conditions,
with the optimized parameters as follows: 5.0 mol % Cu(OTf)2, 5.0
Concurrent with our investigations, two radical couplings utilizing
alkyl nitriles2h and dialkyl peroxides,2i-j were reported (Scheme 1b).
The philicities of the radicals generated in these reactions significantly
influence the overall scope of the transformations, wherein favorable
matching of the alkene and alkyl radical polarities is essential.7 Efficient
reactivity is therefore accomplished by employing electronically acti-
vated alkenes and further enhanced with super-stoichiometric loadings
mol % 2,2’-bipyridine (bpy), 1.1 equiv K3PO4, 2.0 equiv , 1.0 equiv
1
styrene, 1.0 equiv N-methylaniline in DCE (0.50 M) at 80 °C for 24 h
under N2. Product 2a can be obtained in an 87% isolated yield on 0.20
mmol scale (See Supporting Information, SI, Tables S1-S10 for opti-
mization studies). Importantly, the reaction is scalable, providing 86%
and 95% yields on 1.0 and 10 mmol scales, respectively.
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Table 1. Scope of Vinylarenes and Aminesa
Table 2. Scope of Electrophilesa
1
2
3
4
O
EWG
R1R2
Ar
5 mol % Cu(OTf)2
5 mol % Ligand
Ar
R3 R4
N
EtO
NR2R3
5 mol % Cu(OTf)2
5 mol % bpy
Ar
O
EWG Br
R1R2
+
+
NR1R2
R1 R2
N
H
or
O
K3PO4, DCE, 80 °C
Ar
H
ꢀꢁ
Br
R2
+
+
EtO
O
R1
R2
K3PO4, DCE, 80 °C
N
R1
5
N
1
Ar
2r-aa
6
7
8
9
Ar
2a-q
OMe
OMe
O
O
O
O
CF3
EtO
NO2
O
O
O
MeO
N
N
Ph
EtO
EtO
N
N
N
Ph
N
Ph
Ph
N
N
2cb
Ph
Ph
Ph
2rb
79%
2sc
2tb
45%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2a
2b
55%
82%
87%
54%
O
O
Ph
OMe
O
O
N
F
F
O
O
O
EtO
F
EtO
EtO2C
F F
EtO
N
EtO
EtO
N
F F
N
N
Ph
F
F
Ph
N
R
Ph
R
Ph
OMe
2ud
45%
2vd
42%
2we,f
2e R = Me, 50%
2f R = H, 50%
2g R = Me, 53%
2h R=H, 50%
2d
42%
61%
N
O
O O
S
O
O
O
Ph
O
O
EtO
ptol
N
EtO
EtO
EtO
N
R
EtO
N
N
N
Ph Ph
Ph Ph
OMe
NO2
Br
2xc
80%, 2.5:1 d.r.
2yg
72%, 2:1 d.r.
2zc R = H, 67%, 10:1 d.r.
2i
60%
2j
2k
2aac R = OMe, 50%, 10:1 d.r.
70%
68%
OMe
O
OMe
O
a Bromide (2.0 equiv), alkene (1.0 equiv), amine (1.0 equiv), K3PO4
(1.1 equiv), Cu(OTf)2 (5 mol %), ligand (5-10 mol %), DCE (0.50
M), 80 °C. With TPEN as ligand. With PMDTA as ligand. With
DPEPA as ligand. e With PEPA as ligand. f With 1.0 equiv bromide and
5.0 equiv alkene. g With BPY as ligand. See SI for ligand structures.
O
EtO
F
EtO
EtO
HN
F
b
c
d
HN
N
F
NO2
F
F
2m
44%
2l
76%
2n
71%
products. It is noteworthy that the Weinreb amide-type electrophile
produces 2s in good yield, retaining the amide moiety for facile elabo-
ration of the carbonyl group. In addition to methyl-bearing esters,
those substituted with fluorine atoms (2u-v) are effective for this trans-
formation, providing access to products of pharmacokinetic value given
the unique properties of the difluoromethyl moiety.10 A differentially
substituted electrophile was also reactive (2x), providing the product in
good yield with moderate diastereoselectivity.
O
OMe
O
N
O
OMe
Ph
EtO
N
N
Ph
Ph
S
2o
68%
2p
2q
52%
83%
a
1
(2.0 equiv), alkene (1.0 equiv), amine (1.0 equiv), K3PO4 (1.1
equiv), Cu(OTf)2 (5 mol %), bpy (5 mol %), DCE (0.50 M), 80 °C.
