A Practical Method for Continuous Production of sp3-Rich Compounds from (Hetero)Aryl Halides and Redox-Active Esters

Article abstract of DOI:10.1002/chem.201905048

A practically useful coupling reaction between aromatic halides and redox-active esters was realized by nickel catalysis through the use of a packed zinc bed column in continuous flow. Multiple reuse of the column showed a negligible decrease in efficiency, affording high space/time yields. A wide range of substrates, including a number of heteroaryl halides and polyfunctional materials were coupled in generally good yields. Longer-time and larger-scale experiments further demonstrates the robustness of the system.

Full text of DOI:10.1002/chem.201905048

A Journal of
Accepted Article
Title: A practical method for continuous production of sp3-rich
compounds from (hetero)aryl halides and redox-active esters
Authors: Yiding Chen, Eiichi Watanabe, Oliver May, and Steven Victor
Ley
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201905048
Link to VoR: http://dx.doi.org/10.1002/chem.201905048
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A practical method for continuous production of sp3-rich
compounds from (hetero)aryl halides and redox-active esters
Eiichi Watanabe[a]‡, Yiding Chen[b]‡, Oliver May[b] and Steven V. Ley*[b]
Abstract: A practically useful coupling reaction between aromatic
halides and redox-active esters was realized via nickel catalysis
through the use of packed zinc bed column in continuous flow.
Multiple reuse of the column showed a negligible decrease in
methods,[14] and with the availability of newly developed flow
columns packed with metallic zinc,[15] we decided to further
explore their deployment in cross-coupling sequences. We
believe using zinc bed columns to be superior to typical batch
procedures for several reasons, especially avoiding excessive
use of zinc powder, problems during downstream processing and
the difficulty of controlling exothermic reactions. Here, we report
a simple, practical improvement to general nickel-catalyzed
decarboxylative cross-coupling processes by utilizing a zinc bed
column in a continuous flow system. This robust procedure
enables access to a wide variety of 3D rich molecules starting
from versatile (hetero)aryl halides, and redox-active esters which
are themselves easily prepared from corresponding carboxylic
acids in flow.
efficiency, affording high space/time yields.
A wide range of
substrates, including number of heteroaryl halides and
a
polyfunctional materials were coupled in generally good yields.
Longer-time and larger-scale experiments further demonstrates the
robustness of the system.
Developing molecular complexity is an important aspect of
modern drug discovery programs and has been associated with
success in progressing compounds into clinical development[1] by
improving target selectivity[2] and safety.[3] Increasing the number
of sp3 centers similarly enhances the three-dimensional
complexity, again improving success rates.[4] As a consequence，
practical and simple methods to construct C(sp3)-C(sp2) bonds
are of fundamental importance.[5] A seminal contribution to this
field was reported by MacMillan and Doyle who utilized an Ir-
photoredox/Ni dual catalyst system to achieve decarboxylative
C(sp3)-C(sp2) cross coupling (Figure 1).[6] In this reaction, the
synergistic combination of photoredox catalysis and nickel
catalysis forges 3D-rich structures from simple and readily
available organic molecules. More importantly, carboxylic acid
starting materials have a higher accessibility compared to other
conventional cross-coupling partners.[7] Following this pioneering
report, synthetic methods that enable medicinal chemists to
generate C(sp3)-enriched compounds by these decarboxylative
pathways have been widely explored.[8] Among these alternative
approaches, Weix et. al reported the use of zinc powder as a
reducing reagent,[9] therefore avoiding expensive iridium
Figure 1. C(sp3)-C(sp2) coupling of redox-active ester and carboxylic acid
catalysts,[6] or the need for preformed pyrophoric organozinc
Pre-activation of the zinc packed Omnifit® cartridge followed a
protocol developed by Alcázar et. al,[15] whereby a solution of
TMSCl and 1-bromo-2-chloroethane in THF was flushed through
the system (See Supporting Information for detailed procedure).
Our initial study utilized similar conditions to the batch procedure
reported by Weix et. al for comparison,[9a] where a mixture of 1-
chloro-4-iodobenzene 1a, redox-active ester 2a together using
NiCl2 glyme complex and di-tert-butyl-2,2-bipyridine ligand in
DMAc were passed through a packed zinc (30 mesh) column with
a residence time of 40 min led to a modest 49% yield of the
coupled product 3a (Table 1, entry1). Subsequent ligand
screening highlighted L1 as being superior, giving an improved
the yield of 98% (entry 2). Encouraged by this success, attempts
were made to shorten the residence time of the reaction in order
to achieve a faster overall cross-coupling process. Following on
an extensive study of residence time and examining various
grades and combinations of zinc powder (see Supporting
Information, Table SI1, Figure SI1), using a mixture of 30 and 325
8d, 11]
reagents[10] and photo-/electrochemical reactors.[8c,
More
recently, Fier et. al also described a metallic zinc mediated cross-
coupling reaction between aryl bromides and redox-active alkyl
sulfones.[12] Despite the relevance and the effectiveness of these
discoveries, activated zinc powder can be challenging to work
with on large scales mainly due to issues of surface variation and
safety.[13] Given our expertise in continuous processing
[a]
[b]
‡
Dr Eiichi Watanabe
New Path Molecular Ltd.
