Flow synthesis of ethyl isocyanoacetate enabling the telescoped synthesis of 1,2,4-triazoles and pyrrolo-[1,2-c]pyrimidines

Article abstract of DOI:10.1039/c5ob00245a

The efficient flow synthesis of important heterocyclic building blocks based on the 1,2,4-triazole and pyrrolo[1,2-c]pyrimidine scaffold has been achieved. Crucially, a telescoped continuous flow process was developed based on the reaction of N-formylglycine with triphosgene to deliver a stream of ethyl isocyanoacetate in situ, which subsequently yielded the desired heterocyclic entities in a telescoped reaction. Additionally, the functionalisation of the pyrrolo[1,2-c]pyrimidine core via subsequent S_EAr reactions was studied revealing insight into a 'halogen dance' phenomenon associated with these medicinally relevant architectures. This journal is

Full text of DOI:10.1039/c5ob00245a

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: M. Baumann, A.
M. Rodriguez Garcia and I. R. Baxendale, Org. Biomol. Chem., 2015, DOI: 10.1039/C5OB00245A.
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

View Article Online
DOI: 10.1039/C5OB00245A
Page 1 of 9
Organic & Biomolecular Chemistry
Journal Name
RSCPublishing
ARTICLE
Flow Synthesis of Ethyl Isocyanoacetate Enabling the
Telescoped Synthesis of 1,2,4-Triazoles and Pyrrolo-
[1,2-c]pyrimidines
Cite this: DOI: 10.1039/x0xx00000x
Marcus Baumann,a Antonio M. Rodriguez Garciaa,b and Ian R. Baxendalea
Received 00th January 2012,
Accepted 00th January 2012
The efficient flow synthesis of important heterocyclic building blocks based on the 1,2,4-
triazole and pyrrolo[1,2-c]pyrimidine scaffold has been achieved. Crucially, a telescoped
continuous flow process was developed based on the reaction of N-formylglycine with
triphosgene to deliver a stream of ethyl isocyanoacetate in situ, which subsequently yielded the
desired heterocyclic entities in a telescoped reaction. Additionally, the functionalisation of the
pyrrolo[1,2-c]pyrimidine core via subsequent SEAr reactions was studied revealing insight into
a ‘halogen dance’ phenomenon associated with these medicinally relevant architectures.
DOI: 10.1039/x0xx00000x
www.rsc.org/
dehydration of N-formylglycine using reactive triphosgene
(Scheme 1).
Introduction
The efficient preparation of novel heterocyclic building blocks
functionalised with suitable derivatisation sites is of paramount
importance to the successful discovery of new bioactive
molecules.[1] Certainly the most effective pharmaceutical and
agrochemical strategy for the generation of propriety leads is
through screening of diverse core structures, which upon
strategic functionalization engenders desirable physiological
properties and yields focused libraries of advanced drug-like
structures. Consequently, the conformational presentation
displayed by the core template impacts strongly on the
available binding and contact points that can be interacted upon
within the biological environment. It is therefore not surprising
that most of today’s top-selling drugs contain at least one
heterocyclic core often acting as its pharmacophore.[2] In order
to efficiently access new chemical scaffolds medicinal chemists
have been increasingly exploiting enabling technologies to
allow access to novel chemical space.[3] Amongst these
technologies flow chemistry approaches have gained
widespread acceptance as a powerful means to overcome
limitations regarding scale-up, reproducibility, safety and
accessible chemical space with numerous publications detailing
the results of such studies.[4]
One particular area where flow chemistry has led to
significantly improved safety profiles compared to traditional
batch synthesis is the in situ generation and subsequent use of
highly reactive, yet hazardous species. Examples include, but
are not limited to, the generation and use of ozone,[5] azides,[6]
diazonium species[7], or elemental fluorine[8] as well as
cryogenic[9] or high temperature[10] reactions.
In this paper we wish to disclose our latest results towards the
flow synthesis of valuable heterocyclic architectures such as
1,2,4-triazoles and pyrrolo[1,2-c]pyrimidines based on the in
situ generation of ethyl isocyanoacetate through the
Scheme 1: Multi-step flow approach towards valuable
heterocyclic scaffolds.
Results and Discussion
Synthesis of ethyl isocyanoacetate in flow
Ethyl isocyanoacetate (3) is a commercially available high
boiling liquid characterised by its pungent odour as well as its
sensitivity towards light and moisture. Despite this it is
frequently used as a key building block in multicomponent
reactions and heterocycle synthesis.[11] Because of these
features we decided to develop a convenient in situ flow
synthesis of ethyl isocyanoacetate starting from readily
available N-formylglycine (
1).[12] As the dehydrating agent we
choose triphosgene ( ), a commercially available crystalline
2
solid.[13] This material is not only easier to handle than many
other dehydrating agents (e.g. COCl2, POCl3, SOCl2 etc.), but
also comprises three equivalents of active dehydrating agent per
molecule. Furthermore, only HCl and CO2 are generated as by-
products through its use. In an initial study we used a
commercially available R2+ Vapourtec flow reactor which was
configured to mix two reagent streams via a T-piece: stream A
contained N-formylglycine (DCM, 0.25 M, 1.0 equiv.), DIPEA
(2 equiv.) and DMAP (0.3 equiv.) and stream B contained
This journal is © The Royal Society of Chemistry 2013
J. Name., 2013, 00, 1-3 | 1

View Article Online
DOI: 10.1039/C5OB00245A
Organic & Biomolecular Chemistry
Page 2 of 9
ARTICLE
Journal Name
1
triphosgene (DCM, 0.0875 M, 0.35 equiv.). Using H-NMR
analysis of aliquots of the product stream it was quickly
established that the desired ethyl isocyanoacetate forms almost
quantitatively at room temperature within a 20 min residence
time (Scheme 2).
Synthesis of 1,2,4-triazoles in flow
Having developed an efficient protocol for the synthesis of
ethyl isocyanoacetate in flow, we next turned our attention to
its reaction with various aryl diazonium species, also prepared
in situ, to furnish a convergent synthesis of 1,2,4-triazoles.[14]
To facilitate the reaction, four stock solutions (solutions 1-4)
were prepared, along with a small collection of aniline starting
materials (solution 5). To perform the multi-step flow sequence
an integrated flow reactor configured as shown in scheme 3 was
constructed. This comprised a Uniqsis FlowSyn with an ALF
delivery and control system, a Vapourtec R2+/R4 unit, two
auxiliary Knauer K100 HPLC pumps and two Polar bear plus
flow reactors (see supplemental information for additional
details). Using this setup a continuous flow stream of
intermediate
united with a solution containing the corresponding diazonium
coupling partner as a convergent assembly process.
