Zn-Mediated Fragmentation of Tertiary Alkyl Oxalates Enabling Formation of Alkylated and Arylated Quaternary Carbon Centers

Article abstract of DOI:10.1021/jacs.8b12801

Zn-mediated reduction of readily accessible dialkyl oxalates derived from tertiary alcohols provides an efficient approach to C-O bond fragmentation and alkyl radical formation. With MgCl₂ as the indispensable additive and Ni as the promoter, trapping the radical with activated alkenes and aryl-Ni intermediates allows for the generation of alkylated and arylated all-carbon quaternary centers.

Full text of DOI:10.1021/jacs.8b12801

Subscriber access provided by YORK UNIV
Communication
Zn-Mediated Fragmentation of Tertiary Alkyl Oxalates Enabling
Formation of Alkylated and Arylated Quaternary Carbon Centers
Yang Ye, Haifeng Chen, Jonathan L. Sessler, and Hegui Gong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b12801 • Publication Date (Web): 20 Dec 2018
Downloaded from http://pubs.acs.org on December 20, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 6
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Zn-Mediated Fragmentation of Tertiary Alkyl Oxalates Enabling
Formation of Alkylated and Arylated Quaternary Carbon Centers
Yang Ye,† Haifeng Chen,† Jonathan L. Sessler, and Hegui Gong*
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
School of Materials Science and Engineering, Center for Supramolecular Chemistry and Catalysis and Department
of Chemistry, Shanghai University, China
C-O bond, Oxalate, Zinc, Cross-coupling, Quaternary Carbon Centers,
Supporting Information Placeholder
acceptor.8,10 In spite of these advances, the direct
ABSTRACT: Zn-mediated reduction of readily accessible
activation of the more readily accessible dialkyl oxalates,
dialkyl oxalates derived from tertiary alcohols provides
such as 3, remains as a nearly unmet challenge.11 We
an efficient approach to C–O bond fragmentation and
thus set out to explore whether it would be possible to
alkyl radical formation. With MgCl2 as the indispensable
use simple dialkyl oxalates to generate C(sp3)–O carbon
additive and Ni as the promoter, trapping the radical
radicals and under nominally less-forcing conditions than
with activated alkenes and aryl–Ni complexes allows for
those provided by most current photocatalysis strategies
the generation of alkylated and arylated all-carbon
(Scheme 1). We also sought to trap the putative tertiary
quaternary centers.
C(sp3) carbon radicals thus broadening the range of
accessible C–C bond coupled products (Scheme 1).
Scheme 1. Tertiary C(sp3)–O Bond Barton
Fragmentation and C–C bond formation.
catalytic photo-induced tertiary alkyl radical generation:
Alcohols are ubiquitous in nature, and in the
laboratory alkyl hydroxyls are among the most accessible
of all organic functional groups. The development of
effective coupling methods based on cleavage of
unactivated C(sp3)–O bonds is synthetically and
theoretically appealing. However, formidable challenges
remain to be addressed.1 Carbon-oxygen bonds are
strong (~95 kcal/mol).2 Thus, forcing conditions are
typically required to achieve useful conversions and even
these are subject to limitations. Conventional Barton-
type deoxygenation methods allow for the homolytic
scission of C(sp3)–O bonds with good efficiency;
however, they rely on the addition of toxic and/or less
atom-efficient tin, silyl and boryl radicals and require the
use of specific thionyl and carbonyl esters.3 Recently, the
generation of alkyl radicals through the photoredox
catalyzed Barton fragmentation of C(sp3)–O bonds has
been reported.4-8 Examples of this latter approach
include Ir-catalyzed oxidative deoxygenations of hemi-
alkyl oxalate salts (e.g., 1, Scheme 1)5-6 and Ru-catalyzed
reductive deoxygenations of tertiary alkyl N-
phthalimidoyl (NP) oxalyl esters (e.g., 2, Figure 1).7-9 Here,
advantage is taken of the strong driving force provided
by the redox active IrIII and RuII photocatalysts in their
excited states. For instance, reduction of 2 (E1/2red = -1.14
e
O
O
O
Ru(bp)2+
.