Building 580
Babraham Research Campus, Cambridge (UK)
Dr Yiding Chen, Mr Oliver May, Prof Steven V. Ley
Department of Chemistry, University of Cambridge
Lensfield Road, Cambridge (UK)
Email: svl1000@cam.ac.uk
Aurthors contributed equally
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201905048
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8d],[16]
mesh of zinc powder successfully reduced the residence time
(Table 1, entry 3 – 6) to only 10 min. Furthermore, more than 10
times reuse of the zinc column showed no lost in efficiency (entry
7). Control experiments demonstrated that both the nickel catalyst
and the ligand were necessary for reaction to occur (entry 8, 9). It
is also worth noting that the preparation of reaction mixture does
not require the use of a glove box or specially dried solvents. The
shorter reaction time in flow (10 min) to a comparable batch (12
h) procedure is noteworthy.
3f and 3g in good yields.[8c,
Trifluoromethoxy 3h and
trifluoromethyl product 3i exemplified the tolerance for electron-
withdrawing groups. With respect to functional-group compatibility,
aryl iodides containing nitrile 1j, ketone 1k, ester 1l, amide 1p and
phenol 1q functionality, some of which can sometimes be
problematic in Kumada and Negishi type coupling, were all well-
tolerated under our cross-coupling conditions.[8b] Variations in the
position of substituents on the phenyl ring led to meta-substituted
compound 3m with 93% yield, while ortho-coordinating groups,
such as ester (3n) and phenyl (3o) led to slightly diminished yield
of 85% and 89% respectively.[16] To further illustrate the
Table 1. Reaction Optimisation
entry
ligand
mesh
tR (min)
LC yield (%)
1a
32
0
3a
1
2
3
4
5
Dtbpy
L1
30
30
30
20
40
40
30
20
20
49
98
100
81
95
L1
0
L1
14
4
L1
30/325
(11:2)
robustness of the protocol, we found that crude redox-active
esters, e.g. 3a, prepared from corresponding carboxylic acids
afforded comparable yields to using the pure isolated active
esters.
6a
7b
8
L1
30/325
(11:2)
10
10
10
10
0
100
100
0
L1
30/325
(11:2)
0
Figure 2. Scope on aryl iodides
none
none
30/325
(11:2)
30
28
9c
30/325
(11:2)
0
Crucial to the success of this method is that heteroaryl halides as
coupling substrates, including several reactive substrates, were
well tolerated. The resulting coupled products were obtained in
good to excellent yields (Figure 3).[17] 4-Iodopyridine derivatives
(1r-t) all gave the corresponding products in useful yields. Among
a) After 3 times use. b) 10 times use. c) Without nickel catalyst
Under optimized conditions, we then assessed the scope of the
reaction with various aryl iodides (Figure 2). Apart from 1-chloro-
4-iodobenzene 1a, 1-bromo-4-iodobenzene 1b also acting as
suitable reaction partner to afford the corresponding coupled
product of 3b nicely illustrating the chemoselectivity of the
process. It is also worth noting that 3b and the boronic pinacol
ester product 3c, both serve as precursors for future
diversification through conventional cross-coupling reactions.
