Iron-Catalyzed Suzuki-Miyaura Cross-Coupling Reactions between Alkyl Halides and Unactivated Arylboronic Esters

Article abstract of DOI:10.1021/acs.orglett.8b02184

An iron-catalyzed cross-coupling reaction between alkyl halides and arylboronic esters was developed that does not involve activation of the boronic ester with alkyllithium reagents nor requires magnesium additives. A combination of experimental and theoretical investigations revealed that lithium amide bases coupled with iron complexes containing deprotonated cyanobis(oxazoline) ligands were best to obtain high yields (up to 89%) in catalytic cross-coupling reactions. Mechanistic investigations implicate carbon-centered radical intermediates and highlight the critical importance of avoiding conditions that lead to iron aggregates. The new iron-catalyzed Suzuki-Miyaura reaction was applied toward the shortest reported synthesis of the pharmaceutical Cinacalcet.

Full text of DOI:10.1021/acs.orglett.8b02184

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Iron-Catalyzed Suzuki−Miyaura Cross-Coupling Reactions between
Alkyl Halides and Unactivated Arylboronic Esters
Michael P. Crockett, Chet C. Tyrol, Alexander S. Wong, Bo Li, and Jeffery A. Byers*
Department of Chemistry, Boston College, Chestnut Hill, Massachusetts 02467, United States
S
* Supporting Information
ABSTRACT: An iron-catalyzed cross-coupling reaction between alkyl halides and arylboronic esters was developed that does
not involve activation of the boronic ester with alkyllithium reagents nor requires magnesium additives. A combination of
experimental and theoretical investigations revealed that lithium amide bases coupled with iron complexes containing
deprotonated cyanobis(oxazoline) ligands were best to obtain high yields (up to 89%) in catalytic cross-coupling reactions.
Mechanistic investigations implicate carbon-centered radical intermediates and highlight the critical importance of avoiding
conditions that lead to iron aggregates. The new iron-catalyzed Suzuki−Miyaura reaction was applied toward the shortest
reported synthesis of the pharmaceutical Cinacalcet.
Considering the efficiency of iron-catalyzed Kumada reac-
ransition-metal-catalyzed cross-coupling reactions have
Temerged as robust methods for the efficient construction tions8e and the sluggishness of the corresponding Suzuki−
of carbon−carbon bonds in organic synthesis.1 Of particular
Miyaura reactions, we reasoned that transmetalation was the key
step. Extensive studies have been carried out to understand how
base additives aid transmetalation in palladium-catalyzed
systems.10 Two viable pathways have emerged: either the base
forms a nucleophilic organoborate species in situ or it converts
the palladium(II) aryl-halide species formed after oxidative
addition to a palladium(II) aryl-hydroxide intermediate that is
bettersuitedfortransmetalationwithboronicacids.11 Hartwig10a
and Denmark10b,c have recently demonstrated that conditions
which lead to the formation of palladium hydroxides are crucial
for successful transmetalation. We hypothesized that application
of analogous conditions to iron-based catalyst systems would
lead to iron-hydroxide or alkoxide intermediates that would be
prone to irreversible aggregation12 and subsequent deactivation
for cross-coupling reactions.
An alternative hypothesis is that unfavorable thermodynamics
hinder transmetalation. To investigate this possibility, a
computational model was developed to evaluate transmetalation
from phenylboronic acid pinacol ester [PhB(pin)] to diphenyl-
phosphinoethane (dppe) iron(II) complexes (Figure S1). This
studyrevealedthatthethermodynamicsfortransmetalationfrom
iron alkoxides are uphill but accessible at room temperature (ΔG
= +5 kcal/mol). Given this finding, the possibility for a boron-to-
industrial importance are cross-coupling reactions that use
boronic esters or acids as transmetalating reagents (i.e., Suzuki−
Miyaura reaction).2 This reaction is typically carried out using
palladium-based catalysts,3 which have demonstrated tremen-
dous utility, but are toxic4 and costly. Moreover, despite
significant advances in ligand design,5 palladium-based catalysts
also demonstrate some substrate scope limitations, most notably
for reactions involving secondary or tertiary alkyl halides.5f
Pioneering work from Fu and co-workers has expanded the
substrate scope limitations of palladium-based catalysts with the
development of many useful nickel-based catalysts.6,7 In parallel,
potentially less toxic iron-based catalysts have also been
developed for similar cross-coupling reactions. However, most
of these methods have been primarily limited to reactions
involving Grignard (i.e., Kumada-type) or alkyl zinc (i.e.,
Negishi-type) transmetalating reagents.8 Iron-catalyzed Suzu-
ki−Miyaura cross-coupling reactions are limited to three
examples, all requiring the addition of alkyllithium reagents
and magnesium additives.8c,9 Herein, a new iron-based catalyst
system is disclosed for the cross-coupling of alkyl halides with
arylboronic esters that avoids activating the boronic ester with
pyrophoric alkyllithium reagents and does not require the
addition of magnesium salts to aid with transmetalation (Figure
1).
