A modular flow reactor for performing Curtius rearrangements as a continuous flow process

Article abstract of DOI:10.1039/b801631n

The use of a mesofluidic flow reactor is described for performing Curtius rearrangement reactions of carboxylic acids in the presence of diphenylphosphoryl azide and trapping of the intermediate isocyanates with various nucleophiles. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b801631n

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www.rsc.org/obc | Organic & Biomolecular Chemistry
A modular flow reactor for performing Curtius rearrangements as a
continuous flow process†
Marcus Baumann,a Ian R. Baxendale,a Steven V. Ley,*a Nikzad Nikbin,a Christopher D. Smitha and
Jason P. Tierneyb
Received 29th January 2008, Accepted 15th February 2008
First published as an Advance Article on the web 12th March 2008
DOI: 10.1039/b801631n
The use of a mesofluidic flow reactor is described for performing Curtius rearrangement reactions of
carboxylic acids in the presence of diphenylphosphoryl azide and trapping of the intermediate
isocyanates with various nucleophiles.
developed a fully automated flow process for performing Curtius
Introduction
rearrangements with in situ trapping of the resultant isocyanate
The Curtius rearrangement is synthetically a very powerful
rearrangement product as the corresponding carbamate or urea
transformation for converting carboxylic acid moieties into their
derivate. Furthermore, the use of polymer-supported scavengers as
chemically diametric amino functionalities.1 As a direct chemical
in-line purification aids has facilitated the isolation of the desired
products without the need for laborious purification.9
interconversion this process has tremendous value, but it also
has an important strategic impact because of the prevalence
of the amide linkage in many pharmaceutical compounds. The
transposition of the coupling partners in an amide bond is a
classical medicinal chemistry tactic to facilitate exploration of
SAR and also when faced with issues of metabolic stability or poor
physiological properties. The Curtius rearrangement simplifies
the synthesis route by avoiding the requirement of generating
paired coupling materials, enabling the direct derivatization of
the complimentary carboxylic acids. Despite the many advantages
offered by this reaction, its use especially at scale has been avoided
because of significant safety concerns regarding the generation
and use of potentially explosive and highly toxic azide promoters
and the associated acyl azide intermediates.
Results and discussion
To conduct the Curtius rearrangements in a convenient fashion
we used the commercially available flow synthesis platform from
VapourTec (R2+ and R4 combination, Fig. 1).10
Flow based chemical processing offers tremendous benefits in
terms of containment and improved safety profiles due to the
small quantities of active ingredients being manipulated at any
single point.2 We have previously exploited these advantages to
gain access to a variety of pharmaceutically important hetero-
cyclic building blocks such as oxazoles,3 triazoles,4 pyrazoles,5
guanidines,6 imidazoles and thiazoles7 as well as using flow tech-
niques in the construction of more architecturally complex natural
products via multi-step sequences.8 Many of the transformations
required the handling of potentially hazardous, highly sensitive or
reactive intermediates under controlled and highly reproducible
conditions. Consequently, the improved safety features derived
from working in a flow mode coupled with the ability to
continuously process material enabling a time-dependent scale-up
is ideally suited to many of the previously ‘forbidden’ chemistries
such as the Curtius rearrangement. For this reason we have
aInnovative Technology Centre, Department of Chemistry, University of
Cambridge, Lensfield Road, Cambridge, UK. E-mail: svl1000@cam.ac.uk;
Fax: +44 1223 336442; Tel: +44 1223 336398
bNeurology Lead Discovery Chemistry, Neurology CEDD, GlaxoSmithKline
R and D, New Frontiers Science Park (North), Third Avenue, Harlow, Essex,
CM19 5AW, UK
† We dedicate this publication to Professor Andrew B. Holmes, friend and
colleague, on the occasion of his 65th birthday.
Fig. 1 VapourTec R2 + and R4 combination flow reactor.
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Scheme 1 General scheme for the Curtius rearrangement of carboxylic acids under continuous flow conditions.
This systemas shownintegrates apumpingand reagentselection
module (R2+; top stage) with a four-channel air-circulated
heating component (R4; lower stage). In its current configuration,
the unit consists of a low pressure input selection valve for
routing either solvents or bulk stock solutions directly to the
two incorporated HPLC pumps. Two additional Rheodyne 6-
port-2-position switching valves are located on the top right of
the R2+ module and can each facilitate reagent or substrate
introduction to the flow lines through the control of individual
reagent loops. The independently governed flow streams are each
driven by a compact self-regulating Knauer K120 HPLC-pump
(operating under a constant 100 psi back-pressure imposed by a
static in-line regulator). Mixing of the streams occurs in a simple
T-piece and the combined flow path is directed into a convection
flow coil (CFC; made from various materials, poly(fluoroacetate)
(PFA) in this system), allowing precisely regulated heating profiles
up to 150 ◦C. A second exchangeable 100 psi back-pressure
regulator was coupled in-line subsequent to the CFC reactor to
allow superheating of the reaction mixture prior to it entering a
glass column11 packed with immobilised scavengers. The direct
collection of the purified product was then easily accomplished by
simply collecting the eluting reaction stream and evaporation of
the solvent. The collection process can be readily automated using
an attached UV-triggered liquid-handler unit.8b,10 Furthermore,
the entire flow process including all the reaction variables such
as flow rate (residence time), pressure and temperature are all
easily modified ‘on-the-fly’. These parameters can be adjusted
via the user interface or through software sequencing enabling
rapid reaction exploration, profiling and final optimisation. All
critical parameters are supervised by scrutiny algorithms enabling
constant safety monitoring by firmware or a linked PC. More
complex sequences of events such as array synthesis can be
achieved through multiple sequential injections of substrates.
Furthermore, the creation and timing of additional auxiliary
operations such as generating solvent washing cycles between
reactions is also readily automated, giving a seamless synthetic
routine.
found to be suitable for certain substrates. Furthermore, the
use of DPPA as the azide source allowed the convenient use of
Amberlyst 21 (A-21), an immobilised trimethylamine equivalent,
as a scavenger for the diphenylphosphonic acid formed in the
activation step as well as any unreacted carboxylic acid. Using the
solid-supported scavenger, A-21, in combination with Amberlyst
15 (sulfonic acid resin; A-15) as a mixed bed scavenger also made
it possible to remove the triethylamine base from the reaction
in a complementary manner. These two scavengers could be
placed either as a 1:1 mixture in a single pre-packed column, or
alternatively, in two separate sequential columns (Scheme 1).
In a general procedure a mixture of triethylamine (2 equiv.),
the appropriate nucleophile (1–3 equiv.) and the carboxylic acid
(1.1 equiv.) were loaded into channel 1 and DPPA (1 equiv.) into
channel 2 (both samples being prepared as solutions in acetonitrile
at 50–66.7 mM concentrations). The two reactant streams were
united using a simple T-mixing piece and the combined fluidic
output directed into a CFC reactor (10 mL volume). A total flow
rate of 0.2–0.5 mL min−1, equating to a reactor residence time
of 20–50 min at a temperature of 120 ◦C, was used to ensure
complete conversion. The resulting flow stream was then purified
by passage through a glass column packed with a mixture of A-21
and A-15 (1:1; 3.5 equiv. each) at ambient temperature. Removal
of the solvent using a Biotage V10 solvent evaporator12 enabled
direct isolation of a wide range of products in both high yield
(>75%) and excellent purity (>90% as determined by LC-MS and
1H-NMR; Fig. 2).
IR sampling studies demonstrated the rapid generation of the
acyl azide13 intermediate even at ambient temperature. However,
in order to effect the subsequent rearrangement step, elevated tem-
peratures were required. Under superheating conditions at 120 ◦C
a variety of benzoic acid derivatives were readily transformed to
their corresponding isocyanate products within a 20 min residence
time. Upon formation, these isocyanates were immediately trapped
by a variety of nucleophiles including alcohols, amines, oximes,
hydrazines and acyl hydrazides.
As indicated, a range of different nucleophiles were successfully
carried through the initial Curtius rearrangement before reacting
with the isocyanate, thereby giving direct access to a small
collection of readily deprotected amine motifs. Consequently,
we were pleased to observe the formation of Cbz- and Alloc-
protected anilines using the described flow procedure (Fig. 2 and
4). However, the synthesis of the Boc-protected aniline 7 (Fig. 2) by
the same approach was found to be more difficult, a fact we ascribe
to the decreased nucleophilicity of tert-butanol. To overcome
this issue, we made use of the previously described R2+ and
Our initial investigations showed that diphenylphosphoryl azide
(DPPA) in combination with 2 equiv. of triethylamine gave the
best results for the direct conversion of carboxylic acids. At
elevated temperatures the Curtius rearrangement product could
be formed and trapped with an in situ nucleophile, avoiding the
need for isolation of the reactive intermediates. The increased
solubility of many of the initially formed salts dictated the need
for a polar solvent; acetonitrile was found to be optimum but
other solvents such as chloroform, DMF and toluene were also
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Fig. 2 Curtius rearrangement products.
