A Radical Approach to Anionic Chemistry: Synthesis of Ketones, Alcohols, and Amines

Article abstract of DOI:10.1021/jacs.9b02238

Historically accessed through two-electron, anionic chemistry, ketones, alcohols, and amines are of foundational importance to the practice of organic synthesis. After placing this work in proper historical context, this Article reports the development, f

Full text of DOI:10.1021/jacs.9b02238

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Article
A Radical Approach to Anionic Chemistry:
Synthesis of Ketones, Alcohols, and Amines
Shengyang Ni, Natalia Muñoz Padial, Cian Kingston, Julien C. Vantourout, Daniel C. Schmitt,
Jacob T. Edwards, Monika Kruszyk, Rohan R. Merchant, Pavel K. Mykhailiuk, Brittany
Sanchez, Shouliang Yang, Matthew Perry, Gary M. Gallego, James J. Mousseau, Michael R.
Collins, Robert Joseph Cherney, Pavlo S. Lebed, Jason S. Chen, Tian Qin, and Phil S. Baran
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 03 Apr 2019
Downloaded from http://pubs.acs.org on April 3, 2019
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A Radical Approach to Anionic Chemistry: Synthesis of Ketones,
Alcohols, and Amines
Shengyang Ni,† Natalia M. Padial,† Cian Kingston,† Julien C. Vantourout,† Daniel C. Schmitt,⊥
Jacob T. Edwards,† Monika M. Kruszyk,† Rohan R. Merchant,† Pavel K. Mykhailiuk,†‡# Brittany B.
Sanchez,§ Shouliang Yang, Matthew A. Perry,⊥ Gary M. Gallego, James J. Mousseau,⊥ Michael R.
Collins, Robert J. Cherney, Pavlo S. Lebed,#¬ Jason S. Chen,§ Tian Qin,† Phil S. Baran*†
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†Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA 92037, United States
⊥Pfizer Medicinal Sciences, Eastern Point Road, Groton, CT 06340, United States
Department of Chemistry, La Jolla Laboratories, Pfizer 10770 Science Center Drive, San Diego, CA 92121, United
States
#Enamine Ltd., Chervonotkatska 78, 02094, Kyiv, Ukraine
‡Taras Shevchenko National University of Kyiv, Chemistry Department, Volodymyrska 64, 01601, Kyiv, Ukraine
¬ChemBioCenter, Taras Shevchenko National University of Kyiv, Volodymyrska 64, 01601, Kyiv, Ukraine
§Automated Synthesis Facility, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA 92037, United States
Bristol-Myers Squibb Company, Research & Development, Rt. 206 & Province Line Rd., Princeton, NJ 08543,
United States
ABSTRACT: Historically accessed through two-electron, anionic chemistry, ketones, alcohols, and amines are of
foundational importance to the practice of organic synthesis. After placing this work in proper historical context, this Article
reports the development, full scope, and a mechanistic picture for a strikingly different way of forging such functional
groups. Thus, carboxylic acids, once converted to redox-active esters (RAEs) can be utilized as formally nucleophilic
coupling partners with other carboxylic derivatives (to produce ketones), imines (to produce benzylic amines), or aldehydes
(to produce alcohols). The reactions are uniformly mild, operationally simple, and, in the case of ketone synthesis, broad
in scope (including several applications to the simplification of synthetic problems and to parallel synthesis). Finally, an
extensive mechanistic study of the ketone synthesis is performed to trace the elementary steps of the catalytic cycle and
provide the end-user with a clear and understandable rationale for the selectivity, role of additives, and underlying driving
forces involved.
often inconvenient to prepare and scarcely available
compared to other feedstock functional groups such as
olefins and carboxylic acids.4 Thus, the search for
Grignard-like reactivity that is milder and more tolerant of
air and moisture continues to the present day.5 Indeed,
groundbreaking findings from Lipshutz, Buchwald,
Krische, and Miura have opened up a realm of mild
nucleophilic additions beginning with olefin precursors.6
We and others have also explored how Mukaiyama-type
reactivity can be harnessed on olefins to add to carbonyl
groups.7
Introduction
Roughly 120 years ago, Grignard invented his eponymous
reaction that converts alkyl halides into nucleophilic
organomagnesium reagents that engage electrophilic C=O
bonds.1 This reaction forms one of the foundational
reactions of organic synthesis and although the precise
mechanism of carbonyl addition is not fully understood, it
is generally regarded (and taught to undergraduates) as a
two-electron (anionic) process.2 Grignard reagents and
related species are routinely used to generate some of the
most useful functional groups such as ketones (via addition
to activated ester or amide derivatives), alcohols (via
addition to aldehydes), and amines (via addition to imines)
as depicted in Figure 1.3 Notwithstanding its indisputable
utility and broad scope, it bears with it a restricted window
of chemoselectivity – certain functional groups are simply
not compatible with the highly basic and nucleophilic
properties of the reagents. Additionally, alkyl halides are
In the quest for practicality, alkyl carboxylic acids are
perhaps the most ubiquitous functional group from the
standpoint of commercial availability.8 They are uniquely
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modular building blocks in that they can be easily
diversified at the alpha-position using anionic chemistry
R1
R2
MX
R1
R2
2e– logic
(conventional
disconnection)
1
2
3
4
5
6
7
8
R3
R3
and then disassembled to lose CO2 and afford a carbon-
centered radical. Radicals derived in this way have a storied
history dating back to Kolbe and Barton’s legendary
findings.9 More recently, we and others have explored how
such radicals could be generated in the same way that alkyl
halide-derived radicals have been for decades using
transition metals.10 Thus far, most recent studies in this
area have been focused on the canonical chemistry of
radicals such as their use in cross-coupling and trapping
with radicalophiles.11
[organometallic]
[activated
acid]
[aldehyde]
[imine]
O
OH
NHA*
R6
R1
R2
R4
R5
R1
R2
R4
R5
R1
R2
R4
R5
R3
R6
R3
R6
R3
9
[ketone]
[alcohol]
[amine]
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O
R4
R5
NA*
O
[aldehydes]
H
The focus of this work was to see if carboxylate-derived
radicals could be engaged in reaction manifolds that have
historically been within the purview of anionic (Grignard)
chemistry. This Article describes the invention, full scope
and limitations, and detailed mechanism of methods for
harnessing radicals derived from redox-active esters
(RAEs) for reactions with electrophilic C=X bonds to
generate ketones, alcohols, and amines.
NHK
R4
R5
R4
R5
R6
HO
H
R6
R6
R1
R2
[carboxylic
acids]
reductive
coupling
[chiral imine]
R3
Giese
[alkyl radical]
O
O
1e– logic
(radical
disconnection)
O
NHPI
R1
OH
R2
R3
R1
R2
N
O
activation
R3
O
Background and Historical Context
[redox-active ester]
[alkyl acid]
The generation of radicals and subsequent interception
with transition metals for the specific purpose of adding to
C=X bonds is not new (Figure 2). In fact, this area has a
long history dating back to the late 1970’s. Figure 2 outlines
the key precedents in this area that have laid the strategic
Figure 1. Polar-bond disconnections via conventional 2e-
logic vs. newly explored radical processes for ketone, alcohol,
and amine synthesis. NHPI = N-hydroxyphthalimide.
