Handling Hazards Using Continuous Flow Chemistry: Synthesis of N1-Aryl-[1,2,3]-triazoles from Anilines via Telescoped Three-Step Diazotization, Azidodediazotization, and [3 + 2] Dipolar Cycloaddition Processes

Article abstract of DOI:10.1021/acs.oprd.6b00292

The conversion of commercially available anilines into triazole products was realized using a telescoped three-reactor flow diazotization, azidodediazotization, and [3 + 2] dipolar cycloaddition process. The diazotization-azidodediazotization sequence was

Full text of DOI:10.1021/acs.oprd.6b00292

Subscriber access provided by Northern Illinois University
Full Paper
Handling hazards using continuous flow chemistry: synthesis of N1-
aryl-1,2,3-triazoles from anilines via telescoped three step diazotization /
azidodediazotization / [3 + 2] dipolar cycloaddition processes
Matthieu Teci, Michael Tilley, Michael A. McGuire, and Michael G. Organ
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00292 • Publication Date (Web): 05 Oct 2016
Downloaded from http://pubs.acs.org on October 5, 2016
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 free 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 accessible to all
readers and 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.
Organic Process Research & Development 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 9
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Handling hazards using continuous flow chemistry: synthesis of N1-
aryl-1,2,3-triazoles from anilines via telescoped three step diazotiza-
tion / azidodediazotization / [3 + 2] dipolar cycloaddition processes.
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
Matthieu Teci,[a] Michael Tilley,[a] Michael. A. McGuire,*[b] Michael G. Organ*[a,c]
[a]
M. Teci, M. Tilley, Professor M. G. Organ, Department of Chemistry, York University, 4700 Keele Street, Toron-
to, Ontario, M3J1P3 (Canada)
[b]
Dr. M. A. McGuire, GlaxoSmithKline Pharmaceuticals Inc., 709 Swedeland Road, PO box 1539, UMW 2810,
King of Prussia, PA 19406, (USA)
[c]
Professor M. G. Organ, Director, Centre for Catalysis Research and Innovation (CCRI) and Department of
Chemistry, University of Ottawa, Ottawa, Ontario, K1N6N5 (Canada)
Email: organ@uottawa.ca
ABSTRACT: The conversion of commercially available anilines into triazole products was realized using a telescoped three-
reactor flow diazotization / azidodediazotization / [3 + 2] dipolar cycloaddition process. The diazotization / azidodediazo-
tization sequence was accelerated by means of an ultrasonic bath resulting in a degassed, segmented effluent. An automated
continuous flow unit controlled by custom software created in-house was used to collect the aryl azide stream and restore it
to a continuous column of the reagent. When combined with a variety of dipolarophiles, 1-aryl-[1,2,3]-triazoles were thus
assembled by either copper catalyzed alkyne-azide cycloaddition (CuAAC) or Huisgen cycloaddition reactions. `
KEYWORDS: anilines, diazotization, triazoles, click chemistry, dipolar cycloaddition, flow
In the past decade, continuous flow organic synthesis has
become increasingly popular owing to the considerable
benefits afforded over conventional batch-style reaction
setups. For example, rather than undergoing tedious reac-
tion scale-up to produce more product on increasing
scales, the same flowed process can simply be flowed long-
er, or in parallel, to produce the desired amount of prod-
uct, a process known as ‘scaling-out’.1 Further, continuous
flow processes also allow a greater control of important
reaction parameters, such as mass and temperature trans-
fer, and therefore operate, in theory at least, exclusively at
steady state once reached.2 Flow is inherently safer,3 al-
lowing several synthetic steps to be telescoped into one
continuous sequence where only small quantities of toxic
or unstable intermediates exist momentarily and are im-
mediately quenched upon contact with the subsequent
reagent stream.4
alkyl / aryl azide component can be synthesized prior to
use,8i, 9 more attractive strategies rely on their in situ for-
mation.10 From the aspect of safety, it is not surprising that
many of these straightforward methodologies have been
successfully adapted in flow. Although there are examples
of telescoped flow syntheses of 1-alkyl-[1,2,3]-triazoles
reported in the literature,11 1-aryl-substituted analogues
are less commonly encountered. To the best of our
knowledge, such continuous flow sequences using anilines
as the starting material have rarely been reported,12 and
more strikingly, we were unable to find any examples of
flow syntheses of 1-aryl-4-aryl-[1,2,3]-triazoles using
commercially available anilines as the starting material.
