Rapid generation and safe use of carbenes enabled by a novel flow protocol with in-line IR spectroscopy

Article abstract of DOI:10.1002/chem.201500416

A powerful new continuous process for the formation and use of donor/acceptor-substituted carbenes is described. The safety profile of diazo group transfer on methyl phenylacetate was determined including kinetic studies in batch and in flow using in-line

Full text of DOI:10.1002/chem.201500416

DOI: 10.1002/chem.201500416
Communication
&
Flow Chemistry |Hot Paper|
Rapid Generation and Safe Use of Carbenes Enabled by a Novel
Flow Protocol with In-line IR spectroscopy
Simon T. R. Müller,[a] AurØlien Murat,[b] Delphine Maillos,[b] Patrick Lesimple,[b] Paul Hellier,[b]
and Thomas Wirth*[a]
need to be shortened in a safe manner. The direct use of the
Abstract: A powerful new continuous process for the for-
mation and use of donor/acceptor-substituted carbenes is
diazo moiety without having to isolate, concentrate, and purify
would also be mandatory for the development of safe and effi-
described. The safety profile of diazo group transfer on
cient processes. To overcome the above-mentioned challenges,
methyl phenylacetate was determined including kinetic
continuous flow microreactor technology possesses great po-
studies in batch and in flow using in-line IR analysis. Batch
tential. It has been applied as the enabling technology for
work-up and liquid chromatography were circumvented
many hazardous reagents and reactions,[15] and several reviews
by developing an optimized liquid/liquid flow separation
emphasize on the great safety profile of continuous flow mi-
method providing aryl diazoacetates in high purity. Fast
croreactor processes. Several research groups have investigat-
screening of reaction conditions in flow with in-line IR
ed the chemistry of diazo compounds in flow.[16] Hayes and co-
analysis allowed rapid reaction optimization. Finally, a mul-
workers studied the decomposition of tosyl hydrazones to
tistep process of diazo group transfer, extraction, separa-
access diazo compounds in continuous flow which were sub-
tion and subsequent diazo decomposition combined with
sequently used in semi-batch for XÀH-type insertion reac-
multiple XÀH insertion reactions was established.
tions.[17] Ley et al. recently communicated the use of manga-
nese dioxide cartridges for the decomposition of hydrazones
to diazo compounds.[18] Several methods for the formation and
use of diazomethane, ethyl diazoacetate, and other diazo de-
rivatives have been reported.[19]
Diazo compounds represent one of the most versatile classes
of reagents in organic chemistry.[1] Model substrates for the di-
verse reactivity are donor/acceptor carbene precursors such as
diazo methyl phenylacetate.[2] This compound has been used
in stereoselective cyclopropanation reactions of alkenes, al-
lenes,[3] and alkynes,[4] in cycloadditions,[5] in intra- and intermo-
lecular CÀH insertions,[6] in asymmetric OÀH,[7] SÀH,[8] and NÀ
H[9] and in other XÀH insertions,[10] in cross-coupling reac-
tions,[11] and in domino[12] and multicomponent reactions.[9,13]
The most common method to synthesize diazo aryl esters is
via diazo group transfer of commercially available sulfonyl
azides onto activated methylene groups.
However, the most important reaction to form donor/ac-
ceptor carbenes, the diazo group transfer onto activated meth-
ylene groups, has not yet been studied in continuous flow.[20]
We were therefore interested in developing a methodology to
access the broad reactivity of donor/acceptor carbenes in
a safe fashion using flow chemistry (Scheme 1).
Diazo group transfer reactions are usually performed at
room temperature for several hours/overnight with subse-
quent work-up and column chromatography. Higher tempera-
tures to reduce the reaction time are not applied for safety
reasons as little is known about the safety profile and kinetics
of diazo transfer reactions.[14] To make the process more effi-
cient and appealing for large-scale applications, reaction times
[a] S. T. R. Müller, Prof. Dr. T. Wirth
School of Chemistry, Cardiff University
Park Place, Main Building, Cardiff CF10 3AT (UK)
E-mail: wirth@cf.ac.uk
Homepage: http://blogs.cardiff.ac.uk/wirth/
[b] A. Murat, D. Maillos, Dr. P. Lesimple, Dr. P. Hellier
Institut de Recherche Pierre Fabre
16 Rue Jean Rostand
81603 Gaillac (France)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500416.
Scheme 1. Formation and utilisation of aryl diazoacetates in batch and flow.
