Continuous-Flow Process for the Synthesis of 5-Nitro-1,4-dihydro-1,4-methanonaphthalene

Article abstract of DOI:10.1021/acs.oprd.8b00281

In this article, we describe a safe and practical process for the synthesis of 5-nitro-1,4-dihydro-1,4-methanonaphthalene (1) via a continuous-flow reactor. The primary procedures in this process involved not merely the production of isoamyl nitrite but also the temperature-programmed Diels-Alder reaction of an aryne (derived from 2-amino-6-nitrobenzoic acid) with cyclopentadiene in the series flow reactor. The continuous-flow process minimized the accumulation of dangerous isoamyl nitrite and the energetic diazonium salt, and the entire reaction time was held down to 250 s.

Full text of DOI:10.1021/acs.oprd.8b00281

Subscriber access provided by TULANE UNIVERSITY
Full Paper
Continuous-flow process for the synthesis of 5-
amino-1,2,3,4-tetrahydro-1,4-methano-naphthalen-9-ol
Zhiyong Tan, Zhen-Hua Li, Guoqiang Jin, and Chuanming Yu
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00281 • Publication Date (Web): 20 Dec 2018
Downloaded from http://pubs.acs.org on December 20, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 20
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Continuous-flow process for the synthesis of
5-amino-1,2,3,4-tetrahydro-1,4-methano-napht
halen-9-ol
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Zhiyong Tana, Zhenhua Lia,* Guoqiang Jina, and Chuanming Yub*
aKey Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of
Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Chao Wang
Road 18th, 310014, Hangzhou, P. R. China
bNational Engineering Research Center for Process Development of Active Pharmaceutical
Ingredients, Collaborative Innovation Center of Yangtze River Delta Region, Green
Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. China
Email: lizhenhua@zjut.edu.cn; ycm@zjut.edu.cn
ACS Paragon Plus Environment

Organic Process Research & Development
Page 2 of 20
1
2
3
4
5
Table of Contents graphic
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Page 3 of 20
Organic Process Research & Development
1
2
3
4
5
6
7
8
Abstract. In this article, we described a safe and practical process for the synthesis of
5-amino-1,2,3,4-tetrahydro-1,4-methano-naphthalen-9-ol (1) via a continuous-flow
reactor. The primary procedures in this process involved not merely the produce of
isoamyl nitrite but also the temperature-programmed Diels-Alder reaction by aryne
(derived from 2-amino-6-nitrobenzonic acid) with cyclopentadiene in the series flow
reactor. The continuous-flow process minimized the accumulation of dangerous
isoamyl nitrite and energetic diazonium salt, and the entire reaction time was hold
down to 250 s.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Keywords. Continuous-flow reaction, Isoamyl nitrite, Diazotization, Diels–Alder
reaction, Aryne
ACS Paragon Plus Environment

Organic Process Research & Development
Page 4 of 20
1
2
3
4
1. Introduction
5
6
7
8
Benzonorbornadienes play increasingly important roles in areas of synthetic
organic chemistry, catalysis, supermolecule, material science and medicinal
chemistry.1 The Diels-Alder reaction of arynes with diene is an efficient route to
benzonorbornadienes. In recent decades, many compounds such as anthranilic acids,
fluoroanisole, bis-(2-iodophenyl)-mercury, 2-(trimethylsilyl)-aryl triflates, triynes, etc
have been utilized to produce the aryne species.2 Among them, inexpensive and
convenient anthranilic acids has an enormous appeal which is regarded as a classical
aryne precursor. Intriguingly, this process is industrially unattractive, for it’s highly
dangerous and often has low yield, especially in large-scale manufacture.3 It is
because of certain unstable reactive species like diazotization reagent,
benzenediazonium and aryne. The objective of this account is to develop a safe and
efficacious way to generate arynes with anthranilic acids.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-amino-6-nitrobenzonic acid (2) was chosen for this study, and its Diels-Alder
reaction product (1) is an important intermediate for the synthesis of some popular
drugs such as benzovindiflupry and isopyrazam.4 Preparation of 1 can be finished by
diazotization of 2-amino-6-nitrobenzonic acid to form diazonium salt, which is
intended to develop the final product by the liberation of nitrogen and carbon dioxide .
Presently, literatures references about this process mostly focus on bench-scale in
batch vessel.5 A serious drawback of this method is the hazardous nature of alkyl
nitrites and diazonium compounds. Alkyl nitrites are easily to form explosive
mixtures with air or oxygen due to they are air sensitive, light sensitive and
flammable.6 What’s more, the energetic intermediates 3 and 4 are extremely
unstable.7 When run under conditions of comparatively high temperature or
non-uniform stirring environment, they may produce explosions of great violence.
Imperfect mixture in the large vessel may bring about the undesired products as a
result of the superior reactivity of the diazonium intermediate salt and aryne (Scheme
1).
As a part of our uninterrupted efforts to study continuous-flow processes, we
determined to adapt the continuous flow synthesis technology to manufacture of 1 to
ACS Paragon Plus Environment

