Taming tosyl azide: The development of a scalable continuous diazo transfer process

Article abstract of DOI:10.1039/c6ob00246c

Heat and shock sensitive tosyl azide was generated and used on demand in a telescoped diazo transfer process. Small quantities of tosyl azide were accessed in a 'one pot' batch procedure using shelf stable, readily available reagents. For large scale diaz

Full text of DOI:10.1039/c6ob00246c

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: A. R. Maguire, B.
J. Deadman, R. M. O'Mahony, D. Lynch, D. C. Crowley and S. G. Collins, Org. Biomol. Chem., 2016, DOI:
10.1039/C6OB00246C.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 9
View Article Online
DOI: 10.1039/C6OB00246C
Journal Name
ARTICLE
Taming tosyl azide: the development of a scalable continuous
diazo transfer process
Benjamin J. Deadman,a† Rosella M. O’Mahony, a Denis Lynch,a Daniel C. Crowley,a Stuart G.
Received 00th January 20xx,
Accepted 00th January 20xx
Collinsa* and Anita R. Maguireb*
DOI: 10.1039/x0xx00000x
Heat and shock sensitive tosyl azide was generated and used on demand in a telescoped diazo transfer process. Small
quantities of tosyl azide were accessed in a ‘one pot’ batch procedure using shelf stable, readily available reagents. For large
scale diazo transfer reactions tosyl azide was generated and used in a telescoped flow process, to mitigate the risks
associated with handling potentially explosive reagents on scale. The in situ formed tosyl azide was used to rapidly perform
diazo tranfer to a range of acceptors, including β‐ketoesters, β‐ketoamides, malonate esters and β‐ketosulfones. An effective
in‐line quench of sulfonyl azides was also developed, whereby a sacrificial acceptor molecule ensured complete
consumption of any residual hazardous diazo transfer reagent. The telescoped diazo transfer process with in‐line quenching
was used to safely prepare over 21 g of an α‐diazocarbonyl in >98% purity without any column chromatography.
www.rsc.org/
Improving the safety profile of chemical processes is a major
driving force behind the adoption of continuous processing
within academia, and also the fine chemical and pharmaceutical
Introduction
Tosyl azide is a heat and shock sensitive reagent which is used
in the Regitz diazo transfer to introduce diazo groups into
organic compounds.1–4 The α‐diazocarbonyl compounds
produced by diazo transfer are an important class of versatile
synthetic intermediates due to their ability to generate reactive
carbenes,5–7
heteroanalogous intermediates.21–26
Despite being routinely used in small scale α‐diazocarbonyl
synthesis, tosyl azide is not suitable for use at larger scales.
Tosyl azide has an impact sensitivity of 50 kg∙cm, and explosive
thermal decomposition can initiate at 120 °C.27 A range of
sulfonyl azides has been developed as safer alternative diazo
transfer reagents.8,27,28 p‐Acetamidobenzenesulfonyl azide
(ABSA) and dodecylbenzenesulfonyl azide (DBSA) are less shock
sensitive than tosyl azide but are still sensitive to heat.
Imidazole‐1‐sulfonyl azide hydrochloride was also developed as
a shelf stable diazo transfer reagent, but a number of safety
issues were later reported.29,30 Polystyrene supported
benzenesulfonyl azide is another stable alternative to tosyl
azide but the cost of this reagent is prohibitive.31 There is no
ideal alternative to tosyl azide and this reagent continues to be
used by many, despite its dangers.28,32–37 Consequently,
progress in how tosyl azide is prepared and used is required.
industries. Enhanced heat and mass transfer, access to extreme
reaction conditions, reproducibility and scale up, in‐line
workups and automated operation have all been reported as
benefits of continuous processing.38–45 The favourable safety
profile of flow processing is perhaps the most compelling
reason for its popularity. Sensitive reagents can be readily
generated and used on demand inside a flow process, negating
the need to stockpile hazardous intermediates or risk of
operator exposure. The high surface‐area‐to‐volume ratios of
tubular reactors also ensures efficient removal of heat, thereby
reducing the risk of reaction runaway.45–47
A number of hazardous intermediates including azides,48–53
diazonium salts,54–59 and diazo compounds,60–72 to name but a
few, have all been accessed using continuous processing
techniques.45–47 There have been few reports of the diazo
transfer process in flow, and to date these have all employed
sulfonyl azides directly as reagents.68,69,73,74 Researchers at
carbenoids,7–20
ketenes
and
other
GlaxoSmithKline
reported
using
2,4,6‐
triisopropylbenzenesulfonyl azide to perform a diazo transfer to
ethyl acetoacetate in a segmented flow system.73 Rutjes and co‐
workers used imidazole‐1‐sulfonyl azide hydrochloride to
prepare benzyl azide in a continuous diazo transfer to benzyl
amine.74 More recently Wirth and co‐workers reported the use
of ABSA in a telescoped flow process whereby diazophenyl
acetate esters were prepared and used in metal catalysed X‐H
insertion and cyclopropanation reactions.68,69 A disadvantage of
all these continuous procedures is that they employ potentially
hazardous sulfonyl azides directly as reagents. Such an
approach limits the scale of the continuous diazo transfer as
these reagents are hazardous to prepare at large scales.
a. Department of Chemistry, Analytical and Biological Chemistry Research Facility,
Synthesis and Solid State Pharmaceutical Centre, University College Cork, Ireland.
b. Department of Chemistry and School of Pharmacy, Analytical and Biological
Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre,
University College Cork, Ireland. Email: a.maguire@ucc.ie.