The diazonium component was readily prepared from the
3 was prepared as described (see above) and was
6
6
precursor aniline or its mono-hydrochloride salts (in MeCN) by
treatment with tert-butyl nitrite at ambient temperature.[15] For
the subsequent cycloaddition reaction the two flow streams
containing
3 and 6 were combined and then in succession
diluted with a stream of pure ethanol and treated with an
aqueous feed of potassium carbonate (5 equiv.). A static mixer
was placed in-line to thoroughly blend the flow stream before it
passed into a heated reaction coil maintained at 75 °C. The
reactor output was collected and worked up by evaporation of
the solvent followed by neutralisation with dilute hydrochloric
acid and partitioning into ethyl acetate. The products were
isolated in high yield and purity after solvent evaporation and
trituration of the crude product with a mixture of diethyl
ether/ethanol 15:1. Pleasingly the above flow protocol proved
general and was applied to the synthesis of a small selection of
1,2,4-triazole products (7a-h) (Figure 1).
Scheme 2: Flow synthesis of ethyl isocyanoacetate (Reactor
flow pathway left to right).
Scheme 3: Multi-step flow approach towards 1,2,4-triazoles.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

View Article Online
DOI: 10.1039/C5OB00245A
Page 3 of 9
Journal Name
Organic & Biomolecular Chemistry
ARTICLE
Synthesis of pyrrolo[1,2-c]pyrimidines in flow
After accomplishing a successful multi-step flow synthesis of
various 1,2,4-triazoles we decided to diversify the protocol
towards the synthesis of another underexploited scaffold - the
pyrrolo[1,2-c]pyrimidine. This structure has shown value for
example as the core structure of various nicotinic acetylcholine
receptor agonists developed to treat CNS disorders[18] and can
be prepared by reacting ethyl isocyanoacetate with readily
available pyrrole-2-carboxaldehyde[19]. After
a
short
optimisation study we found that treatment of a flow stream of
ethyl isocyanoacetate with a secondary stream containing
pyrrole-2-carboxaldehyde
(10, 0.25 M, 1.0 equiv.) and
piperidine (6 equiv.) in DCM afforded the desired pyrrolo[1,2-
c]pyrimidine structure 11 after passing through a flow coil
maintained at slightly elevated temperature (85 °C, 26 min
residence time, Scheme 5; Figure 2).
Figure 1: Representative [1,2,4]-triazoles prepared in flow.
Derivatization of 1,2,4-triazoles
In order to briefly evaluate the feasibility of these [1,2,4]-
triazoles (7a-h) to serve as building blocks towards future
research efforts we decided to specifically study the
functionalization of the 5-position of the heterocyclic core. To
this end regioselective bromination was affected by treating 7h
with a mixture of NaH and NBS in dry THF [16](Scheme 4).
Pleasingly, after 10 h reaction time, complete consumption of
the starting material and clean formation of the desired product
Scheme 5: Multi-step flow approach towards pyrrolo[1,2-
c]pyrimidine.
8
was observed. After purification 8 was subjected to a small
number of Suzuki cross coupling reactions in order to
synthesise 9a-e.[17] Although this reaction required prolonged
reaction times at elevated temperatures (8-10 h at 120 °C) the
desired Suzuki cross coupling products were formed
chemoselectively and isolated in reasonable yield allowing
further efforts to be directed towards the diversification of these
scaffolds.
Figure 2: Flow reactor used for the synthesis of pyrrolo[1,2-
c]pyrimidine.
In order to avoid any issues of precipitate formation within the
flow system (i.e. piperidine-HCl salts) a working concentration
of 0.25 M was targeted resulting in a theoretical throughput of
5.71 g/h. The desired pyrrolo[1,2-c]pyrimidine product could
be isolated in 85% yield and high purity (>95% by 1H-NMR) as
a beige solid after extraction and evaporation of the volatiles.
This crude material was of sufficient quality to be used in
further reactions however an analytical sample was further
purified by column chromatography to furnish a yellow solid
Scheme 4: Functionalization study of triazole 7h
.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 3

View Article Online
DOI: 10.1039/C5OB00245A
Organic & Biomolecular Chemistry
Page 4 of 9
ARTICLE
Journal Name
(78%). The reactor could be run under semi-continuous The data correlated in Table 1, implies a distinct kinetic preference
operation delivering ~30 g over the course of a standard for reaction at the C7 over C5 position due to enhanced
working day (8 h) including start-up/shut down and cleaning of delocalisation into the adjacent ring, however the most stable
the system.
products are those with substitution at C5. Further DFT studies, also
Having established convenient access to multigram quantities confirmed the nucleophilic character of the specified C5 and C7
of this pyrrolo[1,2-c]pyrimidine core (11) we decided to positions of the pyrrolo[1,2-c]pyrimidine (Figure 3). We were
evaluate its functionalization via electrophilic aromatic therefore confident that a regioselective functionalization of the
substitution reactions. Specifically we intended to establish pyrrolopyrimidine could be achieved.
whether this scaffold could be decorated in a regioselective
manner allowing access to versatile architectures for future
synthesis programmes. We therefore performed a number of
Density Functional Theory (DFT) calculations to compare the
intermediates originating from addition to the most likely C7
and C5 positions of the pyrrole subunit (Scheme 6, Table 1).
The geometries of the species were optimised with the 6-
311++G(2df,2pd) basis set (for iodine the cc-pVTZ-PP basis
set[20] with the Stuttgarts pseudopotential[21] was used)
employing Truhlar functionals, M06-2X,[22] which have been
shown to successfully describe such systems thermochemistry,
kinetics, and non-covalent interactions. The computational
calculations were performed using Gaussian 09 program
suite;[23] frequency analysis was also performed to confirm the
nature of the stationary points and to obtain zero-point energies
(ZPEs). Solvent effects on molecular geometries and energies
were estimated by means of Polarization Continuum Models
c]pyrimidine (11). (green electrophilic regions; blue nucleophilic
(PCM)[24] with DCM as the solvent.
Figure 3. Dual descriptor Fukui function of pyrrolo[1,2-
regions)
We subsequently prepared
a
number of pyrrolo[1,2-
c]pyrimidine derivatives (12a-i) confirming that the most
reactive site was indeed the C7 position of the pyrrole moiety
followed by the C5 position. This analysis was largely enabled
1
by single crystal X-ray diffraction experiments as H- and 13C-
NMR experiments were not always conclusive (Scheme 7).
Scheme 6. General schematic of the DFT calculations performed on
the electrophilic attack on the pyrrolopyrimidine moiety.
Table 1. Collected Gibbs free energies on the structures.