Page 5 of 20
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
address these safety issues.8 Continuous-flow technology has some promising
advantages over batch methods, including precise regulate of stoichiometry, short
holding time, low backmixing, high repeatability, easy industrialized, and generally
better yields.9 By increasing surface-to-volume ratio under flow conditions, the mass
and heat transfer can be improved considerably. Moreover, potential safety problems
in operating exothermic reactions combined with energetic intermediates are
minimized because of the much smaller on-line volume.10
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2. Results and Discussion
Switch from Batch to Continuous-Flow Esterification. Isoamyl nitrite is widely
used in pharmaceutical chemicals, and the study of diazotization with isoamyl nitrite
has already been carried out.11 As such, a large number of methods for the synthesis
of isoamyl nitrite have been documented.12 One of the most economical methods is to
take NaNO2/HCl as the esterifying reagent. Nevertheless, large amounts of yellow
smoke spewed from the batch vessel during the pilot production process. Then, in this
paper, it was hypothesized that isoamyl nitrite decomposed violently in the vessel and
released highly toxic nitric oxide. The reason lies in the strong action of back mixing
on isoamyl nitrite and hydrochloric acid solution. Therefore, it is important to separate
isoamyl nitrite from the reaction vessel in time. Several groups have investigated the
use of the continuous system for the generation and online separation of potentially
hazardous products.13 Analogously, we utilized a continuous-flow reactor to produce
isoamyl nitrite, and the reaction mixture was separated in a liquid-liquid separator
under nitrogen protection, which maintained the least possible on-line volume of
isoamyl nitrite.
ACS Paragon Plus Environment

Organic Process Research & Development
Page 6 of 20
1
2
3
4
Scheme 1. Schematic for the preparation of isoamyl nitrite a
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aIsoamylol in 1.1 equivalent of hydrochloric acid flow through P1; aqueous solution of sodium
nitrite flow through P2 . Residence loop I is a PTFE tube with 1.5 mm i.d. and 3 mm o.d.. The
static mixer (PTFE, 1.5 mm i.d., 3 mm o.d., 10 mm length, two mixing elements with a twist angle
of 90°) and loop I were in the same thermostatic bath. The liquid-liquid separator is a separating
funnel with a jacket in which the cooling fluid at 0 °C can be passed.
The continuous-flow setup is shown in Scheme 1. Two individual feed streams (a
mixture of isoamylol and hydrochloric acid; aqueous solution of sodium nitrite) were
introduced into a loop reactor (PTFE, 1.5 mm i.d., and 3 mm o.d.) via a T-joint (PTFE,
1.5 mm i.d.) and static mixer by two peristaltic pumps (P1, P2, Baoding Longer,
China), respectively. The dosage of isoamylol, hydrochloric acid and sodium nitrite
was put in-line with their ratios in batch.12c In particular, the static mixer and reaction
loop was sink into the constant-temperature bath, and the reaction mixture flowed into
a liquid-liquid separator. Then, the organic phase was applied to the next step directly,
and the water phase was removed by the valve. The test parameters were methodically
explored through the variation of holding time (τ1) and temperature (T1). 4.5 M
isoamylol in 1.1 equivalent of hydrochloric acid flow through P1 with a velocity of 1.0
mL/min, and 5.5 M sodium nitrite solution flow through P2 with a velocity of 0.9
mL/min. The purity of isoamyl nitrite became one of the most important indexes since
we expected the isoamyl nitrite to be used for the next step directly after extraction by
the liquid-liquid separator under nitrogen protection. The results were exhibited in
Figure 1. The maximum purity of 96% (GC isoamylol content: 3%) was gained when
τ1 = 200 s and T1 = 0 °C, and an excellent yield of 94% was achieved in the
meanwhile. Neither long τ1 with high T1 nor short τ1 with low T1 can improve the
purity of isoamyl nitrite. The increase of the temperature could quicken the rate of the
ACS Paragon Plus Environment

Page 7 of 20
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
esterification reaction. Nonetheless, higher temperature together with longer holding
time leaded to the reduction of purity. The dosage of sodium nitrite was subsequently
investigated. Molar flow ratios of isoamylol to sodium nitrite were differed by means
of accommodating the flow rate of sodium nitrite solution. The results showed that
sodium nitrite seemed to be slightly higher than 1.05 equiv, while much fewer doses
leaded to the low conversion rate of isoamylol.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Effect of temperature and holding time on esterification. The purity of isoamyl nitrite
were detected by GC chromatography.
Switch from Batch to Continuous-Flow Diazotation. With esterification
parameters in hand, we undertook the optimization of Diels-Alder reaction with aryne.
For abounding industrial procedures covered, the diazotization of aromatic amines
had been well studied.14 In the reported procedure for the conversion of 2 to 1, 18
equivalents of cyclopentadiene were added, and the mixture was heated to reflux
overnight. Then, the reaction mixture was filtered, and 1 was gained in 58% yield
after column chromatographic separation.5a,15 The drawbacks of this process are
chiefly in the safety concerns and low yield, and therefore the method for producing
aryne by heating 2 failed to get the attention of industry. Several mechanistic
pathways have been considered to account for the various byproducts when
benzenediazonium 2-carboxylate is allowed to decompose in the presence of
nucleophilic reagents.16 Many undesired coupling products may be formed easily in
the inadequate stirring vessel (Scheme 2). Apparently, side reactions were mainly
caused by 3 and 4, and the application of the flow reaction technology is a powerful
ACS Paragon Plus Environment