† Current Affiliation: Department of Chemistry, Imperial College London, United
Kingdom
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 9
ARTICLE
Journal Name
View Article Online
DOI: 10.1039/C6OB00246C
Table 1. Optimization of reaction conditions for continuous diazo transfer to ethyl
acetoacetate (3a) using tosyl azide.
Scheme 1. In situ generation and use of diazo transfer reagents.
We were therefore interested in developing a continuous
diazo transfer procedure which used relatively stable and
readily available reagents to generate the diazo transfer
reagent on demand (Scheme 1). Herein, we describe our work
towards the in situ generation of tosyl azide, and its application
in a rapid continuous diazo transfer process. A number of safety
features were also developed to facilitate safe scale up of the
process, including spectroscopic monitoring of tosyl azide and
an in‐line quench system to consume any residual tosyl azide.
The safe generation and use of these reagents has the potential
to make this chemistry accessible within the pharmaceutical
and fine chemical industries.
Entry
Equiv. of Base
Temperature Time Conversion
(°C)
25
(min)
10
(%)a
1
2
3
4
5
6
0.8
1.0
53
25
10
60
1.05
1.10
1.5
25
10
75
25
10
80
Results and Discussion
Continuous diazo transfer using batch prepared tosyl azide
25
10
77
2.0
25
10
74
The continuous diazo transfer process was initially investigated
by employing tosyl azide which had been previously prepared in
batch.1,2 Under typical batch conditions, the diazo acceptor
molecule is reacted with tosyl azide in the presence of a base,
such as NEt3, DBU or K2CO3, at ambient temperature over a
period of up to 24 hours.3,4,28,75–77 Reaction times longer than
several hours can be difficult to achieve in tubular reactors, so
we sought to optimize the continuous diazo transfer reaction
over a short reaction time of 10 min (Table 1). It has previously
been reported that the diazo transfer requires only catalytic
quantities of base to proceed.78,79 Under the short reaction time
7
8
1.05
1.05
1.05
1.05
1.05
40
50
25
25
25
10
10
25
50
75
78
58
9
82
10
11
93
100
a) Conversion determined by 1H NMR spectroscopy.
utilized in this study, the conversion of ethyl acetoacetate (3a
to the α‐diazo‐ ‐keto ester 4a was less than 60% when one or
)

The reaction time required to achieve complete
consumption of the diazo transfer reagent was investigated
(Table 1, entries 9–11). While the diazo transfer progressed
quickly over the first 10 min, it was observed to subsequently
slow down, with 82% and 93% conversions obtained at 25 and
50 min respectively. After a reaction time of 75 min the diazo
transfer had run to completion (Table 1, entry 11).
With optimized reaction conditions in hand we turned our
attention to an investigation of the substrate scope. An initial
substrate screen identified that several substrates required
reaction times in excess of 75 min. Consequently, a diazo
transfer residence time of 2 h was selected for the 1st
generation continuous diazo transfer process (Table 2). Diazo
transfer to ethyl acetoacetate (3a, Table 2, entry 1) and benzyl
acetoacetate (3d, Table 2, entry 4) went to completion, as
determined by 1H NMR spectroscopy. The tert‐butyl (3b, Table
2, entry 2) and isoamyl (3c, Table 2, entry 3) acetoacetate esters
underwent diazo transfer more slowly and conversions of only
less equivalents of base was employed (Table 1, entries 1 & 2).
The conversion increased to 75–80% when a slight excess of
base was employed (Table 1, entries 3 & 4), but larger excesses
of base (1.5 and 2.0 equivalents) had no beneficial effect on the
reaction progress over 10 min (Table 1, entries 5 & 6).
The influence of temperature on the continuous diazo
transfer was also investigated. In contrast to the results
reported by Wirth et al. where continuous diazo transfers using
ABSA required elevated reaction temperatures of 60 °C for
completion, we observed that the flow reaction with tosyl azide
progressed well at only 25 °C (Table 1, entry 3).68 Raising the
reactor temperature to 40 °C had a negligible effect on the
reaction progress (Table 1, entry 7), and as a further increase
had no positive impact (Table 1, entry 8), higher temperatures
were not further investigated. Given the heat sensitive nature
of diazo transfer reagents it is a distinct advantage to have a
process which only requires ambient conditions to achieve good
reaction rates.
2 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 9
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
View Article Online
DOI: 10.1039/C6OB00246C
Table 2. Substrate scope of the 1st generation continuous diazo transfer process.
Scheme 2. Batch test of ‘one pot’ tosyl azide generation and diazo transfer.
a slow diazo transfer with only a 20% conversion being obtained
after 2 h (Table 2, entry 6). It was hypothesized that this reduced
conversion could be due to the lower acidity of the methylene
protons in diethyl malonate (3f) (pKa ~13) compared to the
ketoester substrates (pKa ~11).80 To facilitate diazo transfer to
less activated substrates we employed 1,8‐diazabicycloundec‐
7‐ene (DBU) as the base (Table 2, entry 7). With the stronger
base DBU, diethyl malonate (3f) underwent complete diazo
transfer in the 2 h residence time. Two β‐ketosulfones (3g, 3h
)
Entry
1
Substrate
Base
NEt3
Conversion
(%)a
Yield
(%)b
were also successfully subjected to the continuous diazo
transfer process (Table 2, entries 8 & 9), with DBU also chosen
as the optimum base for the transfer.
