Rational Design of an Iron-Based Catalyst for Suzuki–Miyaura Cross-Couplings Involving Heteroaromatic Boronic Esters and Tertiary Alkyl Electrophiles

Article abstract of DOI:10.1002/anie.201914315

Suzuki–Miyaura cross-coupling reactions between a variety of alkyl halides and unactivated aryl boronic esters using a rationally designed iron-based catalyst supported by β-diketiminate ligands are described. High catalyst activity resulted in a broad substrate scope that included tertiary alkyl halides and heteroaromatic boronic esters. Mechanistic experiments revealed that the iron-based catalyst benefited from the propensity for β-diketiminate ligands to support low-coordinate and highly reducing iron amide intermediates, which are very efficient for effecting the transmetalation step required for the Suzuki–Miyaura cross-coupling reaction.

Full text of DOI:10.1002/anie.201914315

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Accepted Article
Title: Rational Design of an Iron-Based Catalyst for Suzuki-Miyaura
Cross-Couplings Involving Heteroaromatic Boronic Esters and
Tertiary Alkyl Electrophiles
Authors: Michael P Crockett, Alexander S Wong, Bo Li, and Jeffery
Allen Byers
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201914315
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10.1002/anie.201914315
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Rational Design of an Iron-Based Catalyst for Suzuki-Miyaura
Cross-Couplings Involving Heteroaromatic Boronic Esters and
Tertiary Alkyl Electrophiles
Michael P. Crockett‡, Alexander S. Wong‡, Bo Li, and Jeffery A. Byers*
Abstract: Suzuki-Miyaura cross-coupling reactions between a variety
of alkyl halides and unactivated aryl boronic esters are described
using a rationally designed iron-based catalyst supported by β-
diketiminate ligands. High catalyst activity resulted in a broad
substrate scope that included tertiary alkyl halides and heteroaromatic
boronic esters. Mechanistic experiments revealed that the iron-based
catalyst benefited from the propensity for β-diketiminate ligands to
support low-coordinate and highly reducing iron amide intermediates,
which are very efficient for effecting the transmetalation step required
for the Suzuki-Miyaura cross-coupling reaction.
Due in part to nearly 40 years of elegant ligand design and
logical catalyst development,[1] the Suzuki-Miyaura cross-
coupling reaction has become one of the most common methods
used in the pharmaceutical industry to construct C–C bonds.[2]
Despite its remarkable utility and broad generality,[3] there remain
underexplored classes of substrates that require further
innovations in catalyst design. One way to identify existing
limitations is by surveying the published articles describing
Suzuki-Miyaura cross-coupling reactions (Figure 1a). As others
have noted,[2] the majority of reported Suzuki-Miyaura reactions
involve the cross-coupling of two sp2-hybridized substrates. This
fact likely contributes to the exploration of mostly flat molecules
as drug candidates. In order to “escape from flatland,”
constructing saturated molecules with stereogenic centers is
desirable.[4] However, the propensity for elimination reactions has
resulted in a smaller number of Suzuki-Miyaura reactions that
involve at least one sp3-hybridized substrate. Fewer still are
examples involving heteroaromatic coupling partners, which can
inhibit catalysis (Figure 1a).[5] The dearth of these substrates is
notable considering that nearly 70% of all pharmaceutical
molecules contain at least one heterocycle.[6] Analysis of the
literature also reveals that most reported alkyl-aryl Suzuki-
Miyaura cross-coupling reactions involve primary alkyl fragments
(Figure 1b). Successful reactions with secondary and tertiary alkyl
coupling partners are rare, particularly when the alkyl fragment is
the electrophilic partner:[7] Only four reports describe using tertiary
alkyl halide substrates.[8]
Figure 1. Journal articles* describing Suzuki-Miyaura reactions for: a)
hybridization
of
nucleophiles/electrophiles
and
types
of
nucleophiles/electrophiles involved in sp2-sp3 cross-coupling reactions (inset),
and b) types of nucleophiles/electrophiles used in sp2-sp3 cross-coupling
reactions for primary, secondary, or tertiary sp3-hybridized substrates. *Details
describing data collection available in the ESI.