∆G (Kcal mol-1)
Entry Compound
M06-2x/6-311++G(2df,2pd)
INT*
PROD*
5-Cl
7-Cl
5-Br
7-Br
5-I
3.23
0.00
1.62
0.00
0.76
0.00
-1.92
0.00
-0.86
0.00
-1.39
0.00
1
2
3
4
5
6
7-I
* The energies are all reported relative to the 7-halo compounds
which were the thermodynamic control compounds.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

View Article Online
DOI: 10.1039/C5OB00245A
Page 5 of 9
Journal Name
Organic & Biomolecular Chemistry
ARTICLE
been demonstrated. These studies have also allowed insights in
Scheme 7. Functionalization of the pyrrolo[1,2-c]pyrimidine the occurrence of halogen dance phenomena during the
core by SEAr reactions (overall isolated yields for 2 steps).
elaboration of the pyrrolo[1,2-c]pyrimidine scaffold. We
believe that this study demonstrates the benefits of modern flow
Whilst this strategy allowed for the efficient and regioselective techniques in the generation and use of hazardous, yet versatile
monofunctionalisation at C7 via halogenation (Cl, Br. I), intermediates towards medicinally relevant structures.
formylation and acetylation reactions, it was noted that the
subsequent introduction of a second electrophilic substituent
did not always furnish the predicted product.
Experimental section
General experimental section
The nitration or bromination of the chlorinated pyrrolo[1,2-
1H-NMR spectra were recorded on either Bruker Avance-400,
c]pyrimidine intermediate did yield the expected reaction
Varian VNMRS-600 or Varian VNMRS-700 instruments and are
products 12a and 12b. However, preparation of the dihalo-
reported relative to residual solvent: CHCl3 (δ 7.26 ppm) or DMSO
structure 12c was only possible when halogenating (use of NBS
(δ 2.50 ppm). 13C-NMR spectra were recorded on the same
or NCS) under neutral conditions. Conducting the chlorination
instruments and are reported relative to CHCl3 (δ 77.16 ppm) or
DMSO (δ 39.52 ppm). Data for H-NMR are reported as follows:
step in the presence of HCl or for prolonged reaction times (i.e.
> 10 h) resulted in the formation of a mixture of 12b and 12c
Additionally, when attempting nitration of substrate it was
1
.
chemical shift (δ/ ppm) (integration, multiplicity, coupling constant
(Hz)). Multiplicities are reported as follows: s = singlet, d = doublet,
t = triplet, q = quartet, p = pentet, m = multiplet, br. s = broad
singlet, app = apparent. Data for 13C-NMR are reported in terms of
chemical shift (δ/ ppm) and multiplicity (C, CH, CH2 or CH3). Data
for 19F-NMR were recorded on the above instruments at a frequency
of 376 MHz using CFCl3 as external standard. DEPT-135, COSY,
HSQC, HMBC and NOESY experiments were used in the structural
assignment. IR spectra were obtained by use of a Perkin Elmer RX1
spectrometer (neat, ATR sampling) with the intensities of the
characteristic signals being reported as weak (w, <20% of tallest
signal), medium (m, 21-70% of tallest signal) or strong (s, >71% of
tallest signal). Low and high resolution mass spectrometry was
performed using the indicated techniques on either Waters LCT
Premier XE or Waters TQD instruments equipped with Acquity
UPLC and a lock-mass electrospray ion source. For accurate mass
measurements the deviation from the calculated formula is reported
in ppm. Melting points were recorded on an Optimelt automated
melting point system with a heating rate of 1 °C/min and are
uncorrected.
8
noted that a mixture of two mono-nitrated products as well as
the di-nitrated scaffold 12d formed very rapidly. Furthermore,
attempted nitration of the 7-mono-iodinated pyrrolo[1,2-
c]pyrimidine core yielded a mixture of nitrated products (12h
,
12i) that after longer reaction time (12 h) would as also
generate small quantities (~15%) of the previously prepared di-
nitrated product 12d. As the identity of 12i had been confirmed
by single crystal X-ray diffraction experiments, we suggest the
occurrence of a ‘halogen dance’ phenomenon in cases where
brominated or iodinated monofunctionalisation products are
subjected to a second SEAr reaction under strongly acidic
conditions. We thus propose that under acidic conditions the
second electrophile is again first introduced at C7 generating a
tetrahedral intermediate 13b (Scheme 8). This structure can
then undergo a [1,3]-shift in which the most weakly bound
halogen migrates to the 5-position of the pyrrolo[1,2-
c]pyrimidine scaffold (i.e. 13c) thus resembling other ‘halogen
dance’ phenomena reported in the literature [25]. Overall, the
strategic use of this rearrangement could lead to otherwise
difficult to access structures and thus opens avenues towards
specifically functionalised pyrrolo[1,2-c]pyrimidine scaffolds.
Further research is now required to fully evaluate and develop
these initial findings.
Single crystal X-ray data were collected at 120.0K on a Bruker
SMART 6000 (sealed tube, graphite monochromator) (compounds
7h and SI12f’) and Bruker D8 Venture (Photon 100 CMOS
detector, IμS microsource, focusing mirrors) (compounds 12a, 12f
and 12i) diffractometers (λMoKα, λ=0.71073Å) equipped with
Cryostream (Oxford Cryosystems) open flow nitrogen cryostates.
The structures were solved by direct methods and refined by full-
matrix least squares on F2 for all data using SHELX [26] and
OLEX2 [27] software. All non-hydrogen atoms were refined with
anisotropic displacement parameters, the H-atoms in the structures
12a, 12f and 12i were placed in calculated positions and refined in
"riding" mode. The H atoms in the other structures were found in the
difference Fourier maps and refined isotropically. Crystallographic
data and parameters of the refinement are given in Table 1 (SI).
Crystallographic data for the structures have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication CCDC-1039437-1039441.
Scheme 8. Proposed mechanism for ‘halogen dance’ under
acidic conditions.
Ethyl
1-(3-chloro-4-fluorophenyl)-1H-1,2,4-triazole-3-
carboxylate, 7a, 71%: Mp 186.3-187.9 °C (decomposed).
Compound description: tan solid.1H NMR (400 MHz, DMSO-d6) δ
9.46 (s, 1H), 8.23 (dd, J = 6.4, 2.7 Hz, 1H), 7.95 (ddd, J = 9.0, 4.2,
2.7 Hz, 1H), 7.69 (t, J = 9.0 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 1.34
(t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 159.6 (C),
157.3 (d, J = 248.6 Hz, CF), 155.2 (C), 145.0 (CH), 133.8 (d, J = 3.4
Hz, C), 122.9 (CH), 121. 5 (d, J = 8.0 Hz, CH), 121.2 (d, J = 19.0
Hz, C), 118.6 (d, J = 22.7 Hz, CH), 61.9 (CH2), 14.5 (CH3). 19F
Conclusions
In conclusion, we have successfully developed a valuable flow
protocol for the synthesis of ethyl isocyanoacetate via
dehydration of N-formylglycine using triphosgene. The
versatility of generating this isocyanide building block in situ
was further exploited by multi-step sequences towards various
1,2,4-triazoles as well as the pyrrolo[1,2-c]pyrimidine scaffold,
whose further functionalization by means of SEAr reactions has
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 5

View Article Online
DOI: 10.1039/C5OB00245A
Organic & Biomolecular Chemistry
Page 6 of 9
ARTICLE
Journal Name
NMR (376 MHz, DMSO-d6) δ -116.21 (s). IR (neat): ν 3116.9 (m), 668.4 (s) cm-1. LC-MS (ESI): 308.1 (M+Na); HRMS (ESI):
1721.4 (s), 1511.9 (m), 1493.3 (s), 1451.0 (s), 1339.7 (m), 1252.7 calculated for C12H11N3O2F3 286.0803, found 286.0795 (M+H, Δ = -
(s), 1202.1 (s), 1089.1 (s), 1051.9 (m), 996.6 (s), 849.9 (s), 828.2 (s), 2.8 ppm).
