Reformatsky and Blaise reactions in flow as a tool for drug discovery. One pot diversity oriented synthesis of valuable intermediates and heterocycles

Article abstract of DOI:10.1039/c6gc02619b

The application of Reformatsky and Blaise reactions for the preparation of a diverse set of valuable intermediates and heterocycles in a one-pot protocol is described. To achieve this goal, a greener activation protocol for zinc in flow conditions has been developed to introduce this metal efficiently into α-bromoacetates. The organozinc compounds were added to a diverse set of ketones and nitriles to obtain a wide range of functional groups and heterocyclic systems.

Full text of DOI:10.1039/c6gc02619b

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Reformatsky and Blaise Reactions in Flow as a Tool for Drug
Discovery. One Pot Diversity Oriented Synthesis of Valuable
Intermediates and Heterocycles.
Received 00th January 20xx,
Accepted 00th January 20xx
L. Huck,a,b M. Berton,a A. de la Hoz,b A. Díaz-Ortizb and J. Alcázara
DOI: 10.1039/x0xx00000x
www.rsc.org/
The application of Reformatsky and Blaise reactions for the both cases, initiation of the reaction requires activation of the
preparation of diverse set of valuable intermediates and zinc metal and this process is usually associated with
a
heterocycles in a one-pot protocol is described. To achieve this exothermal runaway issues that can continue during the
goal, a greener activation protocol for zinc in flow conditions has addition of the corresponding reagents.
O
S
O
S
been developed to introduce this metal efficiently into α-
bromoacetates. The organozinc compounds were added to a
diverse set of ketones and nitriles to obtain a wide range of
functional groups and heterocyclic systems.
R3
N
O
HN
O
N
R1
N
N
Zn
H2
O
Br
O
H2
N
O
O
F
Br
Br
F
R2
F
HSP90 inhibitors
O
Diversity Oriented Synthesis (DOS) has recently been identified
as a tool for the discovery of novel, biologically interesting
small molecules and it increases the likelihood of finding
R
HN
MeOOC
O
O
O
O
O
N
H
O
O
O
Br
Zn-Cu
O
O
O
O
OH
CO2Me
O
modulators for
a A
broad range of biological targets.1
H
OH
OH
H
OH
R= H, Me
Novel bicyclic nucelosides
52%
fundamental requirement for DOS is the availability of
synthetically versatile starting materials that are capable of
undergoing a variety of chemical transformations to convert
them into several products with different molecular skeletons
through the variation of reagents alone.2 Thus, diverse
syntheses of heterocyclic scaffolds in one-pot protocols prior
to further modifications are highly desirable in Medicinal
Chemistry.3
Scheme 1. Reformatsky reaction for biologically active
products.
In recent years, flow chemistry has become established as an
enabling technology that, amongst other advantages, allows
very efficient heat transfer, good control of reaction
temperature and enhanced mass transfer.6 These
characteristics overcome the problems associated with highly
exothermic reactions and dangerous or air- and moisture-
sensitive compounds, which are commonly present in
Reformatsky and Blaise reactions. Moreover, in continuous
flow reactors the levels of hazardous waste are reduced. The
Suitable procedures for C–C bond formation are key elements
in DOS. The Reformatsky and Blaise reactions are very useful
tools for this purpose as new C–C bonds are formed under
mild conditions and the reactions have good functional group
tolerance. For this reason, these reactions have been used in
the synthesis of biologically active products (Scheme 1).4
However, two main drawbacks limit the application of these
reactions in a more general way. The first is the formation of
ability to optimize
a reaction using small quantities of
reactants minimises the waste generated during the screening
and decrease the volume of waste generated at the clean-up
steps. This effect is enhanced by the use of catalysis.7 These
characteristics make this technology a green and sustainable
alternative in chemical research and production.
