A convenient and stable synthon for ethyl azide and its evaluation in a [3 + 2]-cycloaddition reaction under continuous-flow conditions

Article abstract of DOI:10.1021/op900078t

Azidoethyl phenyl sulfide, a readily accessible and reasonably stable synthon for ethyl azide with acceptable thermal safety properties, was investigated in a preliminary design space evaluation of a [3 + 2]-cycloaddition with cyanoacetamide under continu

Full text of DOI:10.1021/op900078t

Organic Process Research & Development 2009, 13, 1401–1406
Full Papers
A Convenient and Stable Synthon for Ethyl Azide and Its Evaluation in a
[3 + 2]-Cycloaddition Reaction under Continuous-Flow Conditions
Rob Tinder,† Roger Farr,† Richard Heid,† Ralph Zhao,† Randy S. Rarig, Jr.,‡ and Thomas Storz*,†
Wyeth Research, Chemical DeVelopment, and Wyeth Analytical and Quality Sciences, 401 North Middletown Road,
Pearl RiVer, New York 10965, U.S.A.
Abstract:
Azidoethyl phenyl sulfide, a readily accessible and reasonably
stable synthon for ethyl azide with acceptable thermal safety
properties, was investigated in a preliminary design space evalu-
ation of a [3 + 2]-cycloaddition with cyanoacetamide under
continuous-flow conditions in the Syrris AFRICA flow reactor.
Figure 1. N1-alkylated triazole carboxamides of interest.
Introduction
ketenimine7 would constitute a concise and attractive approach
Triazoles and their derivatives are important constituents of
to the desired scaffold. Unfortunately, the hazardous properties
many biologically active molecules.1-3 For one of our develop-
of most small molecular weight alkyl azides preclude utilization
ment platforms, we required a straightforward and scaleable
of this strategy on any meaningful scale.8
access to simple N1-alkylated 5-amino-1,2,3-triazole carboxa-
We hypothesized that by incorporation of a large sulfur
mides A (Figure 1).
substituent into the ꢀ-position both thermal stability and safety
The issues inherent to this structural scaffold are exemplified
properties of the resulting azide building block should improve
by one of our target compounds, the known 5-amino-1-ethyl-
and hence render this approach more practical from a process
1H-1,2,3-triazole-4-carboxamide 1.4 The only reported synthesis4,5
point of view. Post cycloaddition, the sulfur substituent should
claimed for this building block suffers from low yield, structural
be easily removable by known techniques, e.g. via RaNi-
ambiguity, as well as considerable safety hazards due to the
mediated desulfurization. To the best of our knowledge, “thio-
employment of ethyl azide (Scheme 1).6
moderated, stability-engineered” monoazides have not been
A safer, selective, and high-yielding synthesis for building
investigated in [3 + 2] cycloadditions towards 1,2,3-triazoles
blocks of type A was needed.
before.
To test this concept, we prepared ꢀ-azidoethyl phenyl sulfide
4 in one step from cheap commercial ꢀ-chloroethyl phenyl
sulfide and sodium azide under nonaqueous conditions (see
Experimental Section).9 It is a colorless liquid which has been
reported as a distillable liquid in the literature9 (bp 65 °C, 0.5
Torr). No safety data for this compound have been reported to
date, so we set out by subjecting 4 to a variety of thermal safety
Results and Discussion
In principle, if completely regioselective, the [3 + 2]
cycloaddition of an organic monoazide with an in situ generated
* Corresponding author. E-mail: storzt@wyeth.com.
† Wyeth Research, Chemical Development.
‡ Wyeth Analytical and Quality Sciences.
(1) Melo, J. O. F.; Donnici, C. L.; Augusti, R.; Ferreira, V. F.; de Souza,
M. C. B. V.; Ferreira, M. L. G.; Cunha, A. C. Quim. NoVa 2006, 29,
569.
