Continuous flow synthesis of toxic ethyl diazoacetate for utilization in an integrated microfluidic system

Article abstract of DOI:10.1039/c3gc41226a

An integrated microfluidic system for multiple reactions and separations of hazardous ethyl diazoacetate is presented. The integrated techniques include: a droplet technique for liquid-liquid and/or gas-liquid separation and in situ generation of the toxic reagent, a dual channel membrane technique based on a cheap polymeric microseparator for liquid-liquid separation, and a capillary microreactor for carrying out cascade reactions in a sequential and continuous manner.

Full text of DOI:10.1039/c3gc41226a

Green Chemistry
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Continuous flow synthesis of toxic ethyl
diazoacetate for utilization in an integrated
microfluidic system†
Cite this: Green Chem., 2014, 16,
116
Received 24th June 2013,
Ram Awatar Maurya,‡a Kyoung-Ik Min‡b and Dong-Pyo Kim*b
Accepted 15th October 2013
DOI: 10.1039/c3gc41226a
www.rsc.org/greenchem
An integrated microfluidic system for multiple reactions and sep- associated with a significant amount of hazardous waste.
arations of hazardous ethyl diazoacetate is presented. The inte- Additionally, the durability and productivity of the microfluidic
grated techniques include: a droplet technique for liquid–liquid device (∼1 mmol per day) were quite low. We therefore set out
and/or gas–liquid separation and in situ generation of the toxic to develop a robust microfluidic set-up for advanced pro-
reagent, a dual channel membrane technique based on a cheap duction of fine chemicals and/or pharmaceuticals using
polymeric microseparator for liquid–liquid separation, and a capil- toxic, explosive and hazardous reagents (such as CH2N2,
lary microreactor for carrying out cascade reactions in a sequential N2CHCOOEt, organic azides, etc.) without compromising on
and continuous manner.
safety or waste hazard concerns.
The reactions of toxic, explosive and unstable reagents in a
microreactor alone only partially address the associated safety
concerns.5 Hence in situ generation and subsequent reaction
of diazo-chemicals in microreactors appears to be the best way
to overcome the safety and hazard concerns.4,6 However for
multi-step reactions in flow it is crucial to separate or purify
the intermediate from the main stream, as the unreacted pre-
cursor, excess reagents, solvent and other impurities may
negatively affect or even prevent subsequent reaction of the
intermediate with other chemicals downstream. The use
of immobilized scavengers or packed bed columns to purify
the intermediate is certainly inappropriate because of the
necessity of periodically changing columns and deposition
of by-products on polymer supports. A liquid–liquid and/or
gas–liquid separation process using a simple microfluidic
system appears more attractive and reasonable.7
Presented in this communication is a microfluidic system
that is integrated to facilitate multiple reactions and multiple
separations involving hazardous materials. In the system, the
toxic and explosive reactant is synthesized in situ and then
reacted to produce a valuable intermediate for the synthesis of
fine chemicals and pharmaceuticals. Complete separation of
the product is made possible through the use of a droplet
microreactor in the system, in which the reactants and the
toxic product separate by themselves, i.e., self-separation
without any input from outside such as heating or a polymer
support, which in turn decreases decomposition of the
product. The construction material for the subsequent separ-
ation and further reaction of the intermediate is such that the
throughput of the final product is two orders of magnitude
higher than that obtained earlier in the one-pot, non-
Developing safe and efficient routes for manipulating toxic,
explosive and hazardous chemicals is an ever present chal-
lenge in chemistry.1 Diazomethane and ethyl diazoacetate are
amongst the most common diazo-compounds, which remark-
ably, have attracted huge interest for fine chemical and
pharmaceutical production.2 Despite their commercial avail-
ability, the storage, transportation, and reaction of diazo-
chemicals have raised significant safety concerns due to their
instability, high reactivity and explosive nature. Although in
most cases the diazo reagents are freshly prepared prior to use,
the potential for detonation of the chemical reagent inventory
cannot be fully ignored. Recently microreactors have attracted
much interest because they could resolve these safety concerns
owing to their miniaturised reaction volume, continuous flow
processing and fast heat and mass transfer ability.1,3
In our earlier communication, we reported the generation
of diazomethane and the successive processes in PDMS dual
channels.4 Despite controlling various parameters, only up to
63% of the total generated diazomethane could be separated
and utilized for further reactions. Thus, it was disadvanta-
geous that the safe manipulation of diazomethane was
aDivision of Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of
Chemical Technology, Hyderabad 500007, India
bNational Creative Research Center of Applied Microfluidic Chemistry (CAMC),
Department of Chemical Engineering, Pohang University of Science and Technology
(POSTECH), Pohang, Republic of Korea. E-mail: dpkim@postech.ac.kr;
Fax: +82-54-279-5598; Tel: +82-54-279-2272
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3gc41226a
‡R. A. Maurya and K.-I. Min equally contributed to this work.