Figure 2. Radical methods for accessing carbonyl compounds: Historical perspective. NHPI = N-hydroxyphthalimide.
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and mechanistic basis for the current studies. Early work
A. Decarboxylative coupling to access alkyl ketones
1
2
3
4
5
6
7
8
in this area focused on the use of electrochemical
techniques to generate alkyl-M species (M = Cd and Mg)
that could be directly added to acyl halides in situ.12 Lund
and co-workers subsequently demonstrated that
anhydrides were also suitable electrophiles in this
transformation.13 One of the key breakthroughs in this area
can be traced to a report by Périchon who laid some of the
groundwork for the cross-electrophile couplings of the
modern era.14 In that work, a sacrificial anode such as zinc
was utilized in an undivided cell along with catalytic nickel
in the presence of a diamine ligand (bpy) to couple simple
alkyl and acyl halides to form ketones. In parallel to these
electrochemical studies, Mukaiyama and co-workers
demonstrated a similar transformation by embedding the
ligand for Ni onto the ester (2-pyridyl ester derivatives)
rather than using an acyl halide.15 Moving to the modern
era, the field of reductive/cross electrophile couplings,
specifically those between alkyl halides and acyl
halides/anhydrides, has flourished with impactful
contributions from the Martin, Gong, Weix, and Reisman
groups among many others.16 Finally, the Gong, Weix, and
Loren teams have reported single examples of the use of
RAEs in place of alkyl halides for ester (Gong) or ketone
(Weix and Loren) synthesis.17 This backdrop of precedent
places our studies in a proper context.
Me Me
Me Me
alkyl
anions
Key intermediate
for total synthesis
of anamarine (2)
2e– logic
O
O
O
O
unavailable
or
O
EtO2C
EtO2C
OTBS
Me Me
+
X
+
X
O
O
Me
Me
OTBS
OTBS
OTBS
Me
O
EtO2C
Me Me
from
1
O
tartaric acid
O
O
HO
9
[previous] 8 Steps
[current] 3 Steps
• [Os] Dihydroxylations
• Redundant PGs
+
Me
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from
lactic acid
O
1e– logic
EtO2C
CO2H
[cheap chiral building blocks]
• Redox-Inefficient
B. Optimization of the Ni-catalyzed decarboxylative ketone formationa
O
Ts
N
HO
Ni(BPhen)Cl2·2DMF (20 mol%)
(PhCO)2O (2.2 equiv), Zn (3.0 equiv)
NTs
3
+
2.0 equiv
O
MgCl2 (1.5 equiv), LiBr (1.0 equiv)
MeCN/THF (2:3, 0.1 M), rt, 3 h
NHPI
O
Ph
5
4
Ph
1.0 equiv
yield (%)b
entry
deviation from above
1
2
3
4
5
6
7
8
9
none
under air
RAE synthesis in situ
76 (73)c
62
65
60
71
62
<10
44
42
46
48
28
51
53
ND
85
20 mol% Ni(acac)2 + 24 mol% Bphen
1.5 equiv 3, 2.0 equiv (PhCO)2O
10 mol % Ni(BPhen)Cl2·2DMF
TCNHPI
Ni(bpy)I2 instead of Ni(BPhen)Cl2·2DMF
Boc2O instead of (PhCO)2O
(tBuCO)2O instead of (PhCO)2O
Mn instead of Zn
MgBr2•Et2O instead of MgCl2
no LiBr
no MgCl2
no (PhCO)2O
acyl chloride instead of [3 + (PhCO)2O]
Ketone Synthesis via Cross-Carboxy Coupling:
Development and Scope
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15
16
Retrosynthetic considerations for the synthesis of complex
ketones inspired our explorations in this area. For example,
as illustrated in Figure 3A, ketone fragment 1 was enlisted
as a key intermediate in a total synthesis of anamarine 2.
Prior routes to this ketone, which conveniently maps onto
readily available tartaric acid, relied on 2e- logic and thus
could not easily take advantage of this inexpensive
building block because anionic chemistry of the type
shown in Figure 3A is not workable.18 Therefore, an olefin-
based route was pursued requiring two asymmetric
dihydroxylations with Os along with extraneous redox
fluctuations and PGs (8 steps overall). In contrast, 1e- logic
pointed to a simple (3 step) means of utilizing feedstock
chiral pool materials: tartaric and lactic acid. The
development of the necessary chemistry to achieve this
simplification was accomplished using model substrates 3
and 4 as outlined in Figure 3B. In its fully optimized
manifestation, a 73% isolated yield of ketone 5 was
obtained from RAE 4 and acid 3 using a carefully
engineered set of reagents in concert with a Ni-catalyst: (1)
benzoic anhydride as activating agent for the carboxylic
acid, (2) Zn powder as reducing agent, and (3) magnesium
and lithium based Lewis-acids (MgCl2 and LiBr). The
experimental simplicity is worth pointing out: all
components are simply added to a flask followed by
addition of solvent and after 3 h of stirring at room
temperature the reaction is stopped. Deviations from the
conditions prescribed above are certainly tolerated.
a
b
0.1 mmol. Yield determined by LC-MS with 1,3,5-trimethoxybenzene as an
c
internal standard. Isolated yield. See Supporting Information for details. NHPI =
N-hydroxyphthalimide, TCNHPI N-hydroxytetrachlorophthalimide, bpy 2,2’-
bipyridine, BPhen = bathophenanthroline, ND = not detected.
=
=
Figure 3. (A) Inspiration for a mild ketone and chemoselective
ketone synthesis and (B) development and optimization of
CCC.
For instance, the following set of modifications resulted in
only 5-15% decrease in yield:running the reaction under air
(entry 2), generating either the RAE (entry 3) or catalyst
(entry 4) in situ, reducing the equivalents of acid and
anhydride (entry 5), or lowering the catalyst loading (entry
6). Key parameters for the success of this reaction include
the specific identity of the RAE (entry 7), Ni-bound ligand
(entry 8), anhydride (entries 9-10), reductant (entry 11), and
Lewis-acids employed (entries 12-14). Unsurprisingly,
inclusion of the anhydride was found to be required for
product formation (entry 15). In addition, the use of an acyl
chloride in place of the in situ combination of carboxylic
acid and anhydride led to even higher conversion (entry
16). For the sake of experimental simplicity and to enable
parallel library synthesis (vide infra), the in situ protocol
was adopted as the standard protocol. An extensive list of
parameters screened can be found in the SI and the role of
each component will be discussed in the mechanism
section (vide infra).