catalysts based on group 10 metals,[9] particularly for cross-
coupling reactions involving alkyl halide electrophiles.[10] However,
group 10 metals have toxicity[11] and long-term viability
concerns,[12] which pose economic and safety challenges for the
pharmaceutical industry. Remarkably efficient cross-coupling
reactions involving abundant and potentially less toxic iron-based
catalysts have recently emerged as viable alternatives, but
transmetalating reagents in these reactions are generally limited
to basic Grignard (i.e. Kumada-type) or difficult-to-handle
organozinc (i.e. Negishi-type) reagents.[13] Iron-based catalysts
used for the Suzuki-Miyaura reaction are rare[14] with many
remaining substrate limitations. The system reported herein
addresses some of these limitations through mechanistically-
motivated catalyst design that led to alkyl-aryl cross-coupling
reactions that tolerate heteroaromatic boronic esters and tertiary
alkyl halides as substrates.
To address these limitations, there have been tremendous
advances in the development of cross-coupling reactions using
[a]
M. P. Crockett,‡ A. S. Wong,‡ B. Li, Prof. Dr. J. A. Byers
Department of Chemistry
Boston College
Recently, we reported that controlling catalyst aggregation
is important for iron-based catalysts to engage in the Suzuki-
Miyaura reaction.[14e] These studies resulted in the working
mechanistic hypothesis presented in Figure 2. In this mechanism,
iron amide intermediate II is formed from reaction of an iron(II)
chloride precursor I with a lithium amide base. This additive
inhibited catalyst aggregation and facilitated transmetalation from
Merkert Chemistry Center, 2609 Beacon St. Chestnut Hill, MA
02467
E-mail: byersja@bc.edu
[‡]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end
of the document.
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10.1002/anie.201914315
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COMMUNICATION
Figure 2. Working mechanistic hypothesis and ligand design features for iron-
based catalysts used in Suzuki-Miyaura cross-coupling reactions.
solid and solution states, which reveal a diamagnetic compound
in the solid state and a paramagnetic compound(s) in solution (µeff
= 3.5). The solution state magnetic moment is too small to be a
high spin iron(II) complex, and is either best described as an
intermediate spin complex or (more likely) represents an
equilibrium mixture of the diamagnetic dimeric species and a high
spin mononuclear species in solution. Regardless to the precise
nature of 3 in solution, combining it with an equivalent of
phenylboronic acid pinacol ester (B(pin)) resulted in an immediate
color change that coincided with changes in the 1H and 11B NMR
spectra consistent with the formation of an iron phenyl complex 4
(Figures S4-S5). This assignment was confirmed by X-ray
crystallography, which revealed that 4 was also dimeric in the
solid state (Figure S1, CCDC #1942400).[20] Finally, treating
complex 4 with bromocycloheptane delivered the cross-coupled
product in nearly quantitative yields with the concomitant
formation of iron halide complex 1-Br (Figure 3).
Figure 3. Stoichiometric reactions relevant to Suzuki-Miyaura cross-coupling
reactions involving iron complexes supported by β-diketiminate ligands.
the boronic ester to form iron(II) aryl intermediate III. Halogen
atom abstraction resulting from reaction between III and the alkyl
halide formed iron(III) complex IV and a carbon-centered radical.
We speculated that product formation and catalyst turnover
occurred either by radical recombination with IV followed by
reductive elimination or by radical rebound with IV. This working
mechanistic hypothesis revealed two ligand design principles that
we used for further catalyst development:[14e] 1) bidentate anionic
ligands with tunable steric bulk positioned proximal to the metal
center were targeted to prevent deleterious iron aggregation; 2)
electron-donating ligands that supported low coordination
numbers were targeted to accelerate transmetalation.