The reduction in yields (Table 2) relative to the conversions,
measured by 1H NMR spectroscopy, is attributed to incomplete
recovery of the product during the KOH wash employed in the
workup. Whilst the conversions were assessed following an
aqueous wash, isolation of the diazo products required a KOH
wash to remove the toluenesulfonamide by‐product of the
diazo transfer.
100
54
46
84
61
61
2
3
4
5
NEt3
NEt3
NEt3
NEt3
80
95
In situ generation and use of tosyl azide
A significant disadvantage of the 1st generation continuous
diazo transfer process was the requirement for tosyl azide to be
prepared in batch mode. The preparation of sulfonyl azide diazo
transfer reagents are hazardous procedures which require
extreme care.3,4,8,27,28,75 In a typical preparation of tosyl azide a
solution of tosyl chloride in MeCN is added slowly to an aqueous
solution of sodium azide. As the substitution reaction is
exothermic, the reaction must be kept at 0 °C to prevent
explosive decomposition of the heat sensitive tosyl azide. In the
subsequent workup, care must also be taken to avoid applying
shock to the touch sensitive product. The touch sensitive nature
of tosyl azide also makes its use in diazo transfer reactions a
particular challenge as it exists as a solid when stored in a
freezer. In our lab it is gently melted before transferring as an
oil with extreme care taken to ensure there are no scratches on
the glassware. To facilitate continuous diazo transfer chemistry
it would be advantageous to have a procedure whereby the
diazo transfer reagent was generated in situ and used without
requiring handling by the operator. To this end, we investigated
options for the in situ formation and use of tosyl azide.
100
100
6
7
NEt3
DBU
DBU
20
–
100
100
53
50
8c
9c
DBU
100
65
Our first attempt to form tosyl azide in situ involved the use
of tetra‐N‐butylammonium azide as an azide salt, which is
soluble in the MeCN solvent system used for the diazo transfer
reaction. This azide salt has previously been employed in flow
reactions as a substitute for sodium azide.52 Unfortunately, in
this case we found no evidence of diazo transfer after the
acceptor molecule was added to a pre‐stirred mixture of tetra‐
N‐butylammonium azide and tosyl chloride in MeCN. Due to the
potentially unstable nature of the reaction species, we did not
examine this reaction any further and instead returned our
a) Conversion determined by 1H NMR spectroscopy after an aqueous wash
workup. b) Yield of diazo product, >90% pure by 1H NMR analysis after KOH
wash workup. c) Reaction run at higher dilution due to substrate solubility:
substrate (0.1 M), base (0.105 M) and tosyl azide (0.11 M).
80% and 95% respectively were obtained. Ethyl benzoyl acetate
3e) underwent complete diazo transfer in the time allowed
(Table 2, entry 5). In contrast, diethyl malonate (3f) underwent
(
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 9
ARTICLE
Journal Name
Scheme 3. Generation and use of alternative diazo transfer reagents.
View Article Online
DOI: 10.1039/C6OB00246C
Table 3. Optimisation of reaction times for the telescoped tosyl azide generation
and diazo transfer in flow.
the tosyl azide formation to only 2 min had no detrimental
effect on the reaction progress (Table 3, entry 2). Due to the
unstable, hazardous nature of tosyl azide we wished to avoid
optimising the tosyl azide formation in isolation. To gain some
insight into the progress of the tosyl azide generation, we
employed an excess (2 equivalents) of the diazo acceptor
molecule 3a. Under these conditions the diazo transfer will not
progress beyond 50% consumption of the acceptor molecule,
and will only reach this maximum if the tosyl azide formation
went to completion. With this strategy, the residence time of
the tosyl azide formation was reduced from 2 min down to 0.5
min (Table 3, entries 3–5). It should be noted that the residence
time of the diazo transfer reaction was concurrently reduced
due to the increased flow rates being employed. The diazo
transfer reaction still went to its theoretical maximum
conversion (50%) with residence times as low as 0.5 min and 8
min for tosyl azide formation and diazo transfer respectively
(Table 3, entry 5). Reducing the equivalents of acceptor
molecule 3a back to one resulted in a slight reduction of the
conversion to 95% (Entry 6), which can be attributed to the
reduced rate of the diazo transfer when only one equivalent of
acceptor is used.
Entry
Generation
Diazo
Eq. of
Acceptor
(3a)
1.0
Conversion
(%)a
Time A (min)
Transfer
Time B (min)
1
2
3
4
5
6
50
2
66
66
66
16
8
100
100
50b
50b
50b
95
1.0
2
2.0
1
2.0
0.5
0.5
2.0
8
1.0
a) Conversion determined by 1H NMR spectroscopy. b) When 2 equivalents of
acceptor were employed a conversion of 50% indicates that tosyl azide
formation was complete.
attention to the use of sodium azide for the in situ reagent
generation.
It has been reported that the diazo transfer can be
performed under aqueous conditions.78 With this in mind, we
explored the in situ formation of tosyl azide and subsequent
diazo transfer reactions in batch mode using a MeCN/water
The batch procedure for in situ generation of the sulfonyl
azide reagent was also applied to acetamidobenzenesulfonyl
chloride (2b) and 2‐napthalenesulfonyl chloride (2c) (Scheme
3). In both cases, the diazo transfer reagent 1b, 1c was formed
within 2 h at ambient temperature. Subsequent reaction of the
in situ generated sulfonyl azides with benzyl acetoacetate (3d
)
1
solvent system (Scheme 2). H NMR spectroscopy of an ethyl
was observed to go to completion within 2 h. Unfortunately, the
sulfonyl azides (1b, 1c) were found to be insoluble in the 1:1
water/MeCN reaction medium and precipitation was observed
prior to the addition of the diazo acceptor 3d, as a solution in
MeCN. While there are strategies for handling precipitation in
flow reactions,81–83 there is an ever present danger that
hazardous solid material will accumulate inside the reactor.
