Generation of hazardous methyl azide and its application to synthesis of a key-intermediate of picarbutrazox, a new potent pesticide in flow

Article abstract of DOI:10.1016/j.bmc.2017.07.005

Generation and reactions of methyl azide (MeN₃) were successfully performed by using a flow reactor system, demonstrating that the flow method serves as a safe method for handling hazardous explosive methyl azide. The reaction of NaN₃ and Me₂SO₄ in a flow reactor gave a MeN₃ solution, which was used for Huisgen reaction with benzoyl cyanide in a flow reactor after minimal washing. The resulting 1-methyl-5-benzoyltetrazole serves as a key intermediate of picarbutrazox (IX), a new potent pesticide.

Full text of DOI:10.1016/j.bmc.2017.07.005

Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Generation of hazardous methyl azide and its application to synthesis of
a key-intermediate of picarbutrazox, a new potent pesticide in flow
a,
Daisuke Ichinari a,b, Aiichiro Nagaki a, , Jun-ichi Yoshida
⇑
⇑
a Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Nishikyo-ku, Kyoto 615-8510, Japan
b Takaoka Laboratory, Takaoka Plant, Nippon Soda Co., Ltd., 300, Mukaino-Honmachi, Takaoka, Toyama 933-8507, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Generation and reactions of methyl azide (MeN3) were successfully performed by using a flow reactor
system, demonstrating that the flow method serves as a safe method for handling hazardous explosive
methyl azide. The reaction of NaN3 and Me2SO4 in a flow reactor gave a MeN3 solution, which was used
for Huisgen reaction with benzoyl cyanide in a flow reactor after minimal washing. The resulting 1-
methyl-5-benzoyltetrazole serves as a key intermediate of picarbutrazox (IX), a new potent pesticide.
Ó 2017 Published by Elsevier Ltd.
Received 12 May 2017
Revised 1 July 2017
Accepted 4 July 2017
Available online xxxx
Keywords:
Flow synthesis
Methyl azide
1. Introduction
Tetrazoles1 are synthetic heterocycles which have been used in
a variety of fields2 including organic chemistry, coordination
chemistry, photographic industry, medicinal chemistry, and explo-
sive production. 5-Substitited-1H-tetrazoles3 serve as core struc-
tures of pharmacologically important compounds4 such as
Losartan,5 Tomelukast,6 AMPA antagonist,7 Ciglitazone analogues,8
and NMDA antagonist.7 1,5-Disubstituted tetrazoles also show
remarkable physiological activities in spite of the lack of acidic
NAH.9 In particular, Picarbutrazox attracts much research interests
because it is active against P. viticola, and P. Infestans. The spectrum
also includes Pythium species which are responsible for damping-
off disease in many crops.10 For this reason, many picarbutrazox
analogues have been developed and patented.11 The late stage cou-
pling of two advanced building blocks, the pyridine carbamate and
1-methyl-5-tetrazolyloxime which can be easily synthesized from
1-methyl-5-benzoyltetrazole, is advantageous from view points of
convergentness and costs (Fig. 1).10a
Various methods for synthesizing 1-methyl-5-benzoyltetrazole
have been developed so far. Conventionally, 1-methyl-5-benzoyl-
tetrazole has been prepared by three-step synthesis via methyla-
tion of unsubstituted tetrazole (Fig. 2a).12 However, this approach
suffers from the regioselectivity problem in the lithiating step,
which eventually leads to difficulty in purification of the product.
Regioselective synthesis from mandelic acid has been developed
Fig. 1. Retrosynthetic strategy for Picarbutrazox having fungicidal activity.
(Fig. 2b), but this method requires five steps.13 Another options is
the three-component coupling reaction of methyl isonitrile, NaN3
and benzoyl chloride (Fig. 2c).14 However, the use of methyl
isonitrile is problematic because of its strong smell. Also, methyl
isonitrile is not commercially available. Another method which
uses ammonium azide and diazomethane is also problematic
because of a risk of explosion and the use of toxic chromium
trioxide (Fig. 2d).15 Therefore,
a more efficient method for
synthesizing 1-methyl-5-benzoyltetrazole is highly desired.
Generation of MeN3 from NaN3 and sulfuric acid ester followed
by cyclization (Huisgen reaction) with benzoyl cyanide provides a
simple two-step synthesis of 1-methyl-5-benzoyltetrazole
(Fig. 3).16 However, the use of MeN3 is problematic, because of
the danger of explosion.17 Also, MeN3 is rather difficult to handle
because of its low boiling point (20 °C).18 In fact, a special batch
device for high-pressure reactions is often required for generation
and reactions of MeN3. In addition, the use of sulfuric acid ester
and HN3 generated by hydrolysis of NaN3 is also dangerous.