The monomer-dimer equilibrium suggested by DOSY and
solution state magnetic moment measurements on
3
A class of ligands adhering to both design principles is the
β-diketiminate ligands (Figure 2). These ligands are better σ-
donors than the less basic cyanobis(oxazoline) ligands previously
used.[14e] Moreover, these ligands are exceptional for stabilizing
low-coordinate iron species,[15],[16] including 3-coordinate iron
alkoxide[15b] and amide[15b] complexes. To test our working
mechanistic hypothesis and to evaluate whether iron complexes
supported by β-diketiminate ligands would be suitable for cross-
coupling reactions, we set out to synthesize discrete iron amide
(e.g. 3) and iron phenyl (e.g. 4) complexes (Figure 3). Iron amide
3 was accessible through the protonolysis[17] of iron alkyl complex
2 with diethylamine.[18] X-ray crystallographic characterization of
3 confirmed the formation of an iron amide species, which was
dimeric by virtue of two µ2-diethylamide ligands (Figure S1, CCDC
#194239).[15b] Contrasting the solid state structure, diffusion-
ordered spectroscopy (DOSY) revealed that 3 is predominately
mononuclear in solution (Figures S2-S3).[19] This assessment has
been further supported by magnetic moments measured in the
demonstrated that the β-diketiminate complexes undergo more
reversible aggregation events than the cyanobis(oxazoline)
complexes. Moreover, the rapid conversion of the iron amide 3 to
the iron phenyl 4 highlights the efficient transmetalation reaction
afforded by the electron-releasing and sterically accommodating
β-diketiminate ligands. Finally, efficient transmetalation occurred
even in the absence of a borate intermediate, which is consistent
with our working mechanistic hypothesis (Figure 2). Notably,
stoichiometric experiments between 1, a preformed amino borate,
and the alkyl halide also produced the cross-coupled product, but
these reactions were lower yielding than the reaction between 4
and cycloheptyl bromide (Figures S6-S7). These findings are
similar to results reported for metal hydroxide complexes
proposed as intermediates in Suzuki-Miyaura reactions catalyzed
by palladium-based complexes, which were found to be more
efficient transmetalating intermediates compared to borates.[21]
Encouraged by the stoichiometric experiments, iron halide
1 was next explored as a precatalyst for the cross-coupling
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between PhB(pin) and bromocycloheptane (Table 1). Using 10%
of complex 1, the catalytic reaction proceeded efficiently to give
>90% of the cross-coupled product (entry 1).[22] Importantly, 1
must be made prior to cross-coupling. Despite similar initial rates,
much lower yields were obtained by combining iron dichloride with
the ligand (entry 2). The rate of the reaction was sensitive to the
identity of the aryl imines installed on the β-diketiminate ligands.
Decreasing steric bulk led to increased rates: complexes
containing 2-aryl imine ligands (5-8, entries 3-6) were superior
compared to complexes containing 2,6-dimethyl aryl imine
ligands (1, 10-12, entry 1 and entries 8-10). Reactions involving
complexes with even bulkier ligands, such as 13, consumed the
starting material efficiently but failed to produce an appreciable
amount of the desired cross-coupled product. Despite this trend,
the ligands had an optimal size because 2-methylphenyl imine
complex 8 (entry 6) was less efficient than 2-ethylphenyl imine
complex 7 (entry 5) and unsubstituted phenylimine complex 9
(entry 7) produced cross-coupling products in low yields despite
efficient conversion of the alkyl halide. Compared to the notable
steric effects, the electronic properties of the ligand minimally
impacted the rate of the reaction. For example, complexes 10-12
(entries 8-10) with various electron donating and withdrawing
groups installed on the ligand generally led to similar reaction
rates as the 2,6-dimethylphenyl imine complex 1 (entry 1).
excess boronic ester could be recovered nearly quantitatively
after the reaction (Figures S11-S12).