by-products, such as self-condensation of the
α
-bromoester
-alkoxyzinc
and retro-aldol condensation of the intermediate
ester in the case of the Reformatsky reaction.5 The second
β
drawback is safety concerns with these transformations. In
Despite the interest in these transformations only two
approaches in flow protocols have been described to date in
the literature. The first study was reported in 1974.8 The
authors presented an imaginative solution for the Reformatsky
reaction by continuously dropping the reagents through an
addition funnel onto the top of a tube containing the zinc
metal. The products were collected at the bottom of the tube
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in a flask containing refluxing benzene. In this way, benzene These optimized conditions were used to explore the reaction
was used as both the solvent and the heat source for the scope using different acetophenones (Figure 1). The
whole set up. The authors reported good to excellent yields of Reformatsky reaction has been explored extensively in batch
the corresponding Reformatsky products, but only eight and effort was therefore focused on those substrates that
examples were reported. The lack of control of some reaction could be of interest from a medicinal chemistry point of
parameters, such as residence time, probably limits the view.11 In this way, ester 3ba, trifluoromethyl 3ca, halide 3da
applicability of this imaginative approach. and methoxy 3ea groups were compatible with the flow
,
More recently, Ley and co-workers disclosed the use of the protocol and products could be obtained in good yields. It is
Reformatsky reaction between an allylbromide and an Ellman worth highlighting that the reaction also tolerated the
sulfoximine for the preparation of sacubitril.9
presence of other reactive groups such as alkyl chlorides (3ha),
After our seminal work on the preparation of organozinc which would allow further modification at that position. The
reagents in tetrahydrofurane (THF) with a packed zinc column reaction was not limited to aromatic ketones as aliphatic
under flow conditions,10 we decided to explore the insertion of ketones were also well tolerated (3fa and 3ga). The use of
this metal into α-bromoesters. For this purpose we selected heterocycles, such as pyridines, in this reaction has rarely been
the Refomatsky reaction as the starting point and optimized described in the literature.11b,12 However, these compounds
the zinc activation and reaction conditions for ketones and
bromoesters.
α
-
are quite important for medicinal chemists. On using the
current methodology acetylpyridines provided the
-hydroxyesters (3ia 3la) in good to excellent
The key factor for the insertion of zinc into a halogenated corresponding
β
–
derivative is the activation protocol. On using the previously yields at 80 °C with LiCl as an additive in order to complete the
reported activation10 ethyl zincbromoacetate concentrations reaction and avoid blockage of the system.
up to 0.15 M were obtained (see supporting information). This
procedure was improved by using a single solution containing
both activating reagents (chlorotrimethylsilane and 1-bromo-
2-chloroethane) at 40 °C. The reagent solution was introduced
directly after activation to obtain the desired organozinc
compound at concentrations up to 0.45 M. Not only an higher
concentration was obtained, but 1,2-dibromoethane was
avoided in the activating protocol and also the amounts of
activator and solvent used were reduced by 75%.
Once the activation had been optimized, a solution of
acetophenone 1a and ethyl bromoacetate 2a was passed
through the zinc column at 40 °C with a calculated residence
time of 3 minutes (Table 1, entry 1). Reaction did not occur
under these conditions and it was decided to increase the
temperature and time simultaneously. It was observed that at
60 °C, with a residence time 6 minutes, the product was
obtained in an acceptable conversion (entry 2). Further
optimization of temperature, time and equivalents of
bromoester allowed us to obtain the product in 92% isolated
yield (entry 4).
Table 1. Optimization of the Reformatsky reaction.
Entry
T (°C)
40
Time (min)
2a (Equiv.)
Conv.a (%)
No reaction
56
1
2
3
4
3
6
1.5
1.5
1.5
2
60
Figure 1. Scope of the Reformatsky reaction.
60
10
82 (78)b
100 (92)b
The scope of different
including molecules containing substituents in the
such as fluorine, methyl or cyclic ester (3ab 3ag). Good to
excellent yields were obtained in all cases. When an
α
-bromoesters was also studied,
60
10
α
-position,
a Conversion by LCMS. b Isolated yield in brackets.
-
α,α-
difluoro-substituted ester was used, compound 3ag was
obtained in an acceptable yield at 100 °C using LiCl as an
2 | J. Name., 2012, 00, 1-3
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additive. This result is remarkable as it is consistent with The use of diazo compounds is potentially hazardous, although
others reported the literature, but in our flow protocol there is the combination with flow chemistry clearly decreases the
no need to use other metal catalysts or additives,13 thus associated risks.
making this approach more sustainable.