(7) For references on the [3 + 2]-cycloaddition of the ketenimine generated
in situ from cyanoacetamide with: (a) benzyl azide Hoover, J. R. E.;
Day, A. R. J. Am. Chem. Soc. 1956, 78, 5832. (b) An alkoxymethyl
azide Yokoyama, M.; Watanabe, S.; Seki, T. Synthesis 1988, 879. (c)
n-Propyl/cyclopentyl azide Haning, H.; Niewoehner, U.; Schenke, T.;
Lampe, T.; Hillisch, A.; Bischoff, E. Bioorg. Med. Chem. Lett. 2005,
15, 3900.
(2) Kale, P.; Johnson, L. B. Drugs Today 2005, 41, 91.
(3) (a) Kadaba, P. K. Curr. Med. Chem. 2003, 10, 2081. (b) Angiolillo,
D. J.; Capranzano, P. Am. Heart J. 2008, 156, 10S.
(4) Dornow, A.; Helberg, J. Chem. Ber. 1960, 93, 2001.
(5) The authors in lit. ref 4 claim that only compound 1 was formed,
although the analytical data (only elemental analysis giVen) support
the isomeric structures 2 and 3 as well. Additional ambiguity is added
by the later observation ofAlbert, A. (J. Chem. Soc., Perkin Trans. I
1981, 2344) that N1-alkylated 5-aminotriazole amides can be in
equilibrium with the corresponding 5-alkylamino-triazoles via Dimroth
rearrangement. For a preparative example of a Dimroth rearrangement
in the scale-up of a pyrrolopyrimidine, see: Fischer, R. W.; Misun,
M. Org. Process Res. DeV. 2001, 5, 581.
(8) For explosive properties of low-molecular weight alkyl azides, see:
(a) Klaeboe, P.; Nielsen, C. J.; Priebe, H.; Schei, S. H.; Sjoegren,
C. E. J. Mol. Struct. 1986, 141, 161. Simple cycloaddition with metal
azides (i.e., sodium azide) followed by N-alkylation is usually not a
viable strategy for the concise synthesis of N1-alkylated triazoles due
to the formation of regioisomeric mixtures, that may be difficult or
even impossible to separate, see: (b) Maksimova, A. V.; Serebryakova,
E. S.; Tikhonova, L. G.; Vereshchagin, L. I. Khim. Geterotsikl. Soedin.
1980, 1688. (c) Livi, O.; Biagi, G.; Ferretti, M.; Lucacchini, A.; Barili,
P. L. Eur. J. Med. Chem. 1983, 18, 471.
(6) For a report of an ethyl azide explosion, see: (a) Burns, M. E.; Smith,
R. H., Jr. Chem. Eng. News 1985, 63, 2.
10.1021/op900078t CCC: $40.75  2009 American Chemical Society
Published on Web 05/28/2009
Vol. 13, No. 6, 2009 / Organic Process Research & Development
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Scheme 1
tests: TSU testing (2 mL neat liquid) showed a significant
exotherm with onset around 155 °C with a maximum dT/dt of
135 °C/min. ARC testing of a neat sample (2.54 g) (undiluted)
showed a significant exotherm starting around 130 °C, with a
heat liberation of 608 J/g (Figure 2).
In order to check for onset of decomposition at temperature
ranges realistically expected for the cycloaddition reaction, a
set of isothermic DSC experiments was carried out. No
exotherms were observed during the hold period in both a 20
h/100 °C and a 72 h/80 °C experiment.10 Overall, we were
encouraged by these data as they indicated a significantly
improved safety profile compared to that of ethyl azide which,
due to its unpredictable and explosive properties,6 should not
be handled in the laboratory at any scale.
Since the reaction still involves a potentially hazardous azide,
we wanted to put an additional engineering control in place to
ensure an inherently safe process. Continuous-flow reactions
have the potential to be much safer than batch reactions, as
only a small amount of reactive and potentially hazardous
material is heated or converted to product at any given time.11
We undertook an initial parallel screening of solvents and bases
for the cycloaddition shown in Scheme 2 towards a potential
continuous-flow process. The results of this screen (Table 1)
provided us with a starting point for further DoE studies in the
Syrris AFRICA continuous flow reactor system (Figure 3).
