Exploiting the Continuous in situ Generation of Mesyl Azide for Use in a Telescoped Process

Article abstract of DOI:10.1002/ejoc.201700871

The hazardous diazo transfer reagent mesyl azide has been safely generated and used in situ for continuous diazo transfer as part of an integrated synthetic process with an embedded safety quench. Diazo transfer to β-keto esters and a β-ketosulfone was successful. In-line phase separation, by means of a continuous liquid–liquid separator, enabled direct telescoping with a thermal Wolff rearrangement.

Full text of DOI:10.1002/ejoc.201700871

A Journal of
Accepted Article
Title: Exploiting the Continuous In Situ Generation of Mesyl Azide for
Use in a Telescoped Process
Authors: Anita Rose Maguire, Rosella M O'Mahony, Denis Lynch,
Hannah L D Hayes, Eilis Ni Thuama, Philip Donnellan,
Roderick C Jones, Brian Glennon, and Stuart G Collins
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700871
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700871
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10.1002/ejoc.201700871
European Journal of Organic Chemistry
FULL PAPER
Exploiting the Continuous In Situ Generation of Mesyl Azide for
Use in a Telescoped Process
Rosella M. O’Mahony,[a] Denis Lynch,[a] Hannah L. D. Hayes,[a] Eilís Ní Thuama,[a] Philip Donnellan,[b]
Roderick C. Jones,[b] Brian Glennon,[b] Stuart G. Collins,*[a] and Anita R. Maguire*[c]
Abstract: The hazardous diazo transfer reagent mesyl azide, has
been safely generated and used in situ for continuous diazo transfer
as part of an integrated synthetic process with an embedded safety
quench. Diazo transfer to β-ketoesters and a β-ketosulfone was
successful. In-line phase separation, by means of a continuous liquid–
liquid separator, enabled direct telescoping with a thermal Wolff
rearrangement.
challenges of employing this hazardous reagent on large scales.[9]
A similar approach has since been employed by Monbaliu as part
of
a
strategy for continuous synthesis of Ritalin.[10] The
development of a modified protocol for in situ generation of mesyl
azide logically extends this methodology, with access to safe and
efficient synthesis and use of diazo compounds as the ultimate
goal.
Mesyl azide is a reagent which enables generation of α-diazo
carbonyls by diazo transfer without the need for chromatographic
purification.[11] Principally, it is employed where the relative ease
of removal of mesyl amide byproduct in a simple aqueous wash
is an important consideration for recovery of the desired diazo
product. Tosyl azide,[1] the most commonly used diazo transfer
reagent produces tosyl amide, which requires use of a base wash
to facilitate partitioning into an aqueous phase. While this
advantage is not unique to mesyl azide, its low cost and the low
molecular weight byproducts/reduced waste treatment burden,
when compared to other suitable reagents, would make it a highly
attractive option, but for the substantial safety challenges
associated with handling this material – specifically significant
heat and shock sensitivity. Although mesyl azide possesses the
same impact sensitivity as tosyl azide (50 kg cm), it has been
shown to decompose at twice the rate.[12] This unfavourable safety
profile has, to date, limited mesyl azide exclusively to use in small
scale (typically <1 g in our lab) syntheses.
Introduction
The Regitz diazo transfer methodology is widely regarded as the
most convenient approach to preparation of α-diazo carbonyl
compounds that bear two activating groups.[1] These synthetically
valuable compounds represent precursors for carbenes[2] and
carbenoids,[3] along with ketenes and their heteroanalogues[4]
reactive intermediates capable of diverse chemistries, often under
mild conditions and with high selectively.
Continuous processing has been firmly established in
facilitating safety improvement to chemical processes, spanning
the pharmaceutical and fine chemical industries and academic
research. The enhanced reaction control in flow that arises from
use of high surface-area-to-volume ratio tubular reactors allows
an efficiency of heat and mass transfer unattainable in batch.
