Flow-Assisted Synthesis: A Key Fragment of SR 142948A

Article abstract of DOI:10.1002/ejoc.201700904

We report a series of multi-step flow operations to deliver an advanced hydrazine intermediate used in the assembly of the neurotensin modulator SR 142948A. Several new reactor configurations have enabled chemical transformations that would be otherwise difficult or dangerous to perform at scale. Overall the flow approach has allowed the preparation of kilogram quantities of the required hydrazine through a short and efficient route.

Full text of DOI:10.1002/ejoc.201700904

A Journal of
Accepted Article
Title: Flow Assisted Synthesis: A key Fragment of SR 142948A
Authors: Matthew Oliver Kitching, Olivia E Dixon, Marcus Baumann,
and Ian Richard Baxendale
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700904
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700904
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European Journal of Organic Chemistry
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Flow Assisted Synthesis: A key Fragment of SR 142948A
Matthew O. Kitching, Olivia E. Dixon, Marcus Baumann, and Ian R. Baxendale*[a]
missing fragment 6 is presented in figure 2, which would ideally
be accessed in a multi-step synthesis from the commercial and
readily available starting material 2-isopropyl aniline (10).
Abstract: We report a series of multi-step flow operations to deliver
an advanced hydrazine intermediate used in the assembly of the
Neurotensin modulator SR142948A. Several new reactor
configurations have enabled chemical transformations that would be
otherwise difficult or dangerous to perform at scale. Overall the flow
approach has allowed the preparation of kilogram quantities of the
required hydrazine via a short and efficient route.
Introduction
Neurotensin (NT, 1) is an endogenously expressed
tridecapeptide first isolated from bovine hypothalamii in 1973.[1]
NT has many roles regulating numerous biological processes
including temperature control,[2] pain sensation,[3] modulation of
appetite[4] and pituitary hormone secretion.[5] As a modulator of
the bodies dopaminergic systems, disruption of NT’s binding has
also been proposed as a possible route to intervention in
disease such as schizophrenia and Parkinson’s.[6] Furthermore,
up regulation of NT receptor (NTR) expression has been
Figure 1. Structures of Neurotensin (1), Meclinertant (2), and SR 142948A (3).
reported to occur in various cancers: Lung,[
7]
Breast,
[8]
Pancreas,[ Pituitary and Prostate therefore investigation of its
physiological mechanisms is an important area of study.[11]
Unfortunately, as a potential therapeutic and investigative tool
NT itself has several drawbacks. As a oligopeptide, NT has
inherent poor stability in vivo and is degraded by several
common endopeptidases and metalloproteases.[12] Its size also
prevents easy passage across the blood brain barrier resulting
in poor bioavailability requiring injection of NT directly into the
CNS[13] and finally, NT is only capable of NTR agonism.
Consequently synthetically viable, easily modified small
molecule probes capable of tailored interaction with the NTR
9]
[10]
Figure 2. Synthetic fragments of SR 142948A (3) and proposed retrosynthesis
of hydrazine 6.
(
agonist/antagonist) represent powerful investigatory tools in
medicinal chemistry.
As part of our synthetic efforts to prepare a tool box of NT
molecular probes we have already explored the preparation of
Meclinertant (2), a NT modulator using a flow chemistry
approach.[ In an extension of this work we herein disclose
efforts towards a synthetically more challenging derivative SR
Results and Discussion
14]
Our strategic plan approach was to perform an acylation on the
commercially available isopropyl aniline (10), necessary to
regulate the subsequent bromination step and furnish selectively
intermediate 8. This would then enable either a cyanation or
carbonylation followed by hydrolysis to access the desired
carboxylic acid 7. Diazotisation and direct reduction would then
yield the corresponding hydrazine product 6. Although
encompassing conceptionally straightforward chemistry many of
these transformations have intrinsic risks associated, especially
when conducted at scale such as exotherms (acylation step), or
issues due to hazardous (diazotisation) or toxic (carbonylation,
cyanation) reagents/intermediates. It was anticipated that
through the adoption of flow processing techniques these risks
could be managed, minimized or completely avoided.
1
42948A (3).[15] We envisaged a convergent synthesis allowing
assembly of this new derivative 3 from three fragments (4-6,
Figure 2), two of which were common to the previous
Meclinertant synthesis (4 & 5), and had already been prepared
at scale.[16] The general retrosynthetic disconnection of to the
[
a]
Dr Matthew O. Kitching, Miss Olivia E. Dixon, Dr Marcus Baumann,
and Prof. Ian R. Baxendale
Department of Chemistry
University of Durham
South Road, Durham, DH1 3LE. UK.
E-mail: i.r.baxendale@durham.ac.uk
Supporting information for this article is given via a link at the end of
the document.
The initial acyl protection of aniline (10→9) was associated with
a large exotherm when dichloroethane solutions of acetic
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European Journal of Organic Chemistry
10.1002/ejoc.201700904
FULL PAPER
anhydride (1.73 M; 3 mL/min; 1.1 equiv.) and aniline 10 (1.57 M;
In total over 120 L of organic solution was processed in a
continuous operation over the course of 167 h (~ seven days)
generating an isolated mass of 11.52 kg of product equating to
96% yield. Furthermore, we were able to establish a refilling
schedule for the input stock solutions (2.5-5 L batches) based
upon their consumption flow rates that enabled the efficient
recycling of recovered DCE from the final evaporation stage.
Consequently the process only required the use of 26.7 L of
DCE amounting to a significant reduction in the amount of
organic solvent used.
3
mL/min) were combined (Scheme 1). Indeed at equivalent
concentrations the reaction required active cooling to prevent
runaway in batch but instead could be easily performed in a
microfludic mixing chip as a flow process, which ensured good
thermal transfer to the surrounding environment. In this way, the
solution could be continuously processed maintaining
a
temperature <55 °C. Beneficially it was discovered that the
following bromination step (9→8) required heating to achieve
complete conversion and that by creating a sandwich assembly
from two additional mixing chips (inputs for the N-
bromosuccinimide) in direct thermal contact with the first
acylation reactor the excess heat produced in the acylation
could be used in a productive fashion to pre-warm the reaction
media for the second step (Figure 3).[17]
a)
b)
Scheme 1. Flow reactor schematic for the synthesis of brominated amide 8.
Figure 3. a) single layer microfluidic chip. b) sandwich chip device for thermal
transfer between reaction steps.
The reaction stream from the first acylation step was therefore
split and directly combined with input streams containing NBS in
dichloroethane (DCE) (0.94 M;
3 mL/min in two parallel
channels; 1.2 equiv.) (Scheme 1). The two flow streams were
reunited and then passed through a further residence time coil
Figure 4. In-line extractor used for organic-aqueous separation.
(
4 x 52 mL) maintained at 70 °C to ensure complete bromination.
The reaction mixture was then quenched and an in-line work-up
was performed (via two parallel streams) by mixing with a
stream of basic sodium sulfite and separated using a mixer-
settler membrane unit. The device was constructed around a
Biotage universal separator[18] which allowed the bifurcation of
the organic product containing phase and the aqueous waste
With kilogram quantities of the bromide 8 in hand, further
derivatization to the corresponding nitrile 11 was undertaken
employing
Experiments were initially evaluated using an automated
microwave setup. Initial investigation of reaction conditions
showed the importance of including a reductant in the reaction
mixture (Table 1: entries 1-4). In the absence of
a
palladium catalyzed approach (Scheme 2).20
(
Figure 4).[14a,19] Run as a continuous process this allowed the
isolation of the amide product 8 by direct evaporation of the DCE.