The generality of the cross-coupling reaction for a variety of
heteroaromatic boronic ester substrates was tested next (Table
2). Catalyst 5 was selected for this purpose because a cursory
exploration of boronic ester substrates demonstrated that 5 led to
higher yields compared to catalyst precursors that were faster in
the reaction between PhB(pin) and bromocycloheptane (e.g., 6-
8).[23] The sterically more encumbered ligand in 5 likely provides
the optimal steric environment to overcome irreversible substrate
binding while maintaining the accessibility needed for
transmetalation. With this precatalyst, several heteroaromatic
boronic ester substrates produced the desired products in
moderate to excellent yields (Table 2a). 2-thiophenyl-B(pin) and
3-thiophenyl-B(pin) produced the desired cross-coupling products
14-17 involving primary and secondary alkyl halides. These
results demonstrate complementary reactivity with electrophilic
aromatic substitution of thiophene rings, which selectively
functionalize at the 2-position, and are prone to rearrangement
when primary alkyl halides are used.[24] In addition to thiophenes,
furans were compatible (18) as well as several nitrogen-
containing heteroaromatic boronic esters (19-23). The latter
substrates often required the reaction to be carried out at 50 °C
or using an excess of boronic ester. Quinolines (19-20), sterically
encumbered pyridines (21) and Boc-protected indoles (22) were
all tolerated. Such substrates were completely inactive when iron
complexes supported by cyanobis(oxazoline) ligands were used
as precatalysts. Substrates more likely to bind to iron, such as
sterically unencumbered pyridines (23) or heterocycles containing
multiple nitrogen atoms (24), did not undergo efficient cross-
coupling using the β-diketiminate ligands.
Table 1. Representative iron(II) β-diketiminate complexes used as
precatalysts for Suzuki-Miyaura cross-coupling of PhB(pin) and bromo-
cycloheptane.
In addition to the enhanced boronic ester substrate scope,
the previously reported alkyl halide substrate scope was
maintained to a high degree. Generally faster and cleaner
reactions were observed using 5 as the precatalyst compared to
cyanobis(oxazoline) complexes (25-30, Table 2a). Primary alkyl
halides (25-26) and secondary alkyl halides (27-31) were well
tolerated with alkyl bromides being superior to alkyl chlorides and
alkyl iodides (Figure S14).[25] One notable exception were
benzylic halide substrates (26), which gave respectable amounts
of product but did not perform as well as with the
cyanobis(oxazoline) complexes.14e In addition to being tolerant to
many heterocycles, the reaction produced useful yields for
substrates containing carbamates (30) and silyl protected
alcohols (31).[26] Moreover, the cross coupling reaction proceeds
well in other solvents (See Figure S16), and can be carried out on
a gram scale as evidenced by the high yields (85%) obtained in a
reaction between PhB(pin) and bromocycloheptane.
Finally, tertiary alkyl halides proved to be excellent
substrates for the cross-coupling reaction (Table 2, 32, 33-37).
Previously, the cyanobis(oxazoline) iron complexes led to low
yields of cross-coupled product with 1-chloroadamantane,[14e] but
the reaction was not general for a variety of tertiary alkyl halides.
In contrast, cross-coupling using 5 resulted in a near quantitative
yield of 32 when 1-chloroadamantane was used as a substrate
(Table 2a). Surveying the precatalysts used in Table 1 revealed
that the fluorinated catalyst 10 was more general for cross-
coupling of a variety of tertiary alkyl chlorides (Table 2b). Using
this catalyst, reactions between tert-butyl chloride and a variety of
b
entry Fe cat.