A series of experiments examining the interplay of temper-
ature, stoichiometry, and base were carried out (Table 2). These
data suggest a complex interaction between temperature and
base resulting in degradation of cyanoacetamide. To examine
this interaction, the data collected between 65 and 95 °C were
analyzed using the historical data feature of Stat-Ease Design
Expert Software. Figure 4 shows a graphical representation of
the interaction between temperature, base, and stoichiometry
of cyanoacetamide. For a given residence time at higher
temperatures, base causes cyanoacetamide to decompose in a
concentration-dependent manner, competing with the productive
reaction pathway.
Only one, the desired 5-amino regioisomer, was formed in
all experiments, as unambiguously proven by 2D-NMR experi-
ments and single crystal X-ray crystallography (Figure 5); the
Dimroth rearrangement product (cf. Scheme 1)5 could not be
detected. Other than small amounts of unreacted starting
material no other product-related side products were observed.
The conditions chosen for a 5 g flow reactor proof-of-concept
experiment are shown in Scheme 3.
We were gratified to find that RaNi-mediated desulfu-
rization of the cycloadduct 5 proceeded cleanly to
complete the proof-of-concept to the N-ethyl triazole 1;
no triazole ring cleavage or Dimroth rearrangement
product was observed (Scheme 4).18 Alternatively, the
cycloadduct 5, which appears to be thermally stable toward
Dimroth rearrangement may also be carried forward and
the reductive desulfurization carried out at a later stage
in the synthetic sequence (data not shown). Since triazoles
are high energy compounds, this has the advantage of
operating with an inherently safer intermediate due to the
more favorable carbon to nitrogen ratio.23
This high-yielding sequence has the potential to be a practical
and safe addition to the synthetic arsenal for N1-alkylsubstituted
5-amino-triazoles, valuable intermediates for the synthesis of
important pharmacophores such as triazolopyridines or triaz-
olopyrimidines and their derivatives.4,13-17
(9) Safety data for this nucleophilic displacement had indicated a >50 °C
window between reaction temperature (75 °C) and decomposition onset
(∼130 °C, data not shown). This new one-step procedure (see
Experimental Section) is more convenient than the only previously
reported four-step synthesis for this building block: (a) Khoukhi, M.;
Vaultier, M.; Carrie, R. Tetrahedron Lett. 1986, 27, 1031 The
corresponding sulfone (2-azidoethyl phenyl sulfone), see: (b) Carboni,
B.; Vaultier, M.; Carrie, R. Tetrahedron 1987, 43, 1799. initially
investigated as cycloaddition partner was quickly abandoned due to
complications (side reactions due to ꢀ-elimination) under the basic
reaction conditions (data not shown).
Conclusions
A safe and readily accessible substitute for ethyl azide has
been identified and its usefulness demonstrated in a [3 +
2]-cycloaddition design space evaluation using the Syrris
AFRICA continuous flow reactor setup. The dipolar cycload-
dition of 2-azidoethyl phenyl sulfide appears to be much cleaner
(10) The isothermal DSC experiment held at 100 °C for 20 h, when cooled
and reramped to 300 °C (heating rate 10 °C/min) showed an exotherm
onset at 160 °C, liberating 560 J/g.
(11) For a recent overview of this rapidly developing field, see the special
issue of Organic Process Research and DeVelopment devoted to
Continuous Processes: Org. Process Res. DeV. 2008, 12, 904.