Fig. 4 Curtius rearrangement products derived from heterocyclic car-
boxylic acids.
Fig. 3 Mixed urea products.
R4 system and a PTFE-tubing reactor located within the cavity
of an Emrys-Optimiser microwave (Scheme 2).14 This microwave
device comprised of a simple multi-layered coil of perfluorinated
polymer tubing wound around a central Teflon core then housed
in the field of the microwave cavity.5,15 Connections to additional
components including the R2+ and R4 unit were easily achieved
through standard HPLC fittings. Microwave heating of this flow
coil at 120 ◦C gave the desired Boc-protected amine 7 within a
2 min residence time in excellent conversion. An in-line column
of A-21 was subsequently used to remove the phosphonic acid
residues and excess acid starting material. In this experiment, the
Scheme 2 Microwave and R2+ and R4 reactor set-up.
residual triethylamine was then removed along with the solvent
under reduced pressure to furnish the product in 89% yield.
The generation of the Fmoc-protected system 10 also required
a modification to the general procedure due to degradation of
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the Fmoc adduct in the presence of the triethylamine and A-21
bases. This problem was easily overcome by the direct substitution
of 2,6-lutidine for triethylamine and PS-2,6-di-tert-butylpyridine
for A-21;16 all other parameters were maintained as previously
described.
Interestingly, in the case of tert-butanol and other hindered
nucleophiles small quantities of the dimerized urea adduct were
observed (3–8%). Presumably, this occurs due to competitive
attack of the isocyanate by residual water followed by decarboxy-
lation and reaction with a second isocyanate. Indeed, attempts to
prepare the free amine products through the use of water as the
nucleophilic component led almost exclusively to the isolation of
the corresponding urea adducts. However, it was found that the
introduction of a short plug of anhydrous magnesium or sodium
sulfate in-line prior to the CFC reactor was sufficient to remove
traces of water in our standard reactions and eliminate these minor
urea side-products.
This observation inspired us to evaluate the potential for
the generation of mixed semicarbazide adducts using hydrazine-
derived nucleophiles. Such materials, although synthetically ex-
tremely useful, are notoriously difficult to handle because of their
limited solubilities in solvents such as MeCN.17 Our approach was
to therefore prepare these products making use of their insolu-
bility to aid in their isolation. In these examples, the hydrazido
nucleophile was placed in a collection flask at the output of the
reactor. The standard procedure was then followed to generate the
isocyanate rearranged product, which was subjected to the same
in-line purification using a mixture of A-21 and A-15. The reaction
stream was constantly fed into the collection flask containing
the awaiting nucleophile, which underwent rapid reaction to
furnish the semicarbazide. This product on forming immediately
precipitated, permitting facile isolation and purification by direct
filtration and drying of the solid product (Fig. 3).
To extend the originally described protocol further and enable
the use of additional heterocyclic carboxylic acid building blocks,
it was necessary to adapt the purification procedure. Certain
products (Fig. 4) could be selectively sequestered from the reaction
mixture directly onto the A-15 resin (5 equiv.) as they exited
the CFC reactor via a ‘catch and release’ protocol.18 A rapid
washing sequence ensured that only the ionically bound product
remained within the column. A relay selection valve then enabled
a secondary stream containing a solution of excess ammonia
in methanol to be eluted through the A-15 trapping column,
liberating the desired product. In certain cases a small plug of silica
gel was also used to remove a dark-coloured unknown impurity
from the reaction mixture, leading to significantly improved
purities (10–15% increase). Evaporation of the solvent along
with carried-through triethylamine then enabled isolation of the
product, again in high yields and excellent purities (Fig. 4).
Although in most cases we only carried out this chemistry on
a 1–5 mmol scale, we were able to very simply configure the
equipment to enable more continuous production of the desired
product, synthesising gram quantities of functionalised material.
We had previously demonstrated a small-scale preparation of ethyl
2-(pyridin-2-yl)quinolin-4-ylcarbamate 25 (Fig. 4; 85%) starting
from the corresponding carboxylic acid; however, we required
larger amounts for use in a ligand encapsulation study. This also
posed an interesting challenge, as in the scaled synthesis of the
carboxylic acid precursor we experienced significant difficulties in
its isolation. Alternatively, the corresponding sodium salt could
be readily attained and so was evaluated as a substitute starting
material for the Curtius rearrangement process. A small solvent
screen indicated that the salt was only suitably soluble in DMF
and short-chain alcohols. Neat ethanol was therefore chosen as
the solvent for channel one (52.5 mM solution of the salt). This
was possible as we had already determined empirically that the
Curtius rearrangement occurred faster than ethanol addition to
the intermediate acyl azide species. However, ethanol is known to
react slowly with DPPA, hence the DPPA reagent delivered from
the second channel was dissolved in MeCN (68 mM, 1.3 equiv.).
Since the starting material possesses two pyridine-like moieties
and was already the sodium salt, no triethylamine was required to
promote the reaction. The two channels were combined using a
standard T-mixing piece leading to four connected CFC reactors
◦
(40 mL total reactor volume) heated at 120 C with a total flow
rate of 2 mL min−1, equating to a 20 min residence time. The
isolation of the product was achieved using A-15 (45 g, 3 equiv.)
placed within a Kontes Chromaflex chromatography column.19
Following a washing sequence (1:1 MeCN–ethanol at 2 mL min−1
for 1 h) the desired product was released by flushing with 20%
triethylamine in methanol (400 mL at 5 mL min−1). In total, seven
5 g batches were prepared and run sequentially, affording over 25 g
of product with an average yield of 75%.
Conclusions
In conclusion, we have demonstrated the clean and safe handling
of hazardous compounds such as azides and acyl azides in the
Curtius rearrangement using a commercially available flow reactor
system from VapourTec. Using DPPA, we were able to generate a
small collection of carbamates, ureas, semicarbazides and related
compounds in high yields (75–95%) and excellent purities (>90%).
Purification was achieved by in-line scavenging of excess starting
materials and spent reagents using a combination of the readily
available low-cost scavenger resins A-15 and A-21. Furthermore,
we have successfully applied this methodology to the synthesis of
carbamate products on larger scales up to 25 g.
Experimental
Unless otherwise stated, reaction solutions were prepared in
1
MeCN in 20 mL glass vials. H-NMR spectra were recorded on
a Bruker Avance DPX-400, DRX-500 or DPX-600 spectrometer
with residual CHCl3, DMSO, MeCN or DCM as the internal
reference (CHCl3 dH = 7.26 ppm; DMSO dH = 2.50 ppm, MeCN
dH = 1.94 ppm; DCM dH = 5.32 ppm). 13C-NMR spectra were
also recorded in either CDCl3, DMSO, MeCN or DCM on the
same spectrometers with the central peak of the residual solvent
as the internal reference (dC = 77.0 ppm; DMSO dC = 39.5 ppm;
MeCN dC = 118.3; DCM dC = 53.8 ppm). COSY, DEPT 135,
HMQC, HMBC and NOESY spectroscopic techniques were used
to aid the assignment of signals in the 13C-NMR spectra. Infrared
spectra were recorded neat on a Perkin-Elmer Spectrum One
FT-IR spectrometer. Letters in the parentheses refer to relative
absorbency of the peak: w, weak, <40% of the main peak; m,
medium, 41–74% of the main peak; s, strong, >74% of the
main peak. LC-MS analysis was performed on an Agilent HP
1100 chromatograph (Luna Max RP column) attached to an
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Table 1 LC-MS conditions
based carbamate. Following evaporation of solvents the desired
product isopropyl-3-chloropyridin-4-ylcarbamate was obtained as
white solid (184 mg, 0.86 mmol; 86%).