R1
Me
Me
t-Bu
i-Pr
Et
R2
Me
Me
H
R3
H
R4 Yield (%)a kapp
krel
1.0
1
2
1
1c
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Me
CF3
Me
Me
Me
91
58
97
95
100
85
28
92
96
95
<1
2.43
2.25
7.95
H
0.9
3.3
3
H
4
H
H
44.0
18.1
18.7
12.3
7.2
5
H
H
45.4
29.9
17.4
6
Me
H
H
H
7
H
H
8
10
Me
Me
Me
i-Pr
Me
Me
H
2.34
1.0
9
11
12
13
Me
3.38
3.47
2.31
1.4
10
11
Me OMe
i-Pr
1.4
H
1.0
aGC yield relative to an internal standard. kapp (x 10-5 s-1) based on
b
consumption of bromocycloheptane. cformed in situ.
These cross-coupling reactions demonstrated notable
advantages compared to our previously reported system.[14e]
Reactions were significantly faster due to prolonged catalyst
lifetimes, which obviated the need for additional equivalents of
ligand required previously (Figures S9-S10). The reaction also
does not require an excess of the boronic ester substrate.
However, reactions using an excess of boronic ester were faster,
slightly more selective, and were void of side reactions so that the
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10.1002/anie.201914315
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COMMUNICATION
Table 2. Substrate scope for cross-coupling reactions using 5 or 10 as catalyst
precursors. Isolated yields are reported with yields based on recovered starting
material appearing in parentheses.
halides of the general formula R2MeCl and larger, which were
completely unreactive under the reaction conditions (e.g., 38-39).
The substrate scope observed complements a nickel-based
catalyst developed by Fu and coworkers that has a broader alkyl
halide substrate scope but is more sensitive to the electronic
nature of the nucleophile.[8a] Moreover, the high reactivity of the
iron-based complexes allowed for cross-coupling reactions to
occur with boronic esters as opposed to the 9-BBN boranes
required in the nickel-catalyzed system.
In conclusion, an iron-based catalyst system was designed
for the efficient cross-coupling of unactivated boronic ester
nucleophiles and alkyl halide electrophiles. The electron-
releasing β-diketiminate ligands used favor reactive intermediates
with low coordination numbers that are beneficial for
transmetalation. Compared to our previous system involving
cyano(bisoxazonline) ligands,[14e] the complexes bearing b-
diketiminate ligands are less prone to ligand dissociation and
a)
N
N
Ar
Fe
Cl
tBu
5 (10 mol%)
Ar B(pin)
(1.5 equiv)
S
+
R
X
R
Ar
LiNMeEt (1.2 equiv)
C6H6, rt, 24 h
(1.0 equiv)
S
Yield (b.r.s.m)
S
7
7
S
14
15
16
17
58% (73)a
82% (88)a
25% (72)a
61% (90)ad
N
N
O
irreversible aggregation. As
a
result, unproductive iron
18
19
20
61% (70)ac
40% (58)ad
75% (93)ad
aggregates are avoided, which led to high catalyst activity that
was leveraged for cross-coupling reactions involving
underrepresented substrate classes, including heteroaromatic
boronic ester nucleophiles and tertiary alkyl halide electrophiles.
Future reaction design will be aimed at reducing catalyst loading
and extending the method to incorporate broader classes of
substrates, including different heteroaromatic nucleophiles, alkyl-
alkyl cross-coupling reactions, and enantioselective variants.
Finally, methodology development will be coupled with
mechanistic studies focused on better understanding the key C–
C bond forming step, which remains poorly understood in catalytic
cross-coupling reactions involving iron complexes.[28]
N
N
N
N
Boc
21
74% (87)a
22
23
BocN
51% (75)ae
32% (56)ad
N
Ph
Ph
Ph
N
6
N
24
0%a
27
26
25
63% (63)ae
50% (62)ae
80% (87)ae
Ph
Ph
Ph Ph
N Cbz
TBS
Ph
O
7
29
30
31
28
32
Acknowledgements
99% (99)ae 67% (95)ae
55% (71)be
95% (99)ae
99% (99)be
F3C
CF3
N
b)
This work was supported by Boston College, the ACS Green
Chemistry Institute Pharmaceutical Roundtable (#2016), and the
ACS Petroleum Research Fund (59542-ND1). The authors thank
Dr. Brian Sparling and Dr. Jason Tedrow for helpful discussions
and feedback. The authors additionally thank Sally Wyman for
assistance with literature surveys.