IrIII
O
O
O
N
O
M
h
h
O
O
O
CO2Bn
1
(E1/2red = -1.14 V)
E1/2red [*Ru(bpy)32+/Ru3+] = -1.33 V
(E1/2red = +1.28 V)
E1/2red[*fac-Ir3+/Ir2+] = +1.21 V
2
tBu
CO2Bn
tertiary alkyl radical generation with chemical reductant (
this work
):
e
O
.
CO2Bn
or Ar-Cl
Me
Zn/MgCl2
O
or
O
Ar
CO2Bn
Ni (cat.)
O
(E1/2red = -1.3 V)
Zn (E1/2red = -0.76 V)
3
all carbon quaternary centers
To date, Michael acceptors have seen considerable use
as productive traps for the tertiary alkyl radicals derived
from Barton C–O bond scission. Overman has
accomplished a number of natural product syntheses,
e.g., cheloviolene A (Figure 1) using such an approach.12
Trapping an alkyl radical with an aryl–Ni(II) intermediate
has been invoked to explain the Ni-catalyzed reductive
or photoredox arylation of tertiary alkyl halides or –
boronated derivatives.13 This has allowed creation of
14-18
arylated all-carbon quaternary stereogenic centers.
Such centers are found in numerous naturally occurring
compounds and active pharmaceutical ingredients
(APIs),19 including morphine and (+)-bionectin A (Figure
1).20-21 Thus, being able to prepare all-carbon quaternary
scaffolds directly using simple tertiary alcohol derivatives
as the starting materials could prove useful. Here, we
report one approach to meeting this synthetic challenge.
Briefly, we have found that a Zn-mediated reduction of
II*/I
V vs SCE in CH3CN) with Ru(bpy)32+(E1/2 −1.33 V vs SCE
in CH3CN) is thermodynamically viable due to the use of
a photoexcited ruthenium complex as the electron donor
and the NP moiety within the esters as the initial electron
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 6
9
dtbbp in place of PBI
iPr-Pybox in place of PBI
NiCl2
NiBr2
45
24
68
46
readily available dialkyl oxalates under Ni-promoted
conditions leads to unprecedented C(sp3)–O bond
fragmentation and generates tertiary alkyl radicals. To
our knowledge, the use of a chemical reductant to
trigger a Barton C–O bond scission has not hitherto been
reported.22 The radical intermediates can be trapped to
generate a range of alkylated and arylated quaternary
products as detailed below.
1
2
3
4
5
6
7
8
10
11
12
13
14
NiI2
69
ZnCl2 instead of MgCl2
no reaction
a
NMR yield using 2,5-dimethyl furan as the internal standard from
a mixture containing other impurities after a quick flash column
chromatography; b Isolated yield (average of 3 independent runs).
Py = pyridine, PBI = 2-(pyridin-2-yl)-1H-benzo[d]imidazole, DMA =
N, N-dimethyl acetamide.
The C–O bond fragmentation method displayed
excellent compatibility for
H
N
9
HO
HO
H
H
O
O
OH
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
Me
O
H
N
S
S
N
O
O
H
NMe
a
broad range of
H
N
H
O
H
H
HO
unsymmetrical oxalates. The tertiary alkyl oxalates
containing geminal dimethyl groups delivered 4b–h in
good to excellent yields (Table 2). The more complex
steroid-tethered tertiary alcohol can be converted to 4c
in 86% yield. Dioxalate resulted in 4h in 61% yield,
whereas the free hydroxyl substrate allowed formation of
4g in 70% yield. The more sterically hindered quaternary
products 4i–l were obtained in excellent yields (Table 2).
The construction of all C(sp3)-quaternary centers starting
from hydroxyls present on 5-, 6-, and 7-membered rings
also proved effective as exemplified by the preparation
of 4m–4p in good to excellent yields. Likewise,
menthone and estrone-derived tertiary oxalates allowed
the generation of products 4q and 4r in good yields. A
bicyclic scaffold derived from hematoxylin delivered a
moderate yield of 4s. An attractive feature of the present
approach is that it can be run at the 10-gram scale using
3m-Ox-OMe and 5 mol% of the Ni salt to drive the
chemistry; 4a was obtained in 74% yield with recovery of
70% of PBI during aqueous workup.