⇑
Corresponding authors.
E-mail addresses: anagaki@sbchem.kyoto-u.ac.jp (A. Nagaki), yoshida@sbchem.
kyoto-u.ac.jp (J.-i. Yoshida).
http://dx.doi.org/10.1016/j.bmc.2017.07.005
0968-0896/Ó 2017 Published by Elsevier Ltd.
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2
D. Ichinari et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
Fig. 2. Previous reports on synthesis of 1-methyl-5-benzoyltetrazole.
a back-pressure regulator was used (Fig. 4). A mixture of NaN3
(1.0–4.0 M) and NaOH (0.20–0.60 M) in water, and a solution
of dimethyl sulfate (3.5–9.0 M) in toluene were introduced
to
M (/ = 1.3 mm) by using plunger pumps. The resulting
solution was passed through R1 (/ = 1.0 mm, L = 1.0 m) and
R2 (/ = 2.18 mm, L = 10 m) in oil bath (T °C). The product
solution was then passed through R3 (/ = 2.18 mm, L = 6.0 m)
which was cooled in an ice-water bath (0 °C) to stop the
reaction. The pressure of the whole system was regulated by
using a back-pressure regulator (0.9 MPa). After a steady state
was reached, an aliquot of the product solution was taken for
5 min. MeN3 is present mainly in the organic layer, although a
small amount of MeN3 is present in the aqueous layer as well.
The yield of MeN3 was determined by HPLC analysis of the both
layers. Total yields are shown in Table 1 (See also Table 2 in the
Section 4). The conversion of NaN3 was also determined by HPLC
analysis of the aqueous layer. The results obtained under various
conditions are summarized in Table 1.
The yield of MeN3 increased with an increase in the tempera-
ture (Table 1, entries 1–5). In addition, the increase in the
NaOH/Me2SO4 ratio caused a decrease in the yield presumably
because of hydrolysis of Me2SO4 by an excess amount of NaOH
(Entries 6–8). In general, it is known that NaN3 is converted to
HN3 under acidic conditions and that HN3 is explosive even at
Fig. 3. Synthesis of 1-methyl-5-benzoyltetrazole.
Recently, chemical synthesis and production in flow reactors
have received research interests from both academia and indus-
try.19–21 Enhanced heat and mass transfers, and the ability of con-
trolling the residence time add great values to this technology. In
addition, process operation in high-temperature/high-pressure
conditions can readily be achieved.22 Moreover, the risks associ-
ated with the use of hazardous materials can be minimized
because only small quantities of reagents and products are exposed
to the reaction conditions at any given time, making transforma-
tions using flow systems much safer.23
Although flow generation and reactions of hazardous HN3,
which can be used for synthesis of 5-substitited-1H-tetrazoles,
have been studied extensively,24 to the best of our knowledge, flow
generation and reactions of MeN3 has not yet been reported.
Herein, we show that generation of MeN3 followed by the reaction
with benzoyl cyanide can be effectively conducted by using a flow
reactor.
room temperature. From
a
viewpoint of process safety
management, appropriate pH control of the aqueous outlet
solution is very important. Therefore, the amount of sodium
hydroxide and dimethyl sulfate as well as their ratio were
examined (Entries 9–12). As shown in entry 12, the use of 0.15
equivalents of NaOH and 1.1 equivalents of Me2SO4 made the
outlet aqeuous solution neutral.
2. Results and discussion
A flow reactor system consisting of two pre-heating units
(P1 (/ = 1000
lm, L = 4 m), and P2 (/ = 1000 lm, L = 4 m)), a
T-shaped mixer (M), three tube reactors (R1, R2, and R3), and
Fig. 4. A schematic diagram of the flow system for generation of MeN3.
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D. Ichinari et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
3
Table 1
Effect of the temperature and the amounts of NaOH and Me2SO4.
a
Entry
T (°C)
NaOH (eq)
Me2SO4 (eq)
Reaction time (min)
Conversion of NaN3 (%)
Yield of MeN3 (%)
pH
1
2
3
4
5
6
7
8
60
80
1.2
1.2
1.2
2.0
2.0
2.0
1.2
1.2
1.1
1.2
1.5
1.1
1.2
1.3
1.1
2.5
2.5
2.5
1.4
1.4
1.3
1.3
1.3
1.3
1.3
1.3
1.3
45
73
81
85
88
70
75
85
91
91
90
86
39
70
77
80
83
54
63
74
80
84
82
81
14.2
14.2
13.1
8.0
100
100
120
120
120
120
120
120
120
120
0.22
0.22
0.70
0.70
0.70
0.05
0.05
0.05
0.15
5.3
12.8
12.6
11.3
4.7
1.1
0.9
9
10
11
12
7.4
a
The total yield of MeN3 in both the organic and aqueous layers.
