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A fully recyclable heterogenized Cu catalyst for the
general carbene transfer reaction in batch and
flow†
Lourdes Maestre,a Erhan Ozkal,b Carles Ayats,b Alvaro Beltran,a M. Mar D´
ıaz´
´
Requejo,*a Pedro J. Perez*a and Miquel A. Peric` s*bc
a
´
A polystyrene-linked tris(triazolyl)methanecopper(I) cationic catalyst operates under heterogeneous
conditions for the reaction of ethyl diazoacetate (EDA) with an array of substrates. Carbon–hydrogen as
well as X–H (X ¼ O, N) functionalization derived from the formal transfer of the carbene moiety
(:CHCO2Et) from the copper center and subsequent insertion have been achieved, the reactions
permitting repeated catalyst recycling and reuse. The addition of the same carbene unit to benzene
leading to a cycloheptatriene derivative (Buchner reaction) or to phenylacetylene (cyclopropenation)
¨
took place at similar rates to the insertion processes and with the same catalyst recyclability. The use of

Received 26th October 2014
Accepted 26th November 2014

this heterogenized cationic Cu catalyst in continuous flow has also been implemented. Key
characteristics of the flow process are its high and constant turnover frequency (TOF) (residence times
of 1 min still lead to full conversion in the reaction with ethanol after 48 h operation) and its suitability

DOI: 10.1039/c4sc03277b
www.rsc.org/chemicalscience

for the sequential performance of different types of carbene transfer reactions with a simple and
affordable experimental setup.

Introduction
The use of transition metal-based catalysts for in situ diazo
compound decomposition and carbene transfer to saturated or
unsaturated substrates constitutes a widely employed tool in
applied organometallic chemistry.1,2 This reaction occurs
through a metallocarbene intermediate, from which the carbene ligand is transferred to a nucleophile, leading to the net
functionalization of the latter (Scheme 1a). This strategy has
been applied to a large number of substrates such as alkenes,
alkynes, imines and arenes as unsaturated reactants, and
several X–H bonds (X ¼ C, O, N, Si) and C–halogen bonds, in
saturated compounds. Well-established protocols for highly
efficient asymmetric transformations are also known.1 Ethyl
diazoacetate (EDA) is widely employed both at the laboratory
and industrial scale (e.g. the Sumitomo process for olen
cyclopropanation), with other substituted diazo compounds
being increasingly employed (Scheme 1b), mainly due to the

benecial effect of the presence of both acceptor and donor
substituents at the carbon bearing the diazo functionality.
Scheme 2 shows examples of the different transformations
reported to date with ethyl diazoacetate as the carbene source
and with transition metal complexes as catalysts.
The aforementioned transformations (Scheme 2) have been
mainly developed with soluble catalysts, under homogeneous
conditions. Therefore, they suffer from the expected difficulties
associated with catalyst separation that, in most cases, lead to
zero recovery of the catalyst. Heterogeneous catalysts for carbene transfer reactions are scarce. Processes studied with these
catalysts have been limited to olen cyclopropanation,3 a few
examples of carbene insertion into C–H bonds4 or N–H bonds,5
and alkyne cyclopropenation.6 We therefore considered that the
development of a catalytic system capable of operating under
heterogeneous conditions and, more importantly, being active

a

Laboratorio de Cat´lisis Homog´nea, Unidad Asociada al CSIC, CIQSO-Centro de
a
e
Investigaci´n en Qu´
o
ımica Sostenible and Departamento de Qu´
ımica y Ciencia de
Materiales, Universidad de Huelva, 21007 Huelva, Spain. E-mail: perez@dqcm.uhu.
es; mmdiaz@dqcm.uhu.es; Tel: +34 959 219956
Institute of Chemical Research of Catalonia (ICIQ), Avda. Pa¨ Catalans 16, 43007,
ısos
Tarragona, Catalonia, Spain. E-mail: mapericas@iciq.es; Tel: +34 977 920 243

b

c

Departament de Qu´
ımica Org`nica, Universitat de Barcelona, 08028 Barcelona, Spain
a

† Electronic supplementary information (ESI) available: Experimental details of
catalyst preparation, catalytic experiments and identication of the products.
See DOI: 10.1039/c4sc03277b

1510 | Chem. Sci., 2015, 6, 1510–1515

Scheme 1 (a) the metal-catalyzed transfer of carbene groups from
diazo compounds. (b) commonly employed diazo reagents.