Cheloviolene A
Morphine
(+)-Bionectin A
Figure 1. Structures of cheloviolene A, morphine, (+)-
bionectin A.
We set out to test the reaction of a tertiary alkyl
methyl oxalate (3a-Ox-Me) with benzyl acrylate. To our
delight, the radical addition/hydrogen abstraction
product 4a was obtained in an optimal 83% isolated
yield when 1.2 equiv of 3a-Ox-Me was used along with a
combination of NiCl2(Py)4/MgCl2/PBI/Zn in DMA (method
A: Table 1, entry 1). Control experiments revealed that
MgCl2, PBI, and Zn were all crucial for the transformation;
in their absence, no reaction occurs (entries 2–4).
However, when the Ni salt was eliminated, 4a was still
obtained in 32% yield (entry 5). This was taken as
evidence that the key addition process is largely
governed by Zn, MgCl2, and PBI. Use of other reductants,
such as Mn and Mg, in lieu of Zn proved unsatisfactory
(entries 6–7). Variation of other reaction parameters,
including the use of different N-containing
ligands/additives, Ni sources and ZnCl2 gave lower yields
(entries 8–14 and Table S1).23
Table 2. Scope of tertiary alkyl methyl oxalates and
alkenes.
Table 1. Optimization of the reaction of 3a-Ox-Me with
benzyl acrylate.
"method A"
(1 equiv)
CO2Bn
NiCl2(Py)4 (10 mol%)
MgCl2 (200 mol%)
O
Me
O
Me
Me
Me
O
OBn
Me
BzO
BzO
PBI (3 equiv)
O
O
Zn (250 mol%)
3a-Ox-Me
(1.2 equiv)
4a
, 83% yield
DMA, 25 o
C
tBu
H
N
O
O
N
N
N
N
tBu
N
N
N
N
DMAP
iPr-Pybox
iPr
iPr
PBI
dtbbp
N
entry variation from the standard yield%a
conditions
1
2
3
4
5
6
7
8
None
w/o MgCl2
w/o PBI
w/o Zn
83b
no reaction
trace
no reaction
32
47
w/o Ni
Mn in place of Zn
Mg in place of Zn
DMAP in place of PBI
no reaction
21
ACS Paragon Plus Environment

Page 3 of 6
Journal of the American Chemical Society
Me
"method B"
Me
Me
O
H
BnO2C
CO2Bn
Ph
NiF2 (10 mol%)
MgCl2 (200 mol%)
1
2
3
4
5
6
7
8
CO2Bn
O
O
Me
O
Me
O
Me
O
Me
Me
4b
H
H
4a
N
BzO
3a-Ox-3a
(1)
: 78%
4c
DMAP (100 mol%)
Zn (250 mol%)
DMA, 25oC
: 86%
BzO
2
(1 equiv)
14
Me
Me
a,b
Me
Me
Me
CO2Bn
CO2Bn
4a
14
not applicable
CO2Bn
1 equiv
0 equiv
TEMPO
0 equiv
2 equiv
TBSO
CO2Bn
Me
77%
MeO
not applicable 35%
4d
4e
4f
: 86%
: 77%
Me
, 79%
Me
OBn
Me
Et
R
Me
Me
HO
Me
Me
BnO2C
O
CO2Bn
Me Me
O
O
Me
Me
CO2Bn
Me
4g
(1 equiv)
O
OMe
O
Me
9
Me
4i
: R = n-Pent: 83%
4j
: R = n-Hept: 76%
Me
(2)
a,b
a,c
method A
4h
: 70%
: 61%
O
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
OBn
O
4t
3t-Ox-OMe
(1.2 equiv)
Me
R
: 76% yield
CO2Bn
CO2Bn
CO2Bn
The role of MgCl2 and PBI was studied next. The
reduction potential of 3a-Ox-Me was determined to be -
1.29 V (vs SCE in CH3CN, Figure S2).23 In the absence of
MgCl2 reduction of these diakyl oxalates using Zn
(reduction potential -0.76 V vs SCE in water) appears
nominally endoergonic, although a strict determination
is not possible from the available data. In this event,
control experiments indicated that Rieke Zn (with a more
reactive surface than most commercial zinc powder)
alone enabled the reaction of 3a-Ox-Me with benzyl
acrylate to give 4a in 4% yield, which rose to 48% upon
the addition of MgCl2 (Table S3).23 Under the present
catalytic conditions using Zn powder, no reaction
occurred in the absence of MgCl2 and PBI (Table 1). We
propose that the role of MgCl2 and PBI is multi-faceted.