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European Journal of Organic Chemistry
10.1002/ejoc.201700904
FULL PAPER
polymethylhydrosilane (PMHS)[21] no conversion was observed
with either supported or solution phase catalysts. Screens of
common supported forms of palladium (Table 1; entries 5, 6, 8,
and 9) showed lower conversion and extended reaction times
compared to the use of solution phase palladium(II) acetate. A
Table 1. Optimisation of microwave cyanation conditions.
Ent.
1
Catalyst[a]
Temp
Additive
Solvent[c]
Time/h
3
1H NMR
Conv. %
°C
Pd(OAc)
2
80
dppf/
DMF/H
2
O
66
solvent screen determined a mixture of DMF/H
optimal results.
2
O (95/5) gave
PMHS
2
3
Pd(OAc)
2
2
80
80
dppf
DMF/H
DMF/H
2
O
O
3
3
0
Pd(OAc)
EnCat[
dppf/
PMHS
2
74
b]
4
5
6
7
8
9
Pd(OAc)
2
80
dppf
DMF/H
DMF/H
DMF/H
DMF/H
DMF/H
DMF/H
DMF/H
2
2
2
2
2
2
2
O
O
O
O
O
O
O
3
3
3
3
3
3
1
2
2
2
0
EnCat [
b]
Pd(OAc)
2
/d
80
PMHS
6
ppf EnCat [
b]
Scheme 2. Optimised batch conditions for synthesis of nitrile compound 11.
Pd-NP
EnCat
80
dppf/
PMHS
77
78
5
To process material on a semi-preparative scale, the automated
microwave reactor was utilized as a sequential batch process
reacting 39 mmol of substrate and allowing 6.8 g of nitrile 11 to
be isolated in 86% yield. Although this approach was convenient
for small laboratory scale preparation generating sufficient
material for further scoping studies, the observed low solubility
of the reagents (only becoming soluble as the reaction
progressed) led us to conclude that this would be a difficult
reaction to translate to continuous flow and therefore alternative
approaches were sought.
Pd(dba)
2
80
dppf/
PMHS
Pd(OAc)
2
80
dppf/
PMHS
Chemdose
Pd(OAc)
2
80
dppf/
PMHS
57
>98
73
63
75
EnCat
10
Pd(OAc)
2
120
120
120
120
dppf/
PMHS
The possibility of performing a carbonylation reaction was
investigated. Again, the initial investigation and optimization
work was conducted using an automated microwave setup. The
use of microwave vials allowed easy introduction of CO gas and
pressurization of the reaction mixture up to 5 bar. Both ethanol
and methanol could be successfully used in the transformation
however ethanol showed the highest conversion while
minimizing the amount of protodehalogenation (as determined
11
Pd(OAc)2
dppf/
PMHS
2
iPrOH/H O
12
Pd(OAc)
2
2
dppf/
PMHS
MeCN/H
2
O
13
14
Pd(OAc)
dppf/
PMHS
1,4-
dioxane/H
O
2
1
by H NMR analysis of the crude reactions).
Pd(OAc)2
120
120
120
120
120
dppf/
PMHS
2
H O
1
1
2
2
1
69
15
16
17
18
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
dppf/
PMHS
DMF
iPrOH
87
dppf/
PMHS
78
dppf/
PMHS
1,4-dioxane
75
Scheme 3. Optimised batch conditions for synthesis of ester 12.
Xantpho
s/
DMF/H
2
O
>98
PMHS
Using the microwave automation
a sequential run of 10
reactions allowed the processing of the bromide 8 on a 59 mmol
scale generating 12 g of material in 81% isolated yield (Scheme
[
a] Standard loading 2.2 mol%. [b] Loading 4.4 mol% based
upon Pd loading. [c] Solvent ratio 95:5
3). Additionally it was observed that the yield for each run was
consistent (indicating catalyst/substrate stability over time) and
the reaction mixtures remained essentially homogeneous
throughout the processing (some indication of Pd black
formation was noted). This immediately allowed us to consider
translation of the conditions to a flow based system.
The direct introduction of CO gas at high pressure to perform
carbonylation chemistry has been widely demonstrated using
several designs including simple tube-in-tube systems.[
However, although the handling and introduction of high
pressure gases to flow systems is achievable, safety restrictions
22]
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European Journal of Organic Chemistry
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may prevent the use of high pressure CO – as was the case for
ourselves. As such, the final design of our flow system was
restricted to a low pressure CO injection system and shows
certain engineering features that are worth highlighting as they
can be easily adopted to solve related issues commonly
encountered in other chemistries, for example the introduction of
semi-volatile amines.
exchange or cleaning of the thimble filter. Finally, the solution
pumped from the sedimentation tank was directed through a
column of QP-TU (a thiourea functionalised resin) to remove
residual metal contaminants before batch collection and solvent
evaporation. The crude product was directly triturated with a
mixture of water:ethanol 20:1 and filtered. The tan coloured solid
was air dried to yield the desired ester product in excellent purity
as assessed by H NMR and LC-MS. During a typical 8 h run
120 g of starting material could be processed in 87% isolated
yield equating to a productivity of 12.7 g/h (58.5 mmol/h).
1
The configuration of the flow reactor used is depicted in
Scheme 4. The system consisted of a mixing chip fed by an
ethanolic solution of the substrates, catalyst and base to be
blended with a low pressure (3 bar, 2.5 mL/min) input of CO
regulated via a flow meter.[23] A plug flow regime was generated
and used directly as the feed for a HPLC pump.[24] The pump
was used to up-regulate the pressure to 10 bar making the
reaction mixture homogeneous and delivering sufficient CO for
efficient carbonylation in the subsequent coil reactor stage
(
Polar Bear Plus[25] ~37 min; 120 °C). It was noted that during
the reaction colloidal palladium particles formed in the coil
reactor (additives like tetraalkyl ammonium salts, DMF and
alternative metal chelating ligands were investigated but failed to
have any effect on the process). This gave no issues with
reactor blocking through aggregation with the particulates being
efficiently progressed through the reactor even over prolonged
reaction periods. However, clogging of the inline backpressure
regulator (BPR), required to maintain the system pressure,
rapidly occurred. In addition, significant and uncontrolled
degassing was also an issue at the exit of the reactor; this was
made more problematic due to the particulates in the system
which were explosively jettisoned from the flow stream leading
to etching of the collecting vessel and creating containment
problems.
Scheme 4. Flow reactor design for carbonylation leading to ester 12.