Organic Process Research & Development
Page 8 of 20
1
2
3
4
5
6
7
8
9
tool to minimize these side reactions. At present, many reports on continuous-flow
diazotization followed by different functional reaction such as chlorosulfonylation,
iododeamination and azo dyes have been published.17 Surprisingly, to the best of our
knowledge, no study has yet described the optimization of Diels-Alder reaction of
aryne (derived from decomposition of benzenediazonium 2-carboxylates) under a
continuous mesoscale process.18 According to our previous works on continuous
processes of diazotization using millimeter scale reactors,8 herein, we plan to apply
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
this technology to the synthesis of 1.
Scheme 2. The reaction mechanism of 1 from 2-amino-6-nitrobenzonic acid
Before we set about developing the continuous-flow diazotation, preliminary
experiments in batch manner were conducted to verify the method. To avoid
hydrolysis of reactive intermediate 3 and 4 to hydroxybenzene as much as possible,
we needed anhydrous diazotization reaction instead of traditional diazotization in the
acidic aqueous solution. Preliminary optimization experiments showed that acid
environment is essential to facilitate the diazotization.19 As indicated by the results,
acid additives could improve the yield of 1 (Table 1, entries 1 and 2). Nevertheless,
we clearly observed a yield decrease when increasing the acidity of the additives
(Table 1, entries 3). The possible reason was that hydrogen ion could not only assist
in the formation of diazonium salt, but accelerate the decomposition of isoamyl nitrite
(Table 1).20 There was an improved product yield of 1 with our preliminary
optimization, and these trials signified a bright possibility to switch to
continuous-flow. But these conditions were too harsh for directly use in a flow reactor
due to the low solube diazonium salt 3.
ACS Paragon Plus Environment

Page 9 of 20
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Table 1. Screening acid additives of cycloaddition in batch
Entrya
Additive
none
Yield(%)
Purityb(%)
1
2
3
4
37
72
67
64
96
95
95
95
CH3COOH
CCl3COOH
CF3COOH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aReaction condition: 2 (0.1 mol), cyclopentadiene (3
equiv.), isoamyl nitrite (1.1 equiv.), additive (1.0
b
equiv.), 50 °C. The analysis of crude 1 based on
HPLC.
In order to avoid being clogged, we designed an initial program to develop a
semi-continuous process involving first the synthesis of diazonium salt in continuous
flow followed by the Diels-Alder reaction in a flask with cyclopentadiene. Choosing a
proper solvent is of great importance to our further experiments. Experiments were
done with the continuous-flow system as depicted in Scheme 3; several inactive
solvents, diethylene glycol dimethyl ether (ether), toluene (aromatic), ethyl acetate
(ester), and 1,2-dichloroethane (halogenated hydrocarbon) were evaluated in this
study. 5.4 mL solvent was added to every 1g of 3. As the experimental results
suggested, diethylene glycol dimethyl ether (DG) was an ideal medium since DG had
better solubility for 3 than other solvents thereby avoiding the pipe plugging. In
addition to that, DMF and DMSO had a good solubility to 3, however they can react
with 4.21
After the reaction solvent was selected, further improvement of this project began
with continuous diazotization, followed by cycloaddition reaction in batch. The figure
of simple experimental instrument was shown in Scheme 3. The device contained two
plunger metering pumps (P3, P4, PTFE, WOOK, China) to introduce the feed streams
of 2 and isoamyl nitrite, respectively. A T-joint (Hastelloy SS316L, 2 mm i.d.) was
coupled with the reaction loop (Hastelloy SS316L, 2 mm i.d., and 4 mm o.d.). The
solution from loop II then got into a T-joint and incorporated with a stream of
cyclopentadiene, which was transfered by pump (P5, PTFE, WOOK, China). The
molar flow ratio among 2, nitrite, and cyclopentadiene was established in terms of
their equivalents in batch. Then, the mixture entered a stirring reaction vessel, which
ACS Paragon Plus Environment