Consequently, access to extreme reaction conditions, ease of
scale-up and increased reproducibility are key features of
continuous systems.[5] Furthermore, the opportunities for
automation, including control and feedback loops, the inherently
rapid dissipation of heat and the facility for in situ generation and
direct use of hazardous species[6] in minimal quantities all
represent significant mitigations against reaction runaway or
operator exposure. These improvements have made flow
chemistry a key enabling technology for valuable synthetic
methodologies that would previously have been avoided due to
the risks posed at large scale.[7]
–
Despite the range of safer alternatives currently available, each
of these diazo transfer reagents has limitations when compared
to mesyl azide. While relatively safer,[12] tosyl azide has a poorer
associated atom economy; tosyl sulfonamide is produced, which
is both more challenging to remove than mesyl sulfonamide and
represents an increased waste disposal requirement. The last
decade has seen the emergence of imidazole-based diazo
transfer reagents, such as the shelf stable imidazole-1-sulfonyl
azide hydrochloride,[13] to enable easy separation of the
sulfonamide byproducts. However, the expense of these
compounds and ongoing safety concerns[14] have curtailed their
use. Economic factors also continue to exclude polystyrene
bound benzenesulfonyl azide[15] from use on large scale. Although
proven to be considerably more stable than mesyl azide,[12] both
The use of azides, diazo compounds and even diazonium salts
in flow is well documented.[8] Following several studies involving
diazo transfer in flow that directly utilized sulfonyl azides, we
recently reported a scalable continuous diazo transfer process
where tosyl azide was generated and used in situ, overcoming the
p-acetamidobenzenesulfonyl
azide
(ABSA)[16]
and
p-
dodecylbenzenesulfonyl azide (DBSA)[17] have similar atom
economy issues to tosyl azide; they remain vulnerable to thermal
decomposition and their sulfonamides usually require
chromatographic separation. Hence, in the absence of an ideal
diazo transfer reagent, the development of a process to
[a]
School of Chemistry, Analytical and Biological Chemistry Research
Facility, Synthesis and Solid State Pharmaceutical Centre,
University College Cork, Ireland.
[b]
[c]
School of Chem & Bioprocess Engineering, Synthesis and Solid
State Pharmaceutical Centre, University College Dublin, Ireland.
School of Chemistry and School of Pharmacy, Analytical and
Biological Chemistry Research Facility, Synthesis and Solid State
Pharmaceutical Centre, University College Cork, Ireland.
E-mail: a.maguire@ucc.ie; stuart.collins@ucc.ie
https://www.ucc.ie/en/abcrf/staff/
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201700871
European Journal of Organic Chemistry
FULL PAPER
adequately mitigate the dangers associated with mesyl azide
while harnessing its advantages was of significant interest.
formation of tosyl azide, approximately 15 min was required for
complete mesyl azide formation. Corresponding reaction
monitoring by IR of mesyl azide formation in batch indicated that
approximately 12 min was required for complete disappearance
of the sodium azide band (2041 cm–1). This observation strongly
suggests that the more lipophilic character of tosyl chloride is a
significant factor in the rate at which the sulfonyl azide is
generated in aqueous acetonitrile.
Results and Discussion
A continuous process for formation and use of tosyl azide 1 in situ
has previously been developed within the group (Scheme 1).[9]
This process involves combining a stream of aqueous sodium
azide with a stream of tosyl chloride 2 in acetonitrile at ambient
temperature leading to rapid generation of tosyl azide 1. This
combined stream is then mixed with a suitable diazo acceptor
substrate and base in a reactor coil at 25 °C, resulting in diazo
transfer. Finally, a quench solution of sodium acetoacetonate (3)
was introduced to the product stream to safely destroy any
residual unreacted tosyl azide, leaving a solution of the desired
diazo carbonyl product along with tosyl amide and aqueous
soluble byproducts.
Table 1. Optimization of reaction conditions for continuous diazo transfer to
ethyl acetoacetate (3a) using in situ generated mesyl azide (6).