3.0 equiv alkene was used.
b
Importantly, secondary electrophiles are also amenable in the three-
component coupling (2w, 2y-aa) including a malonate (2w), which
provides access to products containing a free methylene unit, following
mono-decarboxylation.11 Given this generality, products with any de-
gree of substitution at the α-carbon can be accessed. The diastereose-
lectivity with secondary α-bromoesters is moderate (2y, 2:1), but the
Under the optimized conditions, the carboamination of a variety of
1
vinylarenes with and various amines can be accomplished (Table 1).
Table S11 in the SI provides a concise summary of conditions for all
substrate combinations. Depending on the degree of substitution of the
nucleophile and of the alkene substrate employed, either acyclic or
cyclic products can be obtained. Notably, electron poor styrenes, which
are unreactive in related carboamination methods,2h-j are suitable sub-
strates for this reaction (2b-d). Electron neutral and rich alkenes are
also excellent substrates, providing the carboaminated products in
analogous secondary sulfone affords the product in high d.r. (2z- ,
aa
10:1). The additional steric encumbrance in the corresponding sulfox-
onium intermediate may be responsible for the enhanced diastereose-
lectivity.12 Interestingly, each electrophile class requires a different
polyamine ligand to achieve significant reactivity. At present, we at-
tribute this phenomenon to the unique range of reduction potentials of
each electrophile class and oxidation potentials of the corresponding
radical addition intermediates. Although more reducing catalysts may
rapidly activate an electrophile, they may be slow to oxidize the radical
intermediate. Thus, a common Cu catalyst of fixed redox reactivity
does not achieve high reactivity across all electrophile classes.6a Ongo-
ing work in our laboratory aims to understand the ligand effects and to
identify a general Cu catalyst for this transformation.
good to excellent yields (2a, ,
2e-h 2l). Steric hindrance proximal to the
alkene does not significantly affect reactivity (2e-h). In cases where
reactivity of the alkene substrate is low, it was generally found that use
of a mild excess leads to improved yields, such as with 2c
.
This carboamination reaction tolerates a wide range of functionali-
ties on both the alkene and amine substrates, retaining handles for
further functionalizations of the products. Vinylarenes bearing pen-
dant aliphatic alkenes undergo carboamination in a site-selective
manner, leaving the aliphatic olefin intact (2e-h). Functionalities
such as trifluoromethyl groups (2b), nitro groups (2c, 2i, 2n), halides
The scope of the amine component in this carboamination reaction
is also broad. In addition to N-methylaniline, secondary arylamine
nucleophiles bearing electron -withdrawing (2i
2v 2z aa) groups perform well in the reaction. It was observed that
products derived from electron -neutral and -rich primary nucleophiles
generally close in situ to form γ-lactams (2d, 2o-p
2x), whereas those
derived from electron withdrawn primary nucleophiles
, ,
2m 2n) and -donating
(
, ,
2d, 2j, 2m), ethers (2e-f 2l 2p-q), and heterocycles (2j, 2l, 2p) are
also tolerated under the reaction conditions.
(
,
-
Several classes of functionalized bromides can be used in addition to
esters (Table 2): imides (2r), amides (2s), ketones (2t), malonates
2w), and sulfones (2z-aa) all provide modest to good yields of the
,
(
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Table 3. Scope of Aliphatic and Internal Alkenesa
good yields and with excellent d.r. (
-
2am ao). Cyclic internal alkenes
1
2
3
4
5
6
7
8
afford the trans carboamination product in >20:1 d.r. (2am), whereas
acyclic internal alkenes provide the cis product in >20:1 d.r. (2an-ao).
In the case of the latter, the reactions are diastereoconvergent; regard-
less of starting configuration of the alkene, the cis γ-lactam product is
obtained selectively. Given this broad scope, substitution at each posi-
tion on the lactam core is easily controlled. Historically, such substitut-
ed γ-lactams require many synthetic operations to assemble; however,
this protocol provides access to a customizable γ-lactam core in a single
step from readily obtainable, inexpensive materials. 1a
R3
O
R1
R2
EtO
5 mol % Cu(OTf)2
5 mol % bpy
R3
NR4R5
R2
O
R4 R5
N
+
R2
R1
ꢀꢁ
Br
+
O
EtO
K3PO4, DCE, 80 °C
H
N
1
R2
R1
2ab-ao
R3
Br
O
O
Ph
N
N
O
9
OMe
N
In addition to exploring the scope of this three-component carbo-
amination reaction, we have also conducted preliminary mechanistic
studies. A series of radical clock experiments were conducted to probe
the fate of the radical addition intermediate. A cyclopropyl moiety
C6H13
C6H13
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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41
42
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Br
2ab
2ac
2ad
45%
71%
31%
R2
O
R1
adjacent to an olefin ( ) was found to open under the reaction condi-
3
Ph
N
O
Ph
N
O
tions, providing the corresponding carboamination product (2al) in
N
OAc
standard
conditions
O
O
O
Ph
O
Ph NH2
+
Br
Ph
+
EtO
1
EtO
2ae R1=H, R2=Me, 54%, 1:1 d.r.