(12) Initial safety testing for this azide substitution reaction was also carried
out showing this reaction mode to be safe (Vide supra). To minimize
reaction hazards, we envisaged flow reactor integration of both
reactions for further development. Appropriate safety measures should
be taken as for all azide reactions; see, for instance: (a) Lunn, G.;
Sansone, E. B. Azides. In: Destruction of Hazardous Chemicals in
the Laboratory, 2nd ed.; Wiley: New York, 1979; p 57. (b) Hagenbuch,
J.-P. Chimia 2003, 57, 773. (c) Wiss, J.; Fleury, C.; Heuberger, C.;
Onken, U. Org. Process Res. DeV. 2007, 11, 1096. (d) Bosch, L.;
Vilarrasa, J. Angew. Chem., Int. Ed. 2007, 46, 3926 (see ref 14).
(13) Biagi, G.; Giorgi, I.; Livi, O.; Scartoni, V.; Lucacchini, A. Farmaco
1996, 51, 395.
(14) Baraldi, P. G.; Manfredini, S.; Simoni, D.; Zappaterra, L.; Zocchi,
C.; Dionisotti, S.; Ongini, E. Bioorg. Med. Chem. Lett. 1994, 4, 2539.
(15) L’Abbe, G.; Vandendriessche, A.; Weyns, N. Bull. Soc. Chim. Belg.
1988, 97, 85.
(16) Cacciari, B.; Spalluto, G. Synth. Commun. 2006, 36, 1177.
(17) Albert, A. J. Chem. Soc., Perkin Trans. I 1975, 345.
(18) To the best of our knowledge, reductive desulfurizations of N-(R- or
ꢀ-{alkyl or aryl}thioalkyl)-1,2,3-triazoles have not been reported to
date.
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Figure 2. Thermal safety data of 2-azidoethyl phenyl sulfide 4.
Scheme 2
and higher yielding compared to those of typical low-molecular
weight alkyl azides.
a DSC instrument (Vide infra). 1H NMR spectra were recorded
at 500 MHz, and 13C NMR spectra were recorded at 200 MHz
on a Bruker DRX-500 NMR instrument. Assignments were
confirmed by the appropriate 2D-NMR experiments. IR spectra
were measured on a Bruker IFS660 spectrometer. Exact mass
determinations were performed on a ABI QSTARXL qtof
instrument (calibrated in positive ion mode with CsI and sex
Experimental Section
Starting materials, reagents, and solvents were obtained from
commercial suppliers and were used without further purification.
All the melting points are uncorrected and were determined on
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Table 1
temperature
prod LC
area % SM solids?
solvent
base
°C
time
14 h
NMP KOtBu
DMF KOtBu
THF KOtBu
EtOH KOtBu
NMP LiHMDS
NMP LiHMDS
THF LiHMDS
EtOH LiHMDS
DMF NaOH
DMF NaOH
THF NaOH
EtOH NaOH
NMP Et3N
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
83
88
33
73
70
70
48
47
100
100
11
44
0
0
0
no
no
14 h
14 h
14 h
14 h
15 min
14 h
14 h
15 min
14 h
14 h
14 h
14 h
14 h
14 h
14 h
52
17
0
yes
no
no
0
29
35
0
yes
yes
no
0
77
47
no
yes
yes
no
DMF Et3N
0
no
THF Et3N
0
no
EtOH Et3N
0
no
pheromone inhibitor iPD1 (Bachem)). For reaction monitoring,
a Waters Acquity UPLC system with a BEH-C18 column (100
mm × 2.1 mm, 1.8 µm particle size) was used, employing a
0.1% H3PO4/CH3CN gradient (0 to 100%, 5 min gradient) and
UV detection (λ ) 220 nm). Safety testing: (A) Differential
Scanning Calorimetry (“DSC”, from TA Instruments, Inc.): The
sample in mg scale is tightly crimped into an aluminum pan
and loaded onto the sample cell holder with an empty crimped
aluminum pan as a reference. The scanning rate is 10 °C/min
or slower, unless otherwise indicated. The thermal event of the
sample is recorded along with the temperature. No pressure data
is available from this testing. (B) Thermal Screening Unit
(“TSU”, from HEL Ltd.): The sample is charged into a 9-mL
(hastelloy C unless otherwise indicated) test cell, which is then
Figure 4. Design Expert response surfaces of the cycloaddition
screen under continuous-flow conditions in the Syrris AFRICA
reactor (1 min residence time) at 65 and 75 °C (base: NaOH,
solvent: NMP).
