Iron-catalysed enantioconvergent Suzuki-Miyaura cross-coupling to afford enantioenriched 1,1-diarylalkanes

Article abstract of DOI:10.1039/d0cc05003b

The first stereoconvergent Suzuki-Miyaura cross-coupling reaction was developed to afford enantioenriched 1,1-diarylalkanes. An iron-based complex containing a chiral cyanobis(oxazoline) ligand framework was best to obtain enantioenriched 1,1-diarylalkanes from cross-coupling reactions between unactivated aryl boronic esters and benzylic chlorides. Enhanced yields were obtained when 1,3,5-trimethoxybenzene was used as an additive, which is hypothesized to extend the lifetime of the iron-based catalyst. Exceptional enantioselectivities were obtained with challenging ortho-substituted benzylic chlorides. This journal is

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DOI: 10.1039/D0CC05003B
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Iron-catalysed enantioconvergent Suzuki-Miyaura cross-coupling
to afford enantioenriched 1,1-diarylalkanes
Chet C. Tyrol,*a Nang S. Yone a , Connor F. Gallin a and Jeffery A. Byers a
The first stereoconvergent Suzuki-Miyaura cross-coupling reaction
was developed to afford enantioenriched 1,1-diarylalkanes. An
Blockbuster pharmaceuticals, such as Zoloft, Detrol and
iron-based complex containing a chiral cyanobis(oxazoline) ligand
framework was best to obtain enantioenriched 1,1-diarylalkanes
from cross-coupling reactions between unactivated aryl boronic
esters and benzylic chlorides. Enhanced yields were obtained when
1,3,5-trimethoxybenzene was used as an additive, which is
hypothesized to extend the lifetime of the iron-based catalyst.
Exceptional enantioselectivities were obtained with challenging
ortho-substituted benzylic chlorides, a motif common in many
pharmaceuticals. In addition to providing access to
enantiomerically enriched 1,1-diaryl alkanes, this method further
expands the coupling partners available to enantioselective cross-
coupling reactions catalysed by iron-based complexes.
Since the renaissance of iron-based catalysts used for cross-
coupling reactions were galvanized by the seminal work of Fürstner
at the turn of the century,1 industrial and academic interest in these
catalysts have increased due to the high abundance and low toxicity
of iron as well as the unique reactivity that these types of catalysts
afford.2a-c Fast reaction kinetics are often observed with iron-based
catalysts, which leads to complementary reactivity compared to
Figure 1 a) Pharmaceuticals containing the 1,1-diarylalkane motif.
b) Enantioconvergent Suzuki-Miyaura cross-coupling of benzylic chlorides
catalysed by iron complexes supported by cyanobis(oxazoline) ligands.
many nickel-based catalysts used for similar reactions.1,3
A
SGLT2 inhibitors all contain the chiral 1,1-diarylalkane motif while
eliciting a range of physiological responses (Figure 1a).10 Despite the
fact that one enantiomer of these drugs is often more potent,11 they
are either sold as racemates, mixtures of diastereomers,12 or are
obtained in enantioenriched form as a result of a late stage
resolution.12,13 These tactics are a likely symptom of synthetic
limitations that have prevented access to enantiomerically enriched
1,1-diaryl alkanes. Consequently, the enantioselective synthesis of
the 1,1-diarylalkane subunit has become a popular contemporary
topic for synthetic organic chemists.14 Current approaches toward
such motifs include asymmetric hydrogenation of 1,1-
diarylalkenes,15 nucleophilic and radical additions to alkenes,16 and
stereospecific17 as well as stereoconvergent18a-b cross coupling
reactions. A method that is noticeably absent from this list is a
stereoconvergent Suzuki-Miyaura cross coupling reaction. Such a
reaction would closely mimic the ubiquitous Suzuki-Miyaura cross
coupling reactions used in the pharmaceutical industry for the
construction of C–C bonds between two sp2-hybridized substrates.19
particularly prolific area of cross-coupling reactions that has
benefited from the development of iron-based catalysts are
reactions
involving
alkyl
halide
electrophiles
and most recently
with
organomagnesium,4a-c organozinc,5a-b
organoboron-based6a-e organometallic nucleophiles. These catalysts
have demonstrated remarkable reactivity, especially for cross
coupling reactions involving sterically demanding substrates and
heteroaromatic boronic esters.7 Despite these advances,
enantioselective cross-coupling reactions that utilize iron-based
catalysts are exceedingly rare and have been greatly overshadowed
by the tremendous achievements in enantioconvergent systems
employing nickel-based catalysts.8 In fact, only three
enantioselective cross coupling reactions that utilize iron-based
catalysts have been reported.9a-c All of these reactions use -
haloesters as electrophiles and none of them use unactivated
boronic esters as nucleophiles. With this report, we expand the
nascent scope of enantioselective iron-based cross-coupling
reactions and advocate for their value in chemical synthesis with the
synthesis of enantioenriched 1,1-diarylalkanes (Figure 1).