Time/min
MeCN (%)
Flow rate/mL min−1
0.00
3.00
5.00
5.50
8.00
5
95
95
5
1
1
1
1
1
(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl-3-methoxyphenyl
carbamate (1). Flow rate: 0.2 mL min−1, yield: 75%, purity: 97%,
Rt = 5.38 min, M + H m/z = 306.4. 1H-NMR (500 MHz, CDCl3):
d/ppm 7.14–7.20 (2H, m), 6.83 (1H, d, J = 8.0 Hz), 6.60 (1H, d,
J = 8.0 Hz), 6.54 (1H, s), 4.64 (1H, td, J = 18.9 Hz, 4.4 Hz),
3.79 (3H, s), 2.08–2.16 (1H, m), 1.96 (1H, m), 1.62–1.72 (2H,
m), 1.45–1.55 (1H, m), 1.36 (1H, tt, J = 11.6, 3.0 Hz), 0.95–
1.13 (2H, m), 0.82–0.92 (7H, m), 0.80 (3H, d, J = 7.0 Hz), 13C-
NMR (125 MHz, CDCl3): d/ppm 160.3 (C), 153.2 (C), 139.4 (C),
129.7 (CH), 110.5 (CH), 109.1 (CH), 103.9 (CH), 75.1 (CH),
55.2 (CH3), 47.3 (CH), 41.3 (CH2), 34.2 (CH2), 31.4 (CH),
26.2 (CH), 23.5 (CH2), 22.0 (CH3), 20.8 (CH3), 16.4 (CH3). IR:
m 3320.3 (w), 2953.5 (m), 2926.2 (m), 2868.9 (m), 1695.1 (s),
1599.3 (s), 1539.7 (s), 1496.4 (s), 1455.6 (s), 1428.4 (s), 1283.9 (s),
1264.3 (s), 1222.7 (s), 1179.0 (m), 1161.0 (m), 1041.0 (s), 852.3 (m),
767.2 (s), 688.1 (m) cm−1. HRMS calculated for C18H28NO3
306.2069, found 306.2078.
5
HPLC/MSD mass spectrometer. Elution was carried out using
a reversed-phase gradient of MeCN–water with both solvents
containing 0.1% formic acid. The gradient is described in Table 1.
For HRMS a LCT Premier Micromass spectrometer was used.
General procedures
One-pot procedure. A solution of 2-bromo-5-methoxybenzoic
acid (230 mg; 1 mmol), triethylamine (280 lL; 2 mmol), DPPA
(215 lL; 1 mmol) and ethanol (100 lL; 2.8 mmol) was prepared
in MeCN (15 mL). The reaction mixture was pumped using the
described R2+ and R4 flow system at a flow rate of 0.5 mL min−1
through a 10 mL PFA CFC heated at 120 ◦C. After exiting the
CFC this flow stream was passed through a single Omnifit glass
column (10 mm i.d. by 150 mm length) filled with A-15 (3 g) and
A-21 (3 g) as scavengers at ambient temperature. Evaporation
of the solvent furnished the desired product ethyl-2-bromo-5-
methoxyphenylcarbamate as a white crystalline solid (229 mg,
0.84 mmol, 84%).
Propan-2-one-O-2-bromophenyl carbamoyl oxime (2). Flow
rate: 0.4 mL min−1, yield: 88%, purity: 98%, Rt = 4.42 min, M +
Na m/z = 293.2. 1H-NMR (400 MHz, CDCl3): d/ppm 8.95 (1H,
s), 8.26 (1H, d, J = 8.0 Hz), 7.54 (1H, d, J = 8.0 Hz), 7.34 (1H,
t, J = 8.0 Hz), 6.96 (1H, t, J = 8.0 Hz), 2.11 (3H, s), 2.08 (3H,
s), 13C-NMR (100 MHz, CDCl3): d/ppm 162.1 (C), 152.5 (C),
135.8 (C), 132.7 (CH), 128.8 (CH), 125.2 (CH), 120.7 (CH),
113.9 (C), 22.4 (CH3), 17.4 (CH3). IR: m 3291.6 (m), 3078.2 (w),
2994.3 (w), 1736.6 (s), 1590.1 (s), 1575.4 (m), 1520.7 (s), 1427.2 (s),
1373.6 (s), 1305.2 (m), 1279.1 (m), 1234.1 (m), 1047.0 (m),
1025.9 (s), 1005.8 (s), 898.6 (s), 837.7 (m), 766.2 (s), 745.1 (s),
655.7 (s) cm−1. HRMS calculated for C10H11N2O2NaBr 292.9902,
found: 292.9903.
Two-pot procedure. A solution of 2-(4-isobutylphenyl)pro-
panoic acid (227 mg; 1.1 mmol), triethylamine (280 lL; 2 mmol)
and allyl alcohol (150 lL; 3.0 mmol) was prepared in MeCN
(10 mL). The solution (channel 1) was mixed via the R2+ and R4
flow system with a second stream (channel 2) containing DPPA
(215 lL; 1 mmol) in MeCN (10 mL) using a T-mixing piece before
the combined streams (individual flow rates 0.25 mL min−1 each)
◦
were directed into a 10 mL CFC heated at 120 C. The solution
(E)-Allyl-3,4-dimethoxystyryl carbamate (3). Flow rate:
0.2 mL min−1, yield: 85%, purity: 94%, Rt = 4.29 min, M + H
m/z = 263.3. 1H-NMR (400 MHz, CDCl3): d/ppm 7.10 (1H, m),
6.75–6.83 (3H, m), 6.70 (1H, s), 5.87–6.00 (2H, m), 5.34 (1H, d,
J = 16.8 Hz), 5.25 (1H, d, J = 10.0 Hz), 4.65 (2H, d, J = 4.4 Hz),
3.87 (3H, s), 3.85 (3H, s), 13C-NMR (100 MHz, CDCl3): d/ppm
153.4 (C), 149.2 (C), 148.0 (C), 129.2 (C), 122.5 (CH), 121.4 (CH),
118.3 (CH2+CH), 111.5 (CH), 110.9 (CH), 107.9 (CH), 66.2 (CH2),
55.9 (CH3), 55.8 (CH3). IR: m 3316.8 (w), 2935.5 (w), 2835.3 (w),
1706.7 (s), 1661.2 (s), 1585.4 (m), 1508.4 (s), 1464.1 (m), 1259.6 (s),
1224.3 (s), 1139.8 (m), 1054.3 (m), 1027.1 (m), 945.8 (m), 856.7 (m),
802.1 (m), 764.8 (m) cm−1. HRMS calculated for C14H18NO4
264.1236, found 264.1235.
was then passed through a single Omnifit glass column (10 mm
i.d. by 150 mm length) filled with A-15 (3 g) and A-21 (3 g) as
scavengers at ambient temperature. The desired product (allyl-1-
(4-isobutylphenyl)ethylcarbamate) was obtained as a colourless
oil (219 mg, 0.84 mmol, 84%) after evaporation of the solvent.
Catch and release procedure. A solution of 3-chloroisoni-
cotinic acid (173 mg; 1.1 mmol), triethylamine (280 lL; 6 mmol)
and isopropanol (200 lL; 4.2 mmol) was prepared in MeCN
(15 mL) (channel 1). A second solution containing DPPA (215 lL;
1 mmol) in MeCN (15 mL) (channel 2) was combined with
the first (individual flow rates 0.25 mL min−1 each) using the
R2+ and R4 flow system. The united flow stream was directed
into a 10 mL CFC heated at 120 ◦C. After exiting the CFC
reactor the reaction mixture passed firstly through an Omnifit
glass column (10 mm i.d. by 150 mm length) filled with A-
21 scavenger (3 g) to remove excess starting material as well
as the diphenylphosphonic acid by-product. The solution then
entered a second similar Omnifit glass column filled with A-15
(3 g) in order to catch the pyridyl-derived product at ambient
temperature. This second Omnifit glass column was then washed
with MeCN (10 mL) to remove any unbound material then eluted
with a solution of ammonia in methanol (1.5 mL, 2 M solution)
dissolved in MeCN (8.5 mL) to release the sequestered pyridyl-
Ethyl-2-biphenyl carbamate (4)20. Flow rate: 0.4 mL min−1,
yield: 77%, purity: 93%, Rt = 4.65 min, M + H m/z = 242.3. 1H-
NMR (400 MHz, CDCl3): d/ppm 8.16 (1H, d, J = 8.0 Hz), 7.33–
7.53 (6H, m), 7.22 (1H, d, J = 8.0 Hz), 7.13 (1H, t, J = 8.0 Hz),
6.63 (1H, s), 4.18 (2H, q, J = 7.6 Hz), 1.26 (3H, t, J = 7.6 Hz), 13C-
NMR (100 MHz, CDCl3): d/ppm 154.0 (C), 138.6 (C), 135.4 (C),
130.5 (CH), 130.2 (C), 129.7 (2CH), 129.5 (2CH), 128.9 (CH),
128.3 (CH), 123.7 (CH), 120.1 (CH), 61.6 (CH2), 14.9 (CH3).
IR: m 3424.7 (w), 3059.3 (w), 2981.7 (w), 1731.6 (s), 1585.2 (m),
1516.1 (s), 1493.8 (s), 1447.3 (s), 1302.9 (m), 1203.6 (s), 1063.1 (s),
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1046.7 (s), 952.0 (m), 745.1 (s), 701.9 (s). HRMS calculated for
C15H15NO2Na 264.1000, found 264.1000.