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Table 1. Scope of the CCC ketone synthesis. Yields of isolated products are indicated in each case. Reaction conditions: RAE (1.0
equiv), carboxylic acid (2.0 equiv), Ni(BPhen)Cl2•2DMF (20 mol%), Zn (3.0 equiv), (PhCO)2O (2.2 equiv), MgCl2 (1.5 equiv), LiBr
a
(1.0 equiv), MeCN/THF (2:3, 0.1 M), rt, 3 h. using benzoyl chlorides (2.0 equiv) instead of [acid + (PhCO)2O]. DIC = N, N’-
diisopropylcarbodiiminde.
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With a set of optimized conditions in hand the scope and
1
versatility of ketone synthesis was systematically explored
employing a range of different carboxylic acids (Table 1).
This “cross-carboxy coupling” (CCC) tolerates a range of 1°,
2°, 3°, and aromatic carboxylic acids to deliver
unsymmetrical ketones in an operationally simple,
chemoselective, and scalable way. 1° RAEs were coupled to
1° (6, 7, 9, 11 and 13), 2° (5, 8, 10, 12, 14-17, 19, 20, 22 and 23),
and bridged 3° (21) carboxylic acids in good yields. A large
variety of functional groups including esters (6), ketones
(7-9, 11, 12 and 19), N-Boc (9, 14, 16 and 23) or N-Tosyl (5,
8, 10, 12, 14-17 and 20) protected amines, amides (22 and
23), ethers (7 and 17), and halogens (10, 13, 15, 20, 22 and
23) were tolerated under the reaction conditions. In
addition, successful functionalization of fenbufen and
indomethacin was achieved to afford compounds 19, 22,
and 23 in 75%, 62% and 53% yield, respectively. 2° and 3°
RAEs were also coupled to a broad range of 1° (21, 24, 31,
36, 39, 41, 43, 48 and 52) and 2° (25-30, 32-35, 37, 38, 40, 42,
44-47, 49-51 and 53) carboxylic acids with similarly
exceptional levels of chemoselectivity, including a diol, an
epoxide, and a Michael acceptor found on mupirocin (39).
Although bridged 3° carboxylic acids and RAEs were well
tolerated, lower yields were observed in the case of
exceedingly sterically encumbered moieties (18). It is
worth noting that the diversification of biotin,19 a highly
polar and oft installed structure in chemical biology was
also successful (41). Strikingly, almost 90% of the
compounds illustrated in Table 1 have never been prepared
before, thereby illustrating the capability CCC to access
new chemical space. For example, the successful coupling
of bridged compounds such as cubane 47 and 2-
oxabicyclo[2.1.1]hexane 52 provides a versatile entry into
these useful phenyl ring bioisosteres.20 Pleasingly, the
developed conditions were easily translated to gram scale
experiments affording compounds 5 and 37 in 68% and
69%, respectively.
2
3
4
5
6
7
8
9
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17
18
19
20
21
22
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. An empirically derived user-guide for CCC.
Returning to the original inspiration for the development
of this method, Figure 4 outlines a series of applications
that serve to simplify synthesis. As depicted in Figure 4A,
building block 1, previously prepared through an 8-step
sequence relying on olefin functionalization,18 could now
be accessed in 3 steps commencing from tartrate-derived
acid 62. Subjecting this acid to CCC using commercial
lactate-derived acid 63 delivered 1 in 52% yield as a single
stereoisomer. It should be noted that in the CCC
stereoselectivity of the RAE fragment is usually eroded via
the planar radical intermediate, however in this case
selectivity is guided by the conformation of the starting
material. In a similar vein, muscone 64, a widely employed
fragrance additive, has previously been prepared through
RCM/hydrogenation of diene 65.21 The preparation of this
simple ketone commences from a relatively expensive
alcohol 66 (by fragrance industry standards) and employs
three reactions to generate one new C–C bond with the
correct ketone oxidation state. In contrast, 10-undecenoic
acid 67 is roughly an order of magnitude less expensive and
can be smoothly converted to the same building block 65
in 68% yield upon CCC with citronellic acid 68. This one-
step process avoids halide waste, water sensitive Grignard
reagents, and excess chromium waste (employed solely for
the purpose of alcohol oxidation). The experimental
simplicity of this method makes it perfectly suited to a
parallel library synthesis workflow. Thus, a curated set of
diverse building blocks from the Pfizer collection were
chosen and subjected to ketone synthesis using 1-
cyclopentane carboxylic acid-derived NHPI ester 69. All
reagents, with the exception of zinc, were added as stock
solutions to facilitate parallel execution in plate format.
HPLC analysis indicated that 19 of the 20 substrates (70-
89) successfully underwent CCC, while 17 provided
sufficient material after isolation (> 1.0 mg) for submission
to standard bioactivity assays. Compound 81 was not
isolated presumably due to the basic work up procedure
used to facilitate isolation. The resulting ketones possess
drug-like properties, conforming with Lipinski’s “rule of
five” (mean molecular weight 371, mean ClogP 4.4, mean
hydrogen bond acceptor count 2.5) and include a range of
common heterocycles.22 This protocol is particularly well-
suited for fragment-based drug discovery (FBDD),23 or as a
When attempting CCC on aryl carboxylic acids, minimal
product formation was observed (see SI for optimization
details). In this instance, modification of the coupling
partner to acyl chlorides, as pioneered by Weix and Loren,17
afforded the desired products in suitable yields (54-58, 60
and 61). Tolerance of protected indole, amine, and ester
functionality was observed (55, 56 and 57 for example),
although an ortho-methoxy group was required in the case
of a pyridine-based substrate (59 and 60).
The range of conceivable coupling partners in CCC is vast
and thus from a practitioner’s perspective it may not be
form (free acid or RAE) whereas benzoyl chlorides are best
employed as the free carboxylic acid component in all
couplings. intuitive as to which acids serve the role of
electrophile/nucleophile. For instance, substrate 21 can be
prepared in either fashion (see SI for additional examples).