N
Ar
Fe
Cl
10
(10 mol%)
Ar B(pin)
(2.0 equiv)
+
Ar
R
X
R
LiNMeEt (1.2 equiv)
C6H6, rt, 24 h
(1.0 equiv)
Yield (b.r.s.m)
OMe
Ph
Supplementary Materials
CF3
35
33
34
36
72% (72)b
All experimental procedures, NMR data, additional conversion
versus time plots, and crystallographic data appear in the
electronic supplementary information. Deposition Numbers
194239 and 1942400 contain the supplementary crystallographic
data for this paper. These data are provided free of charge by the
92% (92)b
58% (58)b
55% (55)b
Et
Et
Ph
Et
Ph
Ph
Ph
37
69% (99)b
39
0%b
38
traceb
joint
Cambridge
Crystallographic
Data
Centre
and
a X = Br. b X = Cl. c 0.1 mmol of electrophile. d at 50 oC. e 2.0 equiv. of B(pin).
Fachinformationszentrum Karlsruhe Access Structures service,
www.ccdc.cam.ac.uk/structures.
electronically diverse boronic esters resulted in moderate to
excellent yields of cross-coupled products (33-36). A bulkier
RMe2Cl substrate also produced cross-coupled product 37 in
good yield and without any isomerization due to chain walking.
Such isomerization can be problematic for nickel-catalyzed cross
electrophile cross-coupling reactions involving tertiary alkyl
halides.[27] The limitation of the current system is with tertiary alkyl
Keywords: Cross-Coupling
•
Iron
•
Suzuki-Miyaura
•
heteroaromatic boronic ester • tertiary alkyl halide
[1] R. J. Lundgren, M. Stradiotto, Chem. Eur. J. 2012, 18, 9758.
[2] D. G. Brown, J. Boström, J. Med. Chem. 2016, 59, 4443.
This article is protected by copyright. All rights reserved.

10.1002/anie.201914315
Angewandte Chemie International Edition
COMMUNICATION
[3] a) J. P. Wolfe, R. A. Singer, B. H. Yang, S. L. Buchwald, J. Am. Chem.
Soc. 1999, 121, 9550; b) F. Izquierdo, C. Zinser, Y. Minenkov, D. B.
Cordes, A. M. Z. Slawin, L. Cavallo, F. Nahra, C. S. J. Cazin, S. P.
Nolan, ChemCatChem 2018, 10, 601; c) A. Fihri, D. Luart, C. Len, A.
Solhy, C. Chevrin, V. Polshettiwar, Dalton Trans. 2011, 40, 3116.
[4] F. Lovering, J. Bikker, C. Humblet, J. Med. Chem. 2009, 52, 6752.
[5] P. Schäfer, T. Palacin, M. Sidera, S. P. Fletcher, Nat. Commun. 2017, 8,
15762.
B. Bedford, Nat. Catal. 2018, 1, 429; e) M. P. Crockett, C. C. Tyrol, A. S.
Wong, B. Li, J. A. Byers, Org. Lett. 2018, 20, 5233; f) T. Iwamoto, C.
Okuzono, L. Adak, M. Jin, M. Nakamura, Chem. Commun. 2019, 55,
1128.
[15] a) J. M. Smith, R. J. Lachicotte, P. L. Holland, Chem. Commun. 2001,
1542; b) N. A. Eckert, J. M. Smith, R. J. Lachicotte, P. L. Holland, Inorg.
Chem. 2004, 43, 3306; c) J. Vela, J. M. Smith, Y. Yu, N. A. Ketterer, C.
J. Flaschenriem, R. J. Lachicotte, P. L. Holland, J. Am. Chem. Soc.
2005, 127, 7857; d) P. L. Holland, Acc. Chem. Res. 2008, 41, 905.