Organic Process Research & Development
Page 10 of 20
1
2
3
4
5
6
7
8
9
is kept warm at 50 °C. After the reaction was completed, the solvent was removed
from the reaction mixture by distillation, and the residues refluxed in hexane to
extract the crude product 1. What calls for special attention is that the formation of
intermediate 3 with the improper solvent would cause serious pipe clogging. What’s
more, 3 was potentially shock sensitive and may violently detonate when dry, and it
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ought to be kept wet with solvent at all times.
Scheme 3. Schematic for the preparation of 1a
aIsoamylol in 1.1 equiv of hydrochloric acid flow through P1; solution of sodium nitrite
flows through P2; 2-amino-6-nitrobenzonic acid in DG flow through P3; isoamyl nitrite flow
through P4; cyclopentadiene flow through P5. Residence loop I is a PTFE tube with 1.5 mm
i.d. and 3 mm o.d., Residence loop II is an SS316L tube with 2 mm i.d. and 4 mm o.d..
We systematically investigated the experimental parameters by shifting holding
time (τ2) and temperature (T2). 1.0 M 2 in 1.0 equivalent of acetic acid in DG were
pumped by P3 (15.0 mL/min). Isoamyl nitrite was pumped by P4 (1.6 mL/min), and
10.0 M cyclopentadiene was pumped by P5 (4.5 mL/min). The cycloaddition reaction
conditions were in-line with the batch methods (50 °C). The results were shown in
figure 2, and the yield was increased with time, but reach a maximum after a lengthy
holding time at less than 5 °C. When the temperature was higher than 10 °C, the yield
was noticeably decreased. That came out of the rate of side reaction overwhelmed the
subsequent Diels-Alder reaction. Increasing the reaction temperature could bring
about the violent decomposition of diazonium salt 3 to byproducts (Scheme 2). The
highest yield of 75% was gained when τ2 = 20 s and T2 = 0 °C.
ACS Paragon Plus Environment

Page 11 of 20
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. Effect of temperature and holding time on diazotization. Yields of 1 were calculated from 2
The dosage of isoamyl nitrite was subsequently investigated. Molar flow ratios of
isoamyl nitrite to 2 changed when aligning the flow rate of isoamyl nitrite.
Experiment data were exhibited in Table 2. A lightly excessive isoamyl nitrite (1.02
equiv) was allowed. The yield of 1 was decreased when too much isoamyl nitrite was
loaded. Reasons were that excessive isoamyl nitrite may drive the decomposition of
diazonium, and an overdose of isoamylol, from the decomposition of isoamyl nitrite,
would have a competitive side reaction with 4.21
Table 2. Effect of the isoamyl nitrite amount
Isoamyl nitrite/2 a
Yieldb (%)
1.00
1.01
1.02
1.03
1.04
70
72
75
75
73
aMolar flow ratios of isoamyl nitrite to 2 .
bYields of 1 were calculated from 2.
Advanced Continuous-Flow Process. The continuous-flow procedure of
esterification and diazotization was victoriously running. But, the improved the yield
of 1 was still not obvious, and the safety issue caused by diazonium accumulation
failed to be completely abolished. An improved procedure was then drafted (Scheme
4). Diazonium 3 and intermediate 4 were formed in different conditions in the
ACS Paragon Plus Environment

Organic Process Research & Development
Page 12 of 20
1
2
3
4
5
6
7
8
9
temperature-programmed loop reactor. Excellent results were obtained by the flowing
1.0 M 2 solution together with isoamyl nitrite for a holding time of 20 s at 0 °C. It was
followed by the introduction of 10.0 M cyclopentadiene into the tube reactor and then
the mixture proceeded to the Diels-Alder reaction in Loop III. The reaction solution
discharged from Loop III was poured continuously into the collection vessel which
doesn't require constant temperature. Residence loop III was immersed in a hot oil
bath, and the temperature was controlled by a thermostat. The nitrogen and carbon
dioxide released in the cycloaddition step may give rise to uncontrollable holding time
in a flow reactor. Thus, a back-pressure regulator (BPR) was selected to be installed
in the tail of the reactor, and the back pressure was set to 100 psi. The flow rate of
three solutions were 15.0, 1.6, and 4.5 mL/min, respectively. The molar flow ratio of
2 to isoamyl nitrite to cyclopentadiene was 1.0:1.02:3.0. The loop II and loop III were
of the same specification (Hastelloy SS316L, 2 mm i.d., and 4 mm o.d.). On the
premise of keeping the same flow rates, holding time (τ3) was researched by changing
the tube length. The temperature (T3) of Loop III was explored according to the batch
process (50 °C). With these restructuring, the yield of 1 was increased to 85% in 99%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
purity when τ3 = 30 s, T3 = 120 °C.22
Scheme 4. Schematic of the advanced experimental setup for the preparation of 1a
a4.5 M isoamylol in 1.1 equiv of hydrochloric acid flow through P1; 5.5 M aqueous solution of
sodium nitrite flow through P2; 1 M 2-amino-6-nitrobenzonic acid in DG flow through P3;
isoamyl nitrite flow through P4; 10 M cyclopentadiene flow through P5. Residence loop I is a
PTFE tube with 1.5 mm i.d. and 3 mm o.d., Residence loop II and III are an SS316L tube
with 2 mm i.d. and 4 mm o.d..
To underline the advantages of the aforementioned optimal flow program, a
comparison with the reaction performance in the batch manner was shown. It was
evident that this advanced continuous-flow process has many advantages in this
ACS Paragon Plus Environment