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Scheme 2 Functionalization of organic substrates by metal-catalyzed
carbene transfer addition or insertion reactions.

enough to promote all the reactions shown in Scheme 2 would
represent a signicant advance. The target catalyst would
ideally exhibit high chemical and mechanical stability, thus
allowing repeated recycling. As an ultimate goal, the implementation of efficient ow versions of the reactions being
considered was sought.
Flow processing7 based on heterogenized catalysts in packed
bed reactors is gaining increasing acceptance for its inherent
advantages over conventional batch processing.8 Some of the
common drawbacks of heterogeneous catalysis in batch, such
as mechanical degradation of the catalyst particles originating
from continuous stirring and inter-cycle deactivation due to the
oxidation and/or hydrolysis of labile catalytic species can be
efficiently avoided with the implementation of continuous ow
processes.9
In spite of its potential, the possibility of performing metalcatalyzed carbene transfer reactions from diazo compounds in
continuous ow has received little attention, and only olen
cyclopropanation10 and intramolecular C–H insertion11a and
N–H insertion11b reactions have been reported under these
conditions.
As the result of a joint effort combining our previous and
separate experiences in the areas of carbene transfer, catalyst
immobilization and ow chemistry, we wish to report in this
contribution the development of a highly efficient heterogenized catalyst for carbene transfer reactions that operates
with an almost complete absence of Cu leaching, and that can
be repeatedly recycled and reused under batch conditions and
used in continuous ow conditions as well for prolonged
periods of time.

Chemical Science

mediators in the copper-catalyzed alkyne–azide cycloaddition
(CuAAC) reaction in a variety of reaction conditions.12 Polystyrene-supported versions of the TTM ligands (PS–TTM) have
also been developed and, in particular, it has been found that
Merrield resins modied by etherication with TTM units
(PS–TTM, Scheme 3) behave as ligands with unlimited recyclablity for CuAAC reactions.13 In practice, however, the resin has
to be recharged every 5–6 cycles with CuCl due to leaching. We
reasoned that a cationic Cu complex would result in a much
stronger interaction with the PS–TTM ligand, and that metal
leaching could be minimized in this manner. Given the wellknown capabilities of copper complexes bearing tripodal
ligands with pyrazolyl groups,14 we anticipated that the corresponding PS–TTM complexes would exhibit similar catalytic
capabilities toward carbene transfer reactions from ethyl
diazoacetate.
The reaction of the polystyrene-supported tris(triazolyl)
methyl complex (PS–TTM, f ¼ 0.495 mmol gÀ1) with
[Cu(MeCN)4][PF6] in dichloromethane at room temperature led
to the direct formation of the cationic complex [(PS–TTM)
Cu(NCMe)][PF6] bearing a labile acetonitrile ligand (Scheme 3).
According to copper elemental analysis, the functionalization of
the Cu-charged resin is f ¼ 0.39 mmol gÀ1, corresponding to a
functionalization yield (100f/fmax) of 89% (see ESI†).
Reaction of ethyl diazoacetate and organic substrates with PS–
TTM–Cu(NCMe)[PF6] as the catalyst: batch conditions
We have chosen some representative reactions (Scheme 4) to
study the capability of [(PS–TTM)Cu(NCMe)][PF6] to transfer the
carbene group, :CHCO2Et, from N2C(H)CO2Et in a catalytic
manner and to evaluate the possibility of catalyst recycling and
reuse under batch conditions. The substrates employed were
cyclohexane, tetrahydrofuran, ethanol and aniline to assess the
catalyst efficiency in insertion reactions, and benzene and
1-phenyl-1-propyne as models for addition reactions (Scheme
4). We have not studied the olen cyclopropanation reaction
given the high number of examples of this process already
described under heterogeneous conditions.8a–c,10
The general procedure consisted of the preparation of a
mixture containing the solid catalyst (5.2 mol%) and the
substrate (in excess, neat or dissolved in dichloromethane) and
the addition of ethyl diazoacetate (the limiting reagent, in one
portion or by slow addition, depending on the substrate) under
an inert atmosphere. Aer complete consumption of EDA, the

Results and discussion
Preparation of the heterogenized catalyst
Very recently the synthesis of a family of tris(triazolyl)methane
(TTM) derivatives has been reported, and the corresponding
(TTM)CuCl complexes have found application as efficient

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Scheme 3

The PS–TTM ligand and its cationic Cu(NCMe) complex.