Although delivering high quality material this approach didn’t
To overcome both of these issues we constructed a simple
membrane partitioned sedimentation tank which also acted as a
controlled gas exhaust. The unit was constructed from a
stainless steel pressure chamber with an embedded
thermocouple and pressure dial. An adjustable pressure release
valve was fitted into the cap to enable controlled discharge of
the CO gas.[26] In our first assembly the input feed delivered the
solution and particulates from the reactor into the sedimentation
chamber and the exit line was fitted with a polytetrafluoroethene
fulfil our target throughput requirements for
a continuous
process and was uneconomic due to the high loading and
associated cost of the palladium and dppf ligand. We therefore
sought other approaches, a strategy which offered simplicity and
directness seemed to be a Sonogashira coupling followed by an
oxidative cleavage of the acetylene to furnish a carboxylic acid
moiety (Scheme 5).
(
PTFE) solvent filter (see SI for additional information).[27] This
output line was connected as a feed to an HPLC pump which
progressed the filtered product solution through the scavenging
column. Although this approach worked well over short
processing times but we noticed that build-up of the particulate
material around the in-line PTFE solvent filter started to impair
the pumping efficiency of the exit HPLC pump by restricting its
input flow. This was easily observed by noting the decline in the
flow rate of the exit solution, indeed, HPLC systems are well
known for having very little tolerance on the pressure drop of the
input line. We found that by alternatively using a extraction
thimble filter[ fitted at the inlet of the sedimentation chamber
and utilizing the pressure drop from the reactor more effective
filtration of the particulate matter could be achieved. In this way
the pressure feed of the solvent for the exiting HPLC remained
constant. The reactor could be run for up to 8 hour before
Scheme 5. New strategic approach to the target structures 13 and 14.
We initially performed a scoping evaluation on the Sonogashira
reaction using a series of automated microwave reactions
systematically assessing; catalysts (palladium and copper
28]
sources),
bases,
solvents,
concentration/stoichiometry,
temperature and reaction times. All reactions were rapidly
assessed as % conversion using calibrated LC-MS analysis (a
summary of the findings appear in the supplementary
information). From this study a set of optimum conditions (90%
particulate build-up required
a scheduled shutdown and
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European Journal of Organic Chemistry
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Scheme 7. Flow Sonogashira coupling reactor.
isolated following column chromatography) were defined that
seemed to also favour translation of the reaction to a flow
processing regime (Scheme 6). We were also able to
It was our initial intention to attempt direct oxidation of the
acetylene product 16 without work-up and isolation. However,
we found that attempts to directly use solutions of the reactor
output under the previously attempted oxidation conditions
demonstrate that in the presence of a basic solution of RuO
2
and
the co-oxidant NaIO (or oxone) oxidative cleavage of the alkyne
4
occurred (3.5 h) to give 94% isolated yield of the corresponding
carboxylic acid product 13.[29]
(
2 4
RuO /NaIO ) inevitably gave an alternative major di-brominated
adduct 17 (Scheme 8). Presumable this product formed through
preferential oxidation of bromide (carried TMG.HBr salt)
generating in situ bromine which adds to the alkyene leading to
1
7
through hydrolysis.[31] This was partially confirmed by
demonstrating that when basic (K CO ) solutions of acetylene
6 in 1:1 solutions of MeOH/H O were treated with bromine the
2
3
1
2
identified product 17 rapidly formed. As all related oxidation
processes would potentially generate the same difficulties we
therefore investigated adding an additional purification stage.
Scheme 6. Optimized conditions for microwave Sonogashira coupling reaction
and oxidative cleavage of the alkyne group.
Based upon these findings we embarked upon the translation of
the Sonogashira step to flow.[30] First however an additional
incubation study (48 h) was performed where the different
reaction components were tested for their stability, compatibility
and prolonged solubility in different combinations (see the SI).
This was conducted to ensure stable stock solutions of the
components could be prepared enabling prolonged processing
without constant manual intervention. From this investigation a
simple two channel flow set-up was conceived; Channel A,
delivered a flow stream comprising of the aryl bromide 8 (2.5 M),
the TMG base and the CuBr in MeOH (Scheme 7). Channel B, a
methanolic solution of the propargylic alcohol (3 M), palladium
Scheme 8 By-product formation in the oxidation of acetylene 16.
3
catalyst and associated PPh ligand. The two streams (1:1 flow
To achieve the reaction stream clean-up we elected to employ a
dual stage scavenging process (Scheme 9) utilising first a
cartridge of Ambersep 900 OH resin (Columns A-E), to
neutralise the TMG.HBr salt, followed by a second cartridge of a
sulfonic acid resin (QP-SA, Columns F-J) which sequestered the
free TMG base. Although a mixed bed of the two resins was also
effective we found it much more efficient to stage the
scavenging sequence as this helped in constructing a simple
automated column exchange process; enabling interchange of
the two types of scavenging columns as they became depleted.
Introduction of replacement columns and ensuring the
washing/regeneration of depleted units was conducted by a
simple multi-port valve system as previously described.[32] For
this process we set the unit to trigger based upon a timing event
to correspond to the sequestering threshold of the various
packed columns as calculated from the flow rate and theoretical
concentration of the TMG input. This generated a flow stage as
depicted in Scheme 9.
rate of 1 mL/min) were united at a simple T-piece mixer before
progressing into a heated coil reactor (2 conjoined 52 mL Polar
Bear plus systems) maintained at 100 °C (microwave optimised
temperature) with a 250 psi BPR used to maintain the system
pressure. The exiting solution indicated
a steady state
conversion of 93% which could be driven to complete
conversion by simply raising the reactor temperature to 105 °C.
This gave a theoretical throughput of 0.15 M/h or 38.9 g/h. The
product could be readily isolated by evaporation of the solvent
and pouring the resulting crude oil obtained into a stirred
solution of 3 M HCl (0 °C). The product precipitated over the
course of ~ 1 h and could be filtered and dried at 40 °C under
vacuum to give an overall isolated yield of 93% (5 h run). To
demonstrate the robustness of the system a continuous 5 day
run was performed collecting the reactor output into individual
batches equating to daily production which were then manually
worked up. Overall a yield of 90% with a deviation of +3.7% was
obtained equating to a total of 4.2 kg of isolated material.
Although this in-line work-up was effective we were still
unable to achieve an efficient oxidative cleavage of the alkyene
(
<42% conversion) without first effecting a solvent swap to the
original acetonitrile/water/CHCl mixture. As we desired to
3
produce a telescoped sequence linking the oxidation to the
Sonogashira step we decided to explore more amenable
chemistries.
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European Journal of Organic Chemistry
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Scheme 10. A Flow ozonolysis of acetylene 16. B Products derived from the
flow ozonolysis.
From the initial ozonolysis runs we were pleased to identify the
oxidative fragmentation products 13, 14, 7, 21 and small
amounts of 2-hydroxy-2-methyl-propanoic acid 19 as well as the
corresponding methyl ester adduct 20. Table 2 summarizes
some of the further informative optimisation results. As can be
seen temperature controls the distribution of aryl products
through direct and secondary hydrolysis, however, it has a
nominal influence on conversion. Concentration and residence
time were found to be the main parameters determining starting
material consumption. The addition of additives such as acids
(
2 3
e.g. HCl, PTSA) or bases (pyridine, DMAP, K CO ) neither
enhance conversion or reaction rates and had only small effects
on product proportions.