O
EWG
NaN3 (0.45 M)
NEt3 in MeCN
-1
in water (0.15 mL.min
)
O
C
O
O
ONa
S
N3
1
3
25 
 = 22 min
C
in MeCN/H2O (1:1)
25 
Concentration
 = 1 min
Entry
MsN3
Formation
time A
Diazo
transfer
time B
[min]
Conversion
[%][a]
[mol L–1
]
TsCl (2)
(0.45 M)
in MeCN (0.15 mL.min-1
)
[min]
O
1
2
3
4
5
6
7
8
9
0.45
0.45
0.45
0.45
0.90
0.80
0.80
0.80
0.80
1
22
22
33
66
66
11
22
33
66
50
66
EWG
33
50
15
15
16
16
16
15
N2
60-89% Yield
73
80
Scheme 1. Previously developed continuous process for in situ generation and
100
49
use of tosyl azide.
Initial work was focused on adapting this approach to continuous
in situ generation and use of tosyl azide to an analogous mesyl
azide process. Among the key features of this methodology,
retaining a room temperature (25 °C) diazo transfer and inclusion
of the in-line sacrificial quench were regarded as most important
for the ultimate safety profile of the system. With this in mind, a
study was undertaken into diazo transfer to ethyl acetoacetate in
flow, utilizing a mixture of mesyl chloride 5 and aqueous sodium
azide to form mesyl azide 6 in situ (Table 1).
60
71
100
[a] Conversion determined by 1H NMR analysis of the crude product
obtained after removal of MeCN under reduced pressure, extraction into
Et2O followed by aqueous wash and removal of solvent in vacuo.
Somewhat surprisingly, the rate of diazo transfer was also found
to be longer for the mesyl azide process compared to use of tosyl
azide. While a residence time of 22 min was found to be sufficient
Interestingly, in contrast to the equivalent process
employing tosyl chloride, where <2 min was required for complete
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10.1002/ejoc.201700871
European Journal of Organic Chemistry
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for complete diazo transfer across a range of acceptor substrates
using in situ generated tosyl azide, in general using mesyl azide
the transformation was found to be complete within 66 min, with
a 33 min residence time giving ~70 % conversion. This result
supports a positive hydrophobic effect[18] on the rate of diazo
transfer from tosyl azide in an aqueous medium. Indeed, the
residence time required for diazo transfer from mesyl azide is
more consistent with that observed for continuous diazo transfer
from pre-formed tosyl azide entirely in acetonitrile, where reaction
times of 1–2 h were needed to achieve reaction completion. The
reaction profile of the quenching process for unreacted mesyl
azide, treatment with the strong diazo acceptor, sodium
acetoacetonate was found to closely mirror that observed for tosyl
azide. Again, the diazo transfer reagent was found to be fully
consumed after less than 2 min exposure to the quench solution,
as indicated by IR analysis – specifically disappearance of the
mesyl azide stretch at 2143 cm–1.
Futhermore, concentration was found to be an important factor
for the residence time required for successful diazo transfer, with
an increased rate of diazo transfer observed as concentration was
increased. A concentration of 0.8M was ultimately chosen to
enable complete diazo transfer while minimizing the potential for
precipitation of inorganic salts from the aqueous acetonitrile
system. Using the optimised conditions for diazo transfer to ethyl
acetoacetate (4a), a substrate scope investigation with in situ
generated mesyl azide was undertaken (Table 2). A range of α-
Table 2. Substrate scope of optimized diazo transfer using in situ generated mesyl azide (6).
Entry
Substrate
Yield in flow (%)[a]
Yield in batch (%)[a]
Conversion
(%)[b]
with aq. KOH
workup
with SALLE
separation
Conversion
(%)[b]
with aq. KOH
workup
with SALLE
separation
1
100
100
100
100
50
51
49
58
56
100
100
100
100
55
52
54
66
62
2
3
4
59
64
44
51
61
50
5
100
68
57
100
68
72
6
7
100
100
63
71
62
70
100
100
55
81
57
84
[a] Yield of diazo product, >95% pure by 1H NMR analysis after workup and without chromatography. [b] Conversion determined by 1H NMR analysis of the
crude product obtained after removal of MeCN under reduced pressure, extraction into Et2O followed by aqueous wash and removal of solvent in vacuo.
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10.1002/ejoc.201700871
European Journal of Organic Chemistry
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diazo-β-ketoesters 7a-f were prepared in moderate to good
yields, along with α-diazo-β-ketosulfone 7g. The higher yield
observed for 7g (Table 2, entry 7) suggested that higher
molecular weight acceptor substrates/product are likely to be
easier to recover during partitioning from the aqueous layer.