Thus, Table 2 presents a convenient user guide for CCC
based on the 16 possible combinations of cross coupling
based on empirical findings. For example, in the case of 1°
and 2° couplings, the starting acids can be used in either
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1
A. Formal synthesis of anamarine
B. Simple, cheap, efficient synthesis of fragrance compound muscone
2
3
4
5
6
7
8
9
O
O
Me
1. PBr3
2. Mg;
citronellal
63
OH anhydride from
lactic acid
Me Me
Me Me Me
OH
2 steps
Ref. 21
O
O
O
O
OTBS
3. PCC
OTBS
Me
[cross-coupling]
52%
Ref. 16
OH
EtO2C
EtO2C
62
[previous]
3 steps
Me
Me
O
O
1
O
65
Me
redox-active ester from
tartaric acid
[previous] 8 steps
[current] 3 steps
dec-9-en-1-ol
(100 g/$90)
66
O
Me
OAc OAc
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
8 steps
Ref. 13
10-undecenoic acid
(500 mL/$68)
Me
OAc OAc
anamarine (2)
HO
[current]
1 step
O
muscone
64
citronellic
acid
68
formal synthesis
O
[cross-coupling]
O
OH
Me
Me
formal synthesis
72%
67
C. Pfizer med-chem intermediates (parallel library synthesis)
O
O
O
Ni(BPhen)Cl2·2DMF (20 mol%)
(PhCO)2O (2.2 equiv), Zn (3.0 equiv)
R1
R1
NHPI
OH
+
MgCl2 (1.5 equiv), LiBr (1.0 equiv)
MeCN/THF (2:3, 0.1 M), rt
>1.0 mg is enough for biological assays
R2
R2
69
0.1 mmol
2 equiv
< 1.0 mg
HPLC Isolated Amount
> 1.0 mg
no product
iPr
O
Ph
N
N
N
N
N
N
O
N
O
N
Ph
Ph
N
O
O
O
70
71
72
73
O
Ph
Ph
CO2Me
O
Me
Me
Ph
N
O
Ph
Br
O
S
N
N
O
O
O
NH
O
74
O
O
O
OMe
NHMe
O
75
76
80
77
HN
O
O
NH
O
O
N
S
O
O
Me
O
Me
Cl
NFmoc
HN
79
Cl
Cl
78
81
N
O
iPr
F
BocN
O
N
N
Ph
O
MeO
Me
O
O
BnN
85
N
O
Me
O
82
83
84
O
O
O
N
Ph
N
O
O
O
N
N
F
O
N
N
NH
F3C
O
86
87
88
89
Figure 4. Applications of CCC to the formal synthesis of anamarine (A), muscone (B), and parallel library synthesis (C). NHPI =
N-hydroxyphthalimide.
diversity incorporating event in multi-step parallel library
construction (e.g. with subsequent reductive amination).
Compelled by ongoing medicinal chemistry projects at
Pfizer, attention then turned to how the putatively
nucleophilic species generated from RAEs under Ni-
catalysis could be engaged by other electrophilic species
such as imines. Prior studies from our labs (Figure 5A)
Asymmetric Synthesis of Benzylic Amines
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Journal of the American Chemical Society
1
2
3
4
5
6
7
8
A. Radical coupling of RAEs with sulfinyl imines
*RN
NHR*
CO2Et
90
[Ni], Zn
(Ref. 7n)
enantiopure
unnatural
R1
R2
CO2Et
amino acids
O
R3
R1
R2
from TCNHPI
NHPI
R3
NHR*
R4
*RN
[chiral amines]
R1
R4
R2
R3
[redox– active ester]
previous
conditions:
< 5% yield
R4 = aryl, alkyl
[chiral imines]
9
10
11
12
13
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16
17
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
B. Optimization of a Ni-catalyzed decarboxylative imine additiona
O
R
N
Ph
S
O
S
HN
R
1.0 equiv
92
O
NHPI
NiCl2∙glyme (25 mol%)
Zn nanopowder (6.0 equiv)
DMF (1.0 M), rt, 2 d
TsN
TsN
91
2.0 equiv
93
R = mesityl
entry
yield (%)b
drb
deviation from above
1
2
3
4
5
6
7
8
9
conditions from Ref. 7n
R = tBu
< 5
ND
n.d.
ND
None
under air
78 (75)c
65
>20:1
>20:1
>20:1
>20:1
ND
>20:1
ND
>20:1
RAE synthesis in situ
from TCNHPI
no NiCl2∙glyme
normal zinc (6 - 9 μm)
no Zn nanopowder
0.2 M
68
31
ND
50
ND
52
10
a 0.1 mmol, Zn nanopowder: 40-60 nm particle size. b Yield and dr determined by
1H NMR with 1,3,5-trimethoxybenzene as an internal standard. Isolated yield.
c
See Supporting Information for details. NHPI = N-hydroxyphthalimide, TCNHPI =
N-hydroxytetrachlorophthalimide, ND = not detected, n.d. = not determined.
Table 3. Scope of the radical addition into chiral imines.
Reaction conditions: RAE (2.0 equiv), sulfinimine (1.0 equiv),
NiCl2•glyme (25 mol%), Zn nanopowder (6.0 equiv), DMF (1.0
M), rt, 2 d. NHPI = N-hydroxyphthalimide. a See SI for
reaction conditions.
Figure 5. (A) Synthesis of amines from RAEs previously
limited to amino acid synthesis and (B) an alternative protocol
to access benzylic amines.
focused on the synthesis of enantiopure amino acids using
the glyoxyl-derived chiral sulfinyl imine reagent 90.11n That
chemistry exhibits remarkable substrate scope and utilizes
a TCNHPI-based RAE in concert with an inexpensive
reducing agent (Zn) and catalyst [Ni(OAc)2•4H2O].
Translation of those exact conditions using the less
electrophilic aryl sulfinyl imines in order to generate
enantiopure benzylic amines furnished only trace product
(Figure 5B, entry 1). Thus, a thorough re-examination of
conditions was pursued culminating in the identification
of a mild and robust set of conditions (entry 3). Three key
modifications relative to prior studies were an increased
concentration (0.2 M vs. 1.0 M, entry 10), use of NHPI
instead of TCNHPI as the RAE (entry 6) and a more
reactive reducing agent (standard zinc powder vs. zinc
nanopowder, entry 8). This unique form of zinc, available
from Sigma-Aldrich,24 was also found to be critical in
radical couplings in DNA-encoded library synthesis.11k
Similar to ketone synthesis via CCC, the reaction tolerates
air/moisture (entry 4) and the RAE can be made in situ to
enable parallel synthesis endeavors (entry 5). Attempts to
utilize the corresponding Ellman imine (R = tBu) failed due
to competitive reduction of the sulfinimine (entry 2).
Interestingly, unlike previous studies where low yields of
product were observed in the absence of Ni-catalyst, the
current reaction completely shuts down without it (with
near quantitative imine recovery, entry 7).
With this new set of conditions in hand a range of 1°, 2°,
and 3° carboxylic acids could be coupled with imine 92 via
the corresponding RAE to rapidly provide a range of chiral
benzylic amines in good yield and high dr (Table 3). Ethers
(95 and 104), esters (98-100 and 103), Boc- and Ts-
protected amines (93, 96, 101, 102, 105 and 106), pyridines
(103-105), and aryl halides (101 and 102) were all tolerated.
Of the substrates screened, the most rapid and high
yielding reactions involved bridgehead RAEs (97-100, and
103) presumably due to the increased stability and
nucleophilicity of the putative radical intermediates. A
notable limitation of this work is that alkyl sulfinyl imines
are not viable coupling partners. The majority of products
in Table 3 are novel (including their deprotected analogs).