2af R1=Ph, R2=H, 46%, 1:1 d.r.
OMe
2ag
62%
2ah
55%
•
3
O
(1)
Ph
Ph
O
HN
Ph
Ph
+
EtO
R
Ph
Ph
EtO
O
N
N
HN
Ph
O
O
Ph
2al
50% yield
2al’
Not Observed
N
EtO
Ph
50% isolated yield (eq. 1). Interestingly, when N,N-diallylaniline ( )
4
2aj
2ak R=Me, 42%
2al R=H, 50%
2ai
35%
was subjected to the reaction conditions, 5-exo-trig cyclization was
observed, affording the carbobromination product (2ap) in 69% isolat-
ed yield and 1.5:1 d.r. instead of the expected carboamination product
77%, 10:1 dr
O
O
Ph
nBu
O
N
N
(
2ap’, eq. 2).14 Our mechanistic proposal invokes the oxidation of radi-
EtO
Ph
Ph
N
Ph
cal addition intermediates to form an oxocarbenium species. We pro-
pose that the formation of this intermediate facilitates this key step in
cases where this oxidation is more difficult, such as with aliphatic al-
kenes or electron poor vinylarenes.15 In the case of both radical clock
experiments, either ring-opening or radical cyclization occurs, making
3
the oxocarbenium ion geometrically difficult to form. For , the radical
is benzylic and oxidation to the cation is facile, even without the inter-
mediacy of the oxocarbenium ion; thus, carboamination can still occur.
2ao
2am
56%, >20:1 d.r.
2an
48%, >20:1 d.r.b
56%, >20:1 d.r.c
73%, >20:1 d.r.b
a 1 (2.0-5.0 equiv), alkene (1.0-5.0 equiv), amine (1.0 equiv), K3PO4
(1.1 equiv), Cu(OTf)2 (5 mol %), bpy (5 mol %), DCE (0.50 M), 80-
100 °C. b From (Z) alkene. c From (E) alkene.
remain acyclic (2m-n). Products 2f and 2h indicate that the steric
properties of the alkene may also influence whether in situ closure
occurs. Diaryl and heterocyclic amines (2j-l) also react smoothly to
give the corresponding products in good yield. Generally, arylamines
are excellent substrates in the reaction, however primary alkylamines
perform well (2o-p). Benzophenone imine is also reactive, providing
access to the corresponding N–H γ-lactam following acidic deprotec-
tion (2q, see SI for details).13
However, for , unassisted oxidation of the radical intermediate would
4
produce an unstable primary carbocation. Consequently, the rate of
bromine atom transfer from Cu becomes competitive with the produc-
tive reaction pathway. It is important to note that products 2ad and 2ap
eliminate the possibility of an atom-transfer radical addition mecha-
nism followed by SN2 amination.
•
standard
O
In the interest of expanding the reaction scope, we focused on ena-
bling the use of internal and aliphatic alkenes as substrates. These rep-
resent challenging substrate classes, as the radical additions are signifi-
cantly slower compared to terminal vinylarenes.7 Aliphatic alkenes are
particularly challenging, as the subsequent oxidation is less favorable.
However, we hypothesized that the oxocarbenium intermediate could
promote this key step. Indeed, only slightly modified reaction condi-
tions elicit reactivity from these olefin classes (Table 3). Typically,
higher temperatures and loadings of the alkene are required to con-
sume the amine nucleophile. Under these reaction conditions, unfunc-
tionalized α-olefins can be employed with aryl- and alkyl- amine nucle-
ophiles (2ab-ac). Functional groups sensitive to basic conditions are
tolerated, including primary alkyl bromides (2ad), terminal epoxides
conditions
EtO
Br
Ph NH2
+
+
EtO
N
O
N
1
Ph
Ph
4
(2)
Ph
NH
Br
EtO
EtO
+
O
O
N
N
Ph
Ph
69% yield
1.5:1 dr
2ap
2ap’
Not Observed
These radical trap experiments provide a clear demonstration of the
importance of the carbonyl moiety to enable the carboamination of less
reactive substrates. However, the results observed with
carboamination of vinylarene substrates could occur without proceed-
ing through an oxocarbenium ion intermediate. Therefore, the
3
indicate that
(
-
2ae af), ketones (2ag), and acetoxy groups (2ah). 1,1-Disubstituted
OEt
standard
O
H
conditions
alkenes are also viable components, enabling the formation of highly
hindered C–N bonds (2ai-aj). Notably, an exocyclic 1,1-disubstituted
olefin produced the corresponding spirocyclic lactam with good yield
and d.r. (2aj, 77%, 10:1 d.r.). Finally, cyclopropyl substituted aliphatic
alkenes can be used to form the ζ-amino carbonyl products in moderate
Br
+
+
N
O
EtO
1
Ph
(3)
O
O
+
EtO
EtO
2am
N
N
Ph
56%, 50:1 trans:cis
Ph
yields (2ak-
al).