Figure 3. Syrris AFRICA flow reactor.
Table 2. Continuous-flow experiments in the Syrris
AFRICA reactor (1 min residence time) using 1 equiv of
azide 4 (base: NaOH, solvent: NMP)
Figure 5. Single crystal X-ray of 5.
temperature cyanoacetamide
base
(equiv)
conversion starting
sealed into an oven. The oven temperature is ramped up to 250
at 2 °C/min, unless otherwise indicated. Sample temperature is
monitored with a thermocouple immersed into the sample.
Pressure and oven temperature are also monitored throughout
the run. The containment volume-test cell, pressure transducer
and piping-is approximately 10 mL. (C) Accelerating Rate
Calorimeter (“ARC”, from Arthur D. Little Inc.): The sample
is charged into an 8.6-mL round-bottom or a 10 mL cylindrical
test cell, made of hastelloy C or titanium. The cell is sealed to
the calorimeter assembly and placed into a thermally insulated
cavity. A thermocouple clipped to the external surface of the
cell is used to track sample temperature, while pressure is
monitored with a transducer. Heating elements, which are
distributed throughout the cavity, are used to increase sample
temperature according to a Heat-Wait-Search (HWS) pattern,
(°C)
(equiv)
(%)
azide (%)
65
65
65
65
75
75
75
75
85
85
85
85
95
95
95
95
1.5
1.5
2
1.5
2
1.5
2
1.5
2
1.5
2
1.5
2
1.5
2
1.5
2
1.5
2
30
98
98
100
47
70
98
76
5
70
2
2
2
0
1.5
1.5
2
46
30
2
2
23
95
40
0
1.5
1.5
2
60
98
95
7
2
5
1.5
1.5
2
93
98
97
100
2
3
2
0
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Scheme 3. Proof-of-concept experiment in the Syrris AFRICA flow reactor
Scheme 4. RaNi desulfurization of 5
followed by the addition of water (700 mL) over 15 min while
maintaining an internal temperature of 20-25 °C. The aqueous
layer was cut and the organic layer washed with 1 M sodium
bicarbonate (100 mL) and water (100 mL). The volatiles were
removed in Vacuo, and the product (oil) was used as is in the
next step without further purification (114 g, 95%). UPLC:
98A%, RT 3.4 min; NMR:9 1H NMR (300 MHz, CDCl3) δ:
3.05 (t, 2 H, CH2-S, J ) 6.9 Hz), 3.40 (t, 2 H, CH2-N, J ) 6.9
Hz), 6.92 - 7.62 (m, 5 H, CH (Ph)). 13C NMR (75 MHz,
CDCl3) δ: 135.0 (Cipso (SPh)), 130.8 (Cortho (SPh)), 129.6 (Cmeta
(SPh)), 127.4 (Cpara (SPh)), 50.7 (NCH2), 34.0 (SCH2).; IR9 (cap
film/KBr, cm-1): 3059w, 2926w, 2867w, 2505w, 2102s, 1687w,
1584m, 1481m, 1439m, 1348m, 1306m, 1256m, 1180w,
1089w, 1025w, 902w, 740s, 692s.
Continuous Flow Reactor Screen (Syrris AFRICA Ex-
periments To Establish Design Expert Response Surfaces).
Stock solutions were prepared and loaded as needed into 10
mL loops of the Syrris AFRICA instrument. Cyanoacetamide
(4 g, 47.5 mmol) was dissolved in 20 mL of NMP. Likewise
2-azidoethylphenylsulfide (4 g, 22.3 mmol) was also dissolved
in 20 mL of NMP. A stock solution of 10 M NaOH was used.