Page 13 of 20
Organic Process Research & Development
1
2
3
4
5
6
Diels-Alder reaction (Table 3). Experimental details can be found in the Experimental
Section.
7
8
9
Table 3. The comparison of the batch process with a continuous process
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methods
Batch
Continuous-flow
Yield(%)
Purity(%)
72
95
85
99
Diazotization:
20 s
Reaction
time
hours
Cycloaddition:
30 s
3. Conclusion
In summary, we have set up an expeditious and high-yielding process for the
synthesis of 5-amino-1,2,3,4-tetrahydro-1,4-methano-naphthalen-9-ol via
a
continuous-flow reactor. Adopting flow technology to minimized safety issues caused
by isoamyl nitrite and unstable diazonium salt intermediate has become an efficacious
way. This continuous process readily adapt to the manufacture of benzonorbornadiene
derivatives and can easily be scaled up with several high-throughput reactors in
parallel.
4. Experimental section
4.1. General
Compound 2 was provided by Hangzhou Beyond & Upgrade Technology Co., Ltd.,
and all other chemicals were purchased from commercial sources and were used
without further purification. Melting points were determined on a Büchi 540 melting
point apparatus and were uncorrected. H (600 MHz) NMR, 13C (100 MHz) NMR
1
spectra were recorded on a Varian spectrometer in CDCl3 using tetramethylsilane
(TMS) as internal standards. Mass spectra were measured with a low-resolution MS
instrument using ESI ionization. HPLC analysis was carried out on an Agilent HPLC
system (series 1200, Agilent Technologies, Germany) equipped with Agilent Welch
Welchrom-C18 reversed-phase column (250 mm × 4.6mm, 5 μm). A mobile phase of
ACS Paragon Plus Environment

Organic Process Research & Development
Page 14 of 20
1
2
3
4
5
6
7
8
9
acetonitrile and water (80:20) was used at a flow rate of 1.0 mL/min and a column
temperature of 25 °C. The UV detector was set at 230 nm to analyze the column
effluent. The HPLC analysis data was reported in area % and not adjusted to
weight %. Gas chromatography (GC) analysis was carried out on an Agilent 7890B
gas chromatograph. GC conditions: nitrogen pressure (0.06 MPa), injection temp.:
200 °C, detector temp.: 210 °C, oven: 60 °C.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4.2. Synthesis of isoamyl nitrite with continuous-flow process
As shown in Scheme 1, isoamylol (88 g, 1.0 mol), aqueous hydrogen chloride
(111.5 g, 1.1 mol ), and sodium nitrite (72.4 g, 1.05 mol) in 115 g H2O were pumped
into the flow reactor via a T-joint and a static mixer by P1 and P2 at flow rates of 1
mL/min and 0.9 mL/min, respectively, after a holding time of 200 s at 0 °C in
residence loop I (PTFE, 1.5 mm i.d., 3 mm o.d.), the mixture flowed through the
outlet and accumulated in the liquid-liquid separator. The water layer is continuously
separated and the organic layer is continuously collected. After the flow reaction was
finished, isoamyl nitrite as pale yellow liquid in 94% yield and 96% purity was
obtained.
4.3. Synthesis of 5-nitro-1,4-dihydro-1,4-methano-naphthalene(1) in batch
Acetic acid (9 g, 0.15 mol) was diluted with 70 mL of dichloromethane. This
solution was held at 40 °C while a solution of 2 (27.3 g, 0.15 mol) and
cyclopentadiene (14.85 g, 0.45 mol) in acetone (60 mL), and isoamyl nitrite (18.43 g,
1.05 mol) was respectively and simultaneously added dropwise within 1 h, then
stirring at 50 °C for 3 h. The reaction mixture was cooled to 25 °C, filtered through a
pad of Celite, and evaporated. The resulting brown oil was refluxing 3 times with
hexane (150 mL), gave 19.9 g of 1 (mp 44.1-45.3 °C), which was dried in vacuum
drying oven. Yield: 72%. Spectral data: 1H NMR (600 MHz, Chloroform-d) δ 7.67 (d,
J = 8.4 Hz, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.04 (dd, J = 8.4, 7.2 Hz, 1H), 6.86 (m, 2H),
4.84 (s, 1H), 3.99 (m, 1H), 2.35 (dt, J = 7.8, 1.2 Hz, 1H), 2.27 (d, J = 7.2 Hz, 1H). 13C
NMR (100 MHz, Chloroform-d) δ 155.73, 148.66, 144.38, 143.84, 142.10, 126.32,
125.43, 119.39, 69.17, 50.32. MS m/z (ESI): 187.1 M+.
4.4. Synthesis of 5-nitro-1,4-dihydro-1,4-methano-naphthalene (1) with advanced
ACS Paragon Plus Environment