This limited number of applications may be a result of
the difficulties associated with concomitant nitrogen evo-
lution during the formation of the aryl azide from the cor-
13
responding aniline precursor.10f,
Notably, working in
Triazoles,5 which have applications in a number of
industrial sectors, have received much interest during the
development of flow methodologies. The syntheses of
benzotriazoles,6 1,2,4-triazoles,7 and in particular 1,2,3-
triazoles8 have all been reported in a flow setting. 1,2,3-
Triazoles are traditionally assembled via [3 + 2] dipolar
cycloaddition reactions, which have been termed “click
reactions” owing to their atom-economy and high efficien-
cy. A plethora of batch methodologies for their preparation
have been developed using an organic azide (1,3-dipole)
and an alkyne or enolate (dipolarophile). Although the
segmented streams represents a major technical challenge
in terms of retaining stoichiometric ratios when another
reactant stream is introduced. In rare cases where N1
-
arylated [1,2,3]-triazoles were synthesized using
continuous flow, the reactive aryl-azide intermediates
were obtained as segmented streams by reacting an aniline
precursor, azidotrimethylsilane (TMS-N3) and t-butyl ni-
trite (t-BuONO) in a heated reactor (Scheme 1).12
Rather than restoring a continuous aryl azide stream,
Stazi et al. directly combined the segmented flow with [3 +
2] cycloaddition reagent solutions. Applying this strategy
a
ACS Paragon Plus Environment

Organic Process Research & Development
Page 2 of 9
fortiori resulted in imbalanced dipole / dipolarophile stoi- nitrogen gas. An intermediate reservoir was introduced to
1
2
3
4
5
6
7
8
chiometric ratios (Scheme 1, Method (1). Alternatively,
Ley et al. designed a two-step sequence where the dipolar-
ophile (malonitrile anion) was delivered in an immobilised
form. In a first step, the segmented aryl azide stream was
directed to a reactor containing a cationic polymeric sup-
port previously primed with malonitrile anion. Once the
triazole was formed, in the absence of a suitable proton
source, it was retained inside the column as its corre-
sponding anion. In a second step, washing the reactor with
a malonitrile solution (the proton source) facilitated both
the recovery of amino-1-aryl-[1,2,3]-triazol-4-carbonitrile
products and regeneration of the supported column
(Scheme 1, Method (2)). This stepwise strategy has limited
scope due to the necessity of anionic dipolarophiles and as
such, cannot be extended to electronically neutral dipolar-
ophiles. Furthermore, retention of the triazole anion onto
the polymeric support inherently prevents measuring
accurate residence times. The system can also never
achieve steady state as the stock supported reagent is
consumed in a continuous manner. Finally, plugs due to
substrate precipitation inside the column were sometimes
encountered.
collect the segmented flow stream, which was subsequent-
ly directed to either Sonogashira or Suzuki-Miyaura cross-
coupling reactors using an automated Continuous Flow
Unit (CFU) a device controlled by software developed in-
house designed to accommodate a broad range of fluids at
high pressure without pulsation This approach minimized
safety issues associated with handling hazardous interme-
diates, allowed ready modification of reaction conditions
to counteract solubility problems as they arose, and al-
lowed each step to be optimized separately, ultimately
producing a wide substrate scope with high yields. Build-
ing up on this previous work, we felt that such a strategy
could rapidly be extended to a telescoped diazotization /
azidodediazotization / [3 + 2] dipolar cycloaddition flow
sequence, thus offering an attractive alternative for the
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
non-segmented, continuous flow synthesis of 1-aryl
-
substituted [1,2,3]-triazole products from anilines
(Scheme 2, Method (2)).
(Het)Ar1 ꢀ NH2
t-BuONO
"H+"
r.t.
+
Ar ꢀ NH2
TMSꢀN3
tꢀBuONO
(Het)Ar1 ꢀ N2
50 ꢀ 60 °C
n-Bu4NI
NaN3
Ar ꢀ N3
r.t.
20 min.
20 min.
sonication
O
O
CN
CN
R
OEt
+
DBU
STEP 1
react
(Het)Ar1 ꢀ I
(Het)Ar1 ꢀ N3
STEP 2
release
80 °C
+
NMe3
CFU
CFU
Sonogashira
or
Suzukiꢀ
Miyaura
reagents
[3 + 2]
NC
CN
60 °C
dipolar
cycloaddition
reagents
60 ꢀ 70°C
20 ꢀ 45 min.
r.t. ꢀ 60°C
20 min.
N
N
Ar
Ar
H2N
N
N
N
N
O
R
CN
EtO
(Method 1)
Stazi, 2010
(Method 2)
Ley, 2011
(Het)Ar1
(Het)Ar2
(Het)Ar1
N
N
N
or
R1
R2
or
(Het)Ar1
N
segmented
stream
continuous
stream
N
N
check valve
(Het)Ar1 Ar2
O
Scheme 1. Reported flowed syntheses of 1-aryl-[1,2,3]-
triazoles from anilines.