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Scheme 4 Reactions studied in this work. sa: slow addition of EDA;
op: EDA added in one portion.

liquid phase was separated by ltration, the catalyst was washed
with dichloromethane (2 Â 5 mL), and fresh reactants were
added for the next reaction cycle. The results of ve consecutive
reaction cycles for the six different reactions in Scheme 4,
keeping the reaction time constant, are shown in Table 1. In all
cases, complete conversion of the starting EDA was recorded.
The reaction crudes were in all cases very clean, the only byproducts being diethyl fumarate and diethyl maleate arising
from the well-known catalytic coupling of two molecules of EDA.
It is worth mentioning that the best catalysts described so far
for the transformations considered usually bear electron-withdrawing groups on the ligand, making the metal electronically

Table 1 Recycling of [(PS–TTM)Cu(NCMe)][PF6] in the carbene
transfer reaction from EDA leading to 1–6a

Avg.
3

4

5

Products

1
2
Yieldb (%)

1
2
3
4
5
6

98
82
99c
97d
88
93

72
86
99
97
80
91

71
94
99
90
82
89

67
95
99
86
82
94

a

76
89
99
94
83
92

All reactions were performed with 5.2 mol% of catalyst loading.
Yields were determined by GC and NMR. c Starting from 4.5 mmol
EDA, 3 was obtained with 99% GC yield and 98% isolated yield. See
ESI for details. d Starting from 4.5 mmol EDA, 4 was obtained with
99% GC yield and 99% isolated yield. See ESI for details.
b

1512 | Chem. Sci., 2015, 6, 1510–1515

Consecutive use of the heterogenized catalyst for different
substrates and reactions under batch conditionsa

Table 2

Cycle #

Catalytic cycle #

75
86
99
99
82
91

poor.1 Since such groups are not present in the structure of the
PS–TTM in the catalyst employed herein the results obtained
with this catalyst can be considered as quite good. Even more
interesting are the catalyst recycling and reuse results. Yields
remained essentially constant over the ve reaction cycles with
the most reactive substrates [tetrahydrofuran (2), ethanol (3),
aniline (4), benzene (5), 1-phenyl-1-propyne (6)], and showed a
slight decrease with the less reactive cyclohexane (1) in the C–H
bond insertion reaction (see ESI† for detailed experimental
protocols). To the best of our knowledge, the results shown in
Table 1 represent the rst example of B¨chner reaction peru
formed under heterogeneous conditions. In addition, the yields
and selectivities recorded for the other studied substrates are,
on average, better than those previously reported with heterogenized catalytic species involving the more expensive rhodium
metal.4c–e,6
As a further assessment of the potential of the [(PS–TTM)
Cu(NCMe)][PF6] catalyst, we decided to explore the possibility of
using a single catalyst sample to carry out in a sequential
manner the different transformations shown in Scheme 4. To
test this possibility, a series of twelve consecutive experiments
was performed with a 100 mg (0.039 mmol) sample of the
catalyst, involving the carbene transfer from EDA (0.75 mmol) to
each of the six substrates (each experiment was performed in
duplicate). The reactions were performed in a Schlenk ask
under an inert atmosphere, and the results are summarized in
Table 2. Interestingly, no decrease in activity could be detected
over the whole series of experiments, and compounds 1–6 were
obtained in yields comparable to those recorded in the recycling
study (Table 1). In addition, no cross-contamination arising
from reactants or products from the previous reaction could be
detected by GC aer washing the catalyst with dichloromethane
(2 Â 5 mL) between cycles. This means, in practice, that a
simple laboratory ask containing a small amount of the
[(PS–TTM)Cu(NCMe)][PF6] catalyst performs as a general carbene transfer reactor, and can be used when required for
different substrates and reaction types falling into this general

Substrate

Conversionb [%]

Product

Yieldb [%]

1
2
3
4
5
6
7
8
9
10
11
12

Cyclohexane
Cyclohexane
Benzene
Benzene
1-Phenyl-1-propyne
1-Phenyl-1-propyne
Aniline
Aniline
Ethanol
Ethanol
Tetrahydrofuran
Tetrahydrofuran

98
97
>99
>99
98
99
99
97
99
98
97
99

1
1
5
5
6
6
4
4
3
3
2
2

73
65
72
62
85
92
99
97
98
98
90
94

a
b

All reactions were performed with 5.2 mol% of catalyst loading.
Yields were determined by GC and NMR. See ESI for details.