First, MgCl2 or the Mg(PBI)Cl2 complex activates Zn by
removal of surface impurities.24 Second, the Lewis acidity
of MgCl2 or Mg(PBI)Cl2 complex may enable its effective
chelation with dialkyl oxalates (Figures S1–S5) and the
radical anionic oxalate intermediates.23,25 This is expected
to favor both the reaction kinetics and thermodynamics.
n
CO2Bn
d
a
a
4m
4n
4o
: R = Me: 86% (74%) n =1, : 62%
4l
4k
: 88%
: 86%
a,b
4p
n = 2, : 72%
: R = Et: 91%
Me
CO2Bn
CO2Bn
O
Me
H
MeO
OBn
OMe
OMe
H
H
H
O
MeO
MeO
Me
Me
a,d
a,b
a,e
4q
4r
4s
: 40% (50%)
: 57%
: 70%
Me
R
Et
N
OEt
OEt
BzO
CO2tBu
P
CO2Me
Et
Me
O
a,b
O
5
6a
6b
6c
: 89%
, R = F: 48%
8
: 72%
a,b
7
: 81%
, R = Me: 85%
a,b
, R = NHAc: 78%
O
OMe
O
O
O
SO2Ph
a,b
O
O
a
a
13
: 71%
a,b
9
: 74%
a,d
12
(cis/trans = 1:1)
: 74%
10
: 81%
11
: 71%
o
a
b
c
The reaction was performed at 40 C. Oxalate (1.5 equiv). Oxalate (1
d
equiv), benzyl acrylate (2.2 equiv). The reaction was run on a 10 gram-
scale using 5 mol% of Ni. e Oxalate (2 equiv).
We also examined the scope of the activated alkenes
that could be used as coupling partners for 3a-Ox-Me.
Acrylates decorated with different alkyl groups on the
ester moieties, and substituents at the internal vinyl
carbon positions were effective as evidenced by the
formation of 5–6 (Table 2). Conjugated vinyl sulfonates,
The Ni–Py type complexes that are thought to result
are expected to participate in and promote the reaction
via a Ni(I) intermediate.26 The chemoselective cleavage of
the C(sp3)–O bonds in unsymmetrical dialkyl oxalates is
ascribed to reversible single-electron transfer from the
Zn to a mixture of radical anions, and vice versa.
Irreversible formation of the more stable tertiary alkyl
radical ultimately dictates the reaction pathway (Scheme
2).
phosphonates,
and
amides,
as
well
as
3-
methylenedihydrofuran-2(3H)-one,
cyclopent-2-en-1-
one, furan-2(5H)-one, and methyl cyclopent-1-ene-1-
carboxylate, could also be used; all generated the
corresponding quaternary products 7–13 in good yields
(Table 2).
We also monitored the progress of the reaction of 3a-
Ox-Me (1.2 equiv) with benzyl acrylate (1 equiv). The
reaction went essentially to completion within 11 hours
under the conditions of Method A; this generated 4a (0.8
equivalents), ~0.3 equivalents of the corresponding
tertiary alcohol, and 0.1 equiv of unreacted oxalate
(Figure S6). Here, the radical anion may abstract a
hydrogen (e.g., from solvent), followed by decomposition
to generate the tertiary alcohol (Scheme 2).27
For the reaction of symmetrical oxalate 3a-Ox-3a with
benzyl acrylate, a combination of NiF2, DMAP, and MgCl2
in DMA gave 4a in an optimal 77% yield (eq 1, method B
and Table S2). The reaction was inhibited completely
when TEMPO was added. Exposure of 3a-Ox-3a to
TEMPO in the absence of benzyl acrylate produced 14 in
35% yield. Moreover, cyclization of 3t-Ox-Me afforded
4t in 76% yield (eq 2). Taken in concert, these findings
provide support for the radical nature of the C–O bond
scission event.