116 | Green Chem., 2014, 16, 116–120
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Table 1 Optimization of the EDA synthesis in the droplet microreactora
Entry
Res. timeb (min)
Extracting solvent
Yield of EDAc (%)
1
2
3
4
5
6
4.0
2.7
2.0
1.3
2.0
2.0
Toluene
Toluene
Toluene
Toluene
CH2Cl2
Et2O
99
98
99
87
75
80
Fig. 1 Schematic illustration of continuous generation, extraction, sep-
aration, and reaction of EDA in an integrated microfluidic system.
a Composition of EDA precursors: 1.50 M EtOOCCH2NH2·HCl in
acetate buffer (acetate conc. 2.0 M, pH 3.5), 1.51 M NaNO2 in water;
experiments were carried out at room temperature; flow rate ratio of
aqueous solutions and extracting solution was 1 : 1 : 1. b Residence
time for both droplet reaction and extraction in PFA capillary (id =
800 μm, length = 120 cm, internal volume = 600 μL), (50 + 50 + 50) μL
min−1 for 4 min, (100 + 100 + 100) μL min−1 for 2 min of the residence
time. c Determined by GC–MS using anisole as an internal standard.
integrated system.4 Ethyl diazoacetate (EDA) was taken as a
model hazardous and explosive reagent to illustrate the
concept. The integrated microfluidic system is shown in Fig. 1.
Our integrated system approach not only allows safer and
more efficient manipulation of hazardous chemicals but also
enables much improved productivity.
The reaction of nitrous acid with glycine ethyl ester hydro-
chloride was selected as the reaction of choice for the synthesis
of EDA since it produces a high yield of EDA under mild con-
ditions.8 However, the reaction is very sensitive to temperature
and is usually carried out by cooling the reaction mixture in
a salt-ice bath. Additionally EDA, once synthesized, must be
quickly extracted as it starts to decompose in the acidic reac-
tion medium.8
Therefore, continuous reaction and extraction using droplet
microreactors could be quite promising for the synthesis of
EDA in a continuous flow system. Droplet microreactors have
emerged as a powerful synthetic tool due to their quick heat
dissipation and the enhanced convectional mixing that occurs
inside droplets.9 Additionally they provide very a large surface
area per unit volume for efficient extraction of EDA from the
acidic reaction mixture which could help to minimize its
decomposition. Thus, a simple microfluidic system composed
of capillary and mixing units was assembled to generate drop-
lets of EDA precursors in organic solvents that can extract
EDA.
For safer and more efficient handling of the hazardous
chemical, a chemically, thermally and mechanically robust
microfluidic device was required. The PDMS dual channel
system has a well known swelling problem in most non-polar
organic solvents.10 We, therefore, decided to use a polyimide
(PI) film microseparator because of its easy fabrication and
excellent mechanical, thermal and chemical stability.11 A dual
channel type of microseparator was fabricated using a com-
mercially available polyimide film and PTFE membrane.
Briefly, two laser ablated PI films and the PTFE membrane
were mechanically bonded in a sandwich manner (for details
of fabrication, see ESI†). The droplet microreactor was then
connected to this PI dual channel separation device, which in
turn was connected with a PFA capillary microreactor for the
cascade reactions (Fig. 1).
ester hydrochloride in acetate buffer (pH 3.5), aqueous NaNO2
and extracting solvent were introduced into the droplet micro-
reactor. Initially we attempted to mix the aqueous solutions of
glycine and NaNO2 and then disperse the mixture into toluene
using two T-junctions (for details, see ESI†). However, there
was a significant loss of EDA when two T-junctions were used,
although cooling of the reaction mixture into ice bath did
diminish degradation. We, therefore, decided to use an X-junc-
tion (see Fig. 1) for mixing the two aqueous solutions and
instant dispersion of the mixture into the extracting solvent to
minimize the decomposition of EDA in the acidic medium.