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class. Thanks to the high catalytic activity of the immobilized
cationic Cu species, turnover numbers (TONs) up to 38 can be
achieved in short reaction times. We are not aware of any report
on a heterogeneous catalyst with such versatility for the functionalization of organic compounds by carbene transfer from
diazo reagents.

Use of the [PS–TTM–Cu(NCMe)][PF6] catalyst under
continuous ow conditions
Upon obtaining successful results in the batch experiments,
with a very stable and consistent performance, we moved to
explore the catalytic system under continuous ow conditions.
In fact, the additional effort required for the implementation of
a ow process only nds adequate compensation when the TOF
exhibited by the catalyst under the operation conditions
remains constant over an extended period of time, so that the
TON achieved with a given sample of catalyst scales linearly
with the operation time.15 The experimental setup used for this
study (Fig. 1) consisted of a vertically mounted and fritted lowpressure Omnit column loaded with the [(PS–TTM)Cu(NCMe)]
[PF6] catalyst (see ESI† for details). A pump was used to feed the
catalytic carbene transfer reactor with a dichloromethane
solution of EDA and the substrate (no reaction takes place in the
absence of catalyst) under an inert atmosphere. A second pump
was used to wash the system with dichloromethane when
required (i.e., when the reactor has to be used with a different
substrate).
The initial optimization of the reaction conditions was performed for the reaction of ethyl diazoacetate with ethanol at
room temperature. The preliminary ow tests dictated some
modications with respect to the conditions optimized for
batch processing. Since the swelling capacity of Merrield
resins is signicantly reduced in ethanol, dilution of this reactant with dichloromethane was required. This efficiently prevented any contraction in the microporous structure of the

Fig. 1

The experimental setup for continuous flow operation.

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Chemical Science

polymer and facilitated optimal contact of the reactants with
the catalytic sites. Gratifyingly, under optimized reaction
conditions involving a ow rate as high as 500 mL minÀ1
(equivalent to 1 min residence time) the formation of the nal
product was achieved in very high yields. Thus, the reaction was
performed using only 0.117 mmol of the [(PS–TTM)Cu(NCMe)]
[PF6] catalyst (300 mg; f ¼ 0.39 mmol gÀ1) and a solution of ethyl
diazoacetate (11.2 mL, 106 mmol) and distilled ethanol (31 mL,
531 mmol) in deoxygenated dichloromethane (1400 mL). To our
delight, even aer 48 h both conversion and chemoselectivity
remained above 90% (Fig. 2). Aer 38 h of operation, a slight
decrease in conversion was observed, most probably due to
contraction of the polymer matrix related to the pressure
generated inside the column by the pumping process. To solve
this issue, dichloromethane was pumped for 30 min at a ow
rate of 500 mL minÀ1. This caused a visible re-swelling of the
polymer matrix and increased the catalytic activity, so that full
conversion was again reached. Aer this reactivation, the
system was operational for at least ten more hours without any
signicant deterioration in conversion.
This very stable continuous ow process led, aer 48 hours
operation, to the isolation of 12.6 g (95.8 mmol) of EtOCH2CO2Et by simple evaporation of the volatiles in the effluent. This
corresponds to a TON of 820 and to a productivity of
17.1 mmolproduct mmolCuÀ1 hÀ1.
Under these rather demanding conditions, the system was
tested for Cu leaching. Very interestingly, quantitative analysis
of the Cu content of samples of the effluent collected aer an
initial stabilization period indicated Cu contents between 0.8
and 1.6 ppm, thus conrming the high stability of [(PS–TTM)
Cu(NCMe)][PF6] under operational conditions.
In addition to their inherent advantages, such as increased
safety, straightforward scale-up and highly simplied work-up,
continuous ow processes based on supported catalysts offer
the additional advantage of allowing the sequential preparation
of small libraries of compounds.16 In the present instance, such
a sequential process would not only be a proof of concept for the
robustness and high activity of the catalyst, but it would also
enable concise access to various carbene insertion products by
sequential synthesis in a ow device. Given the high productivities showcased by the [(PS–TTM)Cu(NCMe)][PF6] catalyst
either in batch or in a simple ow process (see above), we
decided to assess the feasibility of this concept for the different

Fig. 2 Continuous flow ethanol insertion to ethyl diazoacetate. Red
dot indicates washing with dichloromethane.