Scheme 2. Chemoselective reduction of dialkyl
oxalates with Zn/MgCl2 and possible pathway for
alcohol formation.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 6
O
O
O
To our delight, using electron-deficient chloroarenes
R
.
R
R
Zn
Znn+
OMe
OMe
OMe
R
1
O
O
O
as the limiting reagent, the coupling of 3a-Ox-Me with
methyl 4-cholorbenzoate provided an inseparable
mixture of 15a and its isomerization product (a ratio of
20:1 for the two products) in 54% yield (Table 3).
Replacing the Me group in 3a-Ox-Me by a tBu moiety, a
reaction with 3a-Ox-tBu as the limiting reagent, gave
15a and its isomerization product (33:1 ratio) in 66%
O
O
O
2
3
4
5
6
7
OOC CO2Me
hydrogen abstraction
O
decompose
O
H
R
R
R
OMe
OMe
O
H
OH
O
O
O
The reaction of readily available 3a-Ox-Me with benzyl
8
9
yield (method C, Table 3). By contrast, methyl 4-
acrylate does not take place under the Ir- or Ru-
catalyzed photoredox conditions (Scheme 1) used for
oxalate cesium salts and NP–oxalates (eq S1–S7).23 In
contrast, our Zn/MgCl2 conditions are unique for alkyl
methyl oxalates to generate tertiary alkyl radicals via C–O
bond fragmentation.22
In the field of cross-electrophile couplings,28-31 C–C
bond forming processes often involve interception of an
alkyl radical by a relatively stable organo-Ni(II) species
generated from the oxidative addition of an electrophile
to Ni(0).13 This prompted us to explore whether direct
coupling of the tertiary alkyl oxalates with other
electrophiles would prove possible.
23
bromobenzoate was less satisfactory (Scheme S7).
It
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
was also noted that electron-neutral 1-chloro-4-
methylbenzene was inert whereas its bromo analog only
delivered the coupling product in 25% yield (Scheme
S7).23 Under these conditions, methyl 4-(tert-
butyl)benzoate was obtained in 5% yield, reflecting
excellent chemoselectivity even for di-tert-alkyl oxalates.
In fact, a wide range of tRalkyl-Ox-tBu with different aryl
chlorides proved viable as substrates (Table 3). The
arylated quaternary products 15b–15f and 16–24 were
obtained in yields comparable to those obtained using
tertiary alkyl bromides.14 Both open-chain and cyclic
tertiary oxalates were compatible. Side reactions arising
from isomerization of the tertiary alkyl groups were
generally negligible, except for more hindered 24.23 This
stands in contrast to what is typically found using alkyl
halides.14 Lastly, the utility of this arylation protocol is
showcased via the late-stage installation of a tertiary
alkyl group into a chlorine-containing commercial drug
fenofibrate (a cholesterol-reducing agent used to treat
cardiovascular disease). Here, coupling with 3a-Ox-tBu
led to a quaternary product 25 in a reasonably good
yield (modified method C, Table 3).
In summary, we have demonstrated that dialkyl
oxalates derived from tertiary alcohols undergo C–O
bond fragmentation to afford tertiary alkyl radicals when
treated with Zn and MgCl2 in the presence of Ni
catalysts. The non-innocent roles of MgCl2 and pyridine-
type additives in the process were attributed to
activation of Zn and oxalates, and stabilization of the
radical anion intermediates. The generation of tertiary
alkyl radicals was evidenced by trapping them with
activated alkenes, TEMPO, radical cyclization and by
creation of arylated quaternary carbon centers under Ni-
catalyzed cross-electrophile coupling conditions. This
work exploits earth-abundant metal species. It thus
provides a tool that can complement and extend the
scope of current methodologies while offering new
mechanistic insights into C–O bond fragmentation.