[16] a) S. C. Bart, E. J. Hawrelak, E. Lobkovsky, P. J. Chirik, Organometallics
2005, 24, 5518; b) E. T. Hennessy, T. A. Betley, Science 2013, 340,
591; c) W.-T. Lee, I.-R. Jeon, S. Xu, D. A. Dickie, J. M. Smith,
Organometallics 2014, 33, 5654.
[6] C. Lamberth, J. Dinges, J. r. Dinges, Bioactive Heterocyclic Compound
Classes : Pharmaceuticals, John Wiley & Sons, Incorporated, Weinheim,
GERMANY, 2012.
[7] J. Choi, G. C. Fu, Science 2017, 356, eaaf7230.
[8] a) S. L. Zultanski, G. C. Fu, J. Am. Chem. Soc. 2013, 135, 624; b) K.
Yotsuji, N. Hoshiya, T. Kobayashi, H. Fukuda, H. Abe, M. Arisawa, S.
Shuto, Adv. Synth. Catal. 2015, 357, 1022; c) Q. Zhou, K. M. Cobb, T.
Tan, M. P. Watson, J. Am. Chem. Soc. 2016, 138, 12057; d) Z. T. Ariki,
Y. Maekawa, M. Nambo, C. M. Crudden, J. Am. Chem. Soc. 2018, 140,
78.
[17] A. B. Biernesser, B. Li, J. A. Byers, J. Am. Chem. Soc. 2013, 135,
16553.
[18] Attempts to synthesize iron amide 3 through salt metathesis reactions
led to a mixture of products, one of which could be identified as 3 in the
1H NMR spectrum.
[9] a) D. A. Everson, D. J. Weix, J. Org. Chem 2014, 79, 4793; b) J. P. G.
Rygus, C. M. Crudden, J. Am. Chem. Soc. 2017, 139, 18124; c) S.
Zhao, T. Gensch, B. Murray, Z. L. Niemeyer, M. S. Sigman, M. R.
Biscoe, Science 2018, 362, 670.
[10] I. D. Hills, M. R. Netherton, G. C. Fu, Angew. Chem. Int. Ed. 2003, 42,
5749.
[19] M. P. Crockett, H. Zhang, C. M. Thomas, J. A. Byers, Chem. Commun.
2019, 55, 14426
[20] DOSY NMR was attempted on complex 4; however, this complex has
much broader peaks than complex 3 and as a result no signal survived
the DOSY pulse sequence.
[21] B. P. Carrow, J. F. Hartwig, J. Am. Chem. Soc. 2011, 133, 2116.
[22] The kinetics of this reaction appear to be much faster than the
stoichiometric reaction. Investigations into this and other mechanistic
possiblities are ongoing and will be reported in due course.
[23] Catalytic reactions using 5 were extremely slow when borates were used
as the transmetalating reagent insstead of free amide (Figure S7).
[24] a) Y. Kamitori, M. Hojo, R. Masuda, T. Izumi, S. Tsukamoto, J. Org.
Chem 1984, 49, 4161; b) Z. Huang, J. Zhang, Y. Zhou, N.-X. Wang, Eur.
J. Org. Chem. 2011, 2011, 843.
[25] The higher reducing ability of the β-diketiminate iron complexes leads to
more facile dimerization of the alkyl halide in cases where the alkyl
halide is activated, which lowers the yield of the reaction (Figure S14).
[26] Substrates containing free alcohols and esters or ketones were not
tolerated under these conditions.
[27] a) X. Wang, S. Wang, W. Xue, H. Gong, J. Am. Chem. Soc. 2015, 137,
11562; b) X. Wang, G. Ma, Y. Peng, C. E. Pitsch, B. J. Moll, T. D. Ly, X.