viability of this intermediate was further established by a thorough
consideration of the stereochemical outcomes from the internal alkene
In addition to terminal alkenes, more hindered internal alkenes read-
ily participate in the reaction, providing highly substituted products in
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2017, 139, 13076-13082. (j) Zhu, N.; Wang, T.; Ge, L.; Li, Y.; Zhang, X.; Bao,
substrates. In the case of 2am, the system is conformationally locked,
and opening of the purported oxoncarbenium would deliver only the
trans product (eq. 3). For the carboamination of b-methylstyrene, the
system may rotate freely, and the thermodynamically more stable trans
oxocarbenium structure may form. Stereoinvertive opening of the
oxocarbenium followed by lactamization delivers selectively the cis
product 2ao (eq. 4). Taken together, these mechanistic probes indicate
that oxocarbenium ion intermediates form when geometrically permit-
ted, though are not required for product formation if the radical addi-
tion intermediate is oxidizable by Cu(II), as is the case for the benzylic
radical preceding the formation of 2al (eq. 1).8, 16
H. Org. Lett. 2017, 19, 4718-4721. (k) Liu, Z.; Wang, Y.; Wang, Z.; Zeng, T.;
Liu, P.; Engle, K. M. J. Am. Chem. Soc. 2017, 139, 11261-11270. (l) Choi, G. J.;
Knowles, R.R. J. Am. Chem. Soc. 2015, 137, 9226−9229. (m) Wang, D.; Wu, L.;
Wang, F.; Wan, X.; Chen, P.; Lin, Z.; Liu, G. J. Am. Chem. Soc. 2017, 139, 6811-
6814. (n) Um, C.; Chemler, S. R. Org. Lett. 2016, 18, 2515-2518.
1
2
3
4
5
6
7
8
3 For general books and reviews see: (a) Renaud, P., Sibi, M. P., Eds. Radicals
in Organic Synthesis; Wiley-VCH: New York, 2001. (b) Giese, B. Radicals in
Organic Synthesis: Formation of Carbon–Carbon Bonds; Pergamon: Oxford,
1986. (c) Hart, D. J. Science 1984, 223, 883-887. (d) Sibi, M. P.; Manyem, S.;
Zimmerman, J. Chem. Rev. 2003, 103, 3263-3295. (e) Zimmermann, J.; Sibi,
M. P. Top. Curr. Chem. 2006, 263, 107-162. (f) Hoffman, R. W. Chem. Soc.
Rev. 2016, 45, 577-583. (g) Matyjaczewski, K.; Xia, J. Chem. Rev. 2001, 101,
2921-2990. (h) Tang, S.; Liu, K.; Liu, C.; Lei, A. Chem. Soc. Rev. 2015, 44,
1070-1082. For redox catalysis involving radicals see: (i) Studer, A.; Curran, D.
P. Angew. Chem. Int. Ed. 2016, 55, 58-102. (j) Romero, N. A.; Nicewicz, D. A.
Chem. Rev. 2016, 116, 10075-10166. (k) Prier, C. K.; Rankic, D. A.; MacMillan,
D. W. C. Chem. Rev. 2013, 113, 5322-5363. (l) Shaw, M. H.; Twilton, J.; Mac-
Millan, D. W. C. J. Org. Chem. 2016, 81, 6898-6926. (m) Skubi, K. L.; Blum, T.
R.; Yoon, T. P. Chem. Rev. 2016, 116, 10035-10074. (n) Narayanam, J. M. R.;
Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40, 102-113. (o) Tucker, J. W.;
Stephenson, C. R. J. J. Org. Chem. 2012, 77, 1617-1622. (p) Douglas, J. J.;
Sevrin, M. J.; Stephenson, C. R. J. Org. Process Res. Dev. 2016, 20, 1134-1147.