Table 2
The detailed conditions and results of the experiments shown in Table 1.
Entry
T
(°C)
NaN3
(mol/L)
Me2SO4
(mol/L)
NaN3
(mL/min)
Me2SO4
(mL/min)
R2 /
(mm)
R2 L
(m)
MeN3 (%)
NaN3 recovery (%)
aqueous layer
Organic
layer
Aqueous
layer
1
2
3
4
5
6
7
8
60
80
2.0
1.0
1.0
2.0
2.0
3.5
3.5
3.5
4.0
4.0
4.0
2.5
4.0
4.0
4.0
4.0
4.0
3.5
3.5
3.5
9.0
9.0
9.0
4.0
9.8
9.8
9.8
4.9
4.9
4.9
15.0
15.0
11.5
12.5
13.5
7.2
2.18
2.18
2.18
3.76
3.76
2.18
2.18
2.18
2.18
2.18
2.18
3.76
10.0
10.0
10.0
5.0
5.0
8.0
8.0
8.0
8.0
8.0
39
62
67
73
75
51
60
71
74
78
76
75
0
55
27
19
15
12
30
25
15
9
8
10
7
8
3
3
3
6
6
6
7
100
100
120
120
120
120
120
120
120
120
25.1
25.1
11.0
10.0
9.0
15.4
14.8
14.2
26.0
9
10
11
12
7.9
8.2
17.0
9
10
14
8.0
5.0
aThe total yield of MeN3 in both the organic and aqueous layers.
Next, we examined a continuous operation of the reaction
under the optimized conditions (entry 12 in Table 1, NaOH
(0.15 eq) and Me2SO4 (1.1 eq)). The operation for 10 min at the
total flow rate of 43 mL/min yielded 39 g of MeN3 (82% yield) in
the organic layer. In general, the productivity of a flow reaction
can be increased by increasing the flow rate, which is one of the
most advantageous features of flow processes over batch pro-
cesses. The operation at a higher total flow rate (69 mL/min) was
successfully carried out for 61 min to yield 383 g of MeN3 (82%
yield) in the organic layer, indicating the feasibility of the produc-
tion on a large scale (9.1 kg/day).
Notably, a high concentration solution of MeN3 (23.9 wt%) in
toluene was obtained by using the present method. After washing
with NaOHaq and H2O, the solution was diluted with toluene to
obtain a 12.0 wt% solution, which was directly used, without fur-
ther purification, for the subsequent Huisgen reaction with benzoyl
cyanide. A flow reactor system consisting of two pre-heating units
78% yield (12.1 g), which can be easily converted into picarbutra-
zox (IX), a new pesticide. It should be emphasized that the reaction
using the flow reactor was conducted safety even at a high
temperature (200 °C) and a high pressure (8 MPa) (Fig. 5).
3. Conclusion
The results described above indicate that the flow method
serves as an effective and safe tool for generation and reactions
of haza6rdous MeN3. 1-Methyl-5-benzoyltetrazole which is a key
intermediate of picarbutrazox (IX), a new pesticide, was success-
fully synthesized by the flow reaction of MeN3 and benzoylnitrile.
This study speaks well for the potentiality of flow microreactor
systems for large-scale production of chemicals using hazardous
compounds. Further work aimed at industrial sacle production is
currently in progress.
(P1 (/ = 1000
T-shaped mixer (M), three tube reactors (R1, R2, and R3), and
back-pressure regulator was used. mixture of MeN3
lm, L = 4 m) and P2 (/ = 2.18 mm, L = 4 m)), a
4. Experimental section
a
A
(12.0 wt%) and PhCOCN (28.9 wt% (1.05 eq)) in toluene (flow rate:
2.8 mL/min) was passed through R1 (/ = 3.36 mm, L = 20.5 m,
65 min) in oil bath (200 °C). The resulting solution was further
diluted with toluene (flow rate: 6.35 mL/min) in M (/ = 2.3 mm).