Ethyl-2-bromo-5-methoxyphenyl carbamate (9)22. Flow rate:
0.5 mL min−1, yield: 84%, purity: 99%, Rt = 4.54 min, M + H
1
m/z = 273.3. H-NMR (400 MHz, CDCl3): d/ppm 7.82 (1H,
Allyl-1-(4-isobutylphenyl)ethyl carbamate (5). Flow rate:
0.5 mL min−1, yield: 84%, purity: 93%, Rt = 4.99 min, M + H
m/z = 262.4. 1H-NMR (400 MHz, d6-DMSO): d/ppm 7.67 (1H,
d, J = 7.6 Hz), 7.19 (2H, d, J = 8.4 Hz), 7.07 (2H, d, J = 8.4 Hz),
5.80–5.95 (1H, m), 5.25 (1H, d, J = 17.2 Hz), 5.14 (1H, d, J =
10.8 Hz), 4.62 (1H, quin., J = 3.6 Hz), 4.37–4.50 (2H, m), 2.39
(2H, d, J = 6.8 Hz), 1.80 (1H, sept., J = 6.8 Hz), 1.34 (3H, m),
0.84 (6H, d, J = 8.0 Hz), 13C-NMR (100 MHz, CDCl3): d/ppm
155.4 (C), 141.0 (C), 132.9 (CH), 129.8 (CH), 129.3 (2CH), 125.7
(2CH), 120.1 (CH), 117.6 (C), 65.5 (CH2), 50.3 (CH), 45.0 (CH2),
30.2 (CH3), 22.3 (2CH3). IR: m 3310.1 (m), 2954.2 (m), 2927.5 (m),
2868.8 (m), 1699.8 (s), 1513.7 (s), 1452.5 (m), 1243.3 (s), 1058.0 (s),
929.4 (m), 846.6 (m), 800.2 (m), 777.7 (m) cm−1. HRMS calculated
for C16H24NO2 262.1807, found: 262.1799.
s), 7.31 (1H, d, J = 8.8 Hz), 7.09 (1H, s), 6.47 (1H, d, J =
8.8 Hz), 4.21 (2H, q, J = 7.2 Hz), 3.76 (3H, s), 1.31 (3H, t, J =
7.2Hz), 13C-NMR (100 MHz, CDCl3): d/ppm 160.1 (C), 153.3(C),
137.0 (C), 132.7 (CH), 111.1 (CH), 105.7 (CH), 103.1 (C), 61.9
(CH2), 55.8 (CH3), 14.8 (CH3). IR: m 3389.0 (m), 3108.3 (w),
2984.7 (w), 2915.7 (w), 2839.6 (w), 1732.5 (s), 1584.6 (s),
1523.6 (s), 1455.1 (m), 1426.7 (m), 1307.6 (m), 1284.7 (m),
1238.9 (s), 1204.9 (s), 1177.7 (s), 1112.7 (m), 1070.1 (m), 1042.3 (s),
1015.9 (m), 866.7 (s), 788.5 (s), 760.1 (s) cm−1. HRMS calculated
for C10H13NO3Br 274.0079, found: 274.0066. X-Ray Data: File
reference CCDC 675720, Formula: C10H12Br1N1O3; Unit cell
parameters: a 4.45490(10), b 11.1152(2), c 21.9618(4), a 90.00,
b 90.00, c 90.00; space group P212121.
Ethyl-3,4-dimethoxybenzyl carbamate (6)21. Flow rate:
0.4 mL min−1, yield: 91%, purity: 98%, Rt = 3.88 min, M + H
m/z = 239.3. 1H-NMR (400 MHz, d3-MeCN): d/ppm 6.79–6.88
(3H, m), 5.92 (1H, s), 4.19 (2H, d, J = 6.0 Hz), 4.06 (2H,
q, J = 6.8 Hz), 3.78 (3H, s), 3.77 (3H, s), 1.20 (3H, t, J =
6.8 Hz), 13C-NMR (100 MHz, d3-MeCN): d/ppm 156.4 (C),
148.9 (C), 148.1 (C), 132.1 (C), 119.1 (CH), 111.4 (CH),
110.9 (CH), 60.0 (CH2), 55.1 (CH3), 55.0 (CH3), 43.7 (CH2),
13.8 (CH3). IR: m 3346.4 (m), 2970.9 (w), 2934.8 (w), 2839.8 (w),
1686.1 (s), 1593.0 (m), 1534.0 (m), 1516.6 (s), 1481.0 (m),
1469.1 (m), 1448.6 (m), 1431.8 (m), 1418.9 (m), 1370.9 (m),
1337.0 (m), 1292.6 (m), 1231.1 (s), 1189.7 (m), 1132.4 (s),
1043.7 (m), 1021.2 (s), 925.8 (m), 806.7 (s), 767.3 (m), 737.1 (m),
717.9 (m) cm−1. HRMS calculated for C12H18NO4 240.1236,
found: 240.1232.
(9H-Fluoren-9-yl)methyl 2-bromo-5-(methoxyphenyl)carbamate
(10). Flow rate: 0.3 mL min−1, yield: 87%, purity: 97%, Rt =
1
5.68 min, M + Na m/z 446.2. H-NMR (600 MHz, d2-DCM):
d/ppm 7.83 (2H, d, J = 7.8 Hz), 7.68 (2H, d, J = 7.8 Hz),
7.42–7.46 (3H, m), 7.37 (2H, t, J = 7.8 Hz), 7.30 (1H, d, J =
9.0 Hz), 7.22 (1H, s), 6.57 (1H, dd, J = 9.0, 3.0 Hz), 4.51 (2H,
d, J = 7.8 Hz), 4.35 (1H, t, J = 7.8 Hz), 3.81 (3H, s), 13C-
NMR (150 MHz, d2-DCM): d/ppm 159.8 (C), 152.9 (C), 143.7
(2C), 141.3 (2C), 136.5 (C), 132.4 (CH), 130.0 (C), 127.8 (2CH),
127.1 (2CH), 125.0 (2CH), 120.2 (CH), 120.0 (2CH), 110.6 (CH),
67.4 (CH2), 55.5 (CH3), 47.0 (CH). IR: m 3404.2 (w), 2952.2 (w),
2169.0 (m), 1736.6 (s), 1587.4 (s), 1520.9 (s), 1488.2 (m), 1452.1 (s),
1429.4 (m), 1304.1 (m), 1284.0 (m), 1244.6 (m), 1206.0 (s),
1182.2 (s), 1076.3 (m), 1045.3 (s), 1018.1 (m), 962.8 (s), 852.5 (m),
786.6 (m), 757.9 (s), 739.9 (s), 688.6 (m) cm−1. HRMS calculated
for C22H19NO3Br 424.0548, found: 424.0549.
tert-Butyl-4-butoxyphenyl carbamate (7). Flow rate: 0.3 mL
min−1, yield: 89%, purity: 96%, Rt = 5.1 min, M m/z = 210.3
(carbamic acid). 1H-NMR (400 MHz, CD2Cl2): d/ppm 7.25 (2H,
d, J = 8.8 Hz), 6.83 (2H, d, J = 8.8 Hz), 6.44 (1H, s), 3.93 (2H,
t, J = 6.8 Hz), 1.76 (2H, quin., J = 6.8 Hz), 1.45–1.55 (11H,
m), 0.98 (3H, t, 6.8 Hz), 13C-NMR (125 MHz, CD2Cl2): d/ppm
155.5 (C), 153.3 (C), 131.7 (C), 120.6 (2CH), 114.9 (2CH), 80.2 (C),
68.2 (CH2), 31.6 (CH2), 28.3 (3CH3), 19.5 (CH2), 13.9 (CH3).
IR: m 3361.6 (m), 2934.7 (m), 2871.1 (w), 1698.6 (s), 1598.0 (w),
1527.0 (s), 1413.7 (m), 1316.2 (w), 1250.4 (s), 1172.7 (s), 1056.2 (m),
1011.5 (m), 829.7 (m), 739.6 (w) cm −1. HRMS calculated for
C15H23NO3Na 288.1576, found 288.1589.
1-Allyl-3(1-(3-fluorophenyl)cyclopentyl)urea (11). Flow rate:
0.4 mL min−1, yield: 89%, Rt = 5.87 min, purity: 97%, M + H
m/z = 263.4. 1H-NMR (600 MHz, CDCl3): d/ppm 7.22 (1H, m),
7.13 (1H, d, J = 8.0 Hz), 7.07 (1H, d, J = 8.0 Hz), 6.85 (1H, t,
J = 8.0 Hz), 5.83 (1H, br. s), 5.64–5-73 (1H, ddt, J = 17.2, 10.0,
5.2 Hz), 5.15 (1H, br. s), 4.99 (1H, ddt, J = 17.2, 1.6, 1.6 Hz),
4.96 (1H, m), 3.59 (2H, t, J = 5.4 Hz), 2.05–2.12 (2H, m), 1.87–
1.97 (2H, m), 1.70–1.80 (4H, m), 13C-NMR (150 MHz, CDCl3):
d/ppm 162.9 (C, JC-F = 243 Hz), 157.9 (C), 149.4 (C), 135.5 (CH),
129.5 (CH), 121.1 (CH), 114.7 (CH2), 113.2 (CH, J = 22 Hz), 112.8
(CH, J = 22 Hz), 65.4 (C), 42.3 (CH2), 40.3 (2CH2), 23.4 (2CH2).