3 : R2 = Ar, R3 = H
4 : R2 = CN, R3 = NH2
(Method 2)
This work
(Method 1)
Following our group’s interest in continuous flow pro-
cesses,14 we have recently designed a telescoped diazotiza-
tion, iododediazotization, cross-coupling flow process, for
the conversion of commercially available anilines into
biarylacetylene and biphenyl products (Scheme 2, Method
(1)).15 Dealing with a high-energy diazonium salt interme-
diate was key to this strategy. Generated from the corre-
sponding aniline, the salt was immediately treated with
tetra-butylammonium iodide to afford aryliodides and
segmented
stream
continuous
stream
Scheme 2. Flow sequential (telescoped) strategy for the
conversion of anilines into biaryl / biarylacetylene com-
pounds (1) and into triazole products (2).
ACS Paragon Plus Environment

Page 3 of 9
Organic Process Research & Development
The flow process consisted of three successive reactors,
RESULTS AND DISCUSSION
1
a fully automated CFU (see supporting information), and
syringes containing the reagent solutions was designed as
depicted in Scheme 3. Customized software developped by
our group was used to control the whole CFU, including its
valve, its pumps, the infusing / refilling sequence and the
flow rates. Following Method A, 1a was the first aniline
evaluated (flowed at 33 µl/min (16.5 µmol/min) and the
corresponding triazole (3a) isolated in 79% yield (Table 2,
entry 1). With this efficient three-reactor flow diazotiza-
tion / azidodediazotization / CuAAC process in hand, we
then evaluated the scope of this transformation using a
variety of anilines. Under Method A conditions, other nitro-
, (alkylthio)-, trifluoromethyl-, and chloro-substituents
were nicely tolerated (Table 2, entries 2 and 3). Aniline 1d
was successfully processed into triazole 3d in 85% yield
(Table 2, entry 4), which is notable for electron-rich sub-
strates as they often react poorly under such diazotiza-
In our approach to a diazotization / azidodediazotiza-
tion / Cu(I) catalyzed Alkyne Azide Cycloaddition (CuAAC)
sequence to access 1-(hetero)aryl-4-aryl-[1,2,3]-triazoles
3, the model substrates chosen to work with are shown in
Table 1. 2-Methoxy-4-nitroaniline (1a) was first treated
with equal amounts of t-BuONO (1.1 equiv.) and me-
thanesulfonic acid (CH3SO3H) (1.1 equiv.) in DMSO to later
aid in solubilizing the triazole products, which often pos-
sess low solubility in organic solvents. The reaction pro-
ceeded cleanly and quantitatively in less than one minute
at room temperature, and sodium azide (NaN3) was then
added to the crude mixture. The azidodediazotization
reaction was then performed at room temperature with
sonication. Proceeding with gas evolution, complete reac-
tion was reached in under 5 minutes. With these results in
hands, we then subjected the crude arylazide mixture to
the CuAAC conditions using 1-ethynyl-4-methylbenzene
and diisopropylamine (0.7 equiv.) as the catalytic mild
base.
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
Table 1. Optimization of the CuAAC reaction in batch.[a]
NO2
tꢀBuONO (1.1 equiv.),
CH3SO3H (1.1 equiv.),
DMSO, r.t, 1 min.
1ꢀEthynylꢀ4ꢀmethylbenzene
(1.3 equiv.),
CuI (x mol%),
NO2
NO2
O
N
O
1,10ꢀphenanthroline (x mol%),
iꢀPr2NH (0.7 equiv.)
O
N
then NaN3 (1.1 equiv.)
DMSO, r.t., Sonication,
5 min.
N3
NH2
N
DMSO, 60°C, 20 min.
1a
2a
3a
CuI
(mol%)
1,10 phenanthroline
(mol%)
Entry
Temp.
Conv.
1
2
3
4
5
6
10
10
5
none
10
5
60°C
60°C
60°C
rt
60%
100%
100%
46%
5
5
2.5
2.5
2.5
2.5
60°C
rt
100%
12%
[a] General conditions: 2ꢀmethoxyꢀ4ꢀnitroaniline (0.5 mmol), tꢀBuONO (0.55
mmol), CH3SO3H (0.55 mmol) in DMSO (2 mL) stirred for 1 min. at room
temperature, then NaN3 (0.55 mmol) in DMSO (1 mL) was added and the
reaction sonicated for 5 minutes. A solution of CuI, 1,10ꢀphenanthroline (if
applicable), and iꢀPr2NH (0.7 equiv.) in DMSO (3 mL) was added, followed
by 1ꢀethynylꢀ4ꢀmethylbenzene (1.3 equiv.), and the solution was heated at
60°C for 20 min. Percentage conversion to 3a was determined by 1HꢀNMR
spectroscopic analysis of the crude mixture.