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(under an inert atmosphere) makes this system one of the most
promising developed to date for metal-mediated continuous
ow processes. Studies aimed at its integration into synthetic
sequences for the synthesis of complex molecules in ow are
currently underway in our laboratories.

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Acknowledgements
This work was funded by MINECO (grants CTQ2011-28942-C02-01
and CTQ2012-38594-C02-01), DEC-Generalitat de Catalunya
(Grant 2014SGR827), Junta de Andaluc´ (P10-FQM-06292) and
ıa
ICIQ Foundation. The ICIQ team also thanks MINECO for
support through Severo Ochoa Excellence Accreditation
2014–2018 (SEV-2013-0319). L. M. thanks MECD for a FPU
fellowship. E. O. thanks ICIQ for a postdoctoral fellowship. C. A.
thanks MINECO for a Juan de la Cierva posdoctoral fellowship.
Fig. 3 Sequential production in flow of a family of compounds
resulting from different carbene transfer reactions. Productivities in
mmolproduct mmolCuÀ1 hÀ1 are shown in parentheses.

types of carbene transfer reactions from EDA considered in this
study. Hence, ve different substrates involving four different
types of carbene transfer (O–H insertion, N–H insertion, C–H
insertion and cyclopropenation) were reacted with EDA in ow
in the presence of the immobilized cationic Cu catalyst in a
sequential manner. Each substrate/EDA combination was
circulated through the packed-bed reactor for 2 h (ow rate ¼
500 mL minÀ1), with the column being rinsed by circulation of
dichloromethane between two consecutive substrates (Fig. 3;
see ESI† for details). Productivities ranging from 2.3
(cyclopropenation) to 17.5 mmolproduct mmolCuÀ1 hÀ1
(O–H insertion) were recorded. Except for the cyclopropenation
case, productivities in ow are signicantly higher (up to four
times) than those recorded for the same reactions in batch (see
ESI†). From a practical perspective, the robustness of the resin
is further veried by the fact that the same 300 mg sample of
[(PS–TTM)Cu(NCMe)][PF6] could be used without any deterioration of activity for the optimization of ow conditions for each
substrate and for the synthesis in ow of the whole family of
compounds resulting from carbene transfer. This remarkable
stability would allow the use of a cartridge packed with
[(PS–TTM)Cu(NCMe)][PF6] as a reusable, general carbene
transfer catalyst that can be mounted/dismounted in a ow
device whenever required.

Conclusions
In summary, we have developed the rst recyclable and highly
efficient heterogenized copper complex for carbene transfer
reactions to various types of substrates both in batch and, for
the rst time, in continuous ow. Remarkably, due to the high
activity of the catalyst, residence times of 1 min can achieve
complete conversion (0.117 mmol catalyst; single pass operation). The combined prole of the [(PS–TTM)Cu(NCMe)][PF6]
catalyst with respect to activity, scope and chemical stability