IR: m 3317.4 (m), 2957.1 (w), 1682.4 (w), 1630.3 (s), 1614.4 (s),
1588.0 (s), 1558.8 (s), 1489.2 (s), 1438.0 (s), 1257.1 (s), 989.4 (m),
912.9 (m), 868.9 (m), 775.1 (s), 689.9 (s) cm−1. HRMS calculated
for C15H20N2OF 263.1560, found 263.1573.
Allyl-4-nitrophenyl carbamate (8). Flow rate: 0.5 mL min−1,
yield: 89%, purity: 91%, Rt = 4.38 min, M − H m/z = 221.2.
1H-NMR (400 MHz, d3-MeCN): d/ppm 8.28 (1H, s), 8.15 (2H,
d, J = 9.2 Hz), 7.63 (2H, d, J = 9.2 Hz), 5.97 (1H, ddt, J = 17.3,
10.2, 5.8 Hz), 5.39 (1H, ddt, J = 17.2, 1.6, 1.6 Hz), 5.30 (1H,
ddt, J = 10.8, 1.6, 1.6 Hz), 4.66 (2H, d, J = 5.6 Hz), 13C-NMR
(100 MHz, d3-MeCN): d/ppm 152.7 (C), 144.9 (C), 132.4 (CH),
130.3 (C), 124.6 (2CH), 117.4 (2CH), 117.0 (CH2), 65.4 (CH2).
IR: m 3376.9 (s), 3113.1 (w), 3090.0 (w), 2949.9 (w), 1732.9 (s),
1685.9 (m), 1613.3 (m), 1596.7 (m), 1546.6 (s), 1508.2 (s),
1493.7 (s), 1412.1 (m), 1321.6 (s), 1305.3 (s), 1245.2 (m), 1206.2 (s),
1110.8 (s), 1056.9 (s), 1001.5 (m), 937.5 (s), 852.2 (s), 765.0 (s),
748.2 (s), 711.4 (m), 691.4 (m), 673.7 (m) cm−1. HRMS calculated
for C10H9N2O4 221.0567, found: 221.0562.
Methylpent-4-en-2-yl carbamate (12)23. Flow rate: 0.2 mL
min−1, yield: 73%, purity: 96%, Rt = 4.42 min. 1H-NMR
(400 MHz, CDCl3): d/ppm 5.70–5.80 (1H, m), 5.04–5.09 (2H,
m), 4.63 (1H, s), 3.77 (1H, m), 3.63 (3H, s), 2.17–2.22 (2H,
m), 1.12–1.15 (3H, m), 13C-NMR (100 MHz, CDCl3): d/ppm
156.3 (C), 134.2 (CH), 117.9 (CH2), 51.8 (CH), 46.4 (CH3), 41.1
(CH2), 20.5 (CH3). IR: m 3319.0 (m), 3076.0 (w), 2971.8 (m),
1698.5 (s), 1598.1 (w), 1533.6 (s), 1454.5 (m), 1336.4 (m), 1257.7 (s),
1226.2 (m), 1192.1 (m), 1104.3 (m), 1070.1 (m), 963.1 (m),
1582 | Org. Biomol. Chem., 2008, 6, 1577–1586
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916.5 (m), 779.2 (m) cm−1. HRMS calculated for C7H13NO2Na
166.0839, found: 166.0838.
743.4 (s) cm−1. HRMS calculated for C14H13BrF3N4O 389.0225,
found: 389.0229.
Ethyl-5-methyl-2-(trifluoromethyl)furan-3-yl carbamate (13).
4-(4-Methoxyphenyl)-1-hexyl semicarbazide (17). Flow rate:
0.4 mL min−1, yield: 88%, purity: 97%, Rt = 3.70 min, M +
Flow rate: 0.4 mL min−1, yield: 86%, purity: 98%, Rt = 4.46 min, M
1
1
m/z = 166.2 (amine). H-NMR (400 MHz, d3-MeCN): d/ppm
H m/z 308.2; H-NMR (600 MHz, d6-DMSO) d/ppm 9.53 (1
7.26 (1H, s), 6.63 (1H, s), 4.16 (2H, q, J = 7.2 Hz), 2.28 (3H, s),
1.26 (3H, t, J = 7.2 Hz), 13C-NMR (125 MHz, CDCl3): d/ppm
154.3 (C), 153.0 (C), 127.7 (C), 120.4 (CF3, q, J = 264.0 Hz),
120.0 (C, q, J = 5.0 Hz), 103.2 (CH), 61.8 (CH2), 14.3 (CH3),
13.6 (CH3). IR: m 3288.7 (m), 2997.5 (w), 1696.9 (s), 1654.4 (s),
1579.1 (m), 1519.2 (m), 1479.1 (m), 1458.9 (m), 1431.0 (m),
1310.0 (s), 1255.9 (s), 1176.1 (s), 1149.9 (s), 1101.1 (s), 1009.9 (s),
958.8 (s), 906.9 (w), 800.9 (s), 774.9 (s), 729.4 (s), 688.1 (m) cm−1.
HRMS calculated for C9H10NO3NaF3 260.0508, found 260.0505.
H, br. s, NH), 8.46 (1 H, br. s, NH), 7.87 (1 H, br. s, NH),
7.32 (2 H, d, J = 8.3 Hz), 6.82 (2 H, d, J = 8.3 Hz), 3.68
(3 H, s, OMe), 2.11 (2 H, t, J = 7.4 Hz), 1.52 (2 H, m), 1.13
(8 H, m), 0.84 (3 H, t, J = 7.2 Hz),13C-NMR (150 MHz; d6-
DMSO) d/ppm 172.58 (C), 156.0 (C), 154.8 (C), 133.1 (C),
120.6 (CH), 114.2 (CH), 55.5 (CH3), 33.57(CH2), 31.54(CH2),
28.95(CH2), 28.83(CH2), 25.3 (CH2), 22.4 (CH2), 14.3 (CH3).
IR: m 3344.4 (m), 3221.0 (m), 3040.5 (m), 1654.7 (s), 1584.8 (s),
1561.5 (s), 1510.7 (s), 1458.1 (s), 1395.2 (s), 1307.9 (m), 1108.3 (m),
1073.6 (s), 1065.6 (m), 1039.5 (m), 900.1 (s), 873.6 (s), 697.6
(s) cm−1. HRMS calculated for C15H23N3O3 293.1739, found
293.1741.
4-(2-Bromophenyl)-1-(4-chlorbenzoyl)semicarbazide
(14).
Flow rate: 0.4 mL min−1, yield: 82%, purity: 98%, Rt =
4.28 min, M + H m/z = 370.2. 1H-NMR (400 MHz, d6-DMSO):
d/ppm 10.52 (1H, s), 9.07 (1H, s), 8.23 (1H, s), 8.00 (1H, d,
J = 7.6 Hz), 7.93 (2H, d, J = 8.0 Hz), 7.50–7.60 (3H, m),
7.30 (1H, t, J = 7.6 Hz), 6.95 (1H, t, J = 7.6 Hz), 13C-NMR
(100 MHz, d6-DMSO): d/ppm 165.8 (C), 155.5 (C), 137.3 (C),
137.1 (C), 132.8 (CH), 131.5 (C), 129.8 (2CH), 129.0 (2CH),
128.5 (CH), 124.6 (CH), 122.4 (CH), 113.6 (C). IR: m 3262.3 (m),
3213.0 (m), 3022.4 (m), 1666.1 (s), 1649.0 (s), 1584.4 (s),
1566.8 (s), 1544.6 (s), 1524.4 (s), 1438.2 (s), 1335.7 (s), 1290.7 (m),
1248.1 (m), 1231.1 (m), 1178.3 (m), 1091.9 (s), 1043.6 (m),
1025.8 (m), 1009.8 (m), 911.9 (s), 842.2 (s), 742.0 (s), 734.7 (s),
667.6 (s) cm−1. HRMS calculated for C14H12N3O2ClBr 367.9801,
found: 367.9797.