Wang, H. Gong, J. Am. Chem. Soc. 2018, 140, 14490; c) A. H. Cherney,
S. J. Hedley, S. M. Mennen, J. S. Tedrow, Organometallics 2019, 38, 97.
[28] a) W. Lee, J. Zhou, O. Gutierrez, J. Am. Chem. Soc. 2017, 139, 16126;
b) A. K. Sharma, W. M. C. Sameera, M. Jin, L. Adak, C. Okuzono, T.
Iwamoto, M. Kato, M. Nakamura, K. Morokuma, J. Am. Chem. Soc.
2017, 139, 16117.
[11] K. S. Egorova, V. P. Ananikov, Organometallics 2017, 36, 4071.
[12] A. J. Hunt, T. J. Farmer, J. H. Clark, in Element Recovery and
Sustainability, The Royal Society of Chemistry, 2013, pp. 1-28.
[13] a) R. Martin, A. Fürstner, Angew. Chem. Int. Ed. 2004, 43, 3955; b) S. K.
Ghorai, M. Jin, T. Hatakeyama, M. Nakamura, Org. Lett. 2012, 14, 1066;
c) M. Nakamura, K. Matsuo, S. Ito, E. Nakamura, J. Am. Chem. Soc.
2004, 126, 3686; d) T. Hatakeyama, Y. Fujiwara, Y. Okada, T. Itoh, T.
Hashimoto, S. Kawamura, K. Ogata, H. Takaya, M. Nakamura, Chem.
Lett. 2011, 40, 1030; e) R. B. Bedford, M. A. Hall, G. R. Hodges, M.
Huwe, M. C. Wilkinson, Chem. Commun. 2009, 6430; f) R. B. Bedford,
E. Carter, P. M. Cogswell, N. J. Gower, M. F. Haddow, J. N. Harvey, D.
M. Murphy, E. C. Neeve, J. Nunn, Angew. Chem. Int. Ed. 2013, 52,
1285; g) M. Guisan-Ceinos, F. Tato, E. Bunuel, P. Calle, D. J. Cardenas,
Chem. Sci. 2013, 4, 1098; h) D. Gärtner, A. L. Stein, S. Grupe, J. Arp, A.
Jacobi von Wangelin, Angew. Chem. Int. Ed. 2015, 54, 10545; i) A.
Hedström, Z. Izakian, I. Vreto, C.-J. Wallentin, O. Norrby, Chem. Eur. J.
2015, 21, 5946.
[14] a) T. Hatakeyama, T. Hashimoto, Y. Kondo, Y. Fujiwara, H. Seike, H.
Takaya, Y. Tamada, T. Ono, M. Nakamura, J. Am. Chem. Soc. 2010,
132, 10674; b) T. Hashimoto, T. Hatakeyama, M. Nakamura, J. Org.
Chem 2012, 77, 1168; c) R. B. Bedford, P. B. Brenner, E. Carter, T. W.
Carvell, P. M. Cogswell, T. Gallagher, J. N. Harvey, D. M. Murphy, E. C.
Neeve, J. Nunn, D. Pye, Chem. Eur. J. 2014, 20, 7935; d) H. M. O’Brien,
M. Manzotti, R. D. Abrams, D. Elorriaga, H. A. Sparkes, S. A. Davis, R.
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10.1002/anie.201914315
Angewandte Chemie International Edition
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Nacnac!
Who’s
there?
A
Michael P. Crockett, Alexander S. Wong,
Bo Li, Jeffery A. Byers*
mechanistically driven approach to
Suzuki-Miyaura cross-coupling with
an iron-based catalyst enables the
facile construction of Csp3–Csp2
bonds with heteroaromatic boronic
esters. Additional advancements
allow for the construction of all
carbon quaternary centers with no
observable isomerization.
Page No. – Page No.
Rational Design of an Iron-Based
Catalyst for Suzuki-Miyaura Cross-
Couplings Involving Heteroaromatic
Boronic Esters and Tertiary Alkyl
Electrophiles
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