For powerful approaches to alkene functionalization via radical additions see:
(q) Margrey, K. A.; Nicewicz, D. A. Acc. Chem. Res. 2016, 49, 1997-2006. (r)
Gentry, E. C.; Knowles, R. R. Acc. Chem. Res. 2016, 49, 1546-1556. For carbo-
amination reactions involving aryl radicals from aryl diazonium precursors see:
(s) Kindt, S.; Wicht, K.; Heinrich, M. R. Org. Lett. 2015, 17, 6122-6125. (t)
9
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EtO
standard
conditions
O
nBu
+
NH2
Br
O
+
H
EtO
1
H
nBu
nBu
O
O
(4)
N
N
+
2ao
48%, 25:1 cis:trans from (Z)
56%, 32:1 cis:trans from (E)
In conclusion, we have developed a three-component carboamina-
tion reaction that couples readily available alkenes, functionalized alkyl
halides, and amines. Yields are good to excellent, and the scope of the
reaction in all three components is broad. Olefin classes that are tradi-
tionally challenging to functionalize through transition metal catalysis
are exceptionally reactive in this system, which we attribute to the in-
termediacy of an oxocarbenium species. The molecules constructed
through this method represent powerful examples of the potential of
base metal catalysis to enable the rapid difunctionalization of olefins.
Future work will focus on developing diastereoselective conditions for
differentially substituted electrophiles, expanding nucleophile scope,
and developing an asymmetric protocol.
Blank, O.; Wetzel, A.; Ullrich, D.; Heinrich, M. R. Eur. J. Org. Chem. 2008
,
3179-3189. (u) Citterio, A.; Minisci, F.; Albinati, A.; Bruokner, S. Tetrahedron
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4(a) Chen, X.; Liu, X.; Mohr J. T. J. Am. Chem. Soc. 2016, 138, 6364−6367.
(b) Xu, T.; Hu, X. Angew. Chem. Int. Ed. 2015, 54, 1307-1311. (c) Fisher, D. J.;
Burnett, G. L.; Velasco, R.; Alaniz, J. R. J. Am. Chem. Soc. 2015, 137, 11614-
11617. (d) Gietter, A. A. S.; Gildner, P. G.; Cinderella, A. P.; Watson, D. A. Org.
Lett. 2014, 16, 3166-3169.
ASSOCIATED CONTENT
Supporting Information
5 (a) Nishikata, T.; Noda, Y.; Fujimoto, R.; Sakashita, T. J. Am. Chem. Soc.
2013, 135, 16372–16375. (b) Tang, S.; Liu, K.; Liu, C.; Lei, A. Chem. Soc. Rev.
2015, 44, 1070-1082.
Experimental procedures and spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
6 (a) Matyjaczewski, K. Macromolecules 2012, 45, 4015−4039. (b) Soejima,
T.; Satoh, K.; Kamigaito, M. J. Am. Chem. Soc. 2016, 138, 944-954.
7
AUTHOR INFORMATION
(a) Fischer, H.; Radom, L. Angew. Chem. Int. Ed. 2001, 40, 1340–1371.
(b) Giese, B.; He, J.; Mehl, W. Chem. Ber. 1988, 121, 2063-2066.
8
Corresponding Author
Kochi, J. K.; Bemis, A.; Jenkins, C. L. J. Am. Chem. Soc., 1968, 90, 4616–
4625.
kamihull@illinois.edu
9 The formation of analogous intermediates has been described by Kochi in
his analysis of the mechanism of oxidative substitution catalyzed by Cu(II).8 In
this report, Kochi found through deuterium labeling experiments that the α- and
β- carbons of homobenzylic radicals scrambled upon oxidation by Cu(II), os-
tensibly due to the intermediacy of a symmetric, cationic intermediate that
undergoes nucleophilic attack by an exogeneous nucleophile.
10 Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. J.
Med. Chem. 2015, 58, 8315−8359.
Author Contributions
‡S.N.G. and T.L.B. contributed equally.
ACKNOWLEDGMENT
The authors would like to thank the NIH (1R35GM125029), the
Sloan Research Foundation, and the University of Illinois for their
generous support of this work.
11 (a) Krapcho, A. P.; Glynn, G. A.; Grenon, B. J. Tetrahedron Lett. 1967, 8,
215-217. (b) Lee, A.; Michrowska, A.; Sulzer-Mosse, S.; List, B. Angew. Chem.
Int. Ed. 2011, 50, 1707-1710.
12
REFERENCES
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16 For additional mechanistic information and a proposed catalytic cycle, see
Supporting Information (SI).
2
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(b) Garlets, Z. J.; White, D. R.; Wolfe, J. P. Asian J. Org. Chem. 2017, 6, 636-
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14725. (i) Qian, B.; Chen, S.; Wang, T.; Zhang, X.; Bao, H. J. Am. Chem. Soc.
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