In the case of substrate 93, the deprotected racemic amine
is expensive (from Sigma-Aldrich, ca. $1/mg).25 The
deprotected analog of 94 has been prepared in racemic
form during the search for new kinase inhibitors by way of
isonipecotic acid through a classical three step sequence
(Weinreb amide, Grignard, reductive amination).26
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Journal of the American Chemical Society
Extending the Scope of Nucleophilic RAE Chemistry:
Page 8 of 15
1
2
Alkyl NHK reactivity
The addition of standard 2e- based nucleophiles to
aldehydes is often beleaguered with competing
enolization/polymerization problems (Figure 6A). The
alkyl Nozaki-Hiyama-Kishi (NHK) reaction provides a
viable solution to this issue but still requires an alkyl halide
precursor.27 Shenvi and co-workers recently reported an
impressive departure from this requirement by utilizing
olefin-derived radicals in a HAT/Cr system to deliver
branched products from terminal olefins.28 At this juncture
it is now self-evident that RAEs represent viable surrogates
for alkyl halides in a myriad of different reactions under Ni-
, Fe-, Co-, Cu-, Ru-, Pd- and Ir-based catalysis.29 The use of
alkyl halides in the classic NHK reaction is rare, and within
the theme of utilizing RAEs to add to C=X bonds this
seemed like a useful reaction to explore (Figure 6A).30
Access to such reactivity via RAEs versus olefins could
provide a complementary solution to give linear rather
than branched products.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
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21
22
23
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25
26
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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
The execution of
a RAE-based alkyl NHK was
straightforward and optimized conditions simply involved
A. Nozaki-Hiyama-Kishi (NHK) reaction with redox-active esters
[limited
scope]
R1
X
2e– logic
organometallic
addition
1e– logic
alkyl
NHK
R1
[M]
R2
X = Br, I
Table 4. Scope of the alkyl NHK reactions with RAEs.
OH
R2
Reaction conditions: RAE (2.0 equiv), aldehydes (1.0 equiv),
CrCl2 (4.0 equiv), TMSCl (2.0 equiv), THF/DMF (3:5, 0.06 M),
+
R1
R1
O
O
[limited FG
compatibilty]
a
O
rt, 1 h. TMS = trimethylsilyl. NHPI = N-hydroxyphthalimide.
[alcohol]
H
R2
H
R1
[this work]
See SI for reaction conditions.
NHPI
[RAE]
the addition of RAE to aldehyde in the presence of CrCl2
and TMSCl (Figure 6B). This is exemplified using model
RAE 4 and aldehyde 107 to deliver TMS-protected alcohol
108 in 79% isolated yield. Although the RAE could be
generated in situ to give a similar yield (entry 2), the
reaction is sensitive to air (entry 3) and should be
conducted using an Ar or N2 balloon. NHPI is the preferred
RAE (entry 4) and Cr is clearly essential for the reaction
(entry 5). The free alcohol could also be obtained in the
absence of TMSCl, albeit in diminished yield (entry 6).31
Unlike the original alkyl NHK using alkyl halides, low
valent transition metal mediators such as CoPc or Ni have
no effect on conversion (entries 7 and 8).30 However, excess
Cr is still required (2.0 equiv leads to diminished yield,
entry 9). Although reversing the stoichiometry of
substrates had no effect, a lower yield was observed with
one equivalent of RAE (entries 10 and 11). The RAE-based
alkyl NHK has admirable scope with regards to functional
group compatibility tolerating N-Boc protected amines
(102, 104 and 105), halogens (110 and 1117-119), and alkenes
(113 and 122). Heterocyclic motifs such as azaindole and
benzimidazole were also tolerated under the reaction
conditions and compound 115 was afforded in 40% yield.
Moreover, it is worth noting that selective addition at the
1,2 position was observed in the case of enone compound
B. Optimization of a decarboxylative NHKa
O
O
OTMS
CrCl2 (4.0 equiv)
TMSCl (2.0 equiv)
O
O
O
O
+
NHPI
Ph
Ph
THF/DMF
(3:5, 0.06 M)
rt, 1 h
4
107
108
2.0 equiv
1.0 equiv
deviation from above
yield (%)b
entry
88 (79)c
74
45
1
2
3
none
RAE synthesis in situ
under air
4
from TCNHPI
61
5
6
7
8
no CrCl2
no TMSCl
with 20 mol% CoPc
with 20 mol% NiCl2·glyme
2.0 equiv CrCl2
ND
48d
88
87
44
9
10
11
1.0 equiv 4, 2.0 equiv 107
1.0 equiv 4, 1.0 equiv 107
86
70
b
a 0.1 mmol. Yield determined by 1H NMR with 1,3,5-trimethoxybenzene as an
c
internal standard.
Isolated yield. See Supporting Information for details.
N-hydroxyphthalimide,
d
Isolated yield of the corresponding alcohol. NHPI
=
TCNHPI = N-hydroxytetrachlorophthalimide, ND = not detected.
Figure 6. (A) Alcohol synthesis through conventional and
radical means and (B) the development of an alkyl-NHK
reaction employing RAEs.