Table 3. Arylation of tertiary alkyl oxalate with aryl
chlorides.a,b
"method C"
Cl
Me
Ar
Me
+
Ni(TMHD)2 (10%)
MgCl2 (300%)
15a
BzO
BzO
Me
OCOCO2
Me
Me
R
BzO
4-MeO-Py (300%)
LiCl (300%)
Ar
15a'
CO2Me
1 equiv
3a-Ox-Me
(R = Me)
1.4 equiv
(R = tBu)
1 equiv
Zn (300%)
54% (20:1)
66% (33:1)
Me
DMA, 25 o
C
3a-Ox-tBu
2 equiv
BzO
Me
Me
Me
Me
Me
BzO
CO2Me
BzO
S
O
R
O
15b
15c
15d
, R = Ac: 60% (30:1)
, R = CF3: 52% (59:1)
, R = CN: 56% (75:1)
15f
: 48% (33:1)
Me
15e
: 53% (30:1)
O
O
Me
Me
O
Me
Me
Me
MeO
F3C
CO2Me
CO2Me
CO2Me
16
: 56%
18
: 67% (30:1)
17
: 61%
Me
Me
Me
Me
Me
Ph
CO2Me
n
CO2Me
X
CO2Me
19
20
, n =1: 53% (25:1)
, n =2: 47% (>10:1)
21
22
, X = O: 50% (66:1)
, X = S: 47%
23
: 45% (99:1)
O
CO2Me
BzO
Me
Me
O
Me
CO2iPr
Me Me
Me
Me
MeO
c
25
: 65%
24
: 41% (6:1)
a
b
Without further notice, tRalkyl-Ox-tBu was used. The ratio in
ASSOCIATED CONTENT
parenthesis refers to that of quaternary product to its isomerization
Supporting Information. Detailed experimental procedures,
characterization of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
c
product after purification.
1.4 quiv of 3a-Ox-tBu, 1.0 equiv of
fenofibrate and 20 mol% of Ni were used at 40 oC. TMHD = 2,2,6,6-
tetramethylheptane-3,5-dionate.
AUTHOR INFORMATION
ACS Paragon Plus Environment

Page 5 of 6
Journal of the American Chemical Society
†
Mediated Deoxygenation. Eur. J. Org. Chem. 2017, 15,
2130–2138.
(12) Slutskyy, Y.; Jamison, C. R.; Zhao, P.; Lee, J.; Rhee, Y. H.;
Overman, L. E. Versatile Construction of 6‑Substituted cis-
These authors contribute equally.
1
2
3
4
Corresponding Author
hegui_gong@shu.edu.cn
2,8-Dioxabicyclo[3.3.0]octan-3-ones:
Short
Enantioselective Total Syntheses of Cheloviolenes A and B
and Dendrillolide C. J. Am. Chem. Soc. 2017, 139, 7192–
7195.
5
6
7
8
ACKNOWLEDGMENT
This work was supported by National Natural Science
Foundation of China (grant nos. 21871173 and 21572140).
(13) Biswas, S.; Weix, D. J. Mechanism and Selectivity in Nickel-
Catalyzed Cross-Electrophile Coupling of Aryl Halides with
Alkyl Halides. J. Am. Chem. Soc. 2013, 135, 16192–16197.
(14) Wang, X.; Wang, S.; Xue, W.; Gong, H. Nickel-Catalyzed
Reductive Coupling of Aryl Halides with Unactivated tert-
Alkyl Halides. J. Am. Chem. Soc. 2015, 137, 11562–11565.
(15) Chen, H.; Jia, X.; Yu, Y.; Qian, Q.; Gong, H. Nickel-Catalyzed
Reductive Allylation of Tertiary Alkyl Halides with Allylic
Carbonates. Angew. Chem. Int. Ed. 2017, 56, 13103–13106.
(16) Zhao, C.; Jia, X.; Wang, X.; Gong, H. Ni-Catalyzed Reductive
Coupling of Alkyl Acids with Unactivated tertiary Alkyl and
Glycosyl Halides. J. Am. Chem. Soc. 2014, 136, 17645–
17651.
(17) Lu, X.; Wang, Y., Zhang, B., Pi, J.-J., Wang, X.-X., Gong, T.-J.,
Xiao, B., Fu, Y. Nickel-Catalyzed Defluorinative Reductive
Cross-Coupling of gem-Difluoroalkenes with Unactivated
Secondary and Tertiary Alkyl Halides. J. Am. Chem. Soc.