Whereas use of tosyl azide avoids the problems asscociated
with solid azide precipitation, the potentially explosive nature
acetate extract of the reaction mixture revealed that ethyl
acetoacetate (3a) had been completely converted to the diazo
product 4a after just 2 h.
Generation and use of tosyl azide in flow
The batch procedure for in situ generation of tosyl azide was
transformed into a continuous process whereby an aqueous
solution of sodium azide was combined with a MeCN solution
of tosyl chloride, and reacted inside a tubular reactor at 25 °C.
A third stream, containing ethyl acetoacetate (3a) and
triethylamine, was then introduced so that the diazo transfer
could proceed within a second tubular reactor which was also
held at 25 °C. A series of experiments were conducted to
determine the residence times required for both the tosyl azide
formation and diazo transfer steps (Table 3). With initial
residence times of 50 min for tosyl azide formation, and 66 min
for diazo transfer, the reaction was observed to go to
completion (Table 3, entry 1). Drastically reducing the time for
of the solid sulfonyl azides 1b, 1c generated in these reactions
meant they could not be safely used in the flow process we
report here.
Reaction monitoring by in‐line infrared spectroscopy
In‐line infrared (IR) spectroscopy has been reported as a
valuable tool for the monitoring of hazardous components in
flow reactions.48,58,68,84–86 Tosyl azide exhibits a strong N=N=N
stretching mode which can be used to assess the purity of the
4 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 9
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
View Article Online
DOI: 10.1039/C6OB00246C
Table 4. Evaluation of methods for the quenching of tosyl azide.
Entry
Quench Method
Time
(min)
120
Resulta
Scheme 4. Hydrolysis of the diazo quench by‐product.
1
2
3
4
None
NaNO2
no tosyl azide quenched
no tosyl azide quenched
no tosyl azide quenched
100% tosyl azide
quenched
sodium nitrite based quench systems on tosyl azide we
conducted a series of tests using FT‐IR and 1H NMR
spectroscopy to check for quenching of the azide (Table 4). A
generous reaction time of 2 h was initially allowed for even
though an effective quench would be required to act much
more rapidly. Reacting tosyl azide with sodium nitrite did not
result in any detectable reduction of the tosyl azide peaks by
either FT‐IR or 1H NMR spectroscopy (Table 4, entry 2).
Employing sodium nitrite and sulfuric acid was similarly
ineffective in quenching tosyl azide (Table 4, entry 3). We
concluded that the free inorganic azide quench method is not
effective for quenching tosyl azide.
120
H2SO4 / NaNO2
Acetylacetone /
NaOH
120
120
5
Acetylacetone /
NaOH
2
100% tosyl azide
quenched
a) Tosyl azide quenching followed by IR spectroscopy at 2135 cm‐1 and 1H
NMR spectroscopy at 7.41 ppm and 7.85 ppm.
batch prepared reagent.3 To verify the complete formation of
tosyl azide from sodium azide and tosyl chloride, the reagents
were mixed and then flowed through an in‐line IR spectrometer
after residence times of between 10 to 120 s. The formation of
tosyl azide was followed by the strong azide band at 2135 cm‐1
while the consumption of sodium azide was concurrently
observed by monitoring 2048 cm‐1. After only 10 s we observed
approximately 60% conversion of sodium azide to tosyl azide.
After 1 min of residence time there was less than 10% of the
sodium azide remaining and after 2 min the formation of tosyl
azide was observed to be complete.
The diazo group exhibits a characteristic band in the IR
spectrum between 1950 and 2300 cm‐1. Wirth and co‐workers
have demonstrated that in‐line IR spectroscopy can be used to
follow the formation of diazomethyl phenylacetate and the
consumption of the diazo acceptor molecule.68,69 When we
As there was a significant need for an effective quench
method for sulfonyl azides, we considered the concept of using
a sacrificial diazo acceptor molecule. Acetylacetone was
dissolved in a sodium hydroxide solution to form sodium
acetylacetonate (5), a reactive acceptor molecule for diazo
transfer. As expected, reacting tosyl azide with an excess of the
acetylacetonate resulted in complete consumption of the tosyl
azide (Table 4, entry 4). Further analysis revealed that the
acetylacetonate quench of tosyl azide was complete in under 2
min (Table 4, entry 5). Implementation of this quench system in
our research did not require any changes to our existing diazo
transfer workup procedures. The excess acetylacetonate (5)
quench reagent is readily soluble in the aqueous partition
during liquid‐liquid extraction workup. A further advantage of
this method is that the diazocarbonyl by‐product of the quench
attempted
a
continuous diazo transfer to diethyl
reaction can be hydrolysed to 1‐diazopropan‐2‐one (6) and
acetoacetamide (3j) the reaction progress was followed by the
appearance of a diazo IR absorption peak at 2113 cm‐1. A
reduction in the tosyl azide absorption at 2135 cm‐1 is also
observed if diazo transfer occurs. By in‐line IR it was observed
that the diazo transfer to diethyl acetoacetamide (3j) went to
approximately 33% conversion when the flow reactor was
operated with a residence time of 8 min for the diazo transfer.