For the final flow process we elected to use
a
concentration of 1 M and flow rates of 2 and 0.85 mL/min for
oxygen and substrate streams respectively at ambient
temperate giving quantitative conversion. This additionally
produced a good match for the concentration of the exiting
stream from the Sonogashira step. However although the
oxidation of alkynes to anhydrides avoids the production of
classical intermediates such as ozonides and peroxides upon
analysis the processed solution still contained low levels of
peroxy species (~10 mg/L).[37] To aid decomposition of these
Scheme 9. Flow process for the synthesis of acetylene 16.
There are only limited studies in the literature regarding the
ozonolysis of alkynes.[33] In addition there is no clear view as to
which substrates yield anhydride or carboxylic acid products
valuable for our study and which substrates result in benzil
derivatives which would be of less use.[34] We however thought it
would be of speculative interest to evaluate the transformation
with regard to our particular substrate 16. We aimed to make
use of the fact the ozonolysis reaction could be performed in an
alcoholic solvent to, in theory, aid the breakdown of the ozonide
intermediates and fragment the intermediate anhydrides if
produced. Ultimately we wished to perform the ozonolysis
directly on the methanolic reactor output used in the preparation
of 16 (Scheme 7). Several flow reactors have been reported for
ozonolysis reactions,[35] however, we elected to use a simple
wavy annular flow[36] ozonolysis design[16b] which we had
previously employed successfully at scale (Scheme 10). This
used a simple T-assembly to inject a flow of the substrate 16
2
residual peroxy species a short packed column of MnO was
added inline which reduced the peroxy components below
detectable levels. Overall a processing capacity of 51 mmol/h
was achieved which would equate to approximately 12 g/h of
1
product. Figure 5 shows a representative H NMR spectra of the
crude reaction mixture directly following evaporation of the
output stream. The final product could be isolated by solvent
evaporation and allowing the crude to crystallise upon standing
in a 65% yield after filtration and washing with cold hexane. The
corresponding carboxylic acid 7 could be obtained quantitatively
by heating the same crude material dissolved in 3 M HCl at
125 °C for 30 min by passage through a tubular flow coil reactor.
from a capillary input into a fast flowing gas flow of the O
reactant.
3
As these acidic conditions met our need for the subsequent
sequence we anticipated using this solution directly in the next
operation.
Table 2. Subset optimisation of flow ozonolysis reaction conditions.
Ent.
Oxygen flow
rate[
Substrate
flow rate
Temp.
°C
Conv. %
Ratio[f]
13:14:7:21
a]
[b]
1
2
3
4
5
1.0
1.5
2.0
3.0
4.0
1.0
1.5
1.5
2.0
2.0
0
0
0
0
0
100
90
15:79:2:4
13:83:2:2
11:86:1:2
10:88:1:1
9:89:1:1
100
86
74
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European Journal of Organic Chemistry
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To access hydrazine 6 would require a further two step
sequence of diazotisation and reduction. Here we were able to
rely on some previously devised flow chemistry involving
reaction of a diazonium salt generated in situ[ with ascorbic
acid to affect the reduction (Scheme 11).[39] As an alternative
and backup approach we also evaluated a more classical
6
7
8
9
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.5
1.5
-78
rt
100
100
97
2:98:0:0
19:73:3:5
18:72:4:6
Nd
38]
1.5[c]
1.5[d]
rt
rt
73
reduction involving a mixture of SnCl
to work well in batch.
2
and HCl which was shown
1
0
1
2
3
4
5
1.5[e]
rt
64
Nd
1.25[e]
To evaluate the transformation of aniline 7 to its hydrazine
derivative 6 we initially started with isolated and purified material
1
1
1
1
1
rt
82
Nd
1.0[e]
0.75[e]
0.85[e]
0.95[e]
rt
96
18:74:2:6
19:76:3:5
18:76:3:3
17:76:3:4
(
Scheme 11 – initially excluding part 2). A bulk solution of 4-
amino-3-isopropylbenzoic acid (7) was prepared in acetonitrile
and pumped at a flow rate of 1.00 mL/min to combine with
second solution of trimethylsilyl chloride in THF also with a flow
rate 1.00 mL/min. The combined flow was directed into a short 5
mL FEP (fluorinated ethylene propylene copolymer) reactor coil
which was maintained at 0 °C (2.5 min residence time). The
exiting stream was further combined with a THF solution of tert-
butyl nitrite (flow rate 1.00 mL/min) and reacted in a 20 mL FEP
coil at rt (6.5 min residence time). A precipitate formed during
the reaction which was collected at the exit of the reactor via
filtration to give the diazonium salt 22 in an excellent 92%
isolated yield.
rt
100
100
96
rt
rt
[
2
a] O flow rate was controlled using a Brukhurst flow meter [b] 0.5 M
in MeOH. [c] 0.7 M in MeOH. [d] 0.9 M in MeOH. [e] 1 M in MeOH. [f]
As determined by UV-LC rounded to nearest %. Nd
determined.
= not
Scheme 11. Flow diazotisation of aniline 7 and part 2 ascorbic acid reduction.
Extending this sequence (Scheme 11 - Reactor part 2) we
incorporated a further pump to deliver an aqueous stream of the
ascorbic acid reductant (flow rate 1.00 mL/min) and passed the
flow stream into a coil reactor (52 mL Polar Bear Plus[28], 85 °C -
13 min residence time). A 250 psi BPR was used to maintain the
system pressure. During passage through the heated reactor the
solution became homogeneous and was collect at the reactor
exit.
A
batch work-up was then used to extract the
corresponding oxamic acid 23 to evaluate the effectiveness of
the sequence.[40] First the output solution was diluted with ethyl
acetate and extracted with 2 M NaOH (pH 10-11). The aqueous
extract was separated, re-acidified and back extracted into ethyl
acetate. The solid material obtained from evaporation of the
2
solvent was crystallized from a 7:1 mixture of THF:Et O to yield
the hydrazine adduct 23 in 76% yield as a pale yellow solid.
Having set a benchmark with the ascorbic acid approach
we next evaluated the alternative tin mediated process as shown
in Scheme 12. Again, using a simple three pump system this
time based upon a peristaltic delivery system (Vapourtec E-
Figure 5. a) 1H NMR of the crude reaction from Ozonolysis – entry 2 Table 1
and b) the expansion of the aromatic region of the same spectra. 400 mHz in
d -DMSO.
6
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European Journal of Organic Chemistry
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FULL PAPER
Series Flow reactor[41]) a solution of the aniline 7 in a 1:2 mixture
of HCl and AcOH (0.2 M) was mixed with a solution of aqueous
NaNO (1.3 M) at a T-piece (PTFE - polytetrafluoroethylene).
2
The mixture was then directed through a FEP flow coil reactor
maintained at 0 °C (2.8 min residence time). A further flow
entering a short residence time flow coil (FEP 5 mL) maintained
at 0 °C. This flow stream containing the intermediate diazonium
was immediately combined with the reducing ascorbic acid
solution and the resulting hydrazine ester adduct which formed
in situ was digested as it passed through a heated flow coil
furnishing the oxamic acid 23. To facilitate a partial workup a
2
stream containing the SnCl in HCl (0.55 M) was united and the
mixture passed into a second heated FEP flow coil (52 ml, 40 °C, quench solution of NaOH was first injected into the flow to
[
28]
Polar Bear Plus
– 23 min residence time). A suspension
generate a basic solution followed by an input of EtOAc to form
a biphasic flow. The organic and product containing aqueous
stream were at this stage phase separated using the previously
described in-line extractor (Figure 4). This resulted in isolation of
a basic solution of the oxamic acid product 23 that could be
subsequently isolated by careful acidification and extraction (of
particular note was that the more aqueous soluble acid 19 was
not found as a contaminant in the product[42]).