Iodonaphthalene 1d and iodophenanthrene 1e also delivered the
corresponding products in an excellent 90% and 91% yield
respectively (3d and 3e). Electron-donating groups such as 4-
iodoanisole 1f and 4-iodothioanisole 1g, which often failed as
coupling partners for similar nickel catalyzed reductive cross-
coupling reactions, here were able to obtain the desired product
these
a gram scale synthesis of 4-(4-piperidinyl)-pyridine
analogue 3t was achieved, whose structure is frequently found in
many functional materials but conventionally requires a 4-step
synthetic sequence from commercially available starting
materials.[18] The crude product was treated with basic a workup
followed by a A-15 resin extraction. The desired product was
acquired in 61% yield with high purity without the need for silica
gel chromatography. Coupling between 3-iodopyridyl substrates
(1u-x) and various redox-active esters were all successful (3u-x),
especially using activated 2-bromo-5-iodopyridine (1v). Although
in this example a trace of 2-substituted byproduct was detected
under the reaction conditions. Lowered yields were noticed when
coupling with 2-iodopyridyl substrates (1y-1aa), where
dehalogenated pyridines were byproducts. Nonetheless a good
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chemoselectivity between bromo- and iodo-substitutions was
clearly demonstrated (3aa). 5-Substituted quinolines (3ab and
3ac) and 4-substituted pyrimidines (3ad and 3ae) were obtained
in good to excellent yields. Particularly worth noting is with aryl
bromide 1ae and 1af, the coupling here could be readily achieved
with bromide substrates using a higher loading of catalyst and an
elongated residence time to give the desired product 3ae and 3af
in 80% and 57% yield respectively, while 3af could not be
obtained from the corresponding iodide. Several other
heteroaromatic coupling partners, for example carbazole 1ag, 5-
iodoindole 1ah as well as the more reactive 3-iodoindoles 3ai and
3aj all produced useful results.
natural products are compatible with the reaction conditions
affording the anticipated cross-coupled product in good yields
(3az-bd). Interestingly, the reaction of redox-active ester 2bd
obtained from gabapentin, provided an unusual product which
was thought to be generated via a 1,5-hydrogen atom transfer
(1,5-HAT) prior to nickel mediated cross-coupling (Figure 4a). As
noted by others,[8d, 9a] the limitation of this procedure was the lack
of reactivity towards tertiary redox-active esters.[20] Adamantane
carboxylic acid and tert-butyl carboxylic acid phthalimide ester
both failed to deliver desired product under our standard
conditions.
Figure 3. Scope on heteroaryl halides
To further exemplify the potential of the reaction, we expanded
the scope with respect to redox-active ester coupling partners
using a few different (hetero)aryl iodides (Figure 4). In addition to
tetrahydropyranyl 2a substrate, other saturated heterocyclic
examples were also viable coupling partners, including N-boc
piperidine 1ak and N-cbz piperidine 1al, providing excellent yields
for the desired C(sp3)-C(sp2) cross-coupling products (3ak and
3al). Comparable reaction efficiency was also observed with
carbocyclic examples 3am and 3an. Primary substituted redox-
active esters underwent successful coupling in high yield despite
the inherent reluctance to generate primary alkyl radicals via
single-electron-transfer process SET.[19] A series of related
compounds were generated, including long-chain alkyl chloride
3ap, mono-(methylacryloylxy)ethyl succinate derivative 3aq,
pyrene containing 3ar, simple alkene 3as, furan 3at, and amino
acids 3au and 3av. α-Amino phthalimide esters 1aw-ay that
generate reactive α-amino C(sp2) species, coupled without
incident, resulting in high yields of 3aw-ay. Of particular note also
was that some active pharmaceutical ingredients (APIs) and
Figure 4. Scope on redox-active esters
To best demonstrate the advantage of this method was its ability
to transfer to a larger-scale experiment. Equipped with a longer
column (i.d.=10.0 mm, length = 120 mm), the reaction set-up was
kept operating for 31 hours to deliver a 11.77 g target product.
After the reaction, the remaining zinc was still functional without
noticeable decline of efficacy. It was also noticed that a small
amount of bicyclohexyl byproduct was produced, presumably
from the radical dimerization of redox-active ester.
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Scheme 1. 10 g-scale synthesis
In summary, we have identified a procedurally simple use of a zinc
packed column as an alternative reductant to photo- or
electrochemical reactor or organometallic reagents for forging
C(sp3)-C(sp2) bonds starting from aryl halides and redox-active
esters. The method is practical and robust, and provides
enhanced substrate compatibility over previously reported
examples. Furthermore, the use of crude redox-active esters
accelerated the synthesis of highly 3D-rich structures from
carboxylic acids and (hetero)aryl halides. Notably, the work
features the ease of scale up by harnessing continuous flow
conditions.
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Y. C. thanks Pfizer for funding the postdoctoral fellowship. The
authors also gratefully acknowledge financial support from
H2020-FETOPEN-2016-2017
commission (SVL; grant agreement number: 737266-ONE
FLOW).
programme
of
European
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Keywords: Continuous flow, redox-active ester, cross-coupling,
packed-column
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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Eiichi Watanabe[a]‡, Yiding Chen[b]‡
Oliver May[b] and Steven V. Ley*[b]
,
Page No. – Page No.
A practical method for continuous
production of sp3-rich compounds
from (hetero)aryl halides and redox-
active esters
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