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1
A. Proposed mechanism (boxed red letters indicate the presence of supporting evidence)
2
3
4
5
6
7
8
9
Initiation
Catalytic cycle
Mechanistic overview
O
O
R1
R2
N
Radical chain mechanism consistent with divergent electroph-
ile reactivity: two-electron oxidative addition (OA) favored by
the anhydride while the RAE favors a one-electron pathway
II
ZnClX
H
2 x
R1
O
A
Ph
O
Ni
N
II or III
N
Ni0
Zn
MgCl2, LiBr
Each step is supported by experimental evidence
N
I
Ruled out formation of organozinc species, separate OA
transmetalation and double OA to the same Ni species
+
B
Ph
N
N
O
N
N
Cl
II
Ni
II
Ni
R1
III
Ni
Byproduct analysis: All components are vital
R1
no MgCl2
no LiBr
no Zn
N
N
N
N
R1
standard
conditions
no
no MgCl2
no LiBr
no MgCl2
X
no Ni
no LiBr
no Zn
(PhCO) O
2
VI
II
O
R2
X = Cl, Br, phth
MgCl2
+
O
C
-CO2, phth
I
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
•R2
Ni R2
F
G
MgClOBz
R2
NHPI
Bars indicate fraction yield of the ketone product, RAE and reduced byproducts
RAE
N
N
Cl
N
N
II
Ni
I
R1
Ni Cl
Kinetic analysis
The main driving forces for the reaction are Zn, MgCl2 and
LiBr (each exhibit positive kinetic orders)
R2
R2
III
Ni
E
•
V
O
III
N
N
Cl
O
0.3 order observed for the RAE, indicating multiple resting
states across the cycle
D
RAE
R1
R1
R2
Zero order in Ni catalyst ≥10 mol % (vide infra)
Zn
IV
O
B. Evidence supporting the mechanistic proposal
O
G Radical chain mechanism
A Formation of mixed and symmetrical anhydrides
( )4
(PhCO)2O (1.1 equiv)
additive (1.0-1.5 equiv)
O
O
O
O
125
Ph
( )4
O
Ar
Ar
131
+
O
standard conditions
MeCN/THF (2:3, 0.1 M)
rt, 30 s
( )
O
( )
Ar
HO
NHPI
OH
2
126
( )
2
2
with different catalyst
loading
+
124
Ar = (p-F)C6H4
F
no additive: >99% 124, 0% 125/126
MgCl2: 0% 124, 75% 125/126 (83:17)
LiBr: 95% 124, 5% 125/126
( )4
129
130
F
Anhydride formation facilitated by MgCl2
Radical cyclizationasafunctionof catalyst loading
13
Isolated mixed anhydride is reactive under the standard conditions (see SI)
80
Oxidative addition
Ligand exchange
B
C
O
70
60
50
40
30
F
Formation of cyclized 13 decrea-
ses with the concentration of Ni
catalyst, consistent with radical
chain mechanism
iBu
N
X
N
OC(O)iBu
iBu
N
N
Cl
O
II
II
Ni
Ni0
Ni
iBu
or
X = Cl, OC(O)iBu
additive (15.0 equiv)
MeCN/THF (2:3, 0.1 M)
rt, 15 min
Cyclopropyl ‘radical clock’ RAE
afforded the ring-opened product
(see SI)
N
I
N
y = 3.9567x - 2.0447
20
R² = 0.996
O
II
III
10
Ligand = tBubpy
0
no additive
with MgCl2
with LiBr
0
5
10
15
20
Results support SET to the RAE
from the Ni catalyst (step F)
Ni(BPhen)Cl2·2DMF loading (mol %)
OA to anhydride is rapid, consist-
ent with previous reports
III (from acyl chloride)
Reduction from Ni(II) to Ni(0)
H
Zn (10.0 equiv)
Ligand exchange fast in the pres-
ence of MgCl2 and slow with LiBr
N
N
Cl
II
Ni
additive (15.0 equiv)
Ni0
MeCN/THF (2:3, 0.1 M)
rt, 1 h
N
I
N
Cl
VI
Oxidative addition by the RAE is
disfavored to radical formation
(see SI)
Ligand = tBubpy
Ni(0)(tBubpy)
no additive
with MgCl2
with LiBr
Positive rate dependencies in
Radical addition
Reductive elimination
O
Zn (3.0 equiv)
D
E
NiCl2(tBubpy)
MgCl2, LiBr and Zn support het-
erogeneous electron transfer as
partially rate-determining
O
N
OC(O)iBu
iBu
II
Ni
+
Ar
Ar
MeCN/THF
(2:3, 0.1 M)
rt, 1 h
iBu
( )
NHPI
( )
2
N
2
UV-vis experiments show LiBr ac-
celerates reduction of Ni(II) speci-
es to a greater degree than MgCl2
O
II
128
82%, 0% RAE
127 (1.0 equiv)
Ar = (p-F)C6H4
(w/o Zn: 88%, 0% RAE)
O
O
N
N
Cl
Zn (3.0 equiv)
II
Ni
+
iBu
Ar
Evaluation of kinetic orders
Orderinacid/anhydride
Ar
MeCN/THF
(2:3, 0.1 M)
rt, 1 h
iBu
( )
( )
NHPI
OrderinRAE
0.05M 0.1M 0.2M
2
2
128
O
0.045
III
0.05
0.04
0.03
0.02
0.01
0
127 (1.0 equiv)
Ar = (p-F)C6H4
0.1M acid/0.11M anhydride
0.04
20%, 70% RAE
(w/o Zn: 8%, 80% RAE)
0.2M acid/0.22M anhydride
0.035
0.3M acid/0.33M anhydride
Complex III from ligand exchange is more prevalent but less reactive
Reactivity without zinc supports initiation by disproportionation
0.03
0.025
0.02
0.015
0.01
0.005
0
MassbalanceofRAE+product at4min
F Reduction of RAE by Ni complex V
60
Ni catalyst protects the RAE from direct
reduction by the Zn (positive order in Ni
observed at lower concentrations)
50
40
30
20
10
0
0.00
0.50
1.00
1.50
2.00
2.50
0
1
2
3
4
5
time (min)
Σ[RAE]0.3Δt
Only decarboxylated and dimer byprod-
ucts were observed w/o Ni
0 order in acid/anhydride supports rapid formation of anhydride and OA
0.3 order in RAE determined by variable time normalization analysis35a
Zero order in Ni ≥10 mol % indicative of
off-cycle pathways
No KIE observed for 13C-labeled RAE, consistent with fast decomposition (see SI)
1 mol % [Ni]
3 mol % [Ni]
5 mol % [Ni]
55
56
57
58
59
60
Figure 7. CCC: The complete mechanistic picture and supporting experiments. Phth = phthalimide.
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Page 10 of 15
123. However only primary RAEs provide synthetically exist in the reaction mixture and both of them can
1
2
3
4
5
6
7
8
useful yields thus mirroring the historic limitations of
alkyl-halide based NHK. In addition, pyridine-containing
building blocks did not afford synthetically useful yields
(121).
participate in the catalytic cycle. The Ni(I)-complex V
produced can then engage another molecule of RAE to
perpetuate the cycle and generate Ni(II)-species VI.41
Alternative pathways to RAE decomposition (to produce
R2•) can be rationalized through disproportionation or via
a Ni/Zn-mediated process (see initiation, Figure 7A).42 To
deconvolute the role of Ni and Zn in the reductive cleavage
of RAEs, the kinetics of this step were studied (inset F).