1514 | Chem. Sci., 2015, 6, 1510–1515

Notes and references
1 (a) M. P. Doyle, R. Duffy, M. Ratnikov and L. Zhou, Chem.
Rev., 2010, 110, 704; (b) A. J. Padwa, J. Org. Chem., 2009, 74,
6421; (c) H. M. L. Davies and J. R. Manning, Nature, 2008,
451, 417; (d) Z. H. Zhang and J. B. Wang, Tetrahedron,
2008, 64, 6577; (e) A. G. H. Wee, Curr. Org. Synth., 2006, 3,
499; (f) H. M. L. Davies and R. E. J. Beckwith, Chem. Rev.,
2003, 103, 2861; (g) M. P. Doyle, Chem. Rev., 1986, 86, 919;
(h) M. P. Doyle, M. A. McKervey and T. Ye, Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds: From
Cyclopropanes to Ylides, Wiley-VCH, Weinheim, 1998.
2 (a) M. M. D´
ıaz-Requejo and P. J. P´rez, Chem. Rev., 2008, 108,
e
3379; (b) M. M. D´
ıaz-Requejo, T. R. Belderra´ M. C. Nicasio
ın,
and P. J. P´rez, Dalton Trans., 2006, 5559.
e
3 For heterogeneous olen cyclopropanation, see: (a)
M. P. Doyle, D. J. Timmons, S. J. Tumonis, H. Gau and
C. E. Blossey, Organometallics, 2002, 21, 1747; (b)
A. Cornejo, J. M. Fraile, J. I. Garc´ E. Garc´
ıa,
ıa-Verdugo,
M. J. Gil, G. Legarreta, V. S. Luis, V. Martinez-Merino and
J. A. Mayoral, Org. Lett., 2002, 4, 3927; (c) D. Rechavi and
M. Lemaire, Chem. Rev., 2002, 102, 3467; (d) T. Nagashima
and H. M. L. Davies, Org. Lett., 2002, 4, 1989; (e)
R. Annunziata, M. Benaglia, M. Cinquini, F. Cozzi and
M. Pitillo, J. Org. Chem., 2001, 113, 2587; (f) M. I. Burguete,
J. M. Fraile, J. I. Garc´ E. Garc´
ıa,
ıa-Verdugo, S. V. Luis and
J. A. Mayoral, J. Org. Chem., 2001, 66, 8893; (g)
M. I. Burguete, J. M. Fraile, J. I. Garc´ E. Garc´
ıa,
ıa-Verdugo,
S. V. Luis and J. A. Mayoral, Org. Lett., 2000, 2, 3905; (h)
M. M. D´
ıaz-Requejo, T. R. Belderrain, M. C. Nicasio and
P. J. P´rez, Organometallics, 2000, 19, 285; (i) M. Glos and
e
O. Reiser, Org. Lett., 2000, 2, 2045; (j) M. P. Doyle,
M. Y. Eismont, D. E. Bergbreiter and H. N. Gray, J. Org.
Chem., 1992, 57, 6103; (k) D. E. Bergbreiter, B. Chen and
M. Morvant, Tetrahedron Lett., 1991, 32, 2731.
4 (a) J. M. Fraile, J. A. Mayoral, N. Ravasio, M. Rold´n,
a
L. Sordelli and N. Zaccheria, J. Catal., 2011, 281, 273; (b)
J. M. Fraile, J. I. Garc´ J. A. Mayoral and M. Rold´n, Org.
ıa,
a
Lett., 2007, 9, 731; (c) H. M. L. Davies and A. M. Walji, Org.
Lett., 2005, 7, 2941; (d) H. M. L. Davies, A. M. Walji and

This journal is © The Royal Society of Chemistry 2015

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5
6

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7

8

9

10

11

T. Nagashima, J. Am. Chem. Soc., 2004, 126, 4271; (e)
H. M. L. Davies and A. M. Walji, Org. Lett., 2003, 5, 479.
M. L. Kantam, S. Laha, J. Yadav and S. Jha, Tetrahedron Lett.,
2009, 50, 4467.
H. M. L. Davies, K. M. Chepiga, Y. Feng, N. A. Brunelli and
C. W Jones, Org. Lett., 2013, 15, 6136.
See for example: (a) C. Wiles and P. Watts, Green Chem.,
2014, 16, 55; (b) J. C. Pastre, D. L. Browne and S. V. Ley,
Chem. Soc. Rev., 2013, 42, 8849; (c) S. Suga, D. Yamada and
J. Yoshida, Chem. Lett., 2010, 39, 404; (d) J. Yoshida,
A. Nagaki and T. Yamada, Chem.–Eur. J., 2008, 14, 7450.
(a) T. Tsubogo, T. Ishiwata and S. Kobayashi, Angew. Chem.,
Int. Ed., 2013, 52, 6590; (b) A. Puglisi, M. Benaglia and
V. Chiroli, Green Chem., 2013, 15, 1790; (c) D. Zhao and
K. Ding, ACS Catal., 2013, 3, 928; (d) T. No¨l and
e
S. L. Buchwald, Chem. Soc. Rev., 2011, 40, 5010; (e)
T. Fukuyama, M. T. Rahman, M. Sato and I. Ryu, Synlett,
2008, 151; (f) I. R. Baxendale, J. J. Hayward, S. Lanners,
S. V. Ley and C. D. Smith in Microreactors in Organic
Synthesis and Catalysis, ed. T. Wirth, Wiley-VCH,
Weinheim, 2008, ch. 4.2; (g) G. N. Doku, W. Verboom,
D. N. Reinhoudt and A. van den Berg, Tetrahedron, 2005,
61, 2733.
For a discussion on the origin of deactivation of immobilized
catalysts in batch, see: R. Marcos, C. Jimeno and
M. A. Peric`s, Adv. Synth. Catal., 2011, 353, 1345.
a
(a) C. Aranda, A. Cornejo, J. M. Fraile, E. Garc´
ıa-Verdugo,
M. J. Gil, S. V. Luis, J. A. Mayoral, V. Mart´
ınez-Merino and
Z. Ochoa, Green Chem., 2011, 13, 983; (b) M. I. Burguete,
A. Cornejo, E. Garc´
ıa-Verdugo, J. Garc´ M. J. Gil,
ıa,
S. V. Luis, V. Mart´
ınez-Merino, J. A. Mayoral and
M. Sokolova, Green Chem., 2007, 9, 1091.
(a) K. Takeda, T. Oohara, N. Shimada, H. Nambu and
S. Hashimoto, Chem.–Eur. J., 2011, 17, 13992; (b)