Ethyl-{4[(1,1-dioxido-4-thiomorpholinyl)methyl]phenyl}carba-
mate (18). Flow rate: 0.3 mL min−1, yield: 95%, purity: 94%, Rt =
1
3.21 min, M + Na m/z = 335.3. H-NMR (400 MHz, CDCl3):
d/ppm 7.34 (2H, d, J = 8.0 Hz), 7.18 (2H, d, J = 8.0 Hz), 7.12
(1H, s), 4.18 (2H, q, J = 7.2 Hz), 3.55 (2H, s), 3.00 (4H, t, J =
4.8 Hz), 2.91 (4H, t, J = 4.8 Hz), 1.26 (3H, t, J = 7.2 Hz), 13C-
NMR (100 MHz, CDCl3): d/ppm 154.0 (C), 138.0 (C), 132.5 (C),
129.9 (2CH), 119.2 (2CH), 61.7 (CH2), 61.4 (CH2), 51.9 (2CH2),
50.9 (2CH2), 14.9 (CH3). IR: m 3342.3 (m), 2984.3 (w), 2821.8 (w),
1719.1 (s), 1599.1 (s), 1538.8 (s), 1316.4 (m), 1287.9 (s), 1266.9 (s),
1223.3 (s), 1115.1 (s), 1070.2 (s), 947.8 (m), 835.5 (m), 768.8 (m),
672.4 (m) cm−1. HRMS calculated for C14H21N2O4S 313.1222,
found 313.1223.
4-(3-Nitro-4-fluorophenyl)-1-(3-methoxybenzoyl)semicarbazide
(15). Flow rate: 0.4 mL min−1, yield: 93%, purity: 98%, Rt =
2.73 min, M + H m/z 315.1;1H-NMR (400 MHz, d6-DMSO):
d/ppm 10.29 (1 H, br. s, NH), 9.34 (1 H, br. s, NH), 8.50 (1 H, br. s,
NH), 8.40 (1 H, dd, J = 6.8, 2.7 Hz), 7.84 (1 H, m), 7.51–7.47 (3
H, m), 7.45 (1 H, t, J = 7.9 Hz), 7.14 (1 H, m), 3.81 (3 H, s, OMe);
13C-NMR (100 MHz; d6-DMSO) d/ppm 166.6 (C), 159.55 (C),
148.7 (C), 137.15 (C), 137.1 (C), 136.7 (C), 134.3 (C), 129.9 (CH),
120.2 (CH), 119.0 (CH), 118.8 (CH), 118.1 (CH), 115.2 (CH),
113.1 (CH), 55.7 (CH3). IR: m 3272.2 (m), 3215.1 (m), 3032.3 (m),
1684.2 (s), 1670.1 (s), 1555.5 (s), 1519.7 (s), 1503.4 (s), 1454.9 (s),
1436.8 (s), 1288.0 (m), 1260.1 (m), 1240.7 (m), 1188.2 (m),
1101.4 (s), 1077.4 (m), 951.4 (s), 863.1 (s), 782.3 (s), 772.9 (s) cm−1.
HRMS calculated for C15H13FN4O5 348.0870, found 348.0877.
Isopropyl-3-chloropyridin-4-yl carbamate (19). Flow rate:
0.4 mL min−1, yield: 86%, purity: 97%, Rt = 3.0 min, M + H
1
m/z = 215.2. H-NMR (400 MHz, CDCl3): d/ppm 8.45 (1H,
s), 8.35 (1H, d, J = 6.4 Hz), 8.14 (1H, d, J = 6.4 Hz), 7.27
(1H, s), 5.05 (1H, sept., J = 6.0 Hz), 1.31 (6H, d, J = 8.0 Hz),
13C-NMR (125 MHz, CDCl3): d/ppm 152.0 (C), 148.9 (2CH),
141.9 (C), 118.8 (C), 112.7 (CH), 70.1 (CH), 21.9 (2CH3). IR:
m 3176.9 (w), 3128.8 (w), 3015.3 (w), 2925.7 (w), 1736.2 (w),
1695.5 (s), 1576.7 (s), 1507.7 (s), 1398.2 (s), 1306.0 (s), 1272.8 (m),
1250.2 (s), 1214.4 (m), 1183.3 (m), 1136.7 (m), 1103.0 (s),
1087.5 (m), 1041.1 (s), 827.9 (m), 715.5 (s), 669.8 (m) cm−1. HRMS
calculated for C9H12N2O2Cl 215.0587, found: 215.0582. X-Ray
Data: File reference: CCDC 675721; Formula: C9H11Cl1N2O2;
Unit cell parameters: a 5.8684(2), b 13.1218(5), c 12.8548(5), a
90.00, b 97.008(2), c 90.00; space group P21/c.
4-(2-Bromophenyl)-1-(6-methyl-4-(trifluoromethyl)picolinoyl)-
semicarbazide (16). Flow rate: 0.5 mL min−1, yield: 91%, purity:
99%, Rt = 4.47 min, M + H m/z = 391.2. 1H-NMR (400 MHz,
d6-DMSO): d/ppm 8.89 (1H, s), 8.84 (1H, s), 8.26 (1H, s), 7.97
(1H, d, J = 7.6 Hz), 7.57 (1H, d, J = 7.6 Hz), 7.31 (1H,
t, J = 7.6 Hz), 6.96 (1H, t, J = 7.6 Hz), 6.91 (1H, s), 6.70
(1H, s), 2.40 (s, 3H), 13C-NMR (125 MHz, d6-DMSO): d/ppm
160.6 (C), 158.9 (C), 155.7 (C), 138.6 (C, q, J = 32 Hz), 136.9 (C),
132.5 (CH), 128.2 (CH), 124.5 (CH), 123.3 (C, q, J = 272 Hz),
122.4 (CH), 114.0 (C), 109.1 (CH), 98.8 (CH), 23.9 (CH3). IR:
m 3315.1 (w), 3226.6 (w), 3038.3 (w), 2983.6 (w), 1653.7 (s),
1586.3 (s), 1553.6 (s), 1513.2 (m), 1455.5 (s), 1438.4 (s), 1404.9 (s),
1386.9 (m), 1363.0 (m), 1281.3 (s), 1242.5 (m), 1169.5 (s),
1127.7 (s), 1119.8 (s), 1101.5 (m), 1026.3 (m), 861.1 (m), 842.6 (m),
1,1-Diethyl-3-(1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthy-
ridin-3-yl)urea (20). Flow rate: 0.3 mL min−1, yield: 75%, purity:
99%, Rt = 4.16 min, M + Na m/z = 325.36. 1H-NMR (400 MHz,
CDCl3): d/ppm 9.01 (1H, s), 8.53 (1H, d, J = 8.0 Hz), 7.70
(1H, s), 7.10 (1H, d, J = 8.0 Hz), 4.47 (2H, q, J = 7.2 Hz),
3.39 (4H, q, J = 7.2 Hz), 2.61 (3H, s), 1.41 (3H, t, J = 7.2 Hz),
1.23 (6H, t, J = 7.2 Hz), 13C-NMR (100 MHz, CDCl3): d/ppm
170.7 (C), 162.4 (C), 155.0 (C), 146.6 (C), 135.9 (CH), 129.1 (CH),
125.2 (C), 119.5 (CH), 116.0 (C), 46.4 (CH2), 42.1 (2CH2), 25.7
(CH3), 15.5 (CH3), 14.2 (2CH3). IR: m 3362.5 (w), 3097.9 (w),
2982.6 (w), 2931.4 (w), 1651.7 (m), 1625.8 (m), 1581.3 (s),
1531.5 (m), 1488.3 (s), 1434.7 (s), 1360.1 (m), 1296.4 (m),
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1243.0 (s), 1161.9 (m), 1127.4 (m), 1083.1 (m), 1053.5 (m),
928.0 (m), 893.1 (m), 781.6 (s), 753.4 (m), 682.1 (m) cm−1. HRMS
calculated for C16H23N4O2 303.1821, found: 303.1821.
810.1 (m), 767.7 (m), 734.3 (m), 671.5 (m) cm−1. HRMS calculated
for C15H22N3O2 276.1712, found: 276.1716. File reference: CCDC
675583; Formula: C15H21N3O2; Unit cell parameters: a 6.1269(1), b
38.152(1), c 6.9750(3), a 90.00, b 114.441(3), c 90.00; space group
P21/n.
Ethylpyrazolo[1,5-a]pyrimidin-3-yl carbamate (21). Flow rate:
0.4 mL min−1, yield: 78%, purity: 94%, Rt = 2.60 min, M +
H m/z = 207.2. 1H-NMR (500 MHz, CDCl3): d/ppm 8.54
(1H, dd, J = 7.1, 1.7 Hz), 8.51 (1H, br s), 8.33 (1H, br
d, J = 2.5 Hz), 7.02 (1H, br s), 6.74 (1H, dd, J = 7.1,
4.0 Hz), 4.26 (2H, q, J = 7.0 Hz), 1.31 (3H, t, J = 7.0 Hz),
13C-NMR (125 MHz, CDCl3): d/ppm 154.3 (C), 147.3 (CH),
138.4 (C), 136.9 (CH), 134.8 (CH), 110.8 (C), 107.7 (CH), 61.6
(CH2), 14.5 (CH3). IR: m 3238.9 (m), 3212.8 (m), 3066.6 (w),
2980.9 (w), 1710.4 (s), 1635.1 (m), 1592.4 (m), 1535.4 (s), 1484.8 (s),
1405.6 (m), 1380.0 (m), 1342.1 (m), 1309.3 (m), 1250.1 (s),
1210.3 (s), 1164.5 (s), 1110.1 (m), 1096.9 (m), 1048.5 (s), 983.4 (m),
880.0 (m), 772.5 (s), 741.7 (s), 671.0 (m) cm−1. HRMS calculated
for C9H11N4O2 207.0882, found 207.0889.