718.9 (s), 667.6 (s), 639.4 (s) cm-1. LC-MS (ESI): 292.1 (M+Na); Ethyl 1-(4-bromophenyl))-1H-1,2,4-triazole-3-carboxylate, 7f,
HRMS (ESI): calculated for C11H10N3O2ClF 270.0446, found 69%: Mp 152.4-143.8 °C. Compound description: white crystalline
1
270.0443 (M+H, Δ = -0.3 ppm).
solid. H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 7.89 (d, J =
Ethyl 1-(m-tolyl)-1H-1,2,4-triazole-3-carboxylate, 7b, 68%: Mp 8.9 Hz, 2H), 7.82 (d, J = 8.9 Hz, 2H), 4.38 (q, J = 7.1 Hz, 2H), 1.34
1
80.2-81.5 °C. Compound description: brown powder. H NMR (400 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 159.6 (C),
MHz, DMSO-d6) δ 9.43 (s, 1H), 7.74 (dt, J = 1.6, 0.8 Hz, 1H), 7.69 155.2 (C), 144.7 (CH), 136.0 (C), 133.2 (2CH), 122.4 (2CH), 121.8
(d, J = 7.8 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.29 (d, J = 7.8 Hz, (C), 61.9 (CH2), 14.6 (CH3). IR (neat): 3133.7 (w), 1718.4 (s),
1H), 4.38 (q, J = 7.1 Hz, 2H), 3.36 (s, 1H), 1.34 (t, J = 7.1 Hz, 3H). 1483.9 (s), 1451.2 (s), 1338.4 (m), 1257.5 (s), 1203.3 (s), 1067.0 (s),
13C NMR (101 MHz, DMSO-d6) δ 159.8 (C), 155.0 (C), 144.4 1029.4 (m), 979.8 (s), 826.9 (s), 668.3 (s) cm-1. LC-MS (ESI):
(CH), 140.1 (C), 136.7 (C), 130.1 (CH), 129.7 (CH), 120.8 (CH), 318.0 (M+Na); HRMS (ESI): calculated for C11H11N3O2Br
117.4 (CH), 61.8 (CH2), 21.3 (CH3), 14.6 (CH3). IR (neat): 3109.9 296.0035, found 296.0036 (M+H, Δ = +0.1 ppm).
(w), 1715.6 (s), 1497.7 (m), 1448.3 (s), 1255.8 (s), 1194.4 (s), Ethyl 1-(3-chlorophenyl))-1H-1,2,4-triazole-3-carboxylate, 7g,
1081.8 (s), 1015.9 (s), 886.1 (m), 848.6 (m), 792.5 (s), 669.4 (s) cm- 68%: Mp 114.6-115.5 °C. Compound description: orange powder.
1. LC-MS (ESI): 254.1 (M+Na); HRMS (ESI): calculated for 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.06 (t, J = 2.0 Hz,
C12H14N3O2 232.1086, found 232.1084 (M+H, Δ = -0.2 ppm).
1H), 7.90 (ddd, J = 8.1, 2.1, 1.1 Hz, 1H), 7.64 (t, J = 8.1 Hz, 1H),
Ethyl 1-(3-methoxyphenyl))-1H-1,2,4-triazole-3-carboxylate, 7c, 7.57 (ddd, J = 8.1, 2.0, 1.0 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 1.34 (t,
53%: Mp 97.4 °C (decomposed). Compound description: dark J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 159.6 (C),
1
brown solid. H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 7.60 – 155.2 (C), 144.9 (CH), 137.9 (C), 134.6 (C), 132.1 (CH), 128.9
7.38 (m, 3H), 7.06 (ddd, J = 8.0, 2.6, 1.9 Hz, 1H), 4.38 (q, J = 7.1 (CH), 120.3 (CH), 119.1 (CH), 61.9 (CH2), 14.5 (CH3). IR (neat):
Hz, 2H), 3.86 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, 3109.6 (w), 1719.9 (s), 1595.0 (m), 1485.9 (m), 1450.6 (s), 1341.9
DMSO-d6) δ 160.7 (C), 159.7 (C), 155.0 (C), 144.6 (CH), 137.8 (C), (m), 1256.3 (s), 1198.1 (s), 1103.1 (s), 1079.9 (s), 1028.7 (s), 993.6
131.3 (CH), 114.9 (CH), 112.4 (CH), 106.0 (CH), 61.8 (CH2), 56.1 (s), 892.9 (s), 846.7 (m), 792.0 (s), 769.0 (s), 667.4 (s) cm-1. LC-MS
(CH3), 14.6 (CH3). IR (neat): 3106.8 (w), 1730.3 (s), 1607.5 (m), (ESI): 274.0 (M+Na); HRMS (ESI): calculated for C11H11N3O2Cl
1504.9 (s), 1469.9 (s), 1281.3 (s), 1240.8 (s), 1193.7 (s), 1174.4 (s), 252.0540, found 252.0535 (M+H, Δ = -0.5 ppm).