2017, 139, 12632–12637.
(18) Primer, D. N.; Molander, G. A. Enabling the Cross-Coupling
of Tertiary Organoboron Nucleophiles through Radical-
Mediated Alkyl Transfer. J. Am. Chem. Soc. 2017, 139,
9847–9850.
(19) Quasdorf, K. W.; Overman, L. E. Catalytic enantioselective
synthesis of quaternary carbon stereocentres. Nature
2014, 516, 181–191.
(20) Kim, J.; Movassaghi, M. Biogenetically-Inspired Total
Synthesis of pidithiodiketopiperazines and Related
Alkaloids. Acc. Chem. Res. 2015, 48, 1159–1171.
(21) Carlé, J. S.; Christophersen, C. Bromo-Substituted
Physostigmine Alkaloids from a Marine Bryozoa Flustra
foliacea. J. Am. Chem. Soc. 1979, 101, 4012–4013.
9
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
REFERENCES
(1) Cornella, J.; Zarate, C.; Martin, R. Metal-catalyzed
activation of ethers via C–O bond cleavage: a new
strategy for molecular diversity. Chem. Soc. Rev. 2014, 43,
8081–8097.
(2) Pedley, J. B.; Naylor, R. D.; Kirby, S. B. Thermochemical Data
of Organic Compounds, 2nd, Ed., Chapman and Hall, New
York 1986.
(3) McCombie, S. W.; Motherwell, W, B.; Tozer, M. J. The
Barton-McCombie Reaction. Organic Reactions (Hoboken,
NJ, United States), 2012, 77, 161–591.
(4) Christopher, R. J.; Overman, L. E. Fragment Coupling with
Tertiary
Radicals
Generated
by
Visible-Light
Photocatalysis. Acc. Chem. Res. 2016, 49, 1578–1586.
(5) Nawrat, C. C.; Jamison, C. R.; Slutskyy, Y.; MacMillan, D. W.
C.; Overman, L. E. Oxalates as Activating Groups for
Alcohols in Visible Light Photoredox Catalysis: Formation
of Quaternary Centers by Redox-Neutral Fragment
Coupling. J. Am. Chem. Soc. 2015, 137, 11270–11273.
(6) Zhang, X.; MacMillan, D. W. C. Alcohols as Latent Coupling
Fragments for Metallaphotoredox Catalysis: sp3–sp2
Cross-Coupling of Oxalates with Aryl Halides. J. Am.
Chem. Soc. 2016, 138, 13862–13865.
(7) Lackner, G. L.; Quasdorf, K. W.; Overman, L. E. Direct
Construction of Quaternary Carbons from Tertiary
Alcohols via Photoredox-Catalyzed Fragmentation of tert-
Alkyl N-Phthalimidoyl Oxalates. J. Am. Chem. Soc. 2013,
135, 15342–15345.
(8) Lackner, G. L.; Quasdorf, K. W.; Pratsch, G.; Overman, L. E.
Fragment Coupling and the Construction of Quaternary
Carbons Using Tertiary Radicals Generated From tert-Alkyl
N-Phthalimidoyl Oxalates By Visible-Light Photocatalysis.
J. Org. Chem. 2015, 80, 6012–6024.
(9) Gao, C.; Li, J.; Yu, J.; Yang, H.; Fu, H. Visible-Light
photoredox Synthesis of Internal Synthesis of Internal
Alkynes Containing Quaternary Carbons, Chem. Commun.
2016, 52, 7292–7294.
(22) In a recent report on Ni-catalyzed reductive coupling of
primary benzyl methyl oxalates with alkyl halides,
oxidative addition of a benzyl C-O bond to Ni(0) was
considered plausible (see pages S37 to S40 in the
Supporting Information for details): Yan, X.-B.; Li, C.-L.; Jin,
W.-J.; Guo, P.; Shu, X.-Z. Reductive Coupling of Benzyl
Oxalates with Highly Functionalized Alkyl Bromides by
Nickel Catalysis. Chem. Sci. 2018, 9, 4529–4534.
(23) See the Supporting Information for details.