As relatively easy separation of the mesyl amide byproduct is the
key benefit of diazo transfer from mesyl azide, in order to exploit
this advantage, a suitable strategy was required to enable the
desired diazo product to be successfully separated from the
aqueous byproducts present in the aqueous acetonitrile product
stream. Ideally, this strategy would allow a fully integrated system,
cleanly affording the α-diazo carbonyl compound in an organic
phase that would provide a substrate solution for an immediate
telescoped transformation involving further reaction of the diazo
completely into the aqueous layer, once more enabling
telescoping.
Following the addition of the salt solution, the two immiscible
phases must be efficiently separated from each other for this to
be practical. Typical separation methodologies at the end of a flow
process would require both phases to be collected prior to using
a separating funnel to remove the waste aqueous phase.
However, this methodology not only disrupts the continuous
nature of the reaction process, but also introduces a step requiring
accumulation and direct handling of a hazardous (potentially
explosive) product. Accordingly,
a continuous liquid–liquid
separator (Figure 1) was designed, manufactured and its use
investigated to overcome these challenges.
species. Salting out liquid–liquid extraction (SALLE) is
a
technique used to separate water from miscible liquids such as
acetone, methanol or acetonitrile.[19] Although reported since the
late 1980s, the technique has not been widely investigated or
used. SALLE involves the addition of concentrated aqueous
sodium chloride solution to induce a phase separation. Altering
the concentration and volume of sodium chloride solution used
allows the degree of separation to be controlled. Addition of 20–
30 % w/v aqueous sodium chloride was found to afford separation
of acetonitrile from the aqueous phase with product recovery
comparable to that obtained using the standard 9 % aqueous
KOH wash, in terms of both yield and purity.
As summarized in Table 2, diazo transfer to the range of
substrates 4a-g was investigated both in batch and in flow using
both the traditional partitioning between aqueous KOH and diethyl
ether and SALLE separation. The results from the batch
experiments show that the SALLE approach is comparable in
terms of efficiency and overall yield to the base extraction, but with
the clear safety and operational advantage of obviating
concentration of acetonitrile solution of the diazo products.
Interestingly, while the yields recovered in flow were slightly
reduced relative to batch, the clear safety benefit, ease of scale
up and potential to telescope with subsequent reactions render
this flow approach advantageous overall. Notably the NMR
spectra of the α-diazo-β-ketoesters 7a-f and α-diazo-β-
ketosulfone 7g recovered from each of the reactions in Table 2
were sufficiently pure to use in further reactions without
chromatographic purification (see SI).
Figure 1. Computer Aided Design (CAD) rendering of the designed liquid–liquid
separator utilised in this work. The mixed organic and aqueous streams enter
the unit from the inlet on the left hand side while the separated organic stream
continuously leaves from the exit port on the top and the waste aqueous stream
exits from the bottom port.
The mixed aqueous and organic phases enter the separator from
the left (Figures 1 & 2) through the single ¼” inlet (reduced to 1
mm internal diameter via needle inlet valve). The unit is designed
to minimize the vertical velocity component of the fluid flow which
facilitates the continuous separation of the immiscible fluids by
gravitational means with the result that the lighter organic stream
exits the separator.
Computational fluid dynamics (CFD) were utilized to model the
fluid velocity profile in the unit and the degree of separation of the
phases (Figure 2). Subsequently the optimized separator design
was 3D printed (from 316L stainless steel) which has a length of
50 mm, an inner diameter (at the wide end) of 30 mm, a radius of
curvature of 15 mm and a wall thickness of 1 mm.
For comparison purposes the SALLE approach was applied to
a diazo transfer to 4b using tosyl azide, and the tosyl amide was
clearly evident in the crude reaction product. Therefore, as
removal of mesyl amide in the phase separation is much more
efficient than that of tosyl amide, use of in situ generated mesyl
azide for diazo transfer offers a distinct advantage over the
comparable tosyl azide transfer process. This is particularly
significant with regards to the potential to telescope diazo transfer
with subsequent reactions which could not be conducted in the
presence of an equimolar quantity of sulfonamide. Furthermore,
the sodium acetylacetonate quench and byproducts partition
Figure 2. Computational Fluid Dynamics (CFD) illustration of the separation
which is continuously occurring in the liquid–liquid separator during operation.