As a proof of concept we were also able to demonstrate
that this final acidification and extraction could also be achieved
as a flow sequence again utilizing the in-line separator. However,
in practice it was found more efficient to simply batch the
product solution and acidify this in bulk prior to extraction.
rapidly formed but could be easily propagated through the
reactor without causing blockage. The reactor output was
dispensed directly onto a sintered filter. After 60 min of operation
the filter cake was washed with water giving 3.48 g, 84%
isolated yield of the hydrazine salt 24 after drying.
The success of the aqueous conditions for the
diazotisation in this latter transformation and the environmental
benefits of the ascorbic acid reduction prompted us to attempt to
assimilate the two processes to furnish an improved protocol.
We also wished to try and telescope the previous acid mediated
hydrolysis of the protected aniline 14 to its corresponding amino
compound 7 into this new assembly. We therefore devised the
modified set-up as depicted in Scheme 13.
Pleasingly, we achieved
a reliable isolated yield of
compound 23 in 80% both for short reactor runs (1-3 h) and over
prolonged usage (full day runs of 8-10 h). This enabled a
reasonable productivity of 34 mmol/h delivering over 8.9 g/h for
the integrated 4 step transformation.
Finally in the context of this project we exemplified that the
target hydrazine adduct 23 could be successfully utilised in the
desired reaction with fragment 4 under thermal conditions to
synthesise pyrazole 25 (Scheme 14). This was achieved by
heating a solution of compounds 4 and 23 in 1,4-dioxane in the
presence of 10 mol% p-TSA at 120 °C for 2.5 h. The reaction
gave an 86% isolated yield of 25 after work-up and purification
by column chromatography.
Scheme 12. Flow diazotisation and Sn mediated reduction starting from acid-
aniline 7.
Scheme 14. Preparation of pyrazole 25 via batch microwave synthesis.
Conclusions
In this work we have developed a set of multi-step flow
sequences starting from the readily available starting aniline 10
to an advanced hydrazine derivative 23. The route generated
has a number of staging points were natural breaks in the
processing allow the batching of intermediates in each case as
bench stable solids (Figure 6). As part of our flow processing
strategy we have made use of some established flow
transformations (e.g. diazotization and reduction) as well as
developing new chemistries (e.g. selective ozonolysis of an
alkyne). This has generated several improvements with regards
to solvent usage (synthesis of 8 and telescoping 16→14),
Scheme 13. Telescoped synthesis of hydrazine adduct 23.
Taking the crude solution of ester 14 (still with 19 and 20
present) as the starting point we carried out the hydrolysis under
the previously determined acidic conditions (Scheme 13). The
processed flow stream then passed through a cooling zone
2
before next being mixed with an aqueous solution of NaNO and
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European Journal of Organic Chemistry
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FULL PAPER
8
2
1
.5, 2.0 Hz, 1H), 7.24 (d, J = 8.5 Hz, 1H), 3.14 (sept., J = 6.8 Hz, 1H),
energy utilization (synthesis of 8) and the number of required
reaction steps. Ultimately we have been able to create a set of
linked flow operations which deliver high quality material with
good productivity (Figure 6). Employing this chemistry we have
successfully generated 4.27 kg of the final hydrazine derivative
13
.05 (s, 3H), 1.18 (d, J = 6.8 Hz, 6H); C NMR (100 MHz, d
6
-DMSO):
68.7 (C), 145.5 (C), 134.3 (C), 128.7 (CH), 128.5 (CH), 128.3 (CH),
118.4 (C), 27.2 (CH ), 23.1 (CH), 22.8 (CH ); IR: 3244.0 (w br), 2963.4
(m), 1655.4 (s), 1518.6 (s), 1482.3 (s) cm ; HRMS: Calcd for
3
3
-
1
+
[
=
(
C
H
8 9
NOBr] = 213.9868, found 213.9871, Δ = 1.4 ppm; Microanalysis: C
51.58% (51.69%), H= 5.51% (5.43%), N = 5.47% (5.76%), Br = 31.2%
31.45%) The structure was unambiguously confirmed by x-ray
23 for use in the synthesis of SR 142948A (3) and other
important derivatives.
crystallography – CCDC reference 1564270.
N-(2-isopropylphenyl)acetamide (9)
mp 71-73 °C; LC-MS: Rt = 3.72, [M]+ = 177.95; 1H NMR (400 MHz,
CDCl
3
): as a mixture of rotamers a:b (1:3), only the major rotamer is
reported: 7.03-7.62 (m, 5H), 3.17-3.20 (m, 1H), 2.98-3.03 (1H, m), 2.21
1
3
(
s, 3H), 1.90 (s, 3H), 1.20-1.26 (d, J = 6.8 Hz, 6H); C NMR (150 MHz,
CDCl ): 169.1 (C), 141.1 (C), 134.1 (C), 126.4 (CH), 126.37 (CH), 125.74
CH), 125.68 (CH), 28.0 (CH ), 24.1 (CH), 23.2 (CH ); IR: 3278.7 (m),
964.3 (m), 1676.5 (m), 1655.0 (s), 1515.9 (s), 1489.6 (s) cm ; HRMS:
3
(
2
3
3
-
1
+
Calcd for [C11H15NONa] = 200.1051, found 200.1044, Δ = 3.5 ppm.
N-(4-cyano-2-isopropylphenyl)acetamide (11)
mp 134-136 °C; LC-MS: Rt = 3.65, [M] = 202.00; 1H NMR (500 MHz,
-
CDCl
3
): 8.09 (m, 1H), 7.55 (d, J = 1.9 Hz, 1H), 7.49 (dd, J = 8.4, 1.9 Hz,
1
H), 7.22 (br. s, NH, 1H), 3.12 (sept., J = 6.8 Hz, 1H), 2.24 (s, 3H), 1.28
13
(
d, J = 6.8 Hz, 6H); C NMR (125 MHz, CDCl
38.6 (C), 130.6 (CH), 129.9 (CH), 123.5 (CH), 119.2 (C), 108.5 (C), 27.9
CH ), 24.8 (CH), 22.7 (CH ); IR: 3248.2 (m br), 2985.0(m), 2225.9 (w),
709.3 (m), 1645.5 (s), 1519.7 (s) cm ; HRMS: Calcd for [C12
03.1184, found 203.1188, 2.0 ppm. The structure was
3
): 168.6 (C), 139.1 (C),
1
(
1
2
Figure 6. Key intermediates and outputs for the flow synthesis towards
compound 23 a synthetic equivalent of target hydrazine 6.
3
3
-1
+
15 2
H N O] =
Δ
=
unambiguously confirmed by x-ray crystallography – CCDC reference
564264.
1
Experimental Section
ethyl 4-acetamido-3-isopropylbenzoate (12)
+
1
For protocols and reactor descriptors see the Supplementary Information.