Scheme 3. Optimized three-step flow diazotization / az-
idodediazotization / CuAAC sequence.
tion reactions. Under the same conditions, hindered ani-
lines such as 2,3-dimethyl-6-nitroaniline (1e) and 2,6-
dimethylaniline (1f) were converted into their respective
products in good yields (Table 2, entries 5 and 6, respec-
tively). Good yields were also obtained for 3-chloro-4-
methoxyaniline (1g) and 4-toluidine (1h) (Table 3, entries
7 and 8, respectively). Ester and sulfonamide groups on
the aniline were also well tolerated (Table 2, entries 9 and
10, respectively), however, in order to overcome solubility
issues encountered with the products, the aniline solution
was diluted down to 0.33 M (Method B). The other solu-
tions (i.e. syringe 2 to 5, Scheme 3) were diluted accord-
ingly and an additional syringe (Syringe 6) infusing neat
DMSO was used to further dilute the effluent from reactor
3, thus avoiding triazole precipitation outside the oil bath.
The corresponding products 3i and 3j were obtained in
In the initial experiment, CuI (10 mol%) was examined
as a catalyst, and after 20 min. at 60°C, 60% of 3a was
formed (Table 1, entry 1). Utilizing 1,10-phenanthroline
(10 mol%), a cost-effective and efficient ligand for copper
in CuAAC reactions,16 gave quantitative conversion to 3a
under the same conditions (Table 1, entry 2). Remarkably,
the loadings of CuI and 1,10-phenanthroline could both be
lowered to 2.5 mol%, and quantitative conversion of the
aryl azide was still observed at 60°C (Table 1, entries 3 and
5). However, running reactions at room temperature re-
sulted in incomplete conversion. (Table 1, entries 4 and 6).
ACS Paragon Plus Environment

Organic Process Research & Development
good yields. Method A was also successfully applied to 3-
Page 4 of 9
1
2
3
4
5
6
7
8
aminopyridine (1k) resulting in triazole 3k in 74% yield
(Table 2, entry 11). In larger scale experiments performed
with 1l, 1i and 1a (5 – 7 mmol), the process was run for 8 h
using ethynylbenzene as the dipolarophile partner result-
ing in triazoles 3l, 3m and 3n in 81%, 79% and 80% yield
respectively.
7
A (78%)
1g
3g
3h
3i
8
9
A (83%)
B (78%)
1h
1i
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
10
11
12
13
B (76%)
A (74%)
1j
3j
Table 2. Scope study for the telescoped diazotization / az-
idodediazotization / CuAAC flow reaction sequence.[a]
1k
3k
A (81%)[b]
1l
1i
3l
B (79%)
Method
(Yield)
[b]
Entry
1
Aniline
1a
Product
3m
A (79%)
A (80%)
14
[b]
5a
5b
1a
3n
[a] General conditions for the telescoped diazotization / azidodediazotizaꢀ
tion / CuAAC reaction sequence: Method A: solution 1 (aniline (1 equiv., 0.5
M), and CH3SO3H (1.1 equiv.) in DMSO), solution 2 (tꢀBuONO, (1.1 equiv.)
in DMSO), solution 3 (NaN3 (1.1 equiv.) in DMSO), solution 4 (CuI (2.5
mol%), iꢀPr2NH (0.7 equiv.) and 1,10ꢀphenanthroline (2.5 mol%) in DMSO),
and solution 5 (1ꢀethynylꢀ4ꢀmethylbenzene (1.3 equiv.) in DMSO) were
placed in their respective syringes (i.e., solution 1 in syringe 1, etc.) and
connected to the continuous flow system as described in Scheme 3. Methꢀ
od B: As in Method A except aniline concentration was 0.33 M. Syringe 6
was loaded with pure DMSO and infused a rate of 400 ꢁL/min. Yields are
based on the volume of the aniline solution infused over 90 min. (2.97 mL,
1.47 mmol of the aniline infused at 16.5 ꢁmol/min) [b] Ethynylbenzene (1.3
equiv.) was used, Yields based on the volume of the aniline solution infused
over 8 hours (15.8 mL, 7.92 mmol of the aniline infused at 16.5 ꢁmol.min).