Aqueous solutions of glycine ester and NaNO2 were allowed
to merge at the X-junction and disperse into the continuous
toluene phase. The hydrophobic PFA capillaries (id = 800 μm)
are quite suitable for forming aqueous droplets in toluene,
which give superior yields of EDA compared to that obtained
using other extracting solvents such as diethyl ether or
dichloromethane (Table 1). The experiments were performed
at ambient temperature and at various flow rates of the
aqueous reactants and the organic extracting solvent. It was
observed that a flow rate ratio of 1 : 1 : 1 (aq. glycine ester,
aq. NaNO2 and toluene) led to well dispersed aqueous droplets
in toluene using the PFA capillary. It is noteworthy that real
time extraction of the synthesized EDA, from the aqueous
droplets into the toluene medium, was efficiently conducted
because of their tiny volume and large surface to volume ratio.
Thus the possibility of decomposition of the synthesized EDA
in the acidic reaction mixture was minimized. A residence
time of 2 min was enough for the droplet reaction, extraction
and separation of EDA, resulting in 99% yields of EDA. Lower
residence times (<2 min) resulted in lower yields of EDA. It is
noteworthy that contrary to batch reactions, nitrosation of
glycine ester in a droplet reaction could be performed at room
temperature without external cooling, revealing the energy
saving characteristics of the microfluidic device. The sub-
sequent continuous separation of the aqueous and organic
To accomplish simultaneous in situ droplet synthesis,
extraction and separation of EDA, solutions of glycine ethyl
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mixture was realized in a microseparator where a PTFE mem- benzaldehyde was incomplete after the 36 min residence time.
brane was sandwiched between the PI dual channels. The thin Better product yields were achieved at higher temperatures.
fluoropolymer membrane with a pore size of 0.45 μm was pre- However, we were pleased to have achieved a high yield of the
ferentially wetted by the organic solvent which allowed desired product in 24 min of residence time using ultrasonic
passage through the membrane holes, while the non-wetting irradiation at 40 °C (Table 2). It is, therefore, obvious that
aqueous phase did not penetrate the membrane. Complete ultrasonic irradiation of the reaction mixture greatly promoted
separation of the aqueous (waste) and organic phases (EDA) the reaction rate, presumably due to enhanced chaotic mixing
was achieved at high flow rates (up to 300 μL min−1) without and the hot-spot effects caused by collapsed bubbles.13 It is
any problems, by regulating the back pressures of aqueous notable that the productivity of the microfluidic set-up was sig-
and organic outlets. It should be pointed out that the reaction nificantly higher (104.98 mmol per day; see ESI† for calcu-
and successive double separation steps were performed in lations) when compared to our earlier PDMS dual channel
a simple microfluidic set up that produced virtually no system (∼1 mmol per day),4 with an increase in the throughput
hazardous waste. The daily output of EDA was calculated to be of two orders of magnitude.
213.84 mmol (for the calculation in detail, see ESI†).
Inspired by the successful cascade reaction of the EDA
Next we focused on the cascade reactions using EDA gener- generated in situ with benzaldehyde, we expanded the scope of
ated in situ. Coupling of EDA with aldehydes is an attractive, the reaction to a series of other aromatic, heteroaromatic and
atom economical organic transformation for the synthesis aliphatic aldehydes. Since aliphatic aldehydes are prone to
of fine chemicals and pharmaceuticals. Although the reaction undergo self aldol reactions in the presence of DBU, we did
was originally known to be catalyzed by strong bases (e.g. butyl- not pre-mix the DBU with the aldehyde solution. Instead, we
lithium, lithiumdiisopropylamide, sodium hydride, potassium kept the DBU and aldehyde in two separate syringes so that all
hydroxide), recently several mild organocatalytic approaches three components, DBU, aldehyde and EDA from PI dual
have been developed.12 In this work, we attempted 1,8-diaza- channel device, could be mixed together at the X-junction (for
bicyclo[5.4.0]undec-7-ene (DBU) catalyzed coupling of benz- a detailed schematic illustration, see ESI†). Using the opti-
aldehyde with EDA generated in situ in the microfluidic system mized protocol (40 °C, ultrasonication, 24 min of residence
(Table 2).