The initial attempt was based on the previous Reformatsky
It is worth noting that the reaction involving 4-chloro-1- conditions using nitrile 5a and ethyl bromoacetate 2a, but only
phenylbutan-1-one
gave
novel
2,2-disubstituted 47% conversion to compound 6aa was observed (Table 3,
etrahydrofurans 4ma–4me under very mild conditions (Figure entry 1). An increase in the residence time in the column did
2). The scaffolds obtained in this ring-closing reaction were not improve the outcome of the reaction (entry 2). For this
quite novel as only a few examples have been reported in the reason it was decided to add a coil reactor to complete the
literature to date. The ester motif present in the molecules can addition of the organozinc reagent to the nitrile (entry 3). This
be considered as a vector for further derivatization.
modification of the setup clearly improved the conversion to
product. Refinement of the residence time, temperature and
equivalents of bromoacetate 2a provided the best conditions
(entry 6).
Table 3. Optimization of the Blaise reaction in flow.
O
O
THF
O
CN
HCl
O
Br
Zn
T1
+
O
6aa
T2
2a
5a
Figure 2. Synthesis of tetrahydrofurans in one step.
5 mL
Entry T1 (°C)
T2 (°C)
---
Time (min)
Equiv. 2a
Conv. (%)
Scale-up of the Reformatsky reaction was also studied. For this
purpose, the reaction of ketone 1a and bromoacetate 2a was
allowed to run for several hours through a column filled with
12 g of metal. In this example, the throughput of 3aa obtained
was around 3.5 g/h and the same isolated yield was obtained
(92%). Only when 75% of the solid zinc was consumed did the
yield drop to 83%. Nevertheless, at this point of the reaction,
22 g of the desired product had been isolated. The remaining
metal in the column was not disposed, the column was then
refilled, reactivated and used in subsequent experiments. To
prove the sustainability of this protocol the space-time
yield6d,14 was calculated and compared to a recent procedure
described in batch for the same compound 3aa in the same
solvent15 (Table 2). Calculations provided a 32 times better
outcome for the flow protocol, thus demonstrating the
improved sustainability and scalability of the process in flow.
1
2
3
4
5
6
7
8
9
60
60
40
40
60
60
60
60
80
3
1.5
1.5
1.5
2.5
1.5
2.5
2.5
2.5
2.5
47
45
80
82
75
86
81
76
54
---
6
120
120
120
120
120
120
120
16
16
16
16
20
25
16
These reaction conditions were used to explore the scope of
the reaction. Different substituents on the aromatic ring, such
as methoxy (6ba and 6fa), trifluoromethyl (6ca), and bromine
Table 2. Preparation compound 3aa in batch and flow.
Flow
92%
Batcha
(
6da), were well tolerated. Different alkyl groups were
Yield
94%
evaluated to extend the scope of the reaction further. For
instance, 4-cyanopiperidine and 5,5,5-trifluorovaleronitrile
were employed and compounds 6ga and 6ja were obtained in
80% and 56% isolated yields, respectively. The reaction is also
Reaction Time
10 min
10.5 g/3 h
1.55 M
3 h
Product Throughput
324 mg/3 h
0.33 M
[1a
]
Space-time Yieldb
700 mg/h·mL
21.6 mg/h·mL
compatible
with
different
heterocycles.
2-
a
b
Batch results from reference 15. Calculated according to
Thiophenecarbonitrile reacted nicely to produce compound
6ea in 93% yield. However, in the case of pyridinecarbonitriles
5h–i the reaction proceeded to product but these precipitated
in the coil and clogged the system. The same outcome was
observed when other solvents, solvent mixtures and additives,
references 6d and 14.
Another approach with great potential in medicinal chemistry
is the use of nitriles as electrophiles to prepare β-ketoesters,
namely the Blaise reaction.16 This class of compounds has a
broad application in the synthesis of biologically active
products and, amongst other alternatives, the Blaise reaction
appears to be one of the most appealing from a sustainability
such
as
dimethylsulphoxide
(DMSO),
toluene,
dimethoxyethane (DME), THF/DMA 1/1, and a 0.5 M solution
of LiCl, were screened. Other known alternatives to dipolar
aprotic solvents, such as acetonitrile and alkylcarbonate
solvents, were not attempted in the Blaise reaction because
they can interfere in the reaction. In flow reactions where
point of view.17 For instance, synthesis of
β-ketoesters in flow
from diazoacetates and aldehydes was recently reported.18
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products are insoluble in THF, the best results were obtained Scheme 2. Blaise reaction as a tool for DOS.