Page 15 of 20
Organic Process Research & Development
1
2
3
4
Continuous-flow process.
5
6
7
8
As shown in Scheme 4, 2-amino-6-nitrobenzoic acid (273 g, 1.5 mol), acetic acid
(90 g, 1.5 mol ) in 1420 g of DG, and isoamyl nitrite (soaking up the organic layer
from liquid-liquid separator) were pumped into the flow reactor via a T-joint by P3
and P4 at flow rates of 15.0 and 1.6 mL/min, respectively, after a holding time of 20 s
at 0 °C in residence loop II (Hastelloy SS316L, 2 mm i.d., 4 mm o.d.);
cyclopentadiene (297 g, 4.5 mol) in 425 g DG was introduced into the reactor via
T-joint by P5 at a flow rate of 4.5 mL/min and contacted with diazonium salt, after
another holding time of 30 s at 120 °C in residence loop III (Hastelloy SS316L, 2mm
i.d., 4 mm o.d.) and the mixture flowed through the end of the loop and discharged the
solution into the collection vessel. The pressure in reactor was regulated under 100 psi
by a BPR. DG and cyclopentadiene was recovered by distillation and the resulting
brown oil was refluxing 3 times with hexane (1500 mL). 242 g of crude product 1 as
pale yellow solid in 86% yield and 99.3% HPLC purity was obtained.
P3 the measurement range of 50.00 mL/min, P4 and P5 had a measurement range of
10.000 mL/min. All plunger metering pumps were set a built-in automatic pressure
shut-down device to prevent reactor from overpressure.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ASSOCIATED CONTENT
Supporting Information
1H/13C NMR, and HPLC spectra for compound 1; GC spectra for isoamyl nitrite.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: lizhenhua@zjut.edu.cn.
*E-mail: ycm@zjut.edu.cn
ORCID
Zhen-Hua Li: 0000-0002-8092-3571
Chuanming Yu: 0000-0002-1345-0778
Notes
The authors declare no competing financial interest
ACS Paragon Plus Environment

Organic Process Research & Development
Page 16 of 20
1
2
3
4
Acknowledgment
5
6
7
8
This work was supported by the National Natural Science Foundation of China
(21376221 and 21506190).We thank Dr. Zhiqun Yu and Mr. Xiaoxuan Xie for
helpful discussions and input.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
References
1. (a) Wang, B. U.; Turner, D. A.; Zujovic´, T.; Hadad, C. M.; Badjic´, J. D. The
Role of Chirality in Directing the Formation of Cup-Shaped Porphyrins and the
Coordination Characteristics of such Hosts, Chem. Eur. J. 2011, 17, 8870 – 8881.
(b) Xu, M. H.; Tu, J. L.; Franzini, R. M. Rapid and Efficient Tetrazine-Induced
Drug Release from Highly Stable Benzonorbornadiene Derivatives, Chem.
Commun. 2017, 53, 6271-6274. (c) Medina, J. M.; Ko, J. H.; Maynard, H. D.; Garg,
N. K. Expanding the ROMP Toolbox: Synthesis of Air-Stable Benzonorbornadiene
Polymers by Aryne Chemistry, Macromolecules 2017, 50, 580−586. (d) Xu, M.;
Galindo-Murillo, R.; Cheatham, T. E. III.; Franzini, R. M. Dissociative Reactions
of Benzonorbornadienes with Tetrazines: Scope of Leaving Groups and
Mechanistic Insights, Org. Biomol. Chem. 2017, 15, 9855–9865.
2. (a) Wentrup, C. The Benzyne Story, Aust. J. Chem. 2010, 63, 979–986. (b) Pindur,
U.; Kim, Y.S. New Electrophilic Reactions of 2,2'-bisindolyls with Acid Chlorides
and Carbodienophiles, J. Hetero. Chem. 1996, 33, 623-631. (c) Dockendorff, C.;
Sahli, S.; Olsen, M.; Milhau, L.; Lautens, M. Synthesis of Dihydronaphthalenes via
Aryne Diels-Alder Reactions: Scope and Diastereoselectivity, J. Am. Chem. Soc.
2005, 127, 15028-15029.
3. (a) Friedman, L.; Logullo, F. M. Arynes via aprotic diazotization of anthranilic
acids, J. Org. Chem. 1969, 34, 3089-3092. (b) Petrillo, G.; Novi, M.; Garbarino, G.;
Dell’Erba, C. A Mild and Efficient SRN1 Approach to Diaryl Sulfides from
Arenediazonium Tetrafluoroborates, Tetrahedron, 1986, 42, 4007-4016.
4. (a) Villani, S. M.; Ayer, K.; Cox, K. D. Molecular Characterization of the sdhB
Gene and Baseline Sensitivity to Penthiopyrad, Fluopyram, and Benzovindiflupyr
ACS Paragon Plus Environment