acetate (Scheme 4).88 During the reaction work‐up both of these
components are readily extracted by washing with aqueous 9%
KOH solution. We have found that treatment of the aqueous
washings with sodium nitrite and dilute sulfuric acid safely
decomposes 1‐diazopropan‐2‐one (6
).89
The quench method for tosyl azide allowed us to safely
proceed with an investigation of the substrate scope of the 2nd
generation continuous diazo transfer process (Table 5). To
further improve the safety of the process, a slight excess (1.05
In‐line quenching of tosyl azide
While continuous processing is ideal for handling reactive
intermediates and reagents safely, it is essential that the
chemist fully considers the consequences of a reactor
malfunction. Even something as simple as a reaction not going
to completion can result in an unexpected build‐up of the
hazardous reactive species within the collection reservoir at the
reactor outlet. One of the most effective ways to minimise this
risk is to introduce a quench stream before the reactor outlet.
The ideal quench stream should react rapidly with the unstable
intermediates to produce stable by‐products. A further
requirement is that the quench should not consume the
product of the reaction.
equivalents) of the diazo acceptor molecules (3a–f, 3i and 3j
)
were employed. In this mode of operation tosyl azide was the
limiting reagent and would thus be completely consumed if the
reaction went to completion. In situations where the reaction
did not go to completion the acetoacetonate quench (
act to remove the remaining tosyl azide.
5) would
The ethyl (3a, Table 5, entry 1), tert‐butyl (3b, Table 5, entry
2), isoamyl (3c, Entry 3) and benzyl (3d, Table 5, entry 4)
acetoacetate esters all underwent diazo transfer to a maximum
conversion of 95% (based on use of 1.05 equivalents of
substrate) with good yields of 68 to 77% obtained. Ethyl benzoyl
Free inorganic azides can be quenched by treatment with
sodium nitrite and sulfuric acid which, when combined produce
the active nitrous acid quench agent.87 To examine the effect of
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 5
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 6 of 9
ARTICLE
Journal Name
View Article Online
DOI: 10.1039/C6OB00246C
acetate (3e, Table 5, entry 5) also underwent efficient diazo to produce over 21 g of benzyl 2–diazo‐3‐oxobutyrate (4d) in
transfer to provide an excellent yield (89%) of the diazo product. 88% yield. This continuous process is particularly notable for
Diazo transfer to diethyl acetoacetamide (3j, Table 5, entry 6) providing the α‐diazocarbonyl product in >98% purity without
was attempted in flow but the reaction proceeded slowly with the need for any column chromatography.
77% conversion being observed after an extended residence
time of 44 min. Less activated diazo acceptors were also
Experimental
Typical Diazo Transfer in Continuous Mode Using Tosyl Azide
studied, but with DBU used as the base instead of triethylamine.
90
While diazo transfer to aryl ketosulfone (3k
)
went to
completion (Table 5, entry 8), diethyl malonate (3f) was found
to react slowly under these conditions, with a conversion of only
65% being observed even after an extended residence time of
66 min (Table 5, entry 7).
A 5 mL solution of ethyl‐3‐oxobutanoate (3a) (0.260 g, 2.0
mmol, 1 eq.) and NEt3 (0.210 g, 2.1 mmol, 1.05 eq.) in MeCN
was prepared along with a 5 mL solution of tosyl azide (0.430 g,
2.2 mmol, 1.1 eq.) in MeCN. The ethyl‐3‐oxobutanoate
(
3a)/NEt3 solution was injected into a sample loop and then
Enabling the large scale synthesis of α‐diazocarbonyls
pumped to a T‐piece where it combined with the tosyl azide
solution which had been injected in a second stream (2 mL at
0.087 mL.min−1). The combined stream passed through a 20 mL
reactor (25 °C, 120 min residence time) before passing through
a back pressure regulator (8 bar). The product stream was
collected and then concentrated under reduced pressure to
A significant advantage of this continuous diazo transfer process
is that readily available shelf stable reagents are used to
generate the hazardous tosyl azide on demand. This makes the
process particularly attractive for the scale up of the diazo
transfer reaction. The diazo transfer to benzyl 3‐oxobutyrate
(
3d, Table 5, entry 4) was operated continuously for ten hours
6 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 9
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
provide a mixture of the α‐diazocarbonyl product (4a) and azides were tested for their effect on tosyl azide VainewdAfrtoiculenOdnlitnoe
DOI: 10.1039/C6OB00246C
toluenesulfonamide by‐product. Reaction conversion of 100% be ineffective. A new quench system, consisting of a sacrificial
was determined by 1H NMR spectroscopy and the α‐ diazo acceptor molecule, was therefore developed and then
diazocarbonyl product (4a) was identified by comparison with successfully applied in the continuous process to remove
the literature data. Tosyl azide quench was not employed when unreacted tosyl azide from the reaction. In‐line infrared (IR)
the reactions were conducted on small scale (<1 mmol).
spectroscopy could also be used to monitor the formation and
consumption of key reaction components. The telescoped
continuous process was used to transfer a diazo group to a
range of acceptor types. Continuous operation of the process
allowed over 21 g of an α‐diazocarbonyl to be produced safely.
The continuous generation and use of tosyl azide has the
potential to make diazo transfer chemistry more accessible to
the pharmaceutical and fine chemical industries.