The red region represents the organic phase and the blue region represents the
aqueous phase.
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10.1002/ejoc.201700871
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As summarized in Scheme 2, in situ generated mesyl azide 6 was
employed to effect diazo transfer to methyl 3-oxoheptanoate (4d).
Addition of brine solution (30% w/v NaCl) followed by passage
through the in-line liquid–liquid separator provided the α-diazo-β-
ketoester 7d in acetonitrile. To demonstrate the ease of
telescoping this diazo transfer with subsequent reactions, 7d was
subjected to thermal Wolff rearrangement[20] via superheating the
solution, with methanol as a ketene trap to form the malonate
derivative 8 without ever isolating or handling either mesyl azide
or the diazo ester 7d, or indeed having significant amounts of
either compound generated at any given time in the process. This
telescoped process transforming 4d to the Wolff rearrangement
product 8 exemplifies the synthetic potential of diazo transfer
employing in situ generated mesyl azide. The principal
component evident in the crude product stream of the telescoped
process was the Wolff rearrangement product 8. The overall yield
from the telescoped process is 31% following chromatography.
Direct comparison of the process efficiency with a conventional
batch process is not possible under thermal, metal free conditions
as 8 does not form under reflux in this solvent system. While Wolff
rearrangements can be effected through microwave heating,[20c,d]
this process is not comparable as it would not be amenable to
scale-up or to telescoping with the diazo transfer step. The
efficiency of the in-line liquid–liquid separator is evidenced by
effective removal of water with no competing reaction with water
observed in the ketene trapping. As O–H insertion into water is a
known side reaction in transformations of diazo carbonyl
compounds, efficient removal of water using this approach (the
SALLE technique with in-line liquid–liquid separator) is a very
significant factor in the broader synthetic potential of this
telescoping of synthesis and reactions of α-diazo carbonyl
compounds.
Scheme 2. Telescoped diazo transfer and thermal Wolff rearrangement.
Experimental Section
Conclusions
General Methods: Solvents were distilled prior to use as follows:
dichloromethane was distilled from phosphorus pentoxide, ethyl acetate
was distilled from potassium carbonate, hexane was distilled prior to use.
Organic phases were dried using anhydrous magnesium sulfate. All
commercial reagents were used without further purification unless
otherwise stated. 1-Phenylsulfonyl-5-phenylpentan-2-one (4g) was
prepared according to literature methods.[21] 1H (400 MHz) and 13C (100.6
MHz) NMR spectra were recorded on a Bruker Avance 400 MHz NMR
spectrometer. All spectra were recorded at 300 K in deuterated chloroform
(CDCl3) unless otherwise stated, using tetramethylsilane (TMS) as internal
standard. Chemical shifts (δH and δC) are reported in parts per million
A practical continuous method for in situ generation of mesyl
azide was developed and employed for preparation of a series of
α-diazo-β-ketoesters and an α-diazo-β-ketosulfone, with an
embedded safety quench. Using the SALLE separation technique
in conjunction with a designed in-line liquid–liquid separator, an
organic product stream—containing the desired diazo compound
in acetonitrile—could be partitioned from the aqueous soluble
byproducts, including mesyl amide, and readily and safely
telescoped with subsequent reaction of the diazo product.
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(3H, s, C(O)CH3). 13C NMR (CDCl3, 100.6 MHz, 300 K) δ = 27.9 (CH3),
28.2 (CH3 x 3 of t-butyl), 83.1 (C), 160.2 (C=O, ester), 190.6 (C=O) ketone,
no signal observed for (C=N2).