with DMA,‡ which provided the corresponding products 6ha
and 6ia in high yields. However, as this solvent has been One of the key advantages of flow chemistry is the possibility
identified as a Substance of Very High Concern, it is clear that of controlling unstable intermediates as they can be reacted as
there is a strong need for better alternatives to solvents like they are formed. In order to explore this opportunity, the
DMA, DMF. The compatibility of the reaction with different Blaise reaction on alkyl bromonitrile 5k was performed. The
bromoacetates was also explored (compounds 6gb
,
6jb and enamine intermediate formed in this reaction is reported to
follow in situ intramolecular C- or N-alkylative reactivity
profiles.19a,b On using the flow protocol described here, the
enamine intermediate could be trapped using phenylhydrazine
6jf).
as
a nucleophile to obtain the corresponding bicyclic
pyrazinone 12 in good yield (Scheme 3). Due to the reactivity
of the resulting enamine, the temperature of the coil was
reduced to 60 °C to avoid the formation of intramolecular
alkylation products. In this way, the reactivity profile of these
intermediates can be reversed using flow to obtain different
compounds to those described previously.
Scheme 3. Controlling reactivity of Blaise reaction using flow.
Conclusions
In summary, a broad-scope flow version of the Reformatsky
and Blaise reactions has been developed. The procedure is
based on an improved and safe on-column activation of zinc,
which produces very pure organozinc derivatives, prior to the
one-pot reaction with the corresponding electrophile. The
protocols have a broad scope and aliphatic, aromatic and
heteroaromatic ketones and nitriles can be used. It is worth
highlighting the heteroaromatic examples as they are the most
challenging and valuable compounds, which are rarely
described in the literature. Different bromoacetates are
Figure 3. Scope of the Blaise reaction.
The intermediates obtained in the Blaise reaction can be
considered as examples of versatile tools for DOS purposes in
tandem transformations.3 It has been demonstrated that the
enamine form can be trapped with different electrophiles.19
However, the nucleophilic trapping of the imine form has not
been described to date. This kind of trapping would yield
different heterocycles and intermediates to the ones obtained
by electrophilic reactions. To demonstrate this point, nitrile 5a
and bromoacetate 2a were allowed to react and the output
from the reactor was collected over different reagents to
explore the approach in a one-pot procedure (Scheme 2).
When the reactor output was collected over hydroxylamine,
suitable for the protocol – including α-substituted compounds.
When -chloroketones were used the corresponding 2,2-
γ
disubstituted tetrahydrofurans were obtained directly from
the column as potential novel valuable cores for drug
discovery. The imine-enamine intermediate obtained in the
Blaise reaction was trapped with different nucleophiles and
electrophiles to provide several valuable heterocycles and
intermediates for medicinal chemistry in a one-pot protocol
that combines the capabilities of flow chemistry and parallel
batch approach. Up to 8 different compounds have been
obtained by flowing compounds through a zinc column
followed by appropriate trapping. The scope included 5-
membered and 6-membered heterocycles, saturated or
unsaturated, bicyclic cores and linear compounds, thus
demonstrating the value of this procedure for DOS. The safe
use of organozinc compounds, a reduced need for solvents,
efficient heat and mass transfer, and simple scale-up all make
the isoxazolone
methylhydroxylamine provided oxime
imine-enamine with phenylhydrazine
8
was obtained. Collection over O-
. Treatment of the
yielded the
9
corresponding N-phenylpyrazolone 10. Electrophilic trapping
using propiolates was also possible and this provided the
corresponding pyridone 11
.
this procedure
a greener alternative to the traditional
synthetic protocols.
4 | J. Name., 2012, 00, 1-3
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The authors thank Prof. D. Tyler McQuade, Dr. Nerea Alonso, Dr.
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in the preparation of this manuscript and Dr. José Manuel Alonso
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‡ DMA Warning! May cause respiratory tract irritation.
Hygroscopic (absorbs moisture from the air). Causes eye and
skin irritation. Combustible liquid and vapour. Harmful if
absorbed through skin or if inhaled. May cause harm to the
unborn child. Target Organs: Blood, kidneys, central nervous
system, liver. Wear appropriate protective eyeglasses, gloves
and clothing.
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