Using the flow manager program, flow rates were calculated
on the basis of the prescribed stoichiometry. Reactions were
performed in a 250 µL, three-input glass reactor chip, heated
to the prescribed temperature prior to equilibration. Ap-
proximately 1.5-fold volume excess was required for the reactor
to reach steady state, and 500 µL of steady-state reaction mixture
was collected using an automated fraction collector, and
analyzed by UPLC.
5-Amino-1-(2-phenylthioeth-1-yl)-1,2-3-triazole-4-carbox-
amide (5). (Continuous Flow Reactor 5 g Proof-of-Concept
Experiment): A medium-scale plugflow reactor consisting of
two pumps, a 4 mL tube reactor, hot plate, and mixing tee (T)
was constructed using equipment from Syrris Ltd. (Syrris FRX
system). A reagent solution was prepared by dissolving 2-cy-
anoacetamide (4.22 g, 50.2 mmol) and 2-azidoethyl phenyl
sulfide (6 g, 33.45 mmol) to 60 mL of NMP. A commercial
stock solution of 10 M aq sodium hydroxide was used directly.
The reactor temperature was set to 70 °C and the reactor
pumped with approximately 1.5 volumes (6 mL) of reagents
at 0.9 mL/min for the reagent solution and 0.1 mL/min for the
sodium hydroxide solution. After the reactor reached equilib-
rium, 38 mL of output was collected into 150 mL of water
while stirring vigorously. The colorless precipitate was filtered
off and the filter cake washed twice with 20 mL of water each
and dried overnight at high vacuum to afford 4.55 g (90%) of
the triazole 5 as a colorless crystalline solid. UPLC: RT 2.4
min, mp (DSC) 155.9 °C. DSC (dynamic): no exotherm up to
250 °C, 1H NMR (500 MHz, DMSO-d6) δ: 3.38 (t, 2 H, CH2-
S, J ) 7.0 Hz), 4.35 (t, 2 H, CH2-N, J ) 7.0 Hz), 6.24 (br s,
unless otherwise indicated. If a self-heat rate of typically 0.02
°C/min or greater is detected during the “Search” phase, the
ARC goes into exotherm mode. In this mode the sample-test
cell system is kept in adiabatic conditions, i.e. the cavity
temperature follows the measured sample temperature. Truly
adiabatic results are obtained from experimental data by
correcting for heat absorption by the test cell. The containment
volume-test cell, pressure transducer and piping-is ap-
proximately 11 mL. Structural measurements were performed
on a Bruker-AXS SMART-CCD diffractometer at low tem-
perature (90 K) using graphite-monochromated Mo K radiation
(Mo K ) 0.71073 Å).19 The data were corrected for Lorentz
and polarization20 effects and absorption using SADABS.21 The
structures were solved by direct methods. All non-H atoms were
refined anistropically. After all of the non-H atoms were located,
the model was refined against F,20 initially using isotropic and
later anisotropic thermal displacement parameters. H atoms were
introduced in calculated positions and refined isotropically.
Neutral atom scattering coefficients and anomalous dispersion
corrections were taken from the International Tables, Vol. C.
All calculations were performed using SHELXTL crystal-
lographic software packages.22
2-Azidoethyl Phenyl Sulfide (4).9
2-Chloroethyl phenyl sulfide (116 g, 671 mm), was charged
to a 2 L three-neck flask equipped with a mechanical stirrer,
nitrogen inlet, and a rubber septum. NMP (500 mL) was then
added followed by 87 g (2.0 equiv, 1.33 M) of sodium azide.
The thin slurry was heated to 75-80 °C,12 maintained at that
temperature for 3 h (reaction monitored by UPLC) and then
cooled to 20 °C in an ice bath. MTBE (500 mL) was added
(19) SMART, Data Collection Software, version 5.630; Bruker AXS Inc.:
Madison, WI, 1997-2002.