The resulting solution was passed through R2 (/ = 3.36 mm,
L 0.5 m, 0.5 min) at 200 °C and was passed through R3 (/ = 4.35 mm,
L = 10 cm) at room temperature to stop the reaction. The resulting
solution was poured into a collector through a back-pressure
regulator (8 MPa) and a tube (/ = 2.18 mm, L = 2.0 m). After a
steady state was reached, an aliquot of the product solution was
taken for 15 min. 1-Methyl-5-benzoyltetrazole was obtained in
4.1. General
Stainless steel (SUS316) union mixers with inner diameter of
1.3 and 2.3 mm were manufactured by BI-Lok Co., Inc. Stainless
steel (SUS304) tube reactors with inner diameter of 1.0, 2.18 and
3.76 mm were purchased from KUZE Co. Ltd. The mixer and tube
reactors were connected with stainless steel fittings (BI-Lok Co.,
Inc., 1/16, 1/8, 3/16 and 1/4OUW). The flow system was dipped
in an oil bath to control the temperature. Solutions were intro-
duced to the flow reactor system using plunger pumps (NIHON
SEIMITSU KAGAKU Model NP-FX-60 and SHIMADZU Model
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4
D. Ichinari et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
MeN3
(12 wt% in toluene)
2.8 ml/min
200 oC
R3
back pressure
regulator
PhCOCN
(1.05 eq)
R2
R1
M
P2
P1
6.35 ml/min
O
toluene
N
0 oC
N
toluene
N
N
Me
78%
Fig. 5. A schematic diagram of the flow system for synthesis of 1-methyl-5-benzoyltetrazole.
LC-10AS). TESCOM Model 44-2300 series or 26-1700 Series were
used as back pressure valve.
HPLC analyses for MeN3 and NaN3 were performed on a SHI-
MADZU LC-20AT liquid chromatograph equipped with a UV detec-
chromatography, wavelength = 210 nm, tR 4.5 min). The conver-
sion of NaN3 was determined by HPLC analysis of the aqueous
layer (reversed phase chromatography, wavelength = 210 nm,
tR 3.1 min). The results obtained with different temperatures,
amounts of sodium hydroxide, and amounts of dimethyl sulfate
are summarized in Tables 1 and 2. The spectral data were identical
to those reported in the literature.18
tor using a HPLC column (Waters X-bridge BEH C18 Column, 5
4.6 mm  250 mm; oven temperature, 40 °C; flow rate 1.0 ml/min
(CH3CN:H2O:KH2PO4:SDS:10% H3PO4 = 400:600:1.2:1.0:0.5
lm,
(v/v/wt/wt/v))). HPLC yield was determined by using ethyl
benzoate, tR (15.2 min) as an internal standard.
HPLC analysis for 1-methyl-5-benzoyltetrazole was performed
on a SHIMADZU LC-10AT liquid chromatograph equipped with an
UV detector using a HPLC column (GL-Science Nucleosil 100-5CN
4.3. Continuous operation of the flow synthesis of MeN3
A flow reactor system consisting of two pre-heating units (P1
(/ = 1000 lm, L = 4 m), and P2 (/ = 1000 lm, L = 4 m)), a T-shaped
Column, 5
l
m, 4.6 mm  250 mm; tR (1-methyl-5-benzoyltetra-
mixer (M), four tube reactors (R1, R2, R3, and R4), and a back-pres-
sure regulator was used. A mixture of NaN3 (4.0 M) and sodium
hydroxide (0.60 M) in water (21 or 34 ml/min), and a solution of
dimethyl sulfate (4.0 M) in toluene (22 or 35 ml/min) were intro-
duced to M (/ = 1.3 mm) by using plunger pumps. The resulting
solution was passed through R1 (/ = 1.0 mm, L = 1.0 m) and
R2 (/ = 3.76 mm, L = 5 m (21 and 22 ml/min) or 8 m ((34 and
35 ml/min))) in oil bath (120 °C), and was then passed through
R3 (/ = 2.18 mm, L = 6.0 m) in ice-water bath (0 °C). The resulting
zole) 15.3 min, tR (PhCOCN) 5.2 min; oven temperature, 40 °C; flow
rate 1.0 ml/min (hexane: ethyl acetate = 20:1). The yield of
1-methyl-5-benzoyltetrazole was determined by using methyl-o-
anisate, tR (9.8 min) as an internal standard (78%, 12.1 g). GC anal-
ysis of unchanged MeN3 was performed on a SHIMADZU GC-14B
gas chromatograph equipped with a flame ionization detector
using packed column (Gaskuropack 5480/100). (tR (MeN3)
4.7 min; initial oven temperature, 100 °C for 10 min; rate of tem-
perature increase, 5 °C/min)) using acetonitrile tR (9.2 min) as an
internal standard.
solution was collected through
a
back-pressure regulator
(0.9 MPa) and a tube (/ = 2.18 mm, L = 2.0 m). After a steady state
was reached, an aliquot of the product solution was taken for
10 min or 61 min. After the reaction solution was separated
into organic layer and aqueous layer, the yield of MeN3, and the
conversion of NaN3 were determined by HPLC.