Large Scale Diazo Transfer in Continuous Mode with In Situ
Generation of Tosyl Azide
A 270 mL solution of benzyl 3‐oxobutyrate (3d), (24.52 g, 0.4725
M, 1.05 eq.) and NEt3 (0.4725 M, 1.05 eq.) in MeCN was
prepared. A 270 mL solution of tosyl chloride (2a) (23.17 g, 0.45
M, 1 eq.) in MeCN and a 270 mL aqueous solution of sodium
azide (7.89 g, 0.45 M, 1 eq.) were prepared. A quench solution
of sodium hydroxide (7.29 g, 0.675 M, 1.5 eq.) and acetyl
acetone (18.25 g, 0.675 M, 1.5 eq.) in a 50:50 mixture of MeCN
and water was also prepared. The tosyl chloride (2a) solution
was pumped (0.45 ml.min‐1) into a T‐piece where it met the
aqueous sodium azide solution (0.45 ml mL.min‐1). The
combined stream passed through a 96 cm tube (1 min residence
time) before it met the benzyl 3‐oxobutyrate (3d)/NEt3 solution
(0.45 ml.min‐1) at a T‐piece. This combined stream passed
through a series of three 10 mL reactor coils (25 °C, 22 min
residence time). The reaction stream was then combined with
Acknowledgements
This work was undertaken as part of the Synthesis and Solid State
Pharmaceutical Centre supported by the Science Foundation
Ireland (grant: SFI SSPC2 12/RC/2275). We also acknowledge the
contribution of Dr. Leslie Ann Clarke, in providing the β-ketosulfone
substrates used in this work. Finally we would like to thank Mettler–
Toledo, for the kind loan of the in-line IR equipment used for our
reaction monitoring studies.
Notes and references
the sodium acetylacetonate (5) solution (0.45 ml.min‐1) at a T‐
1
2
3
M. Regitz, Tetrahedron Lett., 1964, 5, 1403–1407.
piece to quench any remaining tosyl azide (1a). The combined
stream passed through a 150 cm tube and a back pressure
regulator (8 bar) before exiting the reactor. The reactor
effluents were collected over a period of 10 h and then
concentrated under reduced pressure. The crude product was
collected in 3 batches. These were concentrated under reduced
pressure to remove acetonitrile. These were then dissolved in
EtOAc (100 mL) and washed with 9% aqueous KOH (2 × 50 mL),
brine (50 mL) and water (50 mL). The organic layer was dried
with anhydrous MgSO4, filtered and then concentrated under
reduced pressure to give the α‐diazocarbonyl product (4d) (21.8
g, >98% purity, 88% yield) as a yellow oil. (UATR)/cm‐1: 2144,
1719, 1656; δH (CDCl3, 400 MHz): 2.52 (3H, s, CH3), 5.31 (2H, s, CH2),
7.26‐7.41 (5H, m, 5 x aromatic CH); δC (CDCl3, 75.5 MHz): 28.3 (CH3),
66.9 (OCH2), 128.4, 128.7, 128.8 (aromatic CH), 135.2 (aromatic C)
161.7 (C=O, ester), 189.9 (C=O, ketone), no signal observed for
(C=N2). The aqueous waste was treated with dilute solutions of
sodium nitrite (20% v/v) and then sulfuric acid (20% v/v) to
safely decompose any sodium azide and 1‐diazopropan‐2‐one
M. Regitz, Angew. Chem. Int. Ed., 1967, 6, 733–749.
H. Heydt, M. Regitz, A. K. Mapp and B. Chen, in Encyclopedia
of Reagents for Organic Synthesis, John Wiley & Sons, Ltd,
Chichester, UK, 2008, DOI: 10.1002/047084289X.rt141.pub2
M. Regitz, J. Hocker and A. Liedhegener, Org. Synth., 1968,
48, 36.
E. J. Corey and A. M. Felix, J. Am. Chem. Soc., 1965, 87, 2518–
2519.
N. R. Candeias, P. M. P. Gois, L. F. Veiros and C. A. M. Afonso,
J. Org. Chem., 2008, 73, 5926–5932.
4
5
6
7
8
9
T. Ye and M. A. McKervey, Chem. Rev., 1994, 94, 1091–1160.
G. Maas, Angew. Chem. Int. Ed., 2009, 48, 8186–8195.
M. P. Doyle, R. Duffy, M. Ratnikov and L. Zhou, Chem. Rev.,
2010, 110, 704–724.
10
M. P. Doyle, M. A. McKervey and T. Ye, Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds: From
Cyclopropanes to Ylides, John Wiley & Sons, New York, 1998.
C. N. Slattery, A. Ford and A. R. Maguire, Tetrahedron, 2010,
66, 6681–6705.
A. Ford, H. Miel, A. Ring, C. N. Slattery, A. R. Maguire and M.
A. McKervey, Chem. Rev., 2015, 115, 9981–10080.
C. J. Flynn, C. J. Elcoate, S. E. Lawrence and A. R. Maguire, J.
Am. Chem. Soc., 2010, 132, 1184–1185.
11
12
13
14
(6) in the aqueous layer.
C. N. Slattery and A. R. Maguire, Org. Biomol. Chem., 2011,
9, 667–669.
15
16
17
V. Ferreira, Curr. Org. Chem., 2007, 11, 177–193.
A. H. Wee, Curr. Org. Synth., 2006, 3, 499–555.
H. M. L. Davies and R. E. J. Beckwith, Chem. Rev., 2003, 103,
2861–904.
Conclusions
We have presented herein a procedure for the in situ
generation and use of tosyl azide from safer, readily available
reagents. This procedure can be conducted in batch mode,
however the true power of the in situ tosyl azide generation is
best realised by using continuous processing to enable diazo
transfer on a large scale. Methods for quenching free inorganic
18
19
M. P. Doyle and D. C. Forbes, Chem. Rev., 1998, 98, 911–936.
A. Padwa and K. E. Krumpe, Tetrahedron, 1992, 48, 5385–
5453.