1029.4 (s), 992.2 (s), 882.3 (s), 772.0 (s), 669.4 (s) cm-1. LC-MS Ethyl 1-(4-chlorophenyl))-1H-1,2,4-triazole-3-carboxylate, 7h,
(ESI): 270.1 (M+Na); HRMS (ESI): calculated for C12H14N3O3 67%: Mp 136.5-137.0 °C. Compound description: white crystalline
1
248.1035, found 248.1035 (M+H, Δ = 0.0 ppm).
solid. H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 7.95 (d, J =
Ethyl 1-(3-fluorophenyl))-1H-1,2,4-triazole-3-carboxylate, 7d, 8.9 Hz, 2H), 7.68 (d, J = 8.9 Hz, 2H), 4.38 (q, J = 7.1 Hz, 2H), 1.34
62%: Mp 214.3 °C (decomposed). Compound description: pale tan (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 159.6 (C),
1
solid. H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 7.84 (dt, J = 155.2 (C), 144.7 (CH), 135.6 (C), 133.4 (C), 130.3 (2CH), 122.2
10.0, 2.3 Hz, 1H), 7.79 (ddd, J = 8.0, 2.3, 0.9 Hz, 1H), 7.65 (td, J = (2CH), 61.9 (CH2), 14.6 (CH3). IR (neat): 3125.9 (w), 1725.3 (m),
8.3, 6.2 Hz, 1H), 7.36 (tdd, J = 8.4, 2.6, 0.9 Hz, 1H), 4.39 (q, J = 7.1 1487.3 (s), 1450.4 (s), 1339.4 (m), 1257.5 (s), 1202.6 (s), 1074.8 (s),
Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) 1028.0 (m), 981.5 (s), 831.2 (s), 668.4 (m) cm-1. LC-MS (ESI):
δ 162.8 (d, J = 245.2 Hz, CF), 159.6 (C), 155.2 (C), 144.9 (CH), 274.1 (M+Na); HRMS (ESI): calculated for C11H11N3O2Cl
138.0 (d, J = 10.6 Hz, C), 132.3 (d, J = 9.2 Hz, CH), 116.4 (d, J = 252.0540, found 252.0541 (M+H, Δ = +0.1 ppm). CCDC 1039438.
3.1 Hz, CH), 115.9 (d, J = 21.1 Hz, CH), 108.0 (d, J = 26.8 Hz, CH), Ethyl 7-chloro-5-nitropyrrolo[1,2-c]pyrimidine-3-carboxylate, 12a,
61.9 (CH2), 14.5 (CH3). 19F NMR (376 MHz, DMSO-d6) δ -110.60 72%, Mp 145 °C (decomposition). Compound description: brown
(s). IR (neat): 3102.2 (w), 1719.8 (s), 1606.1 (s), 1496.3 (s), 1449.2 solid. 1H NMR (600 MHz, CDCl3) δ 9.06 (s, 1H), 8.96 (s, 1H), 7.51
(s), 1341.6 (m), 1260.4 (s), 1199.4 (s), 1004.4 (m), 862.5 (s), 783.3 (s, 1H), 4.50 (q, J = 7.2 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H). 13C NMR
(s), 667.9 (s) cm-1. LC-MS (ESI): 258.1 (M+Na); HRMS (ESI): (151 MHz, CDCl3) δ 163.3 (C), 138.6 (C), 135.5 (CH), 129.0 (C),
calculated for C11H11N3O2F 236.0835, found 236.0835 (M+H, Δ = 127.9 (C), 115.5 (CH), 112.5 (CH), 111.5 (C), 62.6 (CH2), 14.3
0.0 ppm).
(CH3). IR (neat): 3132.5 (w), 1727.3 (s), 1617.9 (w), 1481.0 (s),
1425.5 (m), 1406.5 (m), 1314.6 (s), 1221.6 (s), 1127.7 (s), 1101.3
Ethyl
1-(3-(trifluoromethyl)phenyl))-1H-1,2,4-triazole-3-
carboxylate, 7e, 55%: Mp 129.3-130.4 °C. Compound description: (s), 1010.2 (m), 973.6 (m), 848.4 (m), 783.7 (s), 759.6 (m) cm-1. LC-
orange powder. 1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.30 MS (ESI): 270.1.0 (M+H); HRMS (ESI): calculated for
(br s, 1H), 8.28 – 8.20 (m, 1H), 7.92 – 7.80 (m, 2H), 4.40 (q, J = 7.1 C10H9N3O4Cl 270.0282, found 270.0287 (M+H, Δ = 1.9 ppm).
Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) CCDC 1039441.
δ 159.6 (C), 155.3 (C), 145.1 (CH), 137.3 (C), 131.8 (CH), 130.94 Ethyl
5-bromo-7-chloropyrrolo[1,2-c]pyrimidine-3-carboxylate,
(q, J = 32.5 Hz, C), 125.7 (q, J = 3.7 Hz, CH), 124.4 (CH), 124.0 (q, 12b, 83%, Mp 109.1-113.0 °C. Compound description: Beige solid.
J = 273.6 Hz, CF3), 117.14 (q, J = 4.0 Hz, CH), 61.9 (CH2), 14.5 1H NMR (400 MHz, CDCl3) δ 8.77 (d, J = 1.6 Hz, 1H), 8.15 (d, J =
(CH3). 19F NMR (376 MHz, DMSO-d6) δ -61.2 (s). IR (neat): 1.6 Hz, 1H), 6.91 (s, 1H), 4.46 (q, J = 7.2 Hz), 1.44 (t, J = 7.2 Hz,
3107.7 (w), 1719.8 (m), 1450.6 (s), 1316.3 (s), 1255.2 (s), 1163.7 3H). 13C NMR (101 MHz, CDCl3) δ 164.4 (C), 134.8 (CH), 131.4
(s), 1116.5 (s), 1081.5 (s), 995.1 (m), 902.9 (m), 807.4 (s), 698.8 (s), (C), 128.7 (C), 117.7 (CH), 115.6 (CH), 110.1 (C), 92.5 (C), 61.9
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

View Article Online
DOI: 10.1039/C5OB00245A
Page 7 of 9
Journal Name
Organic & Biomolecular Chemistry
ARTICLE
(CH2), 14.4 (CH3). IR (neat): 1699.8 (s), 1524.7 (m), 1445.7 (m), (CHO), 163.9 (C), 140.2 (CH), 138.6 (C), 138.1 (C), 134.6 (CH),
1422.2 (m), 1368.0 (m), 1288.4 (s), 1232.1 (s), 1086.4 (m), 1019.8 126.3 (CH), 116.9 (CH), 62.5 (CH2), 60.5 (C), 14.4 (CH3). IR
(m), 813.1 (m), 776.5 (s), 711.1 (m), 593.5 (s) cm-1. LC-MS (ESI): (neat): 3100.3 (w), 2979.5 (w), 1717.2 (s), 1642.2 (s), 1471.4 (m),
303.4 (M+H); HRMS (ESI): calculated for C10H9N2O2ClBr 1431.6 (s), 1342.7 (s), 1268.3 (s), 1235.5 (s), 1139.2 (s), 1019.2 (s),
302.9536, found 302.9541 (M+H, Δ = 1.7 ppm).
764.1 (s), 729.6 (s), 695.8 (m), 612.0 (m) cm-1. LC-MS (ESI): 366.9
Ethyl 5-chloro-7-bromopyrrolo [1,2-c]pyrimidine-3-carboxylate, (M+Na); HRMS (ESI): calculated for C11H9N2O3INa 366.9556,
12c, 79%:, Mp 110 °C (decomposition). Compound description: found 366.9557 (M+Na, Δ = 0.3 ppm).