Strikingly, if a RAE is exposed to standard reaction
conditions in the absence of Ni, it undergoes rapid
Mechanistic Inquiry
The synthetic utility of RAEs to function as nucleophilic
(Grignard-like) reagents for the addition to C=X bonds
presents an exciting opportunity to interrogate this unique
chemical reactivity. For this purpose, the CCC described
above was chosen for in-depth study.32 Figure 7A outlines
the complete mechanistic picture of this transformation
supported by kinetics, radical-clock studies, UV
spectroscopy, isotopic labeling, and byproduct analysis.33
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
decomposition to
a
mixture of dimerized and
decarboxylated products without any ketone product (see
byproduct analysis, Figure 7A and the SI for the kinetic
profile). The chart in inset F illustrates the “buffering”
effect of Ni to slow down Zn-induced RAE consumption
and increase product formation as the catalyst loading is
increased. This creates a complex kinetic picture with
slight positive orders in Ni at low catalyst loading and
saturation kinetics observed at higher loadings (>10%)
possibly indicative of off-cycle pathways. This data,
combined with that mentioned in insets D and E, support
a Ni-based pathway for radical formation from the RAE. A
positive kinetic order of 0.3 in the concentration of RAE is
observed, suggesting it is involved in one of multiple rate-
determining in this complex mechanistic pathway (see
evaluation of kinetic orders, Figure 7).43
A catalytic cycle that is fully consistent with the data
(Figure 7A, see high level summary) consists of initial
oxidative addition by the electrophilically activated
(anhydride or acyl chloride) carboxy group (R1-CO2H) to a
tBubpy-ligated Ni(0)-species I. Here, MgCl2 serves to
facilitate the formation of a mixed anhydride species as
verified in control studies outlined in inset A.34 The critical
oxidative addition step occurs rapidly to furnish acyl-
bound Ni(II)-carboxylate species II. Indeed, zero-order
kinetics in acid/anhydride were measured, as evidenced in
the kinetic orders, Figure 7. Selective insertion by I into the
desired C-O bond is likely dictated by electronics, wherein
the electron-rich alkyl component better stabilizes
electron-deficient Ni(II) species II.35 This step was
confirmed through the discrete preparation of Ni(0)-
complex I (see inset B and C) and exposure to either a
symmetrical anhydride or acyl chloride which both
resulted in near instantaneous oxidative addition to
complexes II and III, respectively.36 Subsequent ligand
exchange (carboxylate for chloride) then occurs as
supported by UV-vis spectroscopy wherein the addition of
MgCl2 appears to convert II to III.37 It is also important to
note that control studies with complex I and the RAE 127
lead to radical-based decomposition pathways rather than
OA products (see SI). Competition experiments between
RAE 127 and acyl chloride in the presence of complex I
show complete consumption of the acyl chloride to the OA
complex III (see SI). As aided by the persistent radical
effect,38 complex III captures a radical derived from the
RAE (R2-CONHPI) to deliver Ni(III) intermediate IV that
undergoes rapid reductive elimination to provide the
ketone product and Ni(I)-complex V.39 The observation of
small amounts of dimerized and decarboxylated
byproducts from the RAE indicates that transient radical
R2• is captured by persistent metalloradical complex III
(see byproduct analysis, Figure 7A and SI). Support for
these two steps stems from the direct reaction of either
complex II or III with RAE 127 (insets D and E).
Presumably due to the differences in disproportionation
rates for II and III, carboxylate complex II does not require
the presence of a reductant whereas chloride complex III
does (see initiation, Figure 7A).40 Thus, either complex may
The key evidence for a radical chain pathway came from
analysis of the extent of cyclization upon exposure of RAE
122 and acid 130 to the standard reaction conditions (see
inset G).44 The direct linear relationship between
concentration of nickel catalyst and the ratio of 131 to 13
forges a mechanistic picture that is consistent with radical
formation from complex V, diffusion of R2• out of the
solvent cage (wherein cyclization is proposed to occur)
before capture by complex III.7d The addition of more Ni
catalyst to the reaction mixture shortens the lifetime of the
radical in solution resulting in diminished cyclization.
Ni(II)-species VI is then reduced by Zn to afford complex I
and complete the cycle. The observation of positive kinetic
orders in Zn, MgCl2, LiBr indicate this step may be partially
rate determining and supports the crucial role that is
experimentally observed for the additives (see SI for
complete kinetic analysis). Indeed, a complete shutdown
of reactivity occurs in the absence of Zn or both MgCl2 and
LiBr (see byproduct analysis, Figure 7A and SI). To evaluate
the effects of each additive on the reduction from complex
VI to complex I, a solution of NiCl2(tBubpy) (inset H,
orange line) was stirred in the presence of Zn for an hour.
The UV spectra (inset H, blue line) clearly demonstrate
formation of Ni(0)(tBubpy) complex I (inset H, purple
line). However, addition of MgCl2 (inset H, grey line) or
LiBr (inset H, green line) accelerated the reduction from
Ni(II) to Ni(0), LiBr to a greater extent. Thus, MgCl2 serves
a triple role in facilitating anhydride formation (as a Lewis
acid), ligand exchange (via salt metathesis), and Ni-
reduction.
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To summarize, although the mechanistic picture
electron chemistry and are amenable to parallel synthesis.
In some cases, the enabled reactivity permits access to
disconnections completely unavailable to the two-electron
world (i.e. Figure 4).
1
2
3
4
5
6
7
8
outlined above is complex, each elementary step is
supported, and the role of each essential additive is
justified. The studies outlined above help in rationalizing
the empirically generated user guide in Table 2 (vide supra)
and should aid in the troubleshooting of difficult couplings
or the large-scale implementation of CCC.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Conclusion
Barton’s pioneering studies taught the community that
there is much value in using carboxylic acids as precursors
to a realm of new chemical space via C–C breaking radical
fragmentations rather than simple dehydrations (to make
amides or esters). Barton esters, Okada’s NHPI esters, and
other RAEs (e.g. TCNHPI, -OAt, or -OBt) as well as redox
active pyridiniums and sulfones all provide a useful way of
breaking bonds in order to modularly install new ones in a
versatile way. This study centered on the use of RAEs to
access products that have heretofore resided within the
scope of two-electron retrosynthetic disconnections. In
accessing common functional groups like ketones,
alcohols, and amines, students are generally taught that
polar bond analysis should lead to nucleophilic and
electrophilic starting materials. Implementing radical
retrosynthetic logic to the same targets results in the use
of RAEs in an unusual way. Thus, these three functional
groups can now be accessed commencing from readily
available carboxylic acids via RAEs (which become the
“nucleophilic” component) with mixed anhydrides, acyl
halides, imines, or aldehydes (the canonical electrophilic
component). Although certain limitations were
encountered (Figure 8), these mild methods offer
enhanced scope and orthogonal access to the same
functionality previously accessed through two-
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Detailed experimental procedures and analytical data (PDF)
AUTHOR INFORMATION
Corresponding Author
*pbaran@scripps.edu
ACKNOWLEDGMENT
Financial support for this work was provided by NIH (GM-
118176), the China Scholarship Council (CSC, S.N.), the Marie
Skłodowska-Curie Global Fellowships (749359-EnanSET,
N.M.P) within the European Union research and innovation
framework programme (2014-2020), the Department of
Defense (NDSEG fellowship to J.T.E.), Bristol-Myers Squibb
(Graduate Fellowship to J.T.E.), Vividion (Graduate
Fellowship to R.R.M.) and the Fulbright Scholar Program
(P.K.M.). We would like to thank Enamine Ltd for providing
samples of several acids. We are grateful to Dr. Dee-Hua
Huang and Dr. Laura Pasternack (Scripps Research) for
assistance with nuclear magnetic resonance (NMR)
spectroscopy and Mr. Andrew Badwal (Pfizer) for high
throughput purification. We also thank Stephen Harwood
(Scripps Research) for helpful advice and David Hill and Prof.
Donna Blackmond (both Scripps Research) for assistance with
the mechanistic studies.