A. Padwa and M. D. Weingarten, Chem. Rev., 1996, 96, 223–
270.
20
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 7
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 8 of 9
ARTICLE
Journal Name
21
22
L. Wolff, Liebigs Ann., 1902, 325, 129–195.
O. C. M. O’Sullivan, S. G. Collins, A. R. Maguire and G. Buche, 54
Angew. Chem. Int. Ed., 2010, 49, 7101–7105. View Article Online
J. Jacq and P. Pasau, Chemistry, 201D4O,I2: 010,.11023292/3C–61O2B203032.46C
B. Ahmed‐Omer, D. A. Barrow and T. Wirth, Tetrahedron
Lett., 2009, 50, 3352–3355.
K. S. Nalivela, M. Tilley, M. A. McGuire and M. G. Organ,
Chem. Eur. J., 2014, 20, 6603–6607.
N. Oger, E. Le Grognec and F.‐X. Felpin, J. Org. Chem., 2014,
79, 8255–8262.
L. Malet‐Sanz, J. Madrzak, S. V. Ley and I. R. Baxendale, Org.
Biomol. Chem., 2010, 8, 5324–5332.
N. Chernyak and S. L. Buchwald, J. Am. Chem. Soc., 2012,
134, 12466–12469.
D. N. Tran, C. Battilocchio, S.‐B. Lou, J. Hawkins and S. V. Ley,
Chem. Sci., 2015, 6, 1120‐1125.
N. M. Roda, D. N. Tran, C. Battilocchio, R. Labes, R. Ingham,
J. Hawkins and S. V. Ley, Org. Biomol. Chem., 2015, 13, 2550‐
2554.
Eur. J. Org. Chem., 2014, 2297–2304.
O. C. M. O’Sullivan, S. G. Collins and A. R. Maguire, Synlett,
2008, 659–662.
55
56
57
58
59
60
61
23
24
25
W. Sander, A. Strehl, A. R. Maguire, S. Collins and P. G.
Kelleher, Eur. J. Org. Chem., 2000, 3329–3335.
G. Bucher, A. Strehl and W. Sander, Eur. J. Org. Chem., 2003,
2153–2158.
W. Kirmse, Eur. J. Org. Chem., 2002, 2193–2256.
F. W. Bollinger and L. D. Tuma, Synlett, 1996, 407–413.
M. Presset, D. Mailhol, Y. Coquerel and J. Rodriguez,
Synthesis, 2011, 2549–2552.
26
27
28
29
30
E. D. Goddard‐Borger and R. V Stick, Org. Lett., 2007, 9,
3797–3800.
N. Fischer, E. D. Goddard‐Borger, R. Greiner, T. M. Klapötke,
B. W. Skelton and J. Stierstorfer, J. Org. Chem., 2012, 77,
1760–1764.
G. M. Green, N. P. Peet and W. A. Metz, J. Org. Chem., 2001,
66, 2509–2511.
62
63
64
V. D. Pinho, B. Gutmann, L. S. M. Miranda, R. O. M. A. de
Souza and C. O. Kappe, J. Org. Chem., 2014, 79, 1555–1562.
V. D. Pinho, B. Gutmann and C. O. Kappe, RSC Adv., 2014, 4,
37419–37422.
F. Mastronardi, B. Gutmann and C. O. Kappe, Org. Lett.,
2013, 15, 5590–5593.
31
32
B. Ma, F.‐L. Chen, X.‐Y. Xu, Y.‐N. Zhang and L.‐H. Hu, Adv.
Synth. Catal., 2014, 356, 416–420.
33
34
J. Wang and J. D. Rainier, Org. Lett., 2015, 17, 266–269.
B. K. Kuruba, N. Shariff, S. Vasanthkumar and L. Emmanuvel, 65
Synth. Commun., 2015, 45, 2454–2461.
H. E. Bartrum, D. C. Blakemore, C. J. Moody and C. J. Hayes,
Tetrahedron, 2013, 69, 2276–2282.
35
36
37
38
39
A. Edwards and M. Rubin, Tetrahedron, 2015, 71, 3237– 66
3246.
J.‐Q. Wu, Z. Yang, S.‐S. Zhang, C.‐Y. Jiang, Q. Li, Z.‐S. Huang 67
H. E. Bartrum, D. C. Blakemore, C. J. Moody and C. J. Hayes,
Chem. Eur. J., 2011, 17, 9586–9589.
L. Kupracz and A. Kirschning, J. Flow Chem., 2013, 3, 11–16.
S. T. R. Müller, A. Murat, D. Maillos, P. Lesimple, P. Hellier
and T. Wirth, Chem. Eur. J., 2015, 21, 7016–7020.
S. T. R. Müller, A. Murat, P. Hellier and T. Wirth, Org. Process
Res. Dev., 2015, DOI: acs.oprd.5b00308.
S. T. R. Müller, D. Smith, P. Hellier and T. Wirth, Synlett,
2014, 25, 871–875.
R. A. Maurya, K.‐I. Min and D.‐P. Kim, Green Chem., 2014,
16, 116–120.
and H. Wang, ACS Catal., 2015, 5, 6453–6457.
G. Cheng, X. Zeng, J. Shen, X. Wang and X. Cui, Angew. Chem.
Int. Ed., 2013, 52, 13265–8.