Ethyl-2-(pyridin-2-yl)quinolin-4-yl carbamate (25). Flow rate:
0.4 mL min−1, yield: 85%, purity: 98%, Rt = 3.65 min, M + H
m/z = 294.3. 1H-NMR (400 MHz, CDCl3): d/ppm 9.19 (1H, s),
8.75 (1H, d, J = 4.0 Hz), 8.57 (1H, d, J = 7.6 Hz), 8.18 (1H, d,
J = 7.6 Hz), 7.80–7.90 (2H, m), 7.71 (1H, t, J = 7.6 Hz), 7.53 (1H,
t, J = 7.6 Hz), 7.45 (1H, s), 7.30–7.35 (1H, m), 4.34 (2H, q, J =
6.8 Hz), 1.37 (3H, t, J = 6.8 Hz), 13C-NMR (100 MHz, CDCl3):
d/ppm 157.2 (C), 156.4 (C), 153.1 (C), 149.3 (CH), 148.6 (C),
141.6 (C), 136.7 (CH), 130.9 (CH), 129.4 (CH), 126.4 (CH),
123.9 (CH), 121.7 (CH), 119.7 (C), 119.1 (CH), 107.3 (CH), 62.0
(CH2), 14.5 (CH3). IR: m 3309.1 (w), 3060.8 (w), 2981.3 (w),
1716.9 (m), 1619.7 (m), 1598.7 (m), 1555.7 (s), 1529.4 (s),
1495.5 (m), 1474.3 (m), 1450.0 (m), 1378.2 (m), 1271.7 (s),
1209.6 (s), 1037.8 (m), 1023.1 (m), 884.1 (m), 797.1 (m), 761.6 (m),
745.8 (m), 681.5 (m) cm−1. HRMS calculated for C17H16N3O2
294.1243, found 294.1237.
Benzyl-5-methylpyrazin-2-yl carbamate (22). Flow rate:
0.4 mL min−1, yield: 87%, purity: 94%, Rt = 4.16 min, M + H
m/z = 244.3. 1H-NMR (500 MHz, d6-DMSO): d/ppm 10.46
(1H, s), 8.96 (1H, s), 8.22 (1H, s), 7.32–7.45 (5H, m), 5.19 (2H, s),
2.42 (3H, s), 13C-NMR (125 MHz, d6-DMSO): d/ppm 153.4 (C),
147.4 (C), 146.6 (C), 141.5 (CH), 136.4 (C), 134.2 (CH), 128.6
(2CH), 128.2 (CH), 128.1 (2CH), 66.3 (CH2), 20.3 (CH3). IR:
m 2979.0 (w), 1719.3 (s), 1567.3 (m), 1510.3 (m), 1438.6 (m),
1453.5 (m), 1353.8 (m), 1227.4 (s), 1054.7 (s), 1030.9 (m),
968.4 (m), 926.3 (m), 894.1 (m), 873.3 (m), 846.2 (m), 797.5 (w),
758.6 (m), 744.5 (s), 706.0 (s) cm−1. HRMS calculated for
C13H14N3O2 244.1086, found 244.1081.
Benzyl-{4[(1,1-dioxido-4-thiomorpholinyl)methyl]phenyl}carba-
mate (26). Flow rate: 0.4 mL min−1, yield: 92%, purity: 92%,
Rt = 4.69 min, M + H m/z = 375.4. 1H-NMR (400 MHz,
d6-DMSO): d/ppm 9.82 (1H, br. s, NH), 7.48–7.26 (7H, m), 7.18
(2H, d, J = 8.0 Hz), 5.13 (2H, s), 3.58 (2H, s), 3.09 (4H, br. s), 2.79
(4H, br. s); 13C-NMR (100 MHz, d6-DMSO): d/ppm 153.7 (C),
138.6 (C), 137.0 (C), 129.7 (CH), 128.8 (2 × CH), 128.5 (2 × CH),
118.4 (CH), 114.2 (CH), 55.1 (CH2), 59.5 (CH2), 50.6 (CH2),
50.3 (CH2); IR: m 3338.0 (m), 2823.4 (w), 1714.0 (s), 1614.9 (m),
1600.5 (m), 1540.0 (s), 1464.1 (m), 1415.0 (m), 1315.1 (s),
1290.9 (s), 1264.4 (s), 1224.8 (s), 1182.6 (s), 1123.7 (s), 1096.8 (s),
1048.1 (s), 1029.0 (s), 946.1 (m), 839.6 (m), 766.9 (s), 740.8 (s),
697.8 (s), 663.0 (s) cm−1; HRMS calculated for C19H22N2O4S
375.1379, found 375.1397.
Allyl-1-methyl-1,2,3,4-tetrahydroquinolin-6-yl carbamate (23).
Flow rate: 0.3 mL min−1, yield 91%, purity: 96%, Rt =
1
3.51 min, M + H m/z = 247.34. H-NMR (400 MHz, CDCl3):
d/ppm 6.95–7.05 (2H, m), 6.54 (1H, d, J = 8.8 Hz), 6.43 (1H, s),
5.90–6.00 (1H, m), 5.35 (1H, d, J = 17.2 Hz), 5.24 (1H, d, J =
10.2 Hz), 4.64 (2H, d, J = 5.2 Hz), 3.17 (2H, t, J = 6.0 Hz),
2.85 (3H, s), 2.74 (2H, t, J = 6.0 Hz), 1.97 (2H, quin., J =
6.0Hz), 13C-NMR (125MHz, CDCl3): d/ppm153.8(C), 143.8 (C),
132.8 (CH), 126.9 (C), 123.6 (C), 121.0 (CH), 118.9 (CH), 117.9
(CH2), 111.4 (CH), 65.6 (CH2), 51.3 (CH2), 39.4 (CH3), 27.8 (CH2),
22.4 (CH2). IR: m 3310.4 (m), 2933.8 (m), 2815.4 (m), 1699.1 (s),
1593.1 (m), 1514.4 (s), 1463.9 (m), 1431.9 (m), 1304.8 (m),
1226.1 (s), 1208.1 (s), 1095.6 (m), 1065.5 (m), 1048.1 (m), 997.1 (m),
930.4 (m), 805.9 (m), 767.0 (m) cm−1. HRMS calculated for
C14H19N2O2 247.1442, found 247.1441.
Allyl-6-oxo-1,6-dihydropyridazin-3-yl carbamate (27). Flow
rate: 0.4 mL min−1, yield: 76%, purity: 95%, Rt = 1.58 min, M +
1
H m/z = 196.2. H-NMR (400 MHz, d6-DMSO): d/ppm 12.58
(1H, s), 10.15 (1H, s), 7.76 (1H, d, J = 10.0 Hz), 6.89 (1H,
d, J = 10.0 Hz), 5.94 (1H, ddt, J = 17.2, 10.8, 5.2 Hz), 5.32
(1H, ddt, J = 17.2, 1.6, 1.6 Hz), 5.10 (1H, ddt, J = 10.8, 1.6,
1.6 Hz), 4.58 (2H, dt, J = 5.6 Hz, 1.6 Hz), 13C-NMR (100 MHz,
d6-DMSO): d/ppm 160.0 (C), 153.9 (C), 141.6 (C), 133.3 (CH),
131.5 (CH), 129.4 (CH), 118.2 (CH2), 65.6 (CH2). IR: m 3077.2 (w),
2952.4 (w), 1720.5 (m), 1657.1 (s), 1592.5 (s), 1518.5 (s), 1456.6 (m),
1391.5 (m), 1313.6 (m), 1216.1 (s), 1130.3 (m), 1062.2 (m),
1003.7 (m), 932.6 (m), 844.5 (m), 824.2 (m), 765.1 (m) cm−1. HRMS
calculated for C8H10N3O3 196.0722, found 196.0724.
(E)-3,7-Dimethylocta-2,6-dienylpyrazin-2-yl carbamate (24).