time), we achieved high yields of aldehyde-EDA adducts
A solution of benzaldehyde in toluene (3.0 M) containing (Fig. 2). It is worth noting that our results for this DBU cata-
20 mol% DBU was allowed to mix with the stream from the lyzed aldol reaction of EDA with aldehydes were comparable
organic outlet of the PI dual channel separator (1.5 M EDA in to, or somewhat better than, the reported results obtained
toluene) to allow the aldol reaction to occur. Flow rates of both using anhydrous solvent and inert atmospheric conditions.12b
reactants were adjusted so that the EDA was a little in excess The use of ultrasonic agitation in the microreactor not only
compared to the benzaldehyde in the reaction mixture (stoichio- decreased the reaction time but also increased the yield. The
metry of EDA to aldehyde = 1.25 : 1).
microfluidic system provides sufficiently pure and anhydrous
The reaction mixture was then introduced into a PFA capil- EDA for DBU catalyzed aldol reactions. The automation,
lary (id = 800 μm, length = 5 m, internal volume = 2.5 mL) and simplicity, high safety, and excellent control over the reaction
the reaction was quenched in saturated aq. NaHCO3. It was parameters facilitates small scale laboratory research of EDA
observed that at room temperature the reaction of EDA with reactions.
To show that the integrated microfluidic system is adapt-
able enough to handle reactions involving separation of
gaseous products, we proceeded to study the synthesis of
Table 2 In situ generation, separation and reaction of EDA with
benzaldehydea
2-keto esters from aldehydes. The reaction is catalysed by
Lewis acids and accompanied by evolution of nitrogen.14
Handling of gas either as a reactant or a bi-product is quite
Entry
Res. time (min)
Temp (°C)
Yieldb (%)
1
2
3
36
36
36
36
36
24
18
rt
42
51
57
55
80
81
72
40
60
80
40
40
40
4
5c
6c
7c
a EDA was generated in situ as in Table 1. Flow rates of EDA and
benzaldehyde containing DBU: (50 + 20) μL min−1 for 36 min, (75 + 30)
μL min−1 for 24 min, (100 + 40) μL min−1 for 18 min of the residence
time. b Isolated yield on 1 mmol scale. c Ultrasonication (power =
330 W, frequency = 40 kHz).
Fig. 2 Cascade generation, separation and reaction of EDA with various alde-
hydes (yields in the parentheses are of isolated product on a 5 mmol scale).
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The integrated microfluidic system has been proven to be
resilient and robust in handling hazardous reagents, even
when subjected to continuous operation of the system over
long periods of time. The durability can readily be attributed
to the chemical inertness of the materials used (PFA, PTFE
and PI). The integrated microfluidic system was repeatedly
used for multiple optimizations and reactions over several
months without any noticeable change in system performance.
Fig. 3 Cascade generation, extraction, separation and reaction of EDA
with adehydes to yield 2-keto esters with subsequent gas–liquid separation.
Conclusions
In conclusion, we have demonstrated the continuous flow
process for reactions and separations of hazardous reagents,
using ethyl diazoacetate as a model reaction, in a safer and
more efficient manner using an integrated microfluidic
system. The integrated techniques include: a droplet technique
for liquid–liquid and/or gas–liquid separation and in situ gene-
ration of the toxic reagent, a dual channel membrane tech-
nique based on a cheap polymeric microseparator, and a
capillary microreactor for carrying out cascade reactions in a
sequential and continuous manner. The novel, safe, microflui-
dic droplet approach allows real time extraction of EDA, a
hazardous reagent chosen because of its importance in produ-
cing intermediates for fine chemicals and pharmaceuticals,
from its acidic reaction mixture. The generation and separa-
tion of EDA are so efficient with 99% yields of EDA that the
toxic hazardous waste produced is almost negligible. This inte-
grated microfluidic approach not only allows safer and more
efficient manipulation of hazardous and explosive EDA but
also allows much improved production of fine chemicals. In
addition, the integrated system can be adapted to accom-
modate different combinations of reactors and phase separa-
tors for the purpose of producing chemicals on demand.
challenging in microreactors as it disturbs the flow rates and
makes control other reaction parameters difficult.
The reaction of EDA with hydrocinnamaldehyde catalyzed
by BF3·OEt2 was taken as a model reaction for the synthesis of
2-keto esters. EDA was generated, extracted and separated as
aforementioned and the outgoing organic phase from the first
PI dual channel separator was connected to a T-junction where
it met with a solution of hydrocinnamaldehyde (3.0 M) con-
taining 5 mol% BF3·OEt2. The flow rates were adjusted in such
a way that the stoichiometric content of EDA was in slight
excess of hydrocinnamalaldehyde. Immediately after mixing
the two solutions (EDA and aldehyde), the reaction mixture
started generating nitrogen and the product stream was
pushed rapidly into the outside collector. Although the yield of
2-keto ester 3h was good (see Fig. 4), the propulsion of the
product stream could be a source of safety problems. There-
fore, to remove the generated nitrogen from the reaction
channel, another PI dual channel separator with a PTFE mem-
brane was added to the system as shown in Fig. 3.