1
brown solid. H NMR (400 MHz, CDCl3) δ 8.75 (d, J = 1.2 Hz, Ethyl 7-iodo-5-nitropyrrolo[1,2-c]pyrimidine-3-carboxylate, 12h,
1H), 8.14 (d, J = 1.2 Hz, 1H), 6.91 (s, 1H), 4.44 (q, J = 7.2 Hz, 2H), 41%, Mp 150 °C (decomposition). Compound description: brown
1.42 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 164.4 (C), solid. 1H NMR (400 MHz, CDCl3) δ 9.05 (d, J = 1.4 Hz, 1H), 8.89
136.0 (CH), 131.1 (C), 128.6 (C), 119.1 (CH), 114.6 (CH), 108.7 (d, J = 1.4 Hz, 1H), 7.79 (s, 1H), 4.52 (q, J = 7.2 Hz, 2H), 1.47 (t, J
(C), 94.4 (C), 61.9 (CH2), 14.4 (CH3). IR (neat): 1701.2 (s), 1524.6 = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 163.4 (C), 140.0
(m), 1420.1 (m), 1361.7 (m), 1313.0 (m), 1283.0 (s), 1243.8 (s), (CH), 138.9 (C), 132.7 (C), 130.7 (C), 123.5 (CH), 115.1 (CH), 63.1
1091.9 (m), 1017.4 (m), 821.5 (s), 774.8 (s), 711.5 (s), 594.5 (s) cm- (C), 62.6 (CH2), 14.3 (CH3). IR (neat): 1699.6 (s), 1486.6 (m),
1. LC-MS (ESI): 324.9 (M+Na); HRMS (ESI): calculated for 1406.2 (s), 1296.4 (s), 1276.6 (s), 1215.5 (s), 1012.2 (s), 779.6 (s),
C10H8N2O2ClBrNa 324.9355, found 324.9358 (M+Na, Δ = 0.9 ppm). 756.3 (s), 598.1 (s) cm-1. LC-MS (ESI): 361.9 (M+H); HRMS
Ethyl 5,7-dinitropyrrolo[1,2-c]pyrimidine-3-carboxylate, 12d, 90%, (ESI): calculated for C10H9N3O4I 361.9638, found 361.9633 (M+H,
1
Mp 100.8-103.3 °C. Compound description: yellow-brown solid. H Δ = -1.4 ppm).
NMR (400 MHz, CDCl3) δ 10.37 (d, J = 1.2 Hz, 1H), 9.18 (d, J = Ethyl 5-iodo-7-nitropyrrolo[1,2-c]pyrimidine-3-carboxylate, 12i,
1.2 Hz), 8.46 (s, 1H), 4.55 (q, J = 7.2 Hz, 2H), 1.49 (t, J = 7.2 Hz, 37%, Mp 170°C (decomposition). Compound description: bright
1
3H). 13C NMR (101 MHz, CDCl3) δ 162.4 (C), 142.3 (C), 138.1 yellow solid. H NMR (400 MHz, CDCl3) δ 10.18 (d, J = 1.2 Hz,
(CH), 131.7 (C), 129.5 (C), 127.6 (C), 115.8 (CH), 115.5 (CH), 63.2 1H), 8.32 (d, J = 1.2 Hz, 1H), 8.07 (s, 1H), 4.55 (q, J = 7.2 Hz, 2H),
(CH2), 14.3 (CH3). IR (neat): 1729.3 (s), 1500.8 (m), 1475.7 (m), 1.50 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 163.4 (C),
1334.1 (s), 1239.2 (s), 1139.2 (m), 1005.6 (s), 815.4 (m), 784.7 (s), 138.4 (CH), 138.1 (C), 137.0 (C), 132.4 (C), 126.6 (CH), 117.1
764.2 (s), 735.8 (s), 611.0 (m) cm-1. LC-MS (ESI): 303.4 (M+Na); (CH), 62.7 (CH2), 60.9 (C), 14.3 (CH3). IR (neat): 1712.2 (m),
HRMS (ESI): calculated for C10H9N4O6 281.0522, found 281.0510 1505.4 (m), 1436.4 (s), 1381.0 (s), 1313.5 (s), 1282.7 (s), 1211.5 (s),
(M+H, Δ = -4.3 ppm).
1020.0 (m), 813.3 (m), 722.6 (s) cm-1. LC-MS (ESI): 361.9 (M+H);
Ethyl 5,7-dibromopyrrolo[1,2-c]pyrimidine-3-carboxylate, 12e, HRMS (ESI): calculated for C10H9N3O4I 361.9638, found 361.9644
1
92%, Mp 113.8-115.5 °C. Compound description: brown solid. H (M+H, Δ = 1.7 ppm). CCDC 1039440.
NMR (400 MHz, CDCl3) δ 8.68 (d, J = 1.6 Hz, 1H), 7.99 (d, J = 1.6
Acknowledgements
Hz, 1H), 6.88 (s, 1H), 4.39 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 7.2 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 164.3 (C), 136.1 (CH), 131.5
(C), 130.2 (C), 121.1 (CH), 115.2 (CH), 95.1 (C), 93.2 (C), 61.8
(CH2), 14.4 (CH3). IR (neat): 1700.7 (s), 1521.5 (w), 1416.9 (s),
1345.0 (s), 1281.7 (s), 1241.1 (s), 1016.2 (s), 823.4 (s), 775.1 (s),
710.9 (s), 593.4 (s) cm-1. LC-MS (ESI): 346.8 (M+H); HRMS
(ESI): calculated for C10H9N2O2Br2 346.9031, found 346.9015
(M+H, Δ = -4.6 ppm).
We gratefully acknowledge financial support through the Royal
Society (M.B. and I.R.B.) and MEC & MINECO for a FPU
fellowship (A.M.R.G.). Furthermore we are very grateful to Dr
D.S.Yufid and Dr A.S.Batsanov (Department of Chemistry,
Durham University) for solving several X-ray crystal structures.
Notes and references
a
Department of Chemistry, Durham University, South Road,
Ethyl 5-bromo-7-(2,2,2-trifluoroacetyl)pyrrolo[1,2-c]pyrimidine-3-
carbox-ylate, 12f, 73%, Mp 106.8-108.3 °C. Compound description:
beige solid. H NMR (400 MHz, CDCl3) δ 10.38 (d, 1H, J = 1.6
Durham, DH1 3LE, United Kingdom.
Universidad de Castilla-La Mancha, Departamento de Química
Orgánica, Facultad de Ciencias y Tecnologías Químicas, Avd.