(ppm) relative to TMS. Splitting patterns in 1H spectra are designated as s
(singlet), d (doublet), t (triplet), q (quartet) and m (multiplet). Infrared
spectra were measured using a Perkin Elmer FTIR UATR2 spectrometer,
or as potassium bromide discs (for solids) on a Perkin-Elmer Paragon
1000 FT-IR spectrometer. Wet flash chromatography was carried out using
Kieselgel silica gel 60, 0.040–0.063 mm (Merck). Thin layer
chromatography (TLC) was carried out on pre-coated silica gel plates
(Merck 60 PF254). Visualisation was achieved by UV (254 nm) light
absorption. Reactions in continuous flow were carried out in 1 mm internal
diameter PFA tubing using either HPLC (working flow rate: 0.05–9.99
mL.min–1) or peristaltic pumps (working flow rate: 0.02–10.00 mL.min–1).
Isopentyl 2-Diazo-3-oxobutanoate (7c):[25] Prepared from 4c according
to the general method and was obtained as a yellow oil that could be used
without any need for further purification. (UATR)/cm–1: 2141, 1721, 1662;
1H NMR (CDCl3, 400 MHz, 300 K) δ = 0.94 (6H, d, J=6.6, 2 x CH3), 1.55–
1.62 (2H, m, OCH2CH2), 1.64–1.75 (1H, m, CH(CH3)2), 2.48 (3H, s,
C(O)CH3), 4.27 (2H, t, J=6.6, OCH2CH2); 13C NMR (CDCl3, 100.6 MHz,
300 K) δ = 22.4 (CH3 x 2), 25.1 (CH), 28.3 (CH3), 37.3 (OCH2CH2), 64.1
(OCH2), 161.5 (C=O, ester), 190.3 (C=O, ketone), no signal observed for
(C=N2).
In-line liquid–liquid separations were achieved using
a 3D printed
separator (316L stainless steel) with a length of 50 mm, an inner diameter
(at the wide end) of 30 mm, a radius of curvature of 15 mm and a wall
thickness of 1 mm. All aqueous waste streams were treated with sodium
nitrite and dilute sulfuric acid prior to disposal, taking all relevant safety
precautions.[22]
Methyl 2-diazo-3-oxoheptanoate (7d):[20c] Prepared from 4d according
to the general method and was obtained as a yellow oil that could be used
without any need for further purification. (UATR)/cm–1: 2141, 1721, 1642;
1H NMR (CDCl3, 400 MHz, 300 K) δ = 0.93 (t, J=7.4, 3H, CH2CH3), 1.33–
1.43 (2H, m, CH2), 1.58–1.65 (2H, m, CH2) 2.85 (t, J=7.5, 2H,
C(O)CH2CH2), 3.84 (3H, s, C(O)CH3); 13C NMR (CDCl3, 100.6 MHz, 300
K) δ = 13.7(CH3), 22.2(CH2), 26.3 (CH2), 39.8 (C(O)CH2), 52.1 (OCH3),
161.7 (C=O, ester), 192.7 (C=O, ketone), no signal observed for (C=N2).
General flow procedure for preparation of diazo compounds 7a–g
(Table 2): A solution of substrate (10 mL, 0.8M, 8.0 mmol, 1.0 eq.) and
trimethylamine (1.15 mL, 8.2 mmol, 1.05 eq.) in acetonitrile was prepared
along with a solution of methanesulfonyl chloride (10 mL, 0.92 g, 8.0 mmol,
1.0 eq.) in acetonitrile and an aqueous solution of sodium azide (10 mL,
0.52 g, 8.0 mmol, 1.0 eq.). A 10 mL quench solution of sodium
acetoacetonate (0.675M in 1:1 acetonitrile/water) was prepared with
sodium hydroxide (0.270 g, 6.75 mmol, 1.5 eq.) and acetylacetone (0.676
g, 6.75 mmol, 1.5 eq.). The flow reactor, including all HPLC pumps, was
purged with the appropriate solvents (4 mL.min–1 for 4 min). The
methanesulfonyl chloride solution was pumped (0.10 mL.min–1) into a T-
piece where it met the aq. sodium azide solution (0.10 mL.min–1). The
combined stream passed through a tube (412 cm, 16 min residence time)
where it met the substrate solution at a T-piece (0.10 mL.min–1). This
combined stream passed into a reactor coil (2 x 10 mL, 25 °C, 66 min
residence time) before meeting the quench solution and then passed
through a tube (50 cm) followed by a back pressure regulator (8 bar). All
reactor effluents were collected in a round bottom flask and the desired
diazo product was isolated using either Method A (aqueous KOH wash) or
Method B (SALLE separation). Method A consisted of concentrating the
reactor effluents under reduced pressure to remove acetonitrile, before the
crude product was extracted with diethyl ether (50 mL) and the organic
layer was washed with 9 % KOH (2 × 20 mL) and water (10 mL). The
organic layer was dried and concentrated under reduced pressure to give
the diazo product. Method B consisted of addition of aq. NaCl solution (30
mL, 30 % w/v) to the reactor effluents to enable separation of an organic
(acetonitrile) layer that was dried and concentrated under reduced
pressure to give the diazo product (see Table 2 for yield). Compounds
synthesised using Method A or B demonstrated comparable spectroscopic
properties.