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Chemical Science

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L. J. Martin, A. L. Marzinzik, S. V. Ley and I. R. Baxendale,
Org. Lett., 2011, 13, 320.
¨
(a) S. Ozçubukçu, E. Ozkal, C. Jimeno and M. A. Peric`s, Org.
a
Lett., 2009, 11, 4680; (b) E. Ozkal, P. Llanes, F. Bravo,
A. Ferrali and M. A. Peric`s, Adv. Synth. Catal., 2014, 356,
a
857.
¨
E. Ozkal, S. Ozçubukçu, C. Jimeno and M. A. Peric`s, Catal.
a
Sci. Technol., 2012, 2, 195.
For representative examples see: (a) C–H insertion:
A. Caballero, E. Despagnet-Ayoub, M. M. D´
ıaz-Requejo,
A. D´
ıaz-Rodr´
ıguez, M. E. Gonz´lez-N´nez, R. Mello,
a
u˜
B. K. Mu˜ oz, W. Solo Ojo, G. Asensio, M. Etienne and
n
P. J. P´rez, Science, 2011, 332, 835; (b) N–H insertion:
e
M. E. Morilla, M. M. D´
ıaz-Requejo, T. R. Belderra´
ın,
M. C. Nicasio, S. Tromenko and P. J. P´rez, Chem.
e
Commun., 2002, 2998; (c) O–H insertion: M. E. Morilla,
M. J. Molina, M. M. D´
ıaz-Requejo, T. R. Belderra´
ın,
M. C. Nicasio, S. Tromenko and P. J. P´rez,
e
Organometallics,
2003,
22,
2914;
(d)
Alkyne
cyclopropenation: M. M. D´
ıaz-Requejo, M. A. Mairena,
T. R. Belderra´
ın, M. C. Nicasio, S. Tromenko and
P. J. P´rez, Chem. Commun., 2001, 1804; (e) Benzene
e
functionalization: M. E. Morilla, M. M. D´
ıaz-Requejo,
T. R. Belderra´
ın, M. C. Nicasio, S. Tromenko and
P. J. P´rez, Organometallics, 2004, 23, 253.
e
S. Kozuch and J. M. L. Martin, ACS Catal., 2012, 2, 2787.
For the sequential synthesis in ow of libraries of
enantiopure compounds, see: (a) C. Ayats, H. A. Henseler
and M. A. Peric`s, ChemSusChem, 2012, 5, 320; (b)
a
R. Mart´
ın-Rap´n, S. Sayalero and M. A. Peric`s, Green
u
a
Chem., 2013, 15, 3295; (c) P. Kasaplar, C. Rodr´
ıguez-Escrich
and M. A. Peric`s, Org. Lett., 2013, 15, 3498; (d) L. Osorioa
Planes, C. Rodr´
ıguez-Escrich and M. A. Peric`s, Chem.–Eur.
a
J., 2014, 20, 2367; (e) C. Ayats, A. H. Henseler, E. Dibello
and M. A. Peric`s, ACS Catal., 2014, 4, 3027.
a

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