1H and 13C NMR spectra were recorded on JOEL-400
(1H 400 MHz and 13C 100 MHz) spectrometer with Me4Si or CDCl3
as a standard in CDCl3. NaN3, dimethyl sulfate, and toluene were
purchased from Wako Co., Inc. Benzoyl cyanide was purchased
from Zaoyang Xianfei High-tech Pesticide Co., Ltd, and was distilled
before use.
4.4. Synthesis of 1-methyl-5-benzoyltetrazole using the flow system
4.2. Synthesis of MeN3 using the flow system
A flow reactor system consisting of a T-shaped mixer (M), four
tube reactors (R1, R2, and R3), and a back-pressure regulator was
used. A mixture of MeN3 (12.0 wt%) and PhCOCN (28.9 wt%
(1.05 eq)) in toluene (flow rate: 2.8 mL/min) was passed through
R1 (/ = 3.36 mm, L = 20.5 m, 65 min) in oil bath (200 °C). The
resulting solution was further diluted with toluene, which was
A flow reactor system consisting of two pre-heating units (P1
(/ = 1000 lm, L = 4 m), and P2 (/ = 1000 lm, L = 4 m)), a T-shaped
mixer (M), four tube reactors (R1, R2, and R3), and a back-pressure
regulator was used. A mixture of NaN3 (1.0–4.0 M) and NaOH
(0.20–0.60 M) in water, and
a
solution of dimethyl sulfate
preheated through two pre-heating units (P1 (/ = 1000
and P2 (/ = 2.18 mm, L = 4 m)) (flow rate: 6.35 mL/min) in
(/ = 2.3 mm). The resulting solution was passed through
lm, L = 4 m)
(3.5–9.0 M) in toluene were introduced to M (/ = 1.3 mm) by
using plunger pumps. The resulting solution was passed through
R1 (/ = 1.0 mm, L = 1.0 m) and R2 (/ = 2.18 mm, L = 10 m) in oil
bath (T °C), and was then passed through R3 (/ = 2.18 mm,
L = 6.0 m) in ice-water bath (0 °C) to stop the reaction. The result-
ing solution was collected through a back-pressure regulator
(0.9 MPa) and a tube (/ = 2.18 mm, L = 1.0 m). After a steady state
was reached, an aliquot of the product solution was taken for
5 min. Then, after the reaction solution was separated into an
organic layer and an aqueous layer, the yield of MeN3 was
determined by HPLC analysis of the organic layer (reversed phase
M
R2 (/ = 3.36 mm, L = 0.5 m, 0.5 min) at 200 °C and was passed
through R3 (/ = 4.35 mm, L = 10 cm) at room temperature to stop
the reaction. The product solution was collected through a back-
pressure regulator (8 MPa) and a tube (/ = 2.18 mm, L = 2.0 m).
After a steady state was reached, an aliquot of the product solution
was taken for 15 min. The amounts of unchanged MeN3 (13%) and
PhCOCN (12%) were determined by GC-FID analysis. The yield of
1-methyl-5-benzoyltetrazole12b was determined by HPLC analysis.
1H NMR (400 MHz, CDCl3) 8.45 (dd, J = 6.4 Hz, 0.8 Hz, 2H), 7.72
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D. Ichinari et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
5
(t, J = 7.2 Hz, 1H), 7.57 (dt, J = 7.6 Hz, 1.6 Hz, 2H), 4.40 (s, 3H); 13C
NMR (100 MHz, CDCl3) 36.8, 128.6, 130.8, 134.6, 134.9, 149.4,
181.0; MS (ESI) m/z calcd for C9H8N4O1 ([M+H]+): 189.0771,
found: 189.0767.
19. (a) Ehrfeld W, Hessel V, Löwe H. Microreactors. Weinheim, Germany: Wiley-
VCH; 2000;
(b) Hessel V, Hardt S, Löwe H. Chemical Micro Process Engineering. Weinheim,
Germany: Wiely-VCH; 2004;
(c) Hessel V, Renken A, Schouten JC, Yoshida J. Micro Process
Engineering. Chichester, United Kingdom: Wiley-Blackwell; 2009;
(d) Wirth T. Microreactors in Organic Chemistry and Catalysis. New York, United
States: Wiley; 2013.
Acknowledgments
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2004;43:406–446;
This work was partially supported by the Grant-in-Aid for Sci-
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Research on Innovative Areas 2707 Middle molecular strategy from
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Please cite this article in press as: Ichinari D., et al. Bioorg. Med. Chem. (2017), http://dx.doi.org/10.1016/j.bmc.2017.07.005