a. Department of Chemistry, Boston College, 2609 Beacon Street, Chestnut Hill, MA
02467 (USA). E-mail: byersja@bc.edu
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Herein, we report the first enantioselective Suzuki-Miyaura explored demonstrated decreased yields and/or selectivities
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cross-coupling reaction between benzylic chlorides and unactivated compared to reactions using iron precatalDyOstI:11.0.T10h3e9r/eDfo0CreC,0150w03aBs
arylboronic-pinacol esters that is made possible by capitalizing on the used for final optimization. Previously, we found that reactions
reactivity of an iron-based catalyst (Figure 1b). Previously it was carried out with additional PhCNBox ligand improved yields,6e but
shown that iron-based complexes supported by chiral here we found that reactions carried out without extra ligand but in
cyanobis(oxazoline) ligands (e.g., 1) are competent catalysts for the presence of 1,3,5-TMB led to appreciably higher yields of 2
Suzuki-Miyaura cross coupling reactions between alkyl halides and despite lower selectivity (see entry 5). Control experiments
unactivated aryl boronic esters.6e Given that the method utilized a confirmed once again that 1,3,5-TMB had little to no effect on
chiral catalyst and tolerated secondary alkyl halides, we selectivity but was important to obtain high yields, particularly in the
hypothesized that it would be suitable for the stereoselective cross- absence of additional ligand (c.f., entries
5 and 6). Finally,
coupling of secondary benzyl halide electrophiles and arylboronic enantioselectivity was improved for a reaction carried out at -15 °C
ester nucleophiles to give enantioenriched 1,1-diarylalkanes. (e.r. = 85:15). However, at this temperature it was necessary to add
Exploratory reactions between (1-chloroethyl)benzene and 2- 5% ligand to maximize yields of 2.
naphthylboronic acid pinacol ester under previously reported
The benzyl halide substrate scope of the reaction was
conditions6e using cyano(bisoxazoline) iron(II) chloride complex 1 as evaluated next (Table 2, top). Benzyl halides containing electron-
the catalyst precursor led to 1,1-diaryl alkane 2 in 64% yield and with donating and electron-withdrawing functional groups led to lower
an enantiomeric ratio (er) of 74:26 (Table 1). A competitive side yields but only modestly affected enantioselectivity (c.f., 2, 13-15).
product was compound 3, which results from the homodimerization Increasing the chain length of the alkyl substituent from methyl to
of the benzyl halide starting material. Importantly, using the butyl lead to slightly lower yields and similar enantioselectivities (c.f.,
preformed iron complex was necessary to obtain 2 in high yield, 2, 16-18). However, introducing branching acjacent to the alkyl
although identical enantioselectivity was observed for a reaction halide led to lower yield and enantioselectivity (e.g., 19). The
carried out by mixing the cyano(bisoxazoline) ligand with iron reaction demonstrated moderate functional group tolerance with
dichloride (entry 2).
Table 2. Substrate scope for the cross-coupling of benzylic
halides and boronic ester scope catalysed by 1.a
Table 1. Suzuki-Miyaura cross-coupling reaction between 1-
chloroethylbenzene and 2-napthylboronic pinacol ester.
R”
1 (10 mol%)
Cl
PhCNBox (5 mol%)
Fecat (10 mol%)
O
O
PhCNBox (X mol%)
Cl
+
B
R
O
(rac)
additive (1 equiv.)
LiNMeEt (1.2 equiv.)