Ethyl 2-Diazo-3-oxo-3-phenylpropanoate (7e):[26] Prepared from 4e
according to the general method and was obtained as a yellow oil that
could be used without any need for further purification. (UATR)/cm–1: 2140,
1719, 1293, 1262; 1H NMR (CDCl3, 400 MHz, 300 K) δ = 1.29 (t, 3H, J=7.0,
CH3), 4.23 (q, J=7.0, 2H, CH2), 7.42-7.62 (5H, m, 5 x ArH). 13C NMR
(CDCl3, 100.6 MHz, 300 K) δ = 14.2 (CH3), 61.6 (CH2), 127.9, 128.3, 132.2
(aromatic CH), 137.16 (aromatic C), 161.0 (C=O, ester), 186.9 (C=O,
ketone), no signal observed for (C=N2).
Benzyl 2-Diazo-3-oxobutanoate (7f):[27] Prepared from 4f according to
the general method and was obtained as a yellow oil that could be used
without any need for further purification. (UATR)/cm–1: 2144, 1719, 1656;
1H NMR (CDCl3, 400 MHz, 300 K) δ = 2.48 (s, 3H, CH3), 5.29 (s, 2H, CH2),
7.26-7.41 (m, 5H, 5 x ArH). 13C NMR (CDCl3, 100.6 MHz, 300 K) δ = 28.3
(CH3), 66.9 (OCH2), 75.5 (C=N2), 128.4, 128.7, 128.8 (aromatic CH), 135.2
(aromatic C) 161.7 (C=O, ester), 189.9 (C=O, ketone).
1-Diazo-1-phenylsulfonyl-5-phenylpentan-2-one (7g):[28] Prepared
from 4g according to the general method and was obtained as a yellow
solid without any need for further purification. mp 80–82 °C; (lit., 78–81
°C); UATR)/cm–1 2122, 1677, 1154. 1H NMR (CDCl3, 400 MHz, 300 K) δ =
1.90 (q, J 7.4, 2H, C(4)H2), 2.53, 2.55 (4H, 2 × overlapping t, J 7.5 × 2,
C(5)H2 and C(3)H2), 7.09–7.11 (2H, m, aromatic H of phenyl group), 7.18–
7.29 (3H, m, aromatic H of phenyl group), 7.49–7.53 (2H, m, aromatic H
of phenylsulfonyl group), 7.64-7.68 (1H, m, aromatic H of phenylsulfonyl
group), 7.89–7.91 (2H, m, aromatic H of phenylsulfonyl group). 13C NMR
(CDCl3, 100.6 MHz, 300 K) δ = 25.0 (C(4)H2), 34.7 (C(5)H2), 38.3 (C(3)H2),
126.1 (CH, aromatic CH), 127.3 (CH, aromatic CH), 128.5 (CH, aromatic
CH), 129.5 (CH, aromatic CH), 134.2 (CH, aromatic CH), 141.1 (C,
aromatic C), 142.0 (C, aromatic ), 188.2 (C=O, ketone), no signal observed
for (C=N2).