LC-MS: Rt = 4.09, [MH] = 250.10, H (400 MHz, d
H), 7.86 (d, J = 1.7 Hz, 1H), 7.74 (dd, J = 8.4, 1.7 Hz, 1H), 7.58 (d, J =
8.4 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.26 (sept., J = 6.8 Hz, 1H), 2.09 (s,
6
-DMSO): 9.46 (s, NH,
1
1H NMR spectra were recorded on a Bruker Avance DPX-400, DRX-600,
Avance 400 QNP Cryo, or Avance 500 Cryo spectrometer with the
13
3H), 1.32 (t, J = 7.1 Hz, 3H), 1.17 (d, J = 6.8 Hz, 6H); C (400 MHz, d
DMSO): 168.8 (C), 165.5 (C), 141.7 (C), 139.6 (C), 126.7 (C), 126.6 (CH),
123.4 (CH), 125.6 (CH), 60.5 (CH ), 26.7 (CH), 23.3 (CH ), 22.9 (CH ),
6
-
residual solvent peak as the internal reference (CDCl
3
= 7.26 ppm, d
6
-
1
DMSO = 2.50 ppm). H resonances are reported to the nearest 0.01 ppm.
2
3
3
1
3
3
14.2 (CH ); IR: 3251.3 (m), 2986.2 (m), 1708.6 (s), 1645.9 (s), 1610.1
C NMR Spectra were recorded on the same spectrometers with the
central resonance of the solvent peak as the internal reference (CDCl
7.16 ppm, d -DMSO = 39.52 ppm). All 13C resonances are reported to
-
1
+
3
=
(m), 1521.1 (s), 1479.6 (m) cm ; HRMS: Calcd for [C14
3
H20NO ]
=
7
6
250.1443, found 250.1448, Δ = 2.0 ppm. Microanalysis: C = 67.22%
(67.45%), H= 7.62 % (7.68%), N = 5.61% (5.62%).
the nearest 0.1 ppm. DEPT 135, COSY, HMQC, and HMBC experiments
were used to aid structural determination and spectral assignment. The
multiplicity of 1H signals are indicated as: s = singlet, d = doublet, t =
triplet, m = multiplet, br. = broad, or combinations of thereof. Coupling
constants (J) are quoted in Hz and reported to the nearest 0.1 Hz. Where
appropriate, averages of the signals from peaks displaying multiplicity
were used to calculate the value of the coupling constant. IR spectra
were obtained by use of a Perkin Elmer RX1 spectrometer (neat, ATR
sampling) with the intensities of the characteristic signals being reported
as weak (w, <20% of tallest signal), medium (m, 21-70% of tallest signal)
or strong (s, >71% of tallest signal). Low and high resolution mass
spectrometry was performed using the indicated techniques on either
Waters LCT Premier XE or Waters TQD instruments equipped with
Acquity UPLC and a lock-mass electrospray ion source. For accurate
mass measurements the deviation from the calculated formula is
reported in ppm. Melting points were recorded on an Optimelt automated
melting point system with a heating rate of 1 °C/min and are uncorrected.
N-(4-carboxy-2-isopropylphenyl)acetamide (13)
white solid; Mp. 214.1-215.8 °C; LC-MS: Rt 1.35, [MH] = 222.8, [2MH]+
+
1
= 443.5; H NMR (400 MHz, d
6
-DMSO) δ 12.83 (s, 1H), 9.47 (s, 1H),
7.87 (d, J = 2.1 Hz, 1H), 7.73 (dd, J = 8.3, 2.1 Hz, 1H), 7.54 (d, J = 8.3
Hz, 1H), 3.35 (sept, J = 6.8 Hz, 1H), 2.10 (s, 3H), 1.17 (d, J = 6.8 Hz,
1
3
6H). C NMR (101 MHz, d
(C), 139.74 (C), 128.01 (C), 127.39 (CH), 127.15 (CH), 126.11 (CH),
27.19 (CH ), 23.82 (CH), 23.46 (CH ); IR: 3255.9 (m), 2968.9 (m), 2555.6
(br. w), 1688.6 (s), 1645.0 (s), 1607.8 (m), 1581.2 (m), 1520.8 (s) cm ;
6
-DMSO) δ 169.34 (C), 167.59 (C), 142.12
3
3
-
1
+
3
H16NO ] = 222.1130, found 222.1137, Δ = 3.2
HRMS: Calcd for [C12
ppm.
methyl 4-acetamido-3-isopropylbenzoate (14)
white solid; Mp. 128.9-130.2 °C;LC-MS: Rt 1.93, [MH] = 236.8, [2MH] =
+
+
1
471.4; H NMR (400 MHz, d
6
-DMSO) δ 9.50 (s, 1H), 7.89 (d, J = 2.1 Hz,
1H), 7.76 (dd, J = 8.4, 2.1 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 3.84 (s, 3H),
13
4
-amino-3-isopropylbenzoic acid (7)
3.27 (sept, J = 6.8 Hz, 1H), 2.11 (s, 3H), 1.17 (d, J = 6.8 Hz, 6H).
C
mp 131-132 °C; LC-MS: Rt = 3.63, [MH] =180.25; 1H NMR (400 MHz,
+
NMR (101 MHz, d -DMSO) δ 169.38 (C), 166.47 (C), 142.12 (C), 140.14
6
d
1
6
1
6
-DMSO): 11.91 (br. s, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.48 (dd, J = 8.4,
.9 Hz, 1H), 6.59 (d, J = 8.4 Hz, 1H), 5.64 (s, NH , 2H), 2.95 (sept., J =
.7 Hz, 1H), 1.16 (d, J = 6.7 Hz, 6H); C NMR (100 MHz, d -DMSO):
67.7 (C), 150.0 (C), 129.7 (C), 128.3 (CH), 126.8 (CH), 117.3 (C), 113.4
); IR: 3504.2 (m), 3389.5 (m), 2957.7 (m),
3
(C), 127.27 (CH), 126.79 (C), 126.97 (CH), 126.09 (CH), 52.42 (CH ),
3 3
27.17 (CH ), 23.83 (CH), 23.40 (CH ); IR: 3256.2 (m), 2963.4 (w), 1720.2
2
13
(s), 1643.7 (s), 1608.1 (m), 1514.0 (s) cm-1
;
HRMS: Calcd for
6
+
[C13
H
18NO
3
] = 236.1287, found 236.1296, Δ = 3.8 ppm.
(CH), 26.1 (CH), 22.1 (CH
3
-
1
+
2
H14NO ] =
N-(4-(3-hydroxy-3-methylbut-1-ynl)-2-isopropylphenyl)acetamide
16)
Off white solid; Mp. 136.2-137.4 °C; LC-MS: Rt 1.89, [MH] = 261.0;
1
1
663.6 (s), 1624.4 (s), 1586.7 (s) cm ; HRMS: Calcd for [C10
80.1025, found 180.1030, 2.8 ppm; The structure was
(
Δ
=
+
unambiguously confirmed by x-ray crystallography – CCDC reference
564268.