1,3,5-TMB (1 equiv.)
1,2-DFB, -15 oC, 24 h
R”
+
B
R
Ph
(rac)
+
LiNMeEt (1.2 equiv.)
solvent, rt, 24 h
O
R’
(1 equiv.)
2-Nap
(2 equiv.)
Ph
Ph
R’
(1 equiv.)
(2 equiv.)
2
3
2-Nap
2-Nap
2-Nap
Entry Fecat PhCNBox
(mol%)
solvent
additive
Yield
er
Yield
2 (%)[a] of 2[b] 3 (%)[a]
F
TBSO
H3C
2
80%
85:15 er
13
63%
81:19 er
14
42%
77:23 er
15
40%
82:18 er
1
2
1
10
20
10
10
0
C6H6
C6H6
none
none
none
64
19
66
73
90
68
90
74:26
74:26
76:24
79:21
75:25
75:25
85:15
9
19
11
9
FeCl2
2-Nap
2-Nap
2-Nap
2-Nap
3
1
1
1
1
1
1,2-DFB[d]
i-Pr
n-Bu
n-Pr
Et
4
1,2-DFB[d] 1,3,5-TMB[c]
1,2-DFB[d] 1,3,5-TMB[c]
16
68%
81:19 er
17
73%
78:22 er
18
69%
79:21 er
19
37%b,c
73:27 er
5
10
18
0
Cl
2-Nap
2-Nap
2-Nap
6
0
1,2-DFB[d]
none
Et
Me
7e
5
1,2-DFB[d] 1,3,5-TMB[c]
Cl
Br
20
21
22
23
64%b,c
77:23 er
45%b,c
93:7 er
67%b,c
95:5 er
35%e
99:1 er
[a] Yields determined by 1H-NMR spectroscopy relative to 1,3,5-
trimethoxybenzene as an internal or external standard. [b] enantiomeric
ratios determined by chiral column HPLC. [c] 1,3,5-trimethoxybenzene.
[d] 1,2-difluorobenzene. [e] -15 oC.
tBu
OCH3
CF3
An evaluation of solvents and stoichiometric additives (see
Table S1) revealed similar yield and selectivity for a reaction carried
out in 1,2-difluorobenzene (1,2-DFB) as the solvent (entry 3). A
modest improvement in yield and selectivity was obtained by using
1,3,5-trimethoxybenzene (1,3,5-TMB) as a stoichiometric additive
(entry 4). With these conditions, we carried out a screen of iron
precatalysts containing various aromatic and aliphatic substituted
cyanobis(oxazoline) ligands (Table S2). Unfortunately, all variants
Ph
Ph
Ph
Ph
2-Nap
24
25
26
27
2
58%d
74:26 er
59%c,d
81:19 er
39%c,d
80:20 er
43%c,d
79:21 er
85%
73:27 er
[a] Yields are isolated yields and enantiomeric ratios were determined by
chiral column HPLC. [b] 15 mol% [Fe], no extra ligand, 2 equiv. 1,3,5-TMB.
[c] LiNMe2 used. [d] 15 mol% Fecat, 7.5 mol% ligand, 2 equiv. 1,3,5-TMB and
-10 oC. [e] 40 mol% [Fe], no extra ligand, 2 equiv. 1,3,5-TMB and -10 oC.
2 | J. Name., 2012, 00, 1-3
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ethers, silyl-protected alcohols, aryl bromides, and aryl chlorides all nor did it impact the selectivity of the reaction. The major difference
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being tolerated. Of particular note was the high enantioselectivities was observed at long reaction times whDeOreI: 1h0i.g1h03e9r/Dy0ieCldCs05w00e3rBe
(er ≥ 93:7) observed for benzylic halides containing ortho-substituted obtained in the presence of 1,3,5-TMB.