Camilo José Cela, 10, 13071 Ciudad Real, Spain.
b
1
Hz), 8.38 (d, 1H, J = 1.6 Hz), 7.86 (q, 1H, J = 2.0 Hz), 4.51 (q, 2H, J
= 7.2 Hz), 1.46 (t, 3H, J = 7.2 Hz). 13C NMR (101 MHz, CDCl3) δ
169.4 (q, J = 37 Hz, C), 163.4 (C), 140.0 (CH), 139.3 (C), 137.9 (C),
129.0 (q, J = 4 Hz, CH), 118.2 (C), 119.5 (q, J = 290 Hz, CF3), 115.1
(CH), 95.9 (C), 62.7 (CH2), 14.3 (CH3). 19F NMR (376 MHz,
CDCl3) δ -71.71 (s). IR (neat): 3086.2 (w), 1736.3 (m), 1662.6 (m),
1351.1 (m), 1214.0 (m), 1155.6 (s), 1098.0 (s), 906.3 (m), 851.2 (m),
756.7 (m), 657.6 (m) cm-1. LC-MS (ESI): 386.9 (M+Na); HRMS
(ESI): calculated for C12H9N2O3BrF3 364.9749, found 364.9750
(M+H, Δ = 0.3 ppm). CCDC 1039439.
Ethyl 5-iodo-7-formylpyrrolo[1,2-c]pyrimidine-3-carboxylate, 12g,
77%, Mp 205 °C (decomposition). Compound description: yellow
solid. 1H NMR (400 MHz, CDCl3) δ 10.23 (d, J = 1.2 Hz, 1H), 9.86
(s, 1H), 8.27 (d, J = 1.2 Hz, 1H), 7.75 (s, 1H), 4.51 (q, J = 7.2 Hz,
2H), 1.47 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 178.2
†
Footnotes should appear here. These might include comments
relevant to but not central to the matter under discussion, limited
experimental and spectral data, and crystallographic data.
Electronic Supplementary Information (ESI) available: See
DOI: 10.1039/b000000x/
1
(a) J.J. Li: Heterocyclic Chemistry in Drug Discovery. Wiley,
2013. ISBN: 978-1-118-14890-7; (b) R.B. Silverman: The
Organic Chemistry of Drug Design and Drug Action.
Elsevier Academic Press: Burlington, MA, 2004; (c) H. Wild,
D. Heimbach and C. Huwe, Angew. Chem. Int. Ed., 2011, 50
7452.
,
2
(a) M. Baumann, I.R. Baxendale, S.V. Ley and N. Nikbin,
Beilstein, J. Org. Chem., 2011,
7
, 442; (b) M. Baumann and
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 7

View Article Online
DOI: 10.1039/C5OB00245A
Organic & Biomolecular Chemistry
Page 8 of 9
ARTICLE
Journal Name
I.R. Baxendale, Beilstein, J. Org. Chem., 2013,
Vitaku, D.T. Smith and J.T. Njardarson, J. Med. Chem., 2014,
57, 10257.
9
, 2265; (c) E.
Sandford, D.S. Yufit, J.A.K. Howard, J. Fray and B. Patel,
Beilstein J. Org. Chem., 2011, , 1048.
(a) D.L. Browne, M. Baumann, B.H. Harji, I.R. Baxendale
and S.V. Ley, Org. Lett., 2011, 13, 3312; (b) J.A. Newby,
D.W. Blaylock, P.M. Witt, J.C. Pastre, M.K. Zacharova, S.V.
7
9
3
(a) L. Malet-Sanz and F. Susanne, J. Med. Chem., 2012, 55,
4062; (b) M. Baumann, I.R. Baxendale and S.V. Ley, Mol.
Divers., 2011, 15, 613; (c) R.L. Hartman, J.P. McMullen and
K.F. Jensen, Angew. Chem. Int. Ed., 2011, 50, 7502; (d) C.
Wiles and P. Watts, Green Chem., 2012, 14, 38; (e) V.
Hessel, B. Cortese and M.H.J.M. de Croon, Chem. Eng. Sci.,
2011, 66, 1426; (f) J. Yoshida, H. Kim and A. Nagaki,
Ley and D.L. Browne, Org. Process Res. Dev., 2014, 18
,
1211; (c) A. Nagaki, A. Kenmoku, Y. Moriwaki, A. Hayashi
and J. Yoshida, Angew. Chem. Int. Ed., 2010, 49, 7543; (d) A.
Nagaki, E. Takizawa and J. Yoshida, Chem. Eur. J., 2010, 16
,
14149.
ChemSusChem, 2010,
4, 331; (g) M.D. Hopkin, I.R. 10 (a) J. Hartwig, S. Ceylan, L. Kupracz, L. Coutable and A.
Baxendale and S.V. Ley, Org. Biomol. Chem., 2013, 11
1822.
,
Kirschning, Angew. Chem. Int. Ed., 2013, 52, 9813; (b) J.
Hartwig, L. Kupracz and A. Kirschning, Chem. Lett., 2012,
41, 562; (c) B. Reichart and C.O. Kappe, Tetrahedron Lett.,
2012, 53, 952; (d) J. Yoshida: Flash Chemistry: Fast Organic
Synthesis in Microsystems; John Wiley & Sons: Chichester,
UK, 2008.
4
(a) I.R. Baxendale, L. Brocken and C.J. Mallia, Green
Process. Synthesis, 2013, , 211; (b) I.R. Baxendale, J. Chem.
2
Tech. Biotech., 2013, 88, 4, 519; (c) J. Wegner, S. Ceylan and
A. Kirschning, Adv. Synth. Cat., 2012, 354, 17; (d) J.C.
Pastre, D.L. Browne, M. O’Brien and S.V. Ley, Org. Process 11 (a) Matsumoto, K. and Suzuki, M. 2001. Ethyl
Res. Dev., 2013, 17, 1183; (e) M.A. Kabeshov, B. Musio,
P.R.D. Murray, D.L. Browne and S.V. Ley, Org. Lett., 2014,
16, 4618; (f) J. Wegner, S. Ceylan and A. Kirschning, Org.
Biomol. Chem., 2012, 10, 7721; (g) P.R.D. Murray, D.L.
Browne, J.C. Pastre, C. Butters, D. Guthrie and S.V. Ley,
Org. Process Res. Dev., 2013, 17, 1192.
Isocyanoacetate; Encyclopedia of Reagents for Organic
Synthesis; (b) Suginome, M. and Ito, Y., Science of Synthesis,
2004, 19, 445; (c) Kotha, S. and Halder S., Synlett, 2010,
337; (d) M. Baumann, I.R. Baxendale, S.V. Ley, C.D. Smith
and G.K. Tranmer, Org. Lett., 2006, , 5231.
12 N-formylglycine is commercially available (CAS 3154-51-6).
3,
8
5
6
(a) M. O’Brien, I.R. Baxendale and S.V. Ley, Org. Lett., 13 S. Fuse, N. Tanabe, and T. Takahashi, Chem. Commun.,
2010, 12, 1596; (b) C. Battilochio, I.R. Baxendale, M, Biava, 2011, 47, 12661.
M.O. Kitching and S.V. Ley, Org. Process Res. Dev., 2012, 14 K. Matsumoto, M. Suzuki, M. Tomie, N. Yoneda and M.