1
1
Indication of rotomeric structure: H NMR (400 MHz, CDCl
m, 1H), 7.55 – 7.40 (m, 1H), 7.29 (s, 1H), 7.13 (t, J = 6.0 Hz, 1H), 2.99
(h, J = 6.8 Hz, 1H), 2.20 – 2.05 (br. s, 3H), 1.65 – 1.50 (m, 6H), 1.17 (d, J
13C NMR (101 MHz, CDCl ) δ 169.29 (C), 140.92 (C),
= 6.8Hz, 7H).
134.11 (C), 129.56 (CH), 129.10 (CH), 125.04 (CH), 120.32 (C), 93.54
3
) δ 7.78 – 7.54
(
N-(4-bromo-2-isopropylphenyl)acetamide (8)
mp 129-132 °C; LC-MS: Rt = 3.84, [MH]+ =213.97; 1H NMR (400 MHz,
3
6
d -DMSO): 9.35 (br. s, NH, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7. 33 (dd, J =
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201700904
FULL PAPER
(
C), 82.00 (C), 65.49 (C), 31.50 (CH
3
), 27.72 (CH
-DMSO) δ 9.37 (s, 1H), 7.34 (d, J = 8.2 Hz,
H), 7.27 (d, J = 2.0 Hz, 1H), 7.17 (dd, J = 8.2, 2.0 Hz, 1H), 3.17 (sept., J
6.8 Hz, 1H), 2.07 (s, 3H), 1.47 (s, 6H), 1.14 (d, J = 6.8 Hz, 6H); 13
-DMSO) δ 169.20 (C), 143.07 (C), 135.54 (C), 129.06
CH), 128.90 (CH), 126.94 (CH), 120.24 (C), 95.87 (C), 80.92 (C), 64.08
C), 32.11 (CH ), 27.27 (CH ), 23.68 (CH), 23.43 (CH ); IR: 3233.2 (br.
3
), 23.99 (CH), 22.94
(CH), 123.5 (C), 112.0 (CH), 26.0 (CH), 22.4 (CH
3
); IR: 3314.9 (w),
1
3 6
(CH ); H NMR (400 MHz, d
3196.2 (w), 2871.3 (br. m), 1687.1 (s), 1609.4 (s), 1507.1 (m), 1278.6 (s);
+
1
=
HRMS: Calcd for [C10
10 2 2
H N O Na] = 221.1266, found 221.1266, Δ = 0.0
C
ppm.
NMR (101 MHz, d
(
(
m), 2971.9 (m), 1658.5 (s), 1577.9 (w), 1520.2 (s) cm ; HRMS: Calcd for
16 2
[C H22NO ] = 260.1651, found 260.1648, Δ = -1.2 ppm.
6
4-(5-(2,6-dimethoxyphenyl)-3-(ethoxycarbonyl)-1H-pyrazol-1-yl)-3-
isopropylbenzoic acid (25)
3
3
3
-
1
mp: 218-220 °C; 1H NMR (400 MHz, CDCl
3
): 7.97 (d, J = 1.8 Hz, 1H),
7.85 (dd, J = 1.8, 8.2 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.23 (t, J = 8.4 Hz,
H), 6.96 (s, 1H), 6.45 (d, J = 8.4 Hz, 2H), 4.44 (q, J = 7.1 Hz, 2H), 3.63
(s, 6H), 2.77 (sept., J = 6.7 Hz, 1H), 1.40 (t, J = 7.1 Hz, 3H) 1.00 (br. s,
+
1
N-(4-(2,2-dibromo-3-hydroxy-3-methylbutanoyl)phenyl)acetamide
17)
Pale brown solid; Mp. 146.2-148.1 °C; LC-MS: Rt 4.70, [MH] = 436.1; H
400 MHz, d -DMSO) 9.50 (s, 1H), 8.25 (d, J = 2 Hz, 1H), 8.03 (dd, J =
.7, 2 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 5.55 (br. s, 1H), 3.27 (sept., J =
1
3
(
6H); C NMR (100 MHz, CDCl
(C), 144.3 (C), 142.5 (C), 138.9 (C), 131.6 (CH), 129.9 (C), 128.8 (CH),
128.6 (CH), 127.1 (CH), 111.5 (CH), 106.8 (C), 103.6 (CH), 61.1 (CH ),
55.6 (CH ), 27.8 (CH), 24.1 (CH ), 14.6 (CH ); IR: 2400-3300 (w br),
1713.9 (s), 1607.6 (m), 1589.9 (m), 1477.1 (m), 1229.1 (s); HRMS: Calcd
3
): 171.2 (C), 162.8 (C), 158.4 (C), 146.4
+
1
(
8
6
6
3
2
3
3
13
6
.8 Hz, 1H), 2.10 (s, 3H), 1.59 (s, 6H), 1.17 (d, J = 6.8 Hz, 6H); C (d -
+
DMSO) 190.0 (C), 168.5 (C), 140.7 (C), 139.9 (C), 131.1 (C), 129.9 (CH),
29.3 (CH), 124.8 (CH), 80.3 (C), 77.3 (C), 27.6 (CH ), 27.2 (CH ), 24.0
CH), 23.5 (CH ); IR 3431.2 (w), 3368.3 (w), 2160.5 (br. w), 2016.6 (w),
670 (s), 1598.7 (m), 1578.4 (m), 1506.0 (s), 1473.8 (m), 1456.9 (m),
for [C24
27 2 6
H N O ]
= 439.1869, found 439.1865, Δ = 0.9 ppm. The
1
(
1
1
3
3
structure was unambiguously confirmed by x-ray crystallography – CCDC
reference 1564267.
3
-
1
374.0 (w), 1356.0 (m), 1259.9 (s), 1211.9 (s), 1184.9 (s) cm ; HRMS:
+
Calcd for [C16
H21Br
2
NO
3
] = 432.9888, found 432.9887, Δ = 0.1 ppm. The
structure was unambiguously confirmed by x-ray crystallography – CCDC
reference 1564265.
Acknowledgements
4
-ethynyl-2-isopropylaniline (18)
We are greatful for financial support from the Royal Society (to
MB and IRB; UF130576 and UFUF150536 to MOK). We would
also like to thank Dr John Davies and Dr Andrew D. Bond at the
Department of Chemistry, University of Cambridge for solving
the X-ray structures of compounds 7, 8, 11, 17, 25 and 8a, 12a
+
1
Brown oil; LC-MS: Rt = 1.90, [MH] = 160.4; H NMR (CDCl
3
) 7.30 (d, J =
.85 Hz, 1H), 7.18 (dd, J = 8.1, 1.85 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H),
.83 (br. s, 2H, NH ), 2.99 (s, 3H), 2.83 (sept., J = 6.8 Hz, 1H), 1.25 (d, J
6.8 Hz, 6H); C NMR (CDCl ) 144.7 (C), 132.6 (C), 131.1 (CH), 130.1
).
1
3
=
2
13
3
(CH), 115.7 (CH), 111.9 (C), 85.4 (C), 75.1 (CH), 28.0 (CH), 22.5 (CH
3
+
HRMS: Calcd for [C11
H14N] = 160.1126, found 160.1126, Δ = 0.0 ppm.
(
see SI for details).
2
-hydroxyisobutyric acid (19)[43]
1
) δ 1.25 (s, 3H); 13C NMR (101 MHz, d
).