Several observations provided additional information about
aryl groups (e.g., 21-23). These substrates are important because
ortho substituted 1,1-diaryl alkanes are common motifs in many
pharmaceuticals (Figure 1a), and they are challenging to obtain in
high enantiopurity using the previous methods reported to
synthesize 1,1-diarylalkanes,18b,20 except for one isolated report.15 To
compensate for the lower reactivity of these demanding substrates,
higher loadings of 1 and 1,3,5-TMB were required. Additionally, using
LiNMe2 instead of LiNMeEt was beneficial to obtain appreciable
yields of 22. In addition to being a common motif in pharmaceuticals,
product 21 is a versatile synthetic intermediate because it can be
used futher as the electrophile in cross coupling reactions, converted
into a nucleophile for cross-coupling reactions through Miyaura
borylation, and undergo protodechlorination.15 To demonstrate the
synthetic utility of the method, we synthesized an intermediate for
an SGLT2 inhibitor used to treat type II diabetes (Figure 1a).21 Using
40 mol% of 1, product 23 was formed in modest yield but with
excellent enantioselectivity (>99:1 er). Elaboration of this
intermediate to the SGLT2 inhibitor has previously been reported
through glycosylation of the aryl bromide,22 which remains
unreacted in the cross-coupling reaction.
the mechanism for stereoinduction in the cross-coupling reaction.23a-
b
Importantly, the enantioselectivity of the reaction remained
constant throughout the reaction (Figure 2). Additionally, when
stereoenriched 2 was introduced at the onset of a cross-coupling
reaction, no loss in its enantiopurity occurred over the course of the
reaction (see Figure S2). Both results demonstrate that the basic
reaction conditions employed do not lead to product epimerization.
In contrast, racemic alkyl halide was recovered from a reaction taken
to partial completion (Figure S3), and the homodimerization product
3 was obtained as a near statistical mixture of all three possible
stereoisomers (S,S:R,R:R,S ~ 1:1:2) (Figure S4). These findings are
most consistent with a stereoconvergent cross-coupling reaction
mechanism that proceeds through a free radical intermediate
formed without kinetic resolution of the alkyl halide. The mechanism
for stereoconvergence is likely through an unselective halogen atom
abstraction step.9a-b,24 To gain information about the nuclearity of the
catalyst during the selectivity determining step,25 stereoselectivity
was evaluated as the catalyst enantiopurity was altered. These
reactions revealed a linear relationship between product and
catalyst enantiopurity (see Figure S5), which suggested that the
selectivity-determining step in the cross-coupling reaction likely
occurs at a metal centre containing one cyanobis(oxazoline) ligand.
Interestingly, reaction of 2-(1-chloroethyl)naphthalene with PhB(pin)
produced 2 with a similar yield but lower enantioselectivity as
obtained for the complementary reaction between 2-napthylboronic
acid pinacol ester and (1-chloroethyl)benzene (Table 2). This
observation suggests that the electrophile and the nucleophile are
present in the selectivity-determining step.
With respect to the boronic ester substrate scope,
arylboronic acid pinacol ester coupling partners derived from
PhB(pin) were less reactive than 2-naphthylboronic acid pinacol ester
(Table 2, bottom). Consequently, reactions involving these
nucleophiles required higher temperatures (-10 °C) and higher
catalyst loadings (15 mol%) to obtain useful yields of cross-coupled
product. Despite these changes, only
a small erosion in
enantioselectivity was observed (e.g., 24-27). As was found with the
benzyl halides, varying the electronic nature of the boronic ester had
minimal effect on enantioselectivity.
A puzzling feature of the reaction was the benefit of using
1,3,5-TMB as an additive. Analysing the reaction over time in the
presence and absence of 1,3,5-TMB provided some insight into the
role of 1,3,5-TMB (Figure 2). These experiments revealed that
addition of 1,3,5-TMB had no effect on the initial rate of the reaction
A possible catalytic cycle is shown in Scheme 1. Precatalyst I
engages in salt metathesis with the lithium amide to form iron(II)
amide II. This intermediate competitively undergoes transmetalation
with the aryl boronic ester to form iron(II) aryl IV and unselective
halogen abstraction to form iron(III) amide-halide III and a carbon-
centred radical. The carbon-centred radical reversibly recombines
with IV to form iron(III) aryl-alkyl species V. Complex V is poised for
reductive elimination to form the formally iron(I) complex VII and the
cross-coupled product. In order to avoid unstable low coordinate
iron species from forming, we suspect that reductive elimination
requires prior coordination of solvent or 1,3,5-TMB to form VI.