16, 798; (c) M. Irfan, T.N. Glasnov and C.O. Kappe, Org.
Lett., 2011, 13, 984.
Miyoshi, Synthesis 1975, 609.
15 D.L. Browne, I.R.Baxendale and S.V. Ley, Tetrahedron 2011,
67, 10296-10303.
(a) C.J. Smith, C.D. Smith, N. Nikbin, S.V. Ley and I.R.
Baxendale, Org. Biomol. Chem., 2011,
9, 1927; (b) H.R. 16 M. Zibinsky and V.V. Fokin, Org. Lett., 2011, 13, 4870.
Sahoo, J.G. Kralj and K.F. Jensen, Angew. Chem. Int. Ed., 17 R. Romagnoli, P.G. Baraldi, O. Cruz-Lopez, C. Lopez Cara,
2007, 46, 5704; (c) L. Kupracz, J. Hartwig, J. Wegner, S.
Ceylan and A. Kirschning, Beilstein J. Org. Chem. 2011, 7
M.D. Carrion, A. Brancale, E. Hamel, L. Chen, R. Bortolozzi,
G. Basso and G. Viola, J. Med. Chem., 2010, 53, 4248.
,
1441. (d) M. Baumann, I.R. Baxendale, S.V. Ley, N. Nikbin, 18 For instance WO 2003070732; WO 2004039366; WO
C.D. Smith and J.P. Tierney, Org. Biomol. Chem., 2008, 2004064836; WO 2004052461.
1577; (e) C.J. Smith, N. Nikbin, S.V. Ley, H. Lange I.R. 19 (a) J.M. Minguez, J.J. Vaquero, J.L. García-Navio and J.
6
,
Baxendale, Org. Biomol. Chem. 2011,
and T.F. Jamison, Angew. Chem. Int. Ed. 2011, 50, 3525. (g)
I.R. Baxendale, S.V. Ley, A.C. Mansfield, C.D. Smith,
9
, 1938; (f) P.B. Palde
Alvarez-Builla, Tetrahedron Lett. 1996, 37, 4263; (b) J.M.
Minguez, J.J. Vaquero, J. Alvarez and O. Catano, J. Org.
Chem., 1999, 64, 7788.
Angew. Chem. Int. Ed. 2009, 48, 4017; (h) F.R. Bou-Hamdan, 20 K.A. Peterson, B.C. Shepler, D. Figgen and H. Stoll, J. Phys.
F. Lévesque, A.G. O'Brien, and P.H. Seeberger, Beilstein J. Chem. A 2006, 110, 13877.
Org. Chem. 2011 , 1124; (i) C. D. Smith, I. R. Baxendale, 21 K.A. Peterson, D. Figgen, E. Goll, H. Stoll and M. Dolg, J.
S. Lanners, J. J. Hayward, S. C. Smith, S.V. Ley, Org. Chem. Phys. 2003, 119, 11113.
Biomol. Chem. 2007, , 1559; (j) C. J. Smith, N. Nikbin, C. 22 (a) Y. Zhao and D.G. Truhlar, Acc. Chem. Res. 2008, 41, 157;
D. Smith, S. V. Ley, I. R. Baxendale, Org. Biomol. Chem.
2011, , 1927. (k) M.M.E. Delville, P.J. Nieuwland, P.
,
7
5
(b) Y. Zhao and D.G. Truhlar, Theor. Chem. Acc. 2007, 120
,
9
215.
Janssen, K. Koch, J.C.M. van Hest and F.P.J.T. Rutjes, Chem. 23 M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.
Eng. J. 2011, 167, 556.
(a) D.X. Hu, M. O’Brien and S.V. Ley, Org. Lett., 2012, 14,
A. Robb, J.R. Cheeseman, G. Scalmani, V. Barone, B.
Mennucci, G.A. Petersson, H. Nakatsuji, M. Caricato, X. Li,
H.P. Hratchian, A.F. Izmaylov, J. Bloino, G. Zheng, J. L.
Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J.
Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H.
Nakai, T. Vreven, J.A. Montgomery Jr., J.E. Peralta, F.
Ogliaro, M.J. Bearpark, J.J. Heyd, E.N. Brothers, K.N.
Kudin, V.N. Staroverov, R. Kobayashi, J. Normand, K.
7
8
4246; (b) L. Malet-Sanz, J. Madrzak, S.V. Ley and I.R.
Baxendale, Org. Biomol. Chem., 2010, , 3312.
(a) C. McPake, C.B. Murray and G. Sandford, Tetrahedron
Lett., 2009, 50, 1674; (b) C. McPake and G. Sandford, Org.
Process Res. Dev., 2012, 16, 844; (c) J.R. Breen, G.
8
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

View Article Online
DOI: 10.1039/C5OB00245A
Page 9 of 9
Journal Name
Organic & Biomolecular Chemistry
ARTICLE
Raghavachari, A.P. Rendell, J.C. Burant, S.S. Iyengar, J.
Tomasi, M. Cossi, N. Rega, N.J. Millam, M. Klene, J.E.
Knox, J.B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R.
Gomperts, R.E. Stratmann, O. Yazyev, A.J. Austin, R.
Cammi, C. Pomelli, J.W. Ochterski, R.L. Martin, K.
Morokuma, V.G. Zakrzewski, G.A. Voth, P. Salvador, J.J.
Dannenberg, S. Dapprich, A.D. Daniels, Ö. Farkas, J.B.
Foresman, J.V. Ortiz, J. Cioslowski and D.J. Fox Gaussian 09
Revision D.01, Gaussian Inc. : Wallingford CT 2009, 2009.
24 (a) S. Miertuš, E. Scrocco and J. Tomasi, Chem. Phys. 1981
,
55, 117; (b) J. Tomasi, R. Cammi, B. Mennucci, C. Cappelli
and S. Corni, Phys. Chem. Chem. Phys. 2002, 4, 5697; (c) J.
Tomasi, B. Mennucci and R. Cammi, Chem. Rev. 2005, 105
,
2999.
25 (a) M. Vicinius Nora de Souza, Current Org. Chem., 2007,
11, 637; (b) M. Schnürch, M. Spina, A. Farooq Khan, M.D.
Mihovilovic and P. Stanetty, Chem. Soc. Rev., 2007, 36
,
1046; (c) M. Schnürch: Recent Progress on the Halogen
Dance Reaction on Heterocycles In: Halogenated
Heterocycles, Topics in Heterocyclic Chemistry, Vol. 27,
2012, pp 185-218, Springer.
26 G.M. Sheldrick, Acta Cryst. 2008, A64, 112-122.
27 O.V. Dolomanov, L.J. Bourhis, R.J. Gildea, J.A.K. Howard
and H. Puschmann, J. Appl. Cryst. 2009, 42, 339-341.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 9