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In-depth investigations of thermal and kinetic properties of
diazo transfer reactions were performed. Kinetic studies as well
as qualitative studies were facilitated by the use of in-line IR
spectroscopy. In-line IR spectroscopy in flow has emerged as
a powerful technology for rapidly optimizing reactions and
precisely determining reaction kinetics.[21]
The diazo transfer onto methyl phenylacetate 1 starts fast
and slows down the further it progresses. p-Acetamidobenze-
nesulfonyl azide 2 and methyl phenylacetate 1 are consumed
at a similar rate. The reaction is complete (>90%) after around
4 h. The reaction shows a second-order kinetic, and the rate
constant of the reaction has been determined to be k=5”
Herein, a new protocol is described in which phenyl diazoa-
cetates are made and used in an efficient and safe manner. Ki-
netic optimization using in-line IR analysis enables rapid forma-
tion of the diazo species in flow. Liquid/liquid separation in
flow using highly hydrophobic solvents circumvents liquid
chromatography and diazo isolation. Furthermore, IR spectros-
copy allows rapid optimization of subsequent donor/acceptor
carbene reactions. A multistep process combining the forma-
tion of diazo functionality, liquid/liquid separation and diverse
intermolecular reactions of the diazo compounds furnishes
high value products safely and in good yields.
10À4 mÀ1 À1 (for details see the Supporting Information).
s
The kinetic data of the diazo transfer in continuous flow was
obtained by using a ReactIRflow cell from Mettler Toledo. To
access several data points quickly and to consume less materi-
al, three different reactors were connected via valves. There-
fore, three data points could be obtained at the same time
corresponding to residence times of 9 min (Reactor 1), 17 min
(Reactor 1 + Reactor 2), and 26 min (Reactor 1 + Reactor 2 +
Reactor 3) (for the detailed setup see Figure S1 in the Support-
ing Information).
As shown in Figure 1, the efficiency of diazo transfer reac-
tions is strongly dependent on the temperature and residence
It was found that the diazo transfer reaction from 1 to diazo
compound
3
is very exothermic with an enthalpy
(À138 kJmolÀ1) that would lead to an adiabatic temperature
rise to 648C (Scheme 2). This surpasses the temperature at
which the decomposition temperature becomes critical (TD24
=
Scheme 2. Diazo group transfer on methyl phenylacetate.
Figure 1. Kinetics of diazo transfer flow versus batch.
548C)[22] (for details see the Supporting Information). A batch
reaction could therefore lead to a thermal runaway. The ensu-
ing decomposition is also highly exothermic (À133 JgÀ1).
Therefore, this reaction needs to be classified into the highest
risk class[23] and excessive safety measures would have to be
undertaken and specialized equipment would be required for
large-scale batch operations.
time. The increase in residence time leads to an almost linear
increase of yield at lower temperatures (258C–508C). Tempera-
ture has also a very positive effect on the yield. At 408C, the
residence time to achieve 39% yield can be reduced by
a factor of three compared to that at 258C. Temperatures
above 608C do not improve yields any further (708C, 26 min,
90% yield). In flow, 89% yield can be obtained in a reaction
time of 26 min at 608C, whereas in batch more than 4 h at
258C are required to obtain the same result. With the values
obtained it was possible to determine the activation energy of
the diazo transfer through Arrhenius plotting EA =
56 kJmolÀ1KÀ1.[26]
Having established a good understanding of the potential
hazards of this diazo group transfer reaction, the kinetics of
the classical batch approach were investigated. Although diazo
group transfer reactions onto arylacetates are highly energetic,
they cannot be considered to be rapid reactions. To assess the
kinetics of diazo transfer reactions, IR analysis using Mettler
Toledo ReactIR was performed. The IR was calibrated against
starting material and product to obtain quantitative data. The
reaction was performed under standard batch reaction condi-
tions[24] and monitored via IR analysis and HPLC. The formation
of diazomethyl phenylacetate 3 was monitored by the diazo
peak at 2097 cmÀ1, while consumption of 1 was monitored via
the carbonyl peak at 1740 cmÀ1. For the diazo concentration
[3], correct data could be obtained directly, whereas in the
case of the carbonyl peak for the starting material 1, the
second derivative had to be applied as otherwise concentra-
tions below 0.1m could not be detected anymore.[25]
There has been a vivid discussion on the benefits of mixing
in continuous flow compared to batch reactions.[27] It has been
clearly demonstrated that rapid reactions with a reaction rate
higher or comparable to mass transfer depend heavily on the
efficiency of mixing[28] as well as biphasic reactions.[29] However,
in the reaction studied here, the observed reduction of reac-
tion time to attain 90% yield can be solely attributed to the
possibility of a higher process temperature. Hence, continuous
flow at 258C behaves equivalently to the batch reaction at
258C. This is in agreement with previous reports on mixing ef-
fects in relatively slow, homogenous reactions.[30]
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After the development of this safe method for the genera-
tion of diazo species rapidly in flow, we investigated ways to
isolate phenyl diazoacetates from the crude reaction mixture
without the need for solvent evaporation and liquid chroma-
tography. Screening several solvents for an in-line liquid/liquid
extraction in flow uncovered hydrocarbon solvents such as n-
hexane and n-heptane to be very efficient and selective sol-
vents for obtaining the diazo compounds in sufficient purities
for further transformations. The efficiency depends also on the
solubility of the diazo product, which can be altered by the
alkyl chain length of the ester. Extraction in flow was per-
formed with a membrane-based extraction system to separate
the aqueous and the organic phase.[31] The final step was the
rapid optimization of a broad range of diazo decomposition re-
actions in flow. Purified diazo methyl phenylacetate was ex-
posed to different substrates under metal catalysis in continu-
ous flow. Rapid optimization was ensured through in-line IR
analysis (Figure 2).