Flow rate: 0.4 mL min−1, yield: 81%, purity: 98%, Rt =
1
4.80 min, M + H m/z = 276.35. H-NMR (500 MHz, CD2Cl2):
d/ppm 9.35 (1H, s), 9.21 (1H, s), 8.25–8.29 (2H, m), 5.45 (1H,
t, J = 6.0 Hz), 5.12 (1H, t, J = 6.0 Hz), 4.75 (2H, d, J =
7.5 Hz), 2.07–2.15 (4H, m), 1.77 (3H, s), 1.67 (3H, s), 1.61 (3H,
s), 13C-NMR (125 MHz, CD2Cl2): d/ppm 153.3 (C), 149.1 (C),
143.6 (C), 141.8 (CH), 139.3 (CH), 136.1 (CH), 132.1 (C),
123.9 (CH), 118.3 (CH), 62.8 (CH2), 39.8 (CH2), 26.6 (CH2), 25.6
(CH3), 17.6 (CH3), 16.5 (CH3). IR: m 3172.0 (w), 2968.0 (m),
2913.0 (m), 2852.8 (m), 1718.0 (s), 1563.4 (s), 1419.1 (s),
1374.7 (m), 1305.2 (m), 1238.4 (s), 1184.8 (m), 1079.5 (s),
1040.7 (s), 1007.2 (m), 932.6 (m), 884.3 (m), 859.8 (m), 828.8 (m),
Benzyl-4-chloropyridin-3-yl carbamate (28). Flow rate:
0.4 mL min−1, yield: 95%, purity: 98%, Rt = 4.09 min, M + H
1
m/z = 263.25. H-NMR (400 MHz, CDCl3): d/ppm 9.39 (1H,
s), 8.23 (1H, d, J = 5.2 Hz), 7.35–7.45 (5H, m), 7.29 (1H, d,
J = 5.2 Hz), 7.11 (1H, s), 5.25 (2H, s), 13C-NMR (100 MHz,
CDCl3): d/ppm 153.1 (C), 145.0 (CH), 142.7 (CH), 135.8 (C),
132.5 (C), 131.9 (C), 129.1 (2CH), 129.0 (CH), 128.9 (2CH),
124.1 (CH), 68.3 (CH2). IR: m 3180.5 (w), 3137.2 (w), 3031.1 (w),
2895.3 (w), 1708.3 (s), 1578.7 (m), 1537.4 (m), 1456.3 (m),
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1456.3 (m), 1416.1 (m), 1397.6 (m), 1311.4 (s), 1242.0 (s),
1219.0 (s), 1088.9 (w), 1065.8 (m), 1039.8 (s), 914.2 (m), 862.3 (m),
815.0 (m), 751.3 (s), 738.5 (s), 694.4 (s), 663.7 (s) cm−1. HRMS
calculated for C13H12ClN2O3 263.0587, found: 263.0585.
3 M. Baumann, I. R. Baxendale, S. V. Ley, C. D. Smith and G. K.
Tranmer, Org. Lett., 2006, 8, 5231–5234.
4 C. D. Smith, I. R. Baxendale, S. Lanners, J. J. Hayward, S. C. Smith
and S. V. Ley, Org. Biomol. Chem., 2007, 5, 1559–1561.
5 C. J. Smith, F. J. Iglesias-Siguenza, I. R. Baxendale and S. V. Ley, Org.
Biomol. Chem., 2007, 5, 2758–2761.
¨
6 C. D. Smith, I. R. Baxendale, G. K. Tranmer, M. Baumann, S. C.
Smith, R. A. Lewthwaite and S. V. Ley, Org. Biomol. Chem., 2007, 5,
1562–1568.
7 L. Tamborini, F. Voica, C. D. Smith, I. R. Baxendale and S. V. Ley,
J. Comb. Chem., 2008, submitted.
8 (a) I. R. Baxendale, J. Deeley, C. M. Griffiths-Jones, S. V. Ley, S. Saaby
and G. K. Tranmer, Chem. Commun., 2006, 24, 2566–2568; (b) I. R.
Baxendale, C. M. Griffiths-Jones, S. V. Ley and G. K. Tranmer, Synlett,
2006, 3, 427–430; (c) I. R. Baxendale, S. V. Ley, C. D. Smith and G. K.
Tranmer, Chem. Commun., 2006, 4835–4837.
Ethyl-5-phenylpyridin-3-yl carbamate (29). Flow rate:
0.4 mL min−1, yield: 79%, Rt = 3.86 min, purity: 92%, M +
1
H m/z = 243.3. H-NMR (400 MHz, d6-DMSO): d/ppm 9.99
(1H, s), 8.63 (1H, s), 8.50 (1H, s), 8.15 (1H, s), 7.63 (2H, d,
J = 7.2 Hz), 7.50 (2H, t, J = 7.2 Hz), 7.41 (1H, t, J = 7.2 Hz),
4.15 (2H, q, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 13C-NMR
(100 MHz, d6-DMSO): d/ppm 154.1 (C), 141.8 (CH), 139.3 (CH),
137.4 (C), 136.5 (C), 135.9 (C), 129.5 (2CH), 128.6 (CH), 127.2
(2CH), 123.2 (CH), 61.0 (CH2), 14.8 (CH3). IR: m 3434.8 (w),
3057.7 (w), 2978.2 (w), 2925.8 (w), 1726.4 (s), 1608.4 (m),
1593.1 (m), 1554.9 (m), 1460.8 (m), 1435.2 (m), 1417.8 (m),
1365.8 (m), 1324.0 (m), 1255.5 (s), 1219.8 (s), 1157.1 (m),
1087.9 (m), 1077.2 (m), 1052.4 (s), 1024.8 (s), 999.6 (s), 913.6 (m),
870.2 (m), 823.0 (m), 757.7 (s), 697.6 (s) cm−1. HRMS calculated
for C14H15N2O2 243.1134, found 243.1140. X-Ray data: File
reference: CCDC 675582; Formula: C14H14N2O2; Unit cell
parameters: a 7.2306(5), b 6.1299(5), c 27.069(2), a 90.00, b
90.00(3), c 90.00; space group Pna21.
9 (a) S. W. Kaldor, M. G. Siegel, B. A. Dressman and P. J. Hahn,
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Jackson, A. G. Leach, D. A. Longbottom, M. Nesi, J. S. Scott, R. I.
Storer and S. J. Taylor, J. Chem. Soc., Perkin Trans. 1, 2000, 3815–
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2000, 1983–1986; (f) D. C. Sherrington, J. Polym. Sci., Part A: Polym.
Chem., 2001, 2364–2377; (g) S. V. Ley and I. R. Baxendale, Chem.
Rec., 2002, 2, 377–388; (h) S. V. Ley and I. R. Baxendale, Nat. Rev.
Drug Discovery, 2002, 1, 573–586; (i) I. R. Baxendale, M. Ernst, W.-R.
Krahnert and S. V. Ley, Synlett, 2002, 1641–1644; (j) S. V. Ley, I. R.
Baxendale, G. Brusotti, M. Caldarelli, A. Massi and M. Nesi, Farmaco,
2002, 57, 321–330; (k) S. V. Ley and I. R. Baxendale, Chem. Rec.,
2002, 2, 377–388; (l) G. Jas and A. Kirschning, Chem. Eur. J., 2003,
5708–5723; (m) A. Kirschning, H. Monenschein and R. Wittenberg,
Chem. Eur. J., 2003, 650–679; (n) S. V. Ley, I. R. Baxendale and R. M.
Myers, in Comprehensive Medicinal Chemistry II, Vol. 3, Drug Discovery
Technologies, ed. J. B. Taylor and D. J. Triggle, Elsevier, Oxford, 2006,
pp. 791–839; For selected applications see; (o) I. R. Baxendale and
S. V. Ley, Bioorg. Med. Chem. Lett., 2000, 10, 1983–1986; (p) I. R.
Baxendale, S. V. Ley and C. Piutti, Angew. Chem., Int. Ed., 2002,
41, 2194–2197; (q) R. I. Storer, T. Takemoto, P. S. Jackson, D. S.
Brown, I. R. Baxendale and S. V. Ley, Chem.–Eur. J., 2004, 10, 2529–
2547.
Acknowledgements
We gratefully acknowledge financial support from the RS Wolfson
Fellowship (to IRB and SVL), Insight Faraday and Syngenta (to
CDS), the Cambridge European Trust and the Ralph Raphael
Studentship award (to MB), GlaxoSmithKline for sponsorship
and support (NN and JPT) and the BP Endowment (to SVL). We
wish to thank J. E. Davies for determining the crystal structures of
compounds 9, 21, 24 and 29. We thank the EPSRC for a financial
contribution towards the purchase of the diffractometer.
10 Vapourtec R2+ and R4 units available from Vapourtec Ltd,
Place Farm, Ingham, Suffolk, IP31 1NQ, UK. Website:
http://www.vapourtec.co.uk.
11 Commercially available OmnifitꢀR glass chromatography columns
with adjustable height end-pieces (plunger). Typically, the polymer-
supported reagent is placed in an appropriately sized OmnifitꢀR column,
usually 10 mm bore by 150 mm length or shorter, and the plungers are
adjusted to relevant bed heights and the polymer swelled/washed with
solvent. Website: http://www.omnifit.com.
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1586 | Org. Biomol. Chem., 2008, 6, 1577–1586
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