Received: July 13, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02184
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the steric environment of the amide was highlighted by
LiNMeEt, which was superior to all other amides evaluated.
Furthermore, catalytic cross coupling could be achieved when
LiNMeEt was used in conjunction with catalytic amounts of 1
(Figure 1c).14
An extensive ligand evaluation (Table S2) revealed that
bisoxazoline (BOX) ligands were exceptionally effective for the
catalytic transformation. Yields were particularly sensitive to
substitution on the bridging carbon of the BOX ligand (Table 1).
Table 1. Reaction Optimization
entry
Fe source
ligand
4 (%)
5 (%)
6 (%)
1
2
3
4
5
6
7
8
9
10
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
10
10
10
10
10
none
7
8
9
9
none
9
9
9
9
25
36
25
58
72
74
82
89
75
69
15
14
16
14
6
0
1
2
2
48
16
26
10
6
10
7
6
a
b
c
Figure 1. Attempted synthesis of (dppe)Fe(OR)2 using (a) salt
metathesis and (b) protonolysis. (c) Stoichiometric reactions between
(dppe)FeCl2 and LiNR2 and activity for alkyl-aryl Suzuki−Miyaura
cross-coupling; *10 mol % (dppe)FeCl2.
bd
13
19
be
1
a
b
c
20% of 9. 48 h. 48 h; 10% of 10 and 60% of LiNMeEt added after
d
e
24 h. 5% of 10 and 9. 1% of 10 and 9.
iron transmetalation proceeding through the intermediacy of an
iron alkoxide complex was tested experimentally. However,
attempts to synthesize a mononuclear iron alkoxide complex
either through a salt metathesis route from (dppe)FeCl2 (i.e., 1,
Figure 1a) or a protonolysis route from (dppe)Fe(CH2SiMe3)2
(i.e., 2, Figure 1b)12c led to a green insoluble material that was
completely inactive for cross-coupling reactions.13
Significantly higher yields were obtained when using the
commercially available cyanoBOX ligand 9 as opposed to
unsubstituted ligand 7 or isopropylidene ligand 8 (entries 2−4).
Yields were further improved to 72% when an additional
equivalent of 9 relative to iron was added (entry 5). The higher
yields observed under these reaction conditions coincided with
reduced amounts of cycloheptane and cycloheptene side
products. We hypothesized that 9 was superior to the other
BOX ligands due to its increased acidity, which led to ligand
deprotonation under the basic reaction conditions. To test this
hypothesis, iron complex 10 containing a monoanionic cyano-
BOX ligand 9 was synthesized and evaluated. This complex was
found to be more effective than the in situ formed catalyst (cf.
entry 6 to entry 4). Yields were once again improved by adding
exogenous ligand to 10 (entry 7), although prolonged reaction
times were required. Alternatively, full conversion of the alkyl
halide and nearly 90% yield was obtained if an additional 10 mol
% of 10 and 0.6 equiv of LiNMeEt were introduced to the
reaction after 24 h (entry 8). Catalyst loadings as low as 1% led to
useful yields of 4, although cycloheptene became more prevalent
at lower catalyst loadings (entries 9−10).