formed. Figure 3 shows the IR spectra of the reaction of diazo
methyl phenylacetate 3 with 3-bromoaniline (4a) to give
access to a-aminoester 5a.
The carbonyl peak of 3 is shifted from 1704 cmÀ1 to
1745 cmÀ1 when the reaction mixture is exposed to higher
temperatures. This is a strong indication for the decomposition
of diazo methyl phenylacetate. Decrease of the primary amine
NÀH bend at 1625 cmÀ1 as well as changes of the aromatic
amine CÀN stretch in the region between 1340 cmÀ1 to
1280 cmÀ1 show the consumption of substrate 4a. Offline
HPLC analysis was used to verify the results obtained by IR
analysis.
The decomposition rate for diazo compound 3 is substrate
independent and behaves similarly for compounds 5a to 5d
with rhodium acetate as catalyst (Figure 4, top). Rhodium-
based catalysts were the most efficient ones when comparing
different metal catalysts (1 mol%) for reaction times of 10 min
(Figure 4, bottom). Interestingly, rhodium octanoate promotes
a higher reaction rate than rhodium acetate. This might be
due to its higher solubility in the organic solvent mixture.
These reactions have been screened with small amounts of
compounds by IR and HPLC/MS analysis only and no isolated
yields are given.
In-line IR spectroscopy gave detailed information on starting
material consumption and on structural motives of products
For an efficient preparative use of phenyl diazoacetates in
flow chemistry, a set-up of diazo formation, liquid/liquid extrac-
tion, and subsequent diazo decomposition was developed as
shown in Figure 5. The addition of sodium nitrite is necessary
to quench any free azide in the solution.[32] A collection vial
was placed after the liquid/liquid separation to eliminate any
risk of pressure build-up within the system. n-Propyl and iso-
butyl esters were used in the full flow set-up as these more hy-
drophobic esters lead to a more efficient extraction than the
methyl ester derivative. As the solution of diazo compound 3
is continuously pumped out of the collection vial, there is no
risk of accumulation.
The two-step process allows access to high-value products
in good yields without the need to isolate the diazo intermedi-
ate (Figure 6). This new process can be applied to alcohols
(6a–6 f), cyclopropanes (6g–6i), thiols (6j), carbamates (6k),
and amines (6m). Aside from its broad applicability, the set-up
Figure 2. Top: Set-up for diazo decomposition reactions in continuous flow
with 3-bromoaniline (4a) as an example. Bottom: Range of substrates ana-
lyzed via in-line IR analysis for NÀH insertion (5a), OÀH insertion (5b), NÀH
insertion of carbamates (5c), SÀH insertion (5d), and cyclopropanation (5e).
Figure 3. IR spectra of the NÀH insertion of diazo methyl phenylacetate 3 at different temperatures; conditions: g 258C; a 508C; c 708C; residence
time: 10 min.
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Figure 6. Reaction scope for two-step process. *=5 equivalents of alkene
used.
diazo compounds, rapid optimization of diazo decomposition
reactions as well as a multistep set-up that provides access to
valuable a-substituted phenylacetates in good yields and high
efficiencies. The method does not require the isolation of the
diazo species and can provide gram quantities of valuable a-
oxyphenyl acetates. In-line IR spectroscopy provided rapid
access to quantitative information on diazo formation and con-
sumption.
Figure 4. Top: Diazo decomposition for products 5a to 5d with Rh2(OAc)4 at
different temperatures for 10 min in flow. Bottom: Comparison of different
metal catalysts for the diazo decomposition to give product 5b at different
temperatures for 10 min in flow.
Acknowledgements
Financial support by Pierre Fabre, France, and the School of
Chemistry, Cardiff University, is gratefully acknowledged. We
thank Dr. J. Goode (Mettler Toledo Autochem Ltd, UK) for
advice and generous loan of the React IR Micro Flow Cell. We
thank the EPSRC National Mass Spectrometry Facility, Swansea,
for mass spectrometric data.
Keywords: continuous flow
· diazo compounds · in-line
analysis · IR spectroscopy · kinetics
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Received: February 1, 2015
Published online on March 25, 2015
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