The PFA capillary microreactor (id = 800 μm, length = 5 m,
internal volume = 2.5 mL) was then connected to a gas–liquid
microseparator (PI dual channel). The PI dual channel separa-
tor completely separated the gas–liquid mixture, which made
it possible to efficiently produce the desired 2-keto ester
without compromising safety. Using the same microfluidic
arrangement, we were able to synthesize a series of 2-keto
esters using various aldehydes. All the reactions were carried
out with the rates of 50 μL min−1 (EDA) and 20 μL min−1 (alde-
hyde). The yields were fairly good with aliphatic aldehydes but
only moderate with aromatic aldehydes such as benzaldehyde
(Fig. 4).
Acknowledgements
This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea government
(MSIP) (No. 2008-0061983 and NRF-2013-Global Ph.D. Fellow-
ship Program).
Notes and references
1 (a) P. B. Palde and T. F. Jamison, Angew. Chem., Int. Ed.,
2011, 50, 3525–3528; (b) M. O’Brien, I. R. Baxendale and
S. V. Ley, Org. Lett., 2010, 12, 1596–1598; (c) M. Irfan,
T. N. Glasnov and C. O. Kappe, Org. Lett., 2011, 13, 984–
987; (d) B. Gutmann, J.-P. Roduit, D. Roberge and
C. O. Kappe, Angew. Chem., Int. Ed., 2010, 49, 7101–7105;
(e) R. Trotzki, M. Nüchter and B. Ondruschka, Green Chem.,
2003, 5, 285–290; (f) D. R. J. Acke and C. V. Stevens, Green
Chem., 2007, 9, 386–390; (g) A. R. Katritzky, S. Zhang and
Y. Fang, Org. Lett., 2000, 2, 3789–3791; (h) K. C. Basavaraju,
S. Sharma, R. A. Maurya and D.-P. Kim, Angew. Chem., Int.
Fig. 4 Automated generation, separation and reaction of EDA with
aldehydes to yield 2-keto esters (yields in parentheses are of isolated
product on 5 mmol scale).
This journal is © The Royal Society of Chemistry 2014
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Ed., 2013, 52, 6735; (i) S. Sharma, R. A. Maurya, K.-I. Min,
G.-Y. Jeong and D.-P. Kim, Angew. Chem., Int. Ed., 2013, 52,
7564.
2 For selected reviews, see: (a) Y. Zhang and J. Wang,
Eur. J. Org. Chem., 2011, 1015–1026; (b) G. Maas, Angew.
Chem., Int. Ed., 2009, 48, 8186–8195; (c) M. P. Doyle and
D. C. Forbes, Chem. Rev., 1998, 98, 911–936;
(d) D. M. Hodgson, F. Y. T. M. Pierard and P. A. Stupple,
Chem. Soc. Rev., 2001, 30, 50–61.
2011, 50, 5943–5946; (c) H. R. Sahoo, J. G. Kralj and
K. F. Jensen, Angew. Chem., Int. Ed., 2007, 46, 5704–5708;
(d) R. L. Hartman, J. R. Naber, S. L. Buchwald and
K. F. Jensen, Angew. Chem., Int. Ed., 2010, 49, 899–
903.
8 (a) E. B. Womack and A. B. Nelson, Org. Synth., Coll., Vol. 3,
1955, 392; (b) W. Wang, K. Shen, X. Hu, J. Wang, X. Liu and
X. Feng, Synlett, 2009, 1655–1658.
9 (a) P. H. Hoang, C. T. Nguyen, J. Perumal and D.-P. Kim,
Lab Chip, 2011, 11, 329–335; (b) P. H. Hoang, H. Park and
D.-P. Kim, J. Am. Chem. Soc., 2011, 133, 14765–14770.
3 For selected reviews and papers on microreactors, see:
(a) R. L. Hartman, J. P. McMullen and K. F. Jensen, Angew.