J. Wegner, S. Ceylan and A. Kirschning, Adv. Synth. Catal.,
2012, 354, 17–57.
68
69
70
T. Wirth, Ed., Microreactors in Organic Chemistry and
Catalysis, Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim, 71
Germany, 2013.
40
41
I. R. Baxendale, L. Brocken and C. J. Mallia, Green Processing 72
and Synthesis, 2013, 2, 211–230.
J. C. Pastre, D. L. Browne and S. V. Ley, Chem. Soc. Rev., 73
2013, 42, 8849–8869.
D. Webb and T. F. Jamison, Chem. Sci., 2010, 1, 675–680.
D. T. McQuade and P. H. Seeberger, J. Org. Chem., 2013, 78, 74
6384–9.
L. J. Martin, A. L. Marzinzik, S. V. Ley and I. R. Baxendale, Org.
Lett., 2011, 13, 320–323.
R. C. Wheeler, O. Benali, M. Deal, E. Farrant, S. J. F.
MacDonald and B. H. Warrington, Org. Process Res. Dev.,
2007, 11, 704–710.
M. M. E. Delville, P. J. Nieuwland, P. Janssen, K. Koch, J. C.
M. van Hest and F. P. J. T. Rutjes, Chem. Eng. J., 2011, 167,
556–559.
H. J. Ledon, in Organic Syntheses, John Wiley & Sons,
Hoboken, NJ, USA, 2003, pp. 66–66.
S. G. Collins, O. C. M. O’Sullivan, P. G. Kelleher and A. R.
Maguire, Org. Biomol. Chem., 2013, 11, 1706–1725.
A. R. Maguire, P. G. Kelleher, G. Ferguson and J. F. Gallagher,
Tetrahedron Lett., 1998, 39, 2819–2822.
42
43
44
45
46
47
48
49
50
R. L. Hartman, J. P. McMullen and K. F. Jensen, Angew.
Chem. Int. Ed., 2011, 50, 7502–7519.
B. Gutmann, D. Cantillo and C. O. Kappe, Angew. Chem. Int.
Ed., 2015, 54, 6688–6728.
B. J. Deadman, S. G. Collins and A. R. Maguire, Chem. Eur. J.,
2015, 21, 2298–2308.
S. T. R. Müller and T. Wirth, ChemSusChem, 2015, 8, 245‐
250.
C. J. Smith, N. Nikbin, S. V. Ley, H. Lange and I. R. Baxendale,
Org. Biomol. Chem., 2011, 9, 1938–1947.
H. R. Sahoo, J. G. Kralj and K. F. Jensen, Angew. Chem. Int.
Ed., 2007, 46, 5704–5708.
75
76
77
78
79
80
E. Tarrant, C. V. O’Brien and S. G. Collins, Green Chem., 2015,
Manuscript submitted.
D. B. Ramachary, V. V. Narayana and K. Ramakumar,
Tetrahedron Lett., 2008, 49, 2704–2709.
D.
H.
Ripin
and
D.
A.
Evans,
2005,
M. E. Kopach, M. M. Murray, T. M. Braden, M. E. Kobierski
and O. L. Williams, Org. Process Res. Dev., 2009, 13, 152–
160.
http://www.evans.rc.fas.harvard.edu/pdf/evans_pKa_tabl
e.pdf, accessed Jan 2016.
R. L. Hartman, Org. Process Res. Dev., 2012, 16, 870–887.
B. J. Deadman, D. L. Browne, I. R. Baxendale and S. V. Ley,
Chem. Eng. Technol., 2014, 38, 259–264.
81
51
P. Zhang, M. G. Russell and T. F. Jamison, Org. Process Res. 82
Dev., 2014, 18, 1567–1570.
52
53
J. C. Brandt and T. Wirth, Beilstein J. Org. Chem., 2009, 5, 30. 83
B. Gutmann, J.‐P. Roduit, D. Roberge and C. O. Kappe,
D. L. Browne, B. J. Deadman, R. Ashe, I. R. Baxendale and S.
V. Ley, Org. Process Res. Dev., 2011, 15, 693–697.
8 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 9 of 9
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
84
C. F. Carter, H. Lange, S. V. Ley, I. R. Baxendale, B. Wittkamp,
J. G. Goode and N. L. Gaunt, Org. Process Res. Dev., 2010,
14, 393–404.
View Article Online
DOI: 10.1039/C6OB00246C
85
86
C. Battilocchio, B. J. Deadman, N. Nikbin, M. O. Kitching, I. R.
Baxendale and S. V. Ley, Chem. Eur. J., 2013, 19, 7917–7930.
S. A. M. W. van den Broek, J. R. Leliveld, R. Becker, M. M. E.
Delville, P. J. Nieuwland, K. Koch and F. P. J. T. Rutjes, Org.
Process Res. Dev., 2012, 16, 934–938.
87
Committee on Prudent Practices for Handling, Storage, and
Disposal of Chemicals in Laboratories, National Research
Council, Prudent Practices in the Laboratory ‐ Handling and
Disposal of Chemicals, National Academies Press, Online
Edi., 1995.
88
89
J. B. Hendrickson and W. A. Wolf, J. Org. Chem., 1968, 33,
3610–3618.
Analysis of an aqueous solution of 1‐diazopropan‐2‐one (6)
by FT‐IR after treatment with sodium nitrite and dilute
sulfuric acid confirmed that the diazo group had been
consumed.
90
L. A. Clarke, PhD Thesis, University College Cork, 2015.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 9
Please do not adjust margins