Iron amides were explored next as possible intermediates for
transmetalation. The computational model predicted that these
intermediates would have favorable thermodynamics for trans-
metalation (−6 kcal/mol), and the steric and electronic
environment about iron amides are more readily tunable
compared to iron alkoxides. When 1 was treated with lithium
diethylamide, a golden homogeneous reaction mixture resulted,
and its 1H NMR spectrum suggested the formation of
predominately one new species (Figure 1c and Figure S2). The
instability of this complex has precluded further characterization,
but we hypothesize that the expected (dppe)Fe(NEt2)2 complex
3 was formed because the desired cross-coupled product 4 was
produced in 38% yield when PhB(pin) and cycloheptyl bromide
were added to the reaction mixture. The only other products
formed were cycloheptane (5) and cycloheptene (6). As
expected, the yield of 4 was strongly dependent on the identity
ofthelithiumamideused (Figure 1c). Stericallydemandingand/
or electron deficient amides gave little to no product (e.g., LDA,
LiHMDS, or LiNMePh). Small amides, such as LiNMe2 and
LiHNBu, were also ineffective. The sensitivity of the reaction to
The reaction scope was explored next (Scheme 1). Primary
andsecondaryalkylbromidesweretolerated(4b, 11b−12b)and
even the tertiary alkyl chlorides 19a and 20a led to some of the
desired cross-coupled product. A marked difference in reactivity
was observed for benzylic substrates with respect to the identity
B
DOI: 10.1021/acs.orglett.8b02184
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or nitrile functional groups). Most reactions proceeded without
formation of side products, leading to high yields based on
recovered starting material; low yields were often a consequence
of catalyst deactivation. Filtration and resubjecting such reaction
mixtures to the reaction conditions led to further 10−25%
improvement in yield as demonstrated for 18 (Scheme 1).
Our mechanistic understanding of the reaction is contextual-
ized within the framework proposed by Nakamura,8c and
supported by Neidig16 for iron-catalyzed Suzuki−Miyaura
cross-coupling reactions between alkyl electrophiles and
preactivated aryl borates (Figure 2a). While this reaction
Scheme 1. Substrate Scope [Isolated Yield (brsm)]
a
b
50 °C. 10 (0.1 mmol) and LiNMeEt (0.6 mmol) added after 24 h.
c
48 h; 10 (0.1 mmol), PhB(pin) (1 mmol), and LiNMeEt (0.6 mmol)
added after 24 h.
of the halide. Typically, alkyl bromides were superior to alkyl
iodides, which were superior to alkyl chlorides (cf. 11a−11c). In
contrast, higher yields were obtained for benzyl chloride (13a)
compared to benzyl bromide (13b). This difference was
attributed to the propensity for benzylic substrates to undergo
homocoupling as a result of radical recombination; similar
homocoupling was not observed for unactivated alkyl halide
substrates. Competitive homocoupling of the secondary benzyl
chloride 15a and allylic chloride 16a led to depressed but still
synthetically useful yields for these substrates. Functionalized
alkylhalides, including aprotected alcohol(17b)andaprotected
amine (18b), were tolerated, leading to clean reactions with high
yields based on recovered starting materials. The reaction also
tolerated different boronic esters (Scheme 1). Cross-coupling
involving naphthylboronic ester 21 proceeded similarly as
PhB(pin). Electron-rich arylboronic esters 22 and 23 demon-
strated reduced efficiency, which is likely due to slower
transmetalation rates.15 Electron-deficient substrates 24 and 25
were competent if the reaction mixture was heated. Alkenylbor-
onic esters (e.g., 26) produced the desired cross coupling
product, albeit in lower yields compared to arylboronic esters.
Unfortunately, heteroaromatic substrates (e.g., 27) were not
tolerated under these conditions nor were substrates with
enolizable functional groups (e.g., alkyl halides containing esters
Figure 2. (a) Working mechanistic hypothesis. Effect of using (b)
[Ph(NMeEt)B(pin)]− 31 or (c) PhB(neo) 32 in reaction.
mechanisminvolvestheinterconversionofiron(II)andiron(III)
intermediates, we cannot rule out alternative pathways, such as
the iron(I)/iron(II)/iron(III) pathway proposed by Norrby and
Bedford.8k,9a Regardless of the precise details, carbon-based
radical intermediates are likely formed here because ring-opened
products are exclusively produced when the radical clock
substrate 28 is used (Scheme 1). Likewise, mixtures of direct
cross-coupling and cross-coupling that occur after ring closure
were also observed when radical clock 29 was used, suggesting
radical lifetimes on the order of 105 s−1.17 Similar results were
obtained by Nakamura,8c which is consistent with our working
hypothesis that the cross-coupling mechanism follows a similar
route (Figure 2a).