Benzene has previously been shown to stabilize iron(I) complexes
supported by the structurally similar -diketiminate ligands.26
Regardless to the precise nature of the reductive elimination, III
formed from halogen atom abstraction can re-enter the catalytic
cycle by a comproportionation reaction with VII to complete the
catalytic cycle by regenerating I and forming an equivalent of II. The
selectivity determining step is radical recombination to form V
and/or reductive elimination.27 Currently, we cannot rule out either
step as the selectivity determining step, but what is clear from our
mechanistic experiments is that the enantiodetermining step(s)
occurs from a single metal centre.
We favour the mechanism shown in Figure 3 as opposed to
other mechanisms that utilize one metal complex throughout the
catalytic cycle for several reasons. One possibility is radical
recombination occurs after halogen atom abstraction from iron(II)
aryl species IV (Figure S6). In such a mechanism, an iron(IV)
intermediate would be formed, which is unlikely under the reducing
Figure 2. Effects on yield (closed symbols) and er (open symbols) of 2 for
the coupling reaction between 1-chloroethylbenzene and 2-
napthylboronic pinacol ester catalysed by 1 in the absence (circles) and
presence (squares) of 1,3,5-TMB (1 equiv.) at -15 C. Ultimate yields are
90% and 75% with and without 1,3,5-TMB, respectively.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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reaction conditions. Another alternative would be C–C bond
formation through an outer sphere radical rebound mechanism to
form the C–C bond (Figure S7). This mechanism avoids forming an
iron(IV) intermediate, but the radical rebound step would be the
selectivity determining step of the reaction if this mechanism were
operative. We disfavour such a step as the selectivity determining
step because it is very similar to the microscopic reverse of halogen
atom abstraction, which is an unselective event. Instead, we favour
the bimetallic mechanism shown in Figure 3 that resembles similar
mechanisms previously proposed for cross coupling reactions
catalysed by iron34a-b and nickel24,28 complexes.
Notes and references
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DOI: 10.1039/D0CC05003B
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O
O
2
N
N
Ar’-B(pin)
Fe
Ph
Ph
Ar
LiNR2
O
NR2
CN
II
CN
X
O
O
O
R
N
N
N
N
Fe
Ph
Ph
Fe
Ph
Ph
unselective
Ar
X
Ar’
IV
CN
I
O
O
R
N
N
selective
Fe
Ph
Ph
R2N
X
CN
CN
+
III
O
H
O
O
O
N
N
N
N
Fe
Fe
Ph
L
Ph
Ph
Ph
Ar’
L
L = solvent, LiNR2, 1,3,5-TMB
CN
Ar
R
VII
V
O
O
N
N
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R
Ar
H
Fe
Ph
Ph
L
Ar’
Ar’
H
Ar
R
VI
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Figure 3. Proposed catalytic cycle for the Suzuki-Miyaura cross-coupling
between benzylic halides and arylboronic pinacol esters catalysed by
iron-cyanobis(oxazoline) complexes.
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synthesize enantioenriched 1,1-diarylalkanes was developed. The
method relies on an iron-based catalyst that proceeds through a
stereoconvergent cross-coupling mechanism between racemic
benzylic chlorides and unactivated aryl boronic esters. The anionic
cyano(bisoxazoline) ligand and 1,3,5-TMB additive employed were
important to extend catalyst lifetime so that high yields could be
obtained. In addition to being the first catalyst reported for this
transformation, the iron-based catalyst demonstrates reactivity that
expands the substrate scope compared to existing nickel-based
catalysts that have previously been developed.18a,18b Most notably
were the high selectivities observed for cross-coupling reactions
involving challenging ortho-substituted diarylalkane substrates.
Perhaps more importantly, the method expands the classes of
electrophiles that can engage in enantioselective cross coupling
reactions effected by iron-based cross-coupling catalysts.
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Conflicts of interest
There are not conflicts to declare.
27) Gutierrez, O.; Tellis, J. C.; Primer, D. N.; Molander, G. A.; Kozlowski, M. C.
J. Am. Chem. Soc. 2015, 137, 4896.
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Acknowledgments
Acknowledgment is made to the Donors of the American Chemical
Society Petroleum Research Fund for support of this research.
4 | J. Name., 2012, 00, 1-3
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