Page 17 of 20
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
in Venturia Inaequalis, Plant Dis. 2016, 100, 1709-1716. (b) Kuznetsov, D.;
Cazenave, A. B.; Rambach, O.; Camblin, P.; Nina, M.; Leipner, J. Foliar
Application of Benzovindiflupyr Shows Non-Fungicidal Effects in Wheat Plants,
Pest manag. Sci. 2018, 74, 665-671. (c) Walter, H.; Tobler, H.; Gribkov, D.; Corsi,
C. Sedaxane, Isopyrazam and Solatenol: Novel Broad-Spectrum Fungicides
Inhibiting Succinate Dehydrogenase (SDH)-synthesis Challenges and Biological
Aspects, Chimia. 2015, 69, 425-434.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5. (a) Dumeunier, R.; Tombler, H. Process for the Preparation of Pyrazole Caraoxylic
Acid Amides, Patent WO 2011/131543, 2011. (b) Gribkov, D.; Stohler, R.; Vettiger,
T.; Rommel, M. Process for the Preparation of Pyrazole Caraoxylic Acid Amides,
Patent WO 2011/131546, 2011.
6. Yasuo Seto Alkyl nitrites, Drugs and Poisons in Humans. Springer, Berlin,
Heidelberg, 2015,153-158, DOI:10.1007/3-540-27579-7_17.
7. Roya,T.; Biju, A. T. Recent advances in molecular rearrangements involving aryne
intermediates, Chem. Commun., 2018, 54, 2580--2594.
8. (a) Guo, S. Z.; Yu, Z. Q.; Yu, C. M. Kilogram-Scale Synthesis of
2,4-Dichloro-5-fluorobenzoic Acid by Air Oxidation under the Continuous-Flow
Process, Org. Process Res. Dev. 2018, 22, 252-256. (b) Yu, Z. Q.; Zhou, P.C.; Liu,
J. M.; Wang, W. Z.; Yu, C. M.; Su, W. K. Continuous-Flow Process for Selective
Mononitration of 1-Methyl-4-(methylsulfonyl)benzene, Org. Process Res. Dev.
2016, 20, 199-203. (c) Yu, Z. Q.; Lv, Y. W.; Yu, C. M.; Su, W. K. A High-Output,
Continuous Selective and Heterogeneous Nitration of p-Difluorobenzene, Org.
Process Res. Dev., 2013, 17, 438–442. (d) Yu, Z. Q.; Lv, Y. W.; Yu, C. M. A
Continuous Kilogram-Scale Process for the Manufacture of o-Difluorobenzene,
Org. Process Res. Dev., 2012, 16, 1669–1672.
9. (a) Hessel, V. Novel Process Windows - Gate to Maximizing Process
Intensification via Flow Chemistry, Chem. Eng. Technol. 2009, 32, 1655-1681.(b)
Wahab, B.; Ellames, G.; Passey, S.; Watts, P. Synthesis of Substituted Indoles
Using Continuous flow Micro Reactors, Tetrahedron 2010, 66, 3861-3865. (c) Riva,
E.; Gagliardi, S.; Mazzoni, C.; Passarella, D.; Rencurosi, A.; Vigo, D.; Rencurosi,
ACS Paragon Plus Environment

Organic Process Research & Development
Page 18 of 20
1
2
3
4
5
6
7
8
9
A. Reaction of Grignard Reagents with Carbonyl Compounds under Continuous
flow Conditions, Tetrahedron 2010, 66, 3242-3247. (d) Wegner, J.; Ceylan, S.;
Kirschning, A. Flow Chemistry - A Key Enabling Technology for (Multistep)
Organic Synthesis, Adv. Synth. Catal. 2012, 354, 17-57. (e) Wiles, C.; Watts, P.
Continuous Flow Reactors: a Perspective, Green Chem. 2012, 14, 38-54.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10. (a) Kulkarni, A. A.; Kalyani, V. S.; Joshi, R. A.; Joshi, R. R. Continuous Flow
Nitration of Benzaldehyde, Org. Process Res. Dev. 2009, 13, 999-1002. (b)
Baxendale, I. R.; Ley, S. V.; Mansfield, A. C.; Smith, C. D. Multistep Synthesis
Using Modular Flow Reactors: Bestmann-Ohira Reagent for the Formation of
Alkynes and Triazoles, Angew. Chem., Int. Ed. 2009, 48, 4017-4021.
11. Perkin, A. G.; Steven, A. B. A product of the action of isoamyl nitrite on
pyrogallol, J. Chem. Soc., Trans. 1906, 89, 802-808.
12. (a) Khakyzadeh, V.; Vahidian, H. R.; Salarian, A. A.; Zolfigol, M. A. Synthesis,
Modeling and Optimization of Cyanide Antidote (3-methylbutyl) Nitrite using
Response Surface Methodology, Res. Chem. Intermed. 2016, 42, 2391-2398 (b)
Soloveichik, S. Process for the Production of Nitrous Esters, Patent US
1954/27114606A, 1954 (c) McDonough, J. A.; Johnston, D. W.; Thompson, P. M.
Point of use Generation of Amyl Nitrite, Patent US 2013/8987496B1, 2013 (d)
Karrer, P.; Balzano, S. Method for Preparing Alkyl Nitrites, Patent US
2003/0149292A1, 2003. (e) Yuan, X. J.; Li, Y.; Li, W. L.; Dong, L. Y. ; Wang, K.;
Fan, X.; Xia, W.; Hu, Y. R.; Xu, H. Y. Method and apparatus for preparing C1-C4
alkyl nitrite, Patent CN 2017/106831439 A, 2017.
13. (a) Movsisyan, M.; Delbeke, E. I. P.; Berton, J. K. E. T.; Battilocchio, C.; Ley, S.
V. Taming Hazardous Chemistry by Continuous Flow Technology, Chem. Soc.
Rev., 2016, 45, 4892--4928. (b) Castano, B.; Gallo, E.; Cole-Hamilton, D.; Dal
Santo, V.; Psaro, R.; Caselli, A.; Continuous flow asymmetric cyclopropanation
reactions using Cu(I) complexes of Pc-L-star ligands supported on silica as
catalysts with carbon dioxide as a carrier, Green Chem., 2014, 16(6), 3202–3209. (c)
Delville, M. M. E.; van Hest, J. C. M.; Rutjes, F. P. J. T. Ethyl diazoacetate
synthesis in flow, Beilstein J. Org. Chem., 2013, 9, 1813–1818.
ACS Paragon Plus Environment