Two key differences between the system reported here and
those reported by Nakamura and Bedford are the identity of the
ligand and the involvement of the amide base. In addition to
forming an anionic cyanoBOX ligand that is less prone to
C
DOI: 10.1021/acs.orglett.8b02184
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dissociation and subsequent iron aggregation compared to
neutralbisphosphines, wealsopositthatthelithiumamidebaseis
necessary to convert the putative iron halide 10 into an iron
amide species (30) that is superior for effecting transmetalation
(Figure 2a). Several trendsobserved during catalystoptimization
are more consistent with an iron amide being involved in
transmetalation as opposed to transmetalation proceeding
through a borate species formed from reaction of the boronic
ester with the amide base. PhB(pin) reacts with LiNMeEt to
make borate species 31, which we have detected by 11B NMR
spectroscopy (Figure S4). However, boronic esters that are
expected to form borate species more readily result in sluggish
reactions (e.g., electron-deficient boronic esters) or nearly no
reaction at all (e.g., 32, Figure 2c). Moreover, when
independently synthesized 31 was added to the cross-coupling
reaction, greatly diminished yields were obtained (6%)
compared to when the lithium amide and boronic ester are
added to the reaction separately (82%) (Figure 2b).18 While
these findings do not definitively rule out the intermediacy of a
borate species, the inhibitory nature observed when such species
predominate makes us favor a pathway that involves iron amide
intermediates as a necessary precursor for transmetalation.
Finally, the utility of the new cross-coupling method was
demonstrated with the synthesis of the pharmaceutical agent
Cinacalcet (a.k.a. Sensipar from Amgen). Cinacalcet is a
calcimimetic19 that is used to treat secondary hyperparathyroid-
ism.20 Most methods currently used for the synthesis of
Cinacalcet rely on noble metal catalysts for its construction
and/or involve the alkene intermediate 33 (Figure 3a).21 We
leading to an efficient coupling reaction between the commodity
chemical 1-bromo-3-chloropropane (34) and arylboronic ester
35. The reaction proceeded in 55% yield with only 10% of
bisarylated product being formed. The alkyl halide 36 could then
be efficiently elaborated to Cinacalcet by using it to alkylate the
commercially available amine 37. This route constitutes a high
yielding synthesis of Cinacalcet (41% overall) in fewer steps than
any of the routes reported in the Amgen patent21c and without
the use of any noble metal catalysts or pyrophoric organometallic
reagents.
In conclusion, these results highlight the importance of
considering the aggregation state of reactive intermediates
involved in iron-catalyzed cross-coupling reactions. The
conditions that were found to be most successful to effect the
Suzuki−Miyaura reaction were those that avoided formation of
iron aggregates. A secondary but important factor for the success
of these reactions was the involvement of anionic ligands and the
use of amide bases, both of which make transmetalation from
boron to iron more facile. Importantly, while these results
demonstrate that mononuclear iron species are critical for
successful cross-coupling reactions between alkyl halides and
unactivated arylboronic esters, it is likely true that other iron-
catalyzed cross coupling reactions require higher ordered iron
species. Exemplifying this point are recent findings pertaining to
iron-catalyzed cross-coupling of vinyl halides and aryl Grignard
reagents, which involve iron cluster intermediates.22 While
extensive mechanistic investigations are still needed to ration-
alize these preferences, aggregation state is nevertheless
important to consider when designing new iron-based catalysts
for cross-coupling reactions.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b02184.
Full experimental procedures, computational models, and
additional experiments (PDF)
XYZ coordinates (PDF)
Accession Codes
CCDC 1854710 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jeffery.byers@bc.edu.
ORCID
Figure 3. Synthesis of cinacalcet: (a) three-step syntheses previously
reported and (b) two-step synthesis using iron-catalyzed alkyl-aryl
Suzuki−Miyaura cross-coupling reaction.
Jeffery A. Byers: 0000-0002-8109-674X
Notes
The authors declare no competing financial interest.
envisioned that the hydrogenation step involved to convert 33 to
Cinacalcet could be avoided if C3−C4 was formed using our
newly developed iron-catalyzed Suzuki−Miyaura reaction,
providing access to the pharmaceutical agent in two steps.
Figure 3b contains the new synthesis, which takes advantage of
the difference in reactivity between alkyl chlorides and bromides,
ACKNOWLEDGMENTS
■
This work was supported by Boston College and the ACS Green
Chemistry Institute Pharmaceutical Roundtable (#2016). The
authors thank Dr. Brian Sparling and Dr. David Moebius at
Amgen for helpful discussions and feedback.
D
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Letter
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Indian Patent 2010CH01403, 2010.
(22)Munoz, S.B.,III;Daifuku,S.L.;Brennessel, W.W.;Neidig,M.L. J.
̃
Am. Chem. Soc. 2016, 138, 7492.
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