(10) A similar process has been widely used for the generation
of alkyl radials by decarboxylation of RCO2NP; cf., e.g.,:
Schnermann, M. J.; Overman, L. E. A Concise Synthesis of
(-)-Aplyviolene Facilitated by a Strategic Tertiary Radical
Conjugate Addition. Angew. Chem, Int. Ed. 2012, 51,
9576–9580.
(24) Formation of Mg(DMAP)Cl2 and Mg(PBI)Cl2 complexes
were confirmed by ICP-AES analysis (see the Supporting
Information). We reason that MgCl2 can remove the
impurities on zinc surface, thus activating the zinc. Similar
benefits have been inferred in the case of LiCl, see: Feng,
C.; Cunningham, D. W.; Easter, Q. T.; Blum S. A. Role of LiCl
in Generating Soluble Organozinc Reagents. J. Am. Chem.
Soc. 2016, 138, 11156–11159.
(25) Metzger, A.; Bernhardt, S.; Manolikakes, G.; Knochel, P.
MgCl2-Accelerated Addition of Functionalized Organozinc
Reagents to Aldehydes, Ketones, and Carbon Dioxide.
Angew. Chem. Int. Ed. 2010, 49, 4665–4668.
(11) In fact, to date only α-hydroxyl groups within hemi-ethyl
red
oxalyl tartrate derivatives (E1/2 = -1.56 V vs SCE) have
been effectively converted to the corresponding relatively
stable α-carbonyl radicals and only under strongly
reducing photocatalytic conditions (ERed[Ir4+/Ir3+*] = –1.73
V). Rackl, D.; Kais, V.; Lutsker, E.; Reiser, O. Synthesis of
Chiral Tetrahydrofurans and Pyrrolidines by Visible-Light-
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 6
(26) The redox potentials of 2,2':6',2''-terpyridine-Ni(I)-Me
(29) Moragas, T.; Correa, A.; Martin, R. Metal-Catalyzed
Reductive Coupling Reactions of Organic Halides with
Carbonyl-Type Compounds. Chem. Eur. J. 2014, 20, 8242–
8252.
(30) Weix, D. J. Methods and Mechanisms for Cross-
Electrophile Coupling of Csp2 Halides with Alkyl
Electrophiles. Acc. Chem. Res. 2015, 48, 1767–1775.
(31) Wang, X.; Dai, Y.; Gong, H. Nickel-Catalyzed Reductive
Couplings. Top. Curr. Chem. 2016, 374, 43–72.
(32) Wang, X.; Ma, G.; Peng, Y; Pitsch, C. E.; Moll, B. J.; Ly, T. D.;
Wang, X; Gong, H. Ni-Catalyzed Reductive Coupling of
Electron-Rich Aryl Iodides with Tertiary Alkyl Halides. J. Am.
Chem. Soc. 2018, 140, 14490–14497.
1
2
3
4
5
6
7
8
complex and 4,4',4''-tri-tert-butyl-2,2':6',2''-terpyridine-
Ni(I)-Me were determined to be -1.32 and -1.44 V (vs
Ag/Ag+ in THF solution), respectively. Jones, G. D.;
McFarland, C.; Anderson, T. J.; Vicic, D. A. Analysis of Key
Steps in the Catalytic Cross-Coupling of Alkyl Electrophiles
Under Negishi-like Conditions. Chem. Commun. 2005,
4211–4213.
(27) Dolan, S. C.; MacMillan, J. A New Method for the
Deoxygenation of Tertiary and Secondary Alcohols, J.
Chem. Soc., Chem. Commun. 1985, 1588-1589.
(28) Knappke, C. E. I.; Grupe, S.; Gärtner, D.; Corpet, M.;
Gosmini, C.; Wangelin, A. J. Reductive Cross-Coupling
Reactions between Two Electrophiles. Chem. Eur. J. 2014,
20, 6828–6842.
9
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
TOC
O
Cl
or
R
OBn
R2
R2
R2
O
Ni (cat.)
R1
O
R1
R1
Zn, MgCl2
Py or PBI
DMA
R4
O
CO2Bn
R
O
R3
R4 = Me, tBu
R3
R3
ACS Paragon Plus Environment