Page 19 of 20
Organic Process Research & Development
1
2
3
4
5
6
14. Zollinger, H. Diazo Chemistry I: Aromatic and Heteroaromatic Compounds;
Wiley-VCH: Weinheim, Germany, 1994.
7
8
9
15. Snow, R. A.; Cottrell, D. M.; Paquette, L. A. Demonstration and Analysis of
Bridging Regioselectivity Operative during di-π-methane Photorearrangement of
Ortho-Substituted Benzonorbornadienes and anti-7,8-benzotricyclo[4.2.2.02,5]deca
-3,7,9-trienes, J. Am.Chem. Soc. 1977, 99, 3734-3744.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
16. Buxton, P. C.; Fensome, M.; Heaney, H.; Mason, K.G. Benzyne Formation and
the Stepwise Decomposition of Benzenediazonium-2-carboxylate:
A
Re-Investigation, Tetrahedron, 1995, 51, 2959-2968.
17. (a) Hessel, V. Novel Process Windows - Gate to Maximizing Process
Intensification via Flow Chemistry, Chem. Eng. Technol. 2009, 32, 1655-1681.(b)
Wahab, B.; Ellames, G.; Passey, S.; Watts, P. Synthesis of Substituted Indoles
Using Continuous flow Micro Reactors, Tetrahedron 2010, 66, 3861-3865. (c) Riva,
E.; Gagliardi, S.; Mazzoni, C.; Passarella, D.; Rencurosi, A.; Vigo, D.; Rencurosi,
A. Reaction of Grignard Reagents with Carbonyl Compounds under Continuous
flow Conditions, Tetrahedron 2010, 66, 3242-3247. (d) Wegner, J.; Ceylan, S.;
Kirschning, A. Flow Chemistry - A Key Enabling Technology for (Multistep)
Organic Synthesis, Adv. Synth. Catal. 2012, 354, 17-57. (e) Wiles, C.; Watts, P.
Continuous Flow Reactors: a Perspective, Green Chem. 2012, 14, 38-54. (f) Yu, Z.
Q.; Tong, G.; Xie, X. X.; Zhou, P. C.; Lv, Y. Y.; Su, W. K. Continuous-Flow
Process for the Synthesis of 2-Ethylphenylhydrazine Hydrochloride, Org. Process
Res. Dev. 2015, 19, 892-896.
18. Browne, D. L.; Wright, S.; Deadman, B. J.; Dunnage, S.; Baxendale, I. R.; Turner,
R. M.; Ley, S. V. Continuous flow reaction monitoring using an on- line
miniature mass spectrometer, Rapid Commun. Mass Spectrom. 2012, 26,
1999–2010
19. Logullo, F. M.; Seitz, A. H.; Friedman, L. Benzenediazonium-2-Carboxylate and
Biphenylene, Org. Synth. 1968, 48, 12-7.
20. Yunker, M. H.; Szulczewski, D.; Higuchi, T. Kinetics of the Degradation of
Isoamyl Nitrite in Ampuls I, J. Am. Pharm. Assoc. 1958, 47, 613-620.
ACS Paragon Plus Environment

Organic Process Research & Development
Page 20 of 20
1
2
3
4
5
6
7
8
9
21. (a) Okuma, K.; Nojima, A.; Nakamura, Y.; Matsunaga, N.; Nagahora, N.; Shioji,
K. B. Reaction of Benzyne with Formamides and Acetylimidazole, Chem. Soc. Jpn.
2011, 84, 328-332. (b) Liu, F. L.; Chen, J. R.; Zou, Y. Q.; Wei, Q.; Xiao, W. J.
Three-Component Coupling Reaction Triggered by Insertion of Arynes into the
S=O Bond of DMSO, Org. Lett. 2014, 16, 3768-3771.(c) Li, H.Y.; Xing, L.J.; Lou,
M.M.; Wang, H.; Liu, R.-H.; Wang, B. Reaction of Arynes with Sulfoxides, Org.
Lett. 2015, 17, 1098-1101.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
22. The yield was based on the amount of 2-amino-6-nitrobenzonic acid. and the
purity was detected by HPLC (see supporting information).
ACS Paragon Plus Environment