H NMR (400 MHz, DMSO-d
DMSO) δ 178.32 (C), 71.18 (C), 27.75 (CH
6
6
-
Keywords: Flow Chemistry • Neurotensin • Ozonolysis •
Sonogashira • multi-step synthesis
3
2
-hydroxyisobutyric acid methyl ester (20)[44]
1
H NMR (400 MHz, DMSO-d
6
) δ 5.30 (br. s, 1H), 3.61 (s, 3H), 1.27 (s,
H); C NMR (101 MHz, DMSO-d ) δ 176.85 (C), 71.55 (C), 52.07 (CH ),
7.72 (CH ).
[
1]
a) R. Carraway, R. S. E. Leeman, J. Biol. Chem. 1973, 248, 6854–
13
6
2
6
3
6861; b) W. H. Rostène, M. J. Alexander, Front. Neuroendocrinol. 1997,
3
18, 115–173.
methyl 4-amino-3-isopropylbenzoate (21)
[2]
E. Popp, A. Schneider, P. Vogel, P. Teschendorf, B. W. Böttigera,
Neuropeptides 2007, 41, 349–354.
Light tan solid; Mp. 96.0-97.8 °C; LC-MS: Rt = 2.23, [MH]+ = 194.7; 1
H
NMR (400 MHz, CDCl
Hz, 1H), 6.66 (d, J = 8.3 Hz, 1H), 4.12 (br. s, 2H), 3.88 (s, 3H), 2.87
3
) δ 7.87 (d, J = 2.0 Hz, 1H), 7.74 (dd, J = 8.3, 2.0
[
[
[
[
3]
4]
5]
6]
P. R. Dobner, Peptides 2006, 240, 2405–2414.
D. Zhao, C. Pothoulakis,Peptides 2006, 27, 24234–2444.
P, Kitabgi, Neurochem. Int. 1989, 14, 111–119.
13
(
sept., J = 6.8 Hz, 1H), 1.30 (d, J = 6.8 Hz, 6H). C NMR (101 MHz,
CDCl ) δ 167.53 (C), 147.96 (C), 131.33 (C), 128.82 (CH), 127.59 (CH),
19.95 (C), 114.64 (CH), 51.58 (CH ), 27.61 (CH), 22.03 (CH ); IR:
468.6 (m), 3367.6 (m), 3247.0 (w), 2954.8 (m), 1671.2 (s), 1601.5 (s),
508.6 (m) cm ; HRMS: Calcd for [C11
94.1190, Δ = 4.6 ppm.
3
a) G. Bissette, C. B. Nemeroff, M. W. Decker, J. S. Kizer, Y. Agid, F.
Javoy-Agid, Ann. Neurology 1985, 17, 324–328. b) G. Chinaglia, A.
Probst, J. M. Palacios, Neuroscience. 1990, 39, 351–360. c) F. St-
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1
3
1
1
3
3
-
1
+
H16NO
2
]
= 194.1181, found
2
29–245; d) L. Ferraro, S. Beggiato, D. O. Borroto-Escuela, L. Ravani,
4
-carboxy-2-isopropylbenzenediazonium chloride (22)
W. T. O'Connor, M. C. Tomasini, A. C. Borelli, L. F. Agnati, T. Antonelli,
S. Tanganelli, K. Fuxe, Curr. Protein & Peptide Sci. 2014, 15, 681–690.
M. Ocejo-García, S. I. Ahmed, J. M. Coulson, P. Woll. J. Lung Cancer
1
H NMR (400 MHz, DMSO-d6) δ 8.92 (d, J = 8.5 Hz, 1H), 8.27 (d, J = 1.8
Hz, 1H), 8.25 (dd, J = 8.5, 1.8 Hz, 2H), 3.51 (sept., J = 6.7 Hz, 1H), 1.37
[
7]
(d, J = 6.7 Hz, 6H);
2001, 33, 1–9.
2
-(2-(4-carboxy-2-isopropylphenyl)hydrazinyl)-2-oxoacetic acid (23)
[8]
9]
F. Souazé, S. Dupouy, V. Viardot-Foucault, E. Bruyneel, S. Attoub, C.
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Yellow solid; Mp. 147.5 °C decomposition; LC-MS: Rt = 0.97, [MH]+
=
1
267.3; H NMR (600 MHz, DMSO-d
6
) δ 12.2 (br. s, 1H), 10.35 (br. s, 1H),
[
7.77 (s, 1H), 7.67 (d, J = 1.5 Hz, 1H), 7.58 (dt, J = 8.5, 1.5 Hz, 1H), 6.62
546–555.
(dd, J = 8.5, 1.5 Hz, 1H), 3.09 (sept., J = 7.1 Hz, 1H), 1.21 – 1.11 (d, J =
13
[10] R. R. Giorgi, T. Chile, A. R. Bello, R. Reyes, M. A. H. Z. Fortes, M. C.
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7
1
.1 Hz, 6H). C NMR (101 MHz, d
62.58 (C), 149.51 (C), 131.35 (C), 128.79 (CH), 126.78 (CH), 120.68
); IR: 3254.2 (br. m), 2972 (m),
6
-DMSO) δ 168.02 (C), 162.61 (C),
(C), 110.71 (CH), 26.33 (CH), 22.81 (CH
3
-
1
+
1667.3 (s), 1606.2 (s), 1520.1 (m) cm ; HRMS: Calcd for [C12H N O ] =
15 2 5
1052–1057.
267.0981, found 267.0993, Δ = 4.5 ppm.
[
11] P. Schaeffer, M. C. Laplace, A. Bernat, V. Prabonnaud, D. Gully, L.
Lespy, J. M. Herbert, J. Cardiovasc. Pharmacol. 1998, 31, 545–550.
2
-(4-carboxy-2-isopropylphenyl)hydrazin-1-ium chloride (24)
+
[12] P. Kitabgi, F. De Nadai, C. Rovère, J. N. Bidard, Ann. N.Y. Acad. Sci.
1992, 668, 30–42.
Light tan solid; Mp. >260 °C decomp.; LC-MS: Rt = 3.50, [MH] =221.1;
1
H (500 MHz, d
6
-DMSO): 12.55 (br. s, 1H), 10.32 (br. s, 1H), 8.40 (s, 1H),
7
.78 (d, J = 1.9 Hz, 1H), 7.76 (dd, J = 8.4, 1.9 Hz, 1H), 6.97 (d, J = 8.4
[13] G. A. Cain, T. E. Christos, A. L. Johnson, R. S. Pottorf, P. N. Confalone,
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13
Hz, 1H), 3.15 (sept., J = 6.8 Hz, 1H), 1.19 (d, J = 6.8 Hz, 6H). C (125
MHz, d -DMSO): 167.2 (C), 145.7 (C), 134.1 (C), 128.0 (CH), 126.5
6
2060.
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European Journal of Organic Chemistry
10.1002/ejoc.201700904
FULL PAPER
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[
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European Journal of Organic Chemistry
10.1002/ejoc.201700904
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Matthew O. Kitching, Olivia E. Dixon,
Marcus Baumann, and Ian R.
Baxendale*
Page No. – Page No.
Flow Assisted Synthesis: A key Fragment of
SR 142948A
Multi-step flow assisted synthesis of an advanced hydrazine building block utilised
in the preparation of SR 142948A.
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