Chem., Int. Ed., 2011, 50, 7502–7519; (b) J. Wegner, 10 J. N. Lee, C. Park and G. M. Whitesides, Anal. Chem., 2003,
S. Ceylan and A. Kirschning, Chem. Commun., 2011, 47, 75, 6544–6554.
4583–4592; (c) Y. Chen, Y. Zhao, M. Han, C. Ye, M. Danga 11 K.-I. Min, T.-H. Lee, C. P. Park, Z.-Y. Wu, H. H. Girault,
and G. Chen, Green Chem., 2013, 15, 91–94; (d) C. P. Park,
R. A. Maurya, J. H. Lee and D.-P. Kim, Lab Chip, 2011, 11,
I. Ryu, T. Fukuyama, Y. Mukai and D.-P. Kim, Angew.
Chem., Int. Ed., 2010, 49, 7063–7067.
1941–1945; (e) B. Pieber and C. O. Kappe, Green Chem., 12 (a) B. M. Trost, S. Malhotra and B. A. Fried, J. Am. Chem.
2013, 15, 320–324; (f) A. Odedra, K. Geyer, T. Gustafsson,
R. Gilmour and P. H. Seeberger, Chem. Commun., 2008,
3025–3027; (g) R. A. Maurya, P. H. Hoang and D.-P. Kim,
Lab Chip, 2012, 12, 65–68.
4 R. A. Maurya, C. P. Park, J. H. Lee and D.-P. Kim, Angew.
Chem., Int. Ed., 2011, 50, 5952–5955.
5 (a) L. J. Martin, A. L. Marzinzik, S. V. Ley and
I. R. Baxendale, Org. Lett., 2011, 13, 320–323;
(b) H. E. Bartrum, D. C. Blakemore, C. J. Moody and
C. J. Hayes, J. Org. Chem., 2010, 75, 8674–8676.
6 (a) M. Struempel, B. Ondruschka, R. Daute and A. Stark,
Green Chem., 2008, 10, 41–43; (b) H. E. Bartrum,
D. C. Blakemore, C. J. Moody and C. J. Hayes, Chem.–Eur.
J., 2011, 17, 9586–9589; (c) D. X. Hu, M. O’Brien and
Soc., 2009, 131, 1674–1675; (b) N. Jiang and J. Wang, Tetra-
hedron Lett., 2002, 43, 1285–1287; (c) W. Yao and J. Wang,
Org. Lett., 2003, 5, 1527–1530.
13 (a) R. H. Liu, R. Lenigk, R. L. Druyor-Sanchez, J. Yang and
P. Grodzinski, Anal. Chem., 2003, 75, 1911–1917;
(b) G. G. Yaralioglu, I. O. Wygant, T. C. Marentis and
B. T. Khuri-Yakub, Anal. Chem., 2004, 76, 3694–3698;
(c) R. L. Hartman, J. R. Naber, N. Zaborenko,
S. L. Buchwald and K. F. Jensen, Org. Process Res. Dev.,
2010, 14, 1347–1357; (d) D. F. Rivas, P. Cintas and
H. J. G. E. Gardeniers, Chem. Commun., 2012, 48, 10935–
10947; (e) B. S. Singh, H. R. Lobo, D. V. Pinjari, K. J. Jarag,
A. B. Pandit and G. S. Shankarling, Ultrason. Sonochem.,
2013, 20, 287–293.
S. V. Ley, Org. Lett., 2012, 14, 4246–4249; (d) Z. Yu, Y. Lv, 14 For selected recent publications on Lewis acid catalyzed
C. Yu and W. Su, Tetrahedron Lett., 2013, 54, 1261–1263;
(e) M. Chen and S. L. Buchwald, Angew. Chem., Int. Ed.,
2013, 52, 4247–4250.
7 (a) J. G. Kralj, H. R. Sahoo and K. F. Jensen, Lab Chip, 2007,
7, 256–263; (b) T. Noël, S. Kuhn, A. J. Musacchio,
K. F. Jensen and S. L. Buchwald, Angew. Chem., Int. Ed.,
reaction of EDA with aldehyde, see: (a) M. R. Fructos,
M. M. Díaz-Requejo and P. J. Pérez, Chem. Commun., 2009,
5153–5155; (b) H. Murata, H. Ishitani and M. Iwamoto,
Tetrahedron Lett., 2008, 49, 4788–4791; (c) W. Li, J. Wang,
X. Hu, K. Shen, W. Wang, Y. Chu, L. Lin, X. Liu and
X. Feng, J. Am. Chem. Soc., 2010, 132, 8532–8533.
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