Ethyl 2-Diazo-3-oxobutanoate (7a):[23] Prepared from 4a according to the
general method and was obtained as a yellow oil that could be used
without any need for further purification. (UATR)/cm–1: 2140, 1720, 1661;
1H NMR (CDCl3, 400 MHz, 300 K) δ = 1.33 (3H, t, J=7.2, OCH2CH3), 2.51
(3H, s, C(O)CH3), 4.32 (2H, q, J=7.2, OCH2CH3). 13C NMR (CDCl3, 100.6
MHz, 300 K) δ = 14.3 (CH3), 28.2 (CH3), 62.4 (CH2), 161.4 (C=O, ester),
190.3 (C=O, ketone), no signal observed for (C=N2).
Procedure for Telescoped Thermal Wolff Rearrangement: The flow
reactor, including all HPLC pumps, was purged with the appropriate
solvents (4 mL.min–1 for 4 min). Methanesulfonyl chloride solution was
pumped (8.0 mL, 0.8M, 0.10 ml.min–1) into a T-piece where it met aq.
sodium azide solution (8.0 mL, 0.8M, 0.10 ml.min–1). The combined stream
passed through a tube (412 cm, 16 min residence time) where it met
substrate solution (7.8 mL, [4d] 0.80M, [trimethylamine] 0.83M, 0.10
mL.min–1) at a T-piece. This combined stream passed into a reactor coil (2
x 10 mL, 25 °C, 66 min residence time) before meeting the quench solution
(13.31 mL, 0.675M, 0.2 ml.min–1) which then passed through a tube (50
cm). The reaction stream then met aq. NaCl solution (30% w/v) at a T-
tert-Butyl 2-Diazo-3-oxobutanoate (7b):[24] Prepared from 4b according
to the general method and was obtained as a yellow oil that could be used
without any need for further purification. (UATR)/cm–1: 2134, 1715, 1660;
1H NMR (CDCl3, 400 MHz, 300 K) δ = 1.55 (9H, s, 3 x CH3 of t-butyl), 2.49
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10.1002/ejoc.201700871
European Journal of Organic Chemistry
FULL PAPER
piece which passed through a 75 cm tube and then passed through a back
pressure regulator (8 bar). The biphasic reactor effluents were then
separated by an in-line liquid–liquid separator. The collected acetonitrile
layer (9 mL), containing diazo product 7d, was directly fed to another
pump. The pump delivered the separated diazo product solution (8 mL,
0.10 ml.min–1) to a T-piece where it met MeOH (0.50 mL.min–1) which then
passed through a reactor coil (3 x 10 mL, 135 °C, 50 min residence time),
and then passed through a back pressure regulator (8 bar). The reactor
effluents were all collected in a round bottom flask and was then
concentrated under reduced pressure. The crude product was purified by
wet flash chromatography using 9:1 hexane/EtOAc as eluent to afford
dimethyl 2-butylmalonate (8)[29] (0.327 g, 31 % yield) as a clear oil.
(UATR)/cm–1: 2957, 1733, 1152. 1H NMR (CDCl3, 400 MHz, 300 K) δ =
0.90 (t, J=7.0 Hz, 3H, CH2CH3), 1.23–1.41 (m, 4H, 2 × CH2), 1.90 (br q,
J=7.6 Hz, 2H, CHCH2), 3.36 (t, J=7.6 Hz, 1H, CH), 3.74 (s, 6H, 2 × OCH3).
13C NMR (CDCl3, 100.6 MHz, 300 K) δ = 13.8 (CH2CH3), 22.3, 28.5, 29.5
(all CH2), 51.7 (CH), 52.4 (OCH3), 170.0 (C=O).
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Acknowledgements
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This work was undertaken as part of the Synthesis and Solid State
Pharmaceutical Centre supported by Science Foundation Ireland
(grant: SFI SSPC2 12/RC/2275) and with use of equipment
provided by Science Foundation Ireland though a research
infrastructure award for process flow spectroscopy (ProSpect)
(grant: SFI 15/RI/3221). The authors wish to acknowledge the
contribution of Janssen Pharmaceutical, for the kind loan of one
the flow chemistry reactors used in this work.
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Keywords: Diazo transfer • Flow Chemistry • Telescoped
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