NOTE
Authors for this paper from independent organizations have
all collaborated with the Baran lab independently on this work
but are not collaborating with one another.
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Carbonyl Compounds. Organic Reactions 2004, 64, 253−626. (b)
Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H. Selective
Grignard-type Carbonyl Addition of Alkenyl Halides Mediated by
chromium(II) Chloride. Tetrahedron Lett. 1983, 24, 5281−5284. (c)
Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.;
Nozaki, H. Reactions of Alkenylchromium Reagents Prepared
from Alkenyl Trifluoromethanesulfonates (Triflates) with
chromium(II) Chloride under Nickel Catalysis. J. Am. Chem. Soc.
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31) Fürstner, A.; Shi, N. A Multicomponent Redox System
Accounts for the First Nozaki-Hiyama-Kishi Reactions Catalytic
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32) For general reviews on the mechanism of Ni-catalyzed cross-
coupling reactions, see: (a) Hu, X. Nickel-catalyzed cross coupling
of non-activated alkyl halides: a mechanistic perspective. Chem.
Sci. 2011, 2, 1867-1886. (b) Tasker, S. Z.; Standley, E. A.; Jamison,
T. F. Recent advances in homogeneous nickel catalysis. Nature
2014, 509, 299-309. (c) Lucas, E. L.; Jarvo, E. R. Keeping Track of
the Electrons. Acc. Chem. Res. 2018, 51, 567-572.
33) Alternative pathways consisting of in situ organometallic
formation, oxidative addition of the two substrates to two
separate Ni species followed by transmetalation or consecutive
double oxidative addition to the same Ni species were ruled out
through the mechanistic experiments in Figure 7 and further
studies fully detailed in the SI. For information on these
mechanistic pathways, see: (a) 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 and (b) Everson, D. A.; Jones, B. A.; Weix, D. J.
Replacing Conventional Carbon Nucleophiles with Electrophiles:
Nickel-Catalyzed Reductive Alkylation of Aryl Bromides and
Chlorides. J. Am. Chem. Soc. 2012, 134, 6146-6159. For previous
DFT studies on the preference for radical chain or consecutive
double oxidative addition pathways in Ni-catalyzed cross-
couplings, see: (c) Ren, Q.; Jiang, F.; Gong, H. DFT study of the
single electron transfer mechanisms in Ni-Catalyzed reductive
cross-coupling of aryl bromide and alkyl bromide. J. Organomet.
Chem. 2014, 770, 130-135. (d) 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.
34) A mixed anhydride was synthesized, isolated and found to be
reactive under the standard conditions, see the SI for full details.
35) (a) Xu, S.; Jiang, J.; Ding, L.; Fu, Y.; Gu, Z.
Palladium/Norbornene-Catalyzed ortho Aliphatic Acylation with
Mixed Anhydride: Selectivity and Reactivity. Org. Lett. 2018, 20,
325-328. Oxidative addition of Ni(bpy) species to cyclic
anhydrides has been shown to be fast and reversible, see: (b)
Johnson, J. B.; Bercot, E. A.; Rowley, J. M.; Coates, G. W.; Rovis, T.
Ligand-Dependent Catalytic Cycle and Role of Styrene in Nickel-
Catalyzed Anhydride Cross-Coupling:ꢀ Evidence for Turnover-
Limiting Reductive Elimination. J. Am. Chem. Soc. 2007, 129, 2718-
2725.
37) The results are consistent with Gong’s report, see: (a) 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. MgCl2 may also influence
the dielectric constant of the solvent: (b) McCann, L. C.; Organ,
M. G. On the Remarkably Different Role of Salt in the Cross-
Coupling of Arylzincs From That Seen with Alkylzincs. Angew.
Chem., Int. Ed. 2014, 53, 4386-4389, while Li salts have been shown
to clean the surface of Zn by removal of organometallic species,
see: (c) 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.
38) For reviews, see: (a) Studer, A. The Persistent Radical Effect in
Organic Synthesis. Chem. Eur. J 2001, 7, 1159-1164. (b) Fischer, H.
The Persistent Radical Effect:ꢀ A Principle for Selective Radical
Reactions and Living Radical Polymerizations. Chem. Rev. 2001,
101, 3581-3610.
39) For a study on the reactivity of a Ni(III) species, see: Zheng, B.;
Tang, F.; Luo, J.; Schultz, J. W.; Rath, N. P.; Mirica, L. M.
Organometallic Nickel(III) Complexes Relevant to Cross-
Coupling and Carbon–Heteroatom Bond Formation Reactions. J.
Am. Chem. Soc. 2014, 136, 6499-6504.
40) In contrast to the results with complexes II and III, no
product formation is observed using Ni(BPhen)Cl2•2DMF without
zinc under the standard reaction conditions (see byproduct
analysis, Figure 7A), indicating this species does not
disproportionate and initiate radical formation.
10
11
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35
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41) For a study on the reactivity of a Ni(I) species, see: Jones, G.
D.; Martin, J. L.; McFarland, C.; Allen, O. R.; Hall, R. E.; Haley, A.
D.; Brandon, R. J.; Konovalova, T.; Desrochers, P. J.; Pulay, P.;
Vicic, D. A. Ligand Redox Effects in the Synthesis, Electronic
Structure, and Reactivity of an Alkyl−Alkyl Cross-Coupling
Catalyst. J. Am. Chem. Soc. 2006, 128, 13175-13183.
42) Such pathways to initiation have also been proposed in cross-
electrophile coupling with alkyl halides, see: ref. 26a
43) The precise kinetic order was determined by variable time
normalization analysis (VTNA), see: (a) Nielsen, C. D. T.; Burés, J.
Visual kinetic analysis. Chem. Sci. 2019, 10, 348-353. The results
contrast our previous investigations wherein zero-order in RAE
was observed, see Ref. 7k and 7m.
44) For selected recent examples of radical chain mechanisms in
Ni-catalysis, see: (a) Ref. 26 (b) Ref. 29a (c) Breitenfeld, J.; Ruiz, J.;
Wodrich, M. D.; Hu, X. Bimetallic Oxidative Addition Involving
Radical Intermediates in Nickel-Catalyzed Alkyl–Alkyl Kumada
Coupling Reactions. J. Am. Chem. Soc. 2013, 135, 12004-12012. (d)
Schley, N. D.; Fu, G. C. Nickel-Catalyzed Negishi Arylations of
Propargylic Bromides: A Mechanistic Investigation. J. Am. Chem.
Soc. 2014, 136, 16588-16593. For general discussion, see: (a) Lucas,
E. L.; Jarvo, E. R. Stereospecific and stereoconvergent cross-
couplings between alkyl electrophiles. Nat. Rev. Chem. 2017, 1,
0065. (b) Weix, D. J. Methods and Mechanisms for Cross-
Electrophile Coupling of Csp2 Halides with Alkyl Electrophiles.
Acc. Chem. Res. 2015, 48, 1767-1775.
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