(20) SAINT Plus, Date Reduction Software, version, 6.45A; Bruker AXS
Inc.: Madison, WI, 1997-2002.
(21) Sheldrick, G. M. SADABS; University of Go¨ttingen: Go¨ttingen,
Germany, 1996.
(22) SHELXTL PC, version 6.12; Bruker AXS Inc.: Madison, WI, 2002.
(23) Compared with cycloadduct 5, the triazole 1 releases almost 3 times
the decomposition energy upon thermally induced decomposition (data
not shown).
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2 H, C(5)-NH2), 6.98 (br s, 1 H, CONH2), 7.22 (br s, 1 H,
CONH2), 7.23 (m, 1 H, CH (Ph)), 7.34 (m, 2 H, CH (Ph)),
7.38 (m, 2 H, CH (Ph)). 13C NMR (125 MHz, DMSO-d6) δ:
164.0 (C ) O), 144.6 (C(5)), 134.7 (Cipso (SPh)), 128.9 (Cortho
(SPh)), 128.8 (Cmeta (SPh)), 126.0 (Cpara (SPh)), 121.7 (C(4)),
44.5 (NCH2), 31.1 (SCH2). IR (KBr disk, cm-1): 3414m,
3315m, 3165m, 2920w, 2852w, 1664s, 1636s, 1569s, 1512m,
1481m, 1438m, 1292m, 1248m, 1090w, 1014w, 944w, 899w,
788w, 750m, 689m. HR-MS: exact mass calculated for
C11H14N5OS × H+: 264.0914, found: 264.0945.
DMSO-d6) δ: 1.30 (t, 3 H, CH3, J ) 7.2 Hz), 4.14 (q, 2 H,
CH2, J ) 7.2 Hz), 6.26 (br s, 2 H, C(5)-NH2), 7.06 (br s, 1 H,
CONH2), 7.41 (br s, 1 H, CONH2). 13C NMR (75 MHz,
DMSO-d6) δ: 164.2 (C ) O), 144.1 (C(5)), 121.7 (C(4)), 38.6
(CH2), 14.0 (CH3). IR (KBr disk, cm-1): 3432m, 3402m, 3311s,
3165m, 2990w, 1672s, 1652s, 1636s, 1571s, 1517m, 1464w,
1433m, 1282m, 1249m, 1192w, 1087w, 1033w, 960w, 759m,
613w. HR-MS: exact mass calculated for C5H9N5O × H+:
156.0879, found: 156.0913.
5-Amino-1-ethyl-1,2-3-triazole-4-carboxamide (1). A mix-
ture of 1.0 g (3.8 mmol) 5 and RaNi 2800 (Aldrich) slurry (∼2
g wet) in methanol (25 mL) was hydrogenated in a Parr Shaker
at 58-60 psi hydrogen pressure at room temperature until
UPLC shows complete conversion (∼48-60 h). The superna-
tant was decanted and the RaNi residue filtered off and washed
with methanol/acetonitrile (1:1, 50 mL). Combined filtrate and
supernatant were evaporated to dryness under reduced pressure,
and the residue was taken up in dichloromethane/methanol
(20:1) and filtered over a small silica gel plug. 1 (550 mg, 90%)
was obtained as a colorless solid after drying at oil pump
vacuum. UPLC: RT 0.8 min, 100%. Mp (DSC) 204.9 °C; DSC
Acknowledgment
We are grateful to Dr. Mahendra Suryan for LC-MS
assistance and Dr. Russ Tsao for the exact mass determinations.
Yumin Gong is thanked for help with NMR structure
determinations.
Supporting Information Available
X-ray structure data. This material is available free of charge
via the Internet at http://pubs.acs.org.
Received for review March 31, 2009.
OP900078T
1
(dynamic): no exotherm up to 250 °C. H NMR (300 MHz,
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Vol. 13, No. 6, 2009 / Organic Process Research & Development