2
3
A (73%)
A (81%)
1b
1c
5c
4
A (85%)
Following this efficient flow synthesis of arylazides, we
began exploring alternative dipolarophiles in an effort to
rapidly assemble other triazole derivatives. For that pur-
pose, Syringe 4 was filled with DMSO solutions of maloni-
trile (2 equiv.) or 1,3-cyclohexanedione (2 equiv.), and
syringe 5 was filled with DBU (2 equiv.) in DMSO (see
supporting
(trifluoro)methylaniline
methoxyaniline (1g) were successfully converted into their
corresponding 5-amino-4-cyano-1,2,3-triazoles products
(4c and 4g) in good yield (Table 3, entries 1 and 2) at room
temperature. Under the same conditions, methyl 4-
1d
1e
1f
3d
5
6
A (81%)
A (78%)
3e
3f
information).
(1c)
4-Chloro-3-
3-chloro-4-
and
ACS Paragon Plus Environment

Page 5 of 9
Organic Process Research & Development
the continuous flow system (see supporting information). Yields are based on
the volume of the aniline solution infused over 90 min (2.97 mL, 1.47 mmol of
the aniline infused at 16.5 ꢁmol/min). [b] Solution 4 was comprised of 1,3ꢀ
cyclohexanedione (2 equiv.) in DMSO. [c] Reactor 3 was heated at 60°C.
aminobenzoate
(1i)
and
4-amino-N,N-
1
2
3
4
5
6
7
8
dimethylbenzenesulfonamide (1j) were readily processed
and no precipitate was observed throughout the flow se-
quence (Table 3, entries 3 and 4). Triazoloquinazoline (4l)
was obtained from 2-aminoacetophenone (1l) following a
subsequent intramolecular condensation between the
amino group and the pendent ketone moiety of the ami-
notriazole product. Finally, when 1,3-cyclohexanedione
was used as the dipolarophile (Table 3, entries 6 and 7),
fused 1-aryl-triazoles were obtained in good yields.
CONCLUSION
In this manuscript, the telescoped synthesis of various
triazole products from a variety of commercially available
anilines has been achieved using a versatile, high-yielding
three-reactor flow process. Following a three steps diazo-
tization / azidodediazotization / [3 + 2] dipolar cycloaddi-
tion strategy, the flowed synthesis of aryl azides was pro-
moted by means of an ultrasonic bath and the degassed
segmented flow stream was collected into an intermediate
reservoir. An automated continuous flow unit controlled
by custom software developed by our group was used to
continuously infuse the azide solution into both CuAAC
and Huisgen dipolar cycloaddition reactors with carefully
controlled stoichiometry, resulting in a wide reaction
scope and good yields of the 1-aryl-[1,2,3]-triazoles prod-
ucts over the three steps.
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
Table 3. Scope study for telescoped diazotization / az-
idodediazotization / Huisgen dipolar cycloaddition flow
reaction sequence.[a]
EXPERIMENTAL SECTION
All anilines,
acid (CH3SO3H), sodium azide (NaN3), copper iodide (CuI),
diisopropylamine ( -Pr2NH), 1-ethynyl-4-methylbenzene,
t-butyl nitrite (t-BuONO), methane sulfonic
i
ethynylbenzene, malonitrile, 1,3-cyclohexanedione, 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) and dimethylsulfox-
ide (DMSO) were purchased from Sigma-Aldrich, Fisher
Scientific and ACROS and used without further purifica-
tion. Analytical Thin Layer Chromatography (TLC) was
performed on EMD 60 F254 pre-coated glass plates and
spots were visualized using UV light (254 nm). Column
chromatography purifications were carried out using the
flash technique on EMD silica gel 60 (230 - 400 mesh).
NMR spectra were recorded on Bruker 300 MHz or 400
Entry
1
Aniline
1c
Product
4c
(Yield)[b]
83%
2
3
80%
74%
1g
4g
1
MHz AVANCE spectrometers. The chemical shifts for H-
NMR spectra are given in parts per million (ppm) refer-
enced to the residual proton signal of the deuterated sol-
vent; coupling constants are expressed in Hertz (Hz). 13C-
NMR spectra were referenced to the carbon signals of the
deuterated solvent. The following abbreviations are used
to describe peak multiplicities: s = singlet, bs = broad
singlet, d = doublet, t = triplet, dd = doublet of doublets,
hex = hextet and m = multiplet. High Resolution Mass
Spectrometry (HRMS) analysis was performed by the Mass
Spectrometry and Proteomics Unit at Queen’s University in
Kingston, Ontario. All continuous flow experiments were
infused using a New Era syringe pump (NE-1600 and NE-
4000). Syringes were purchased from Becton Dickinson
and company. Flow system polymer tubing and reactors
were purchased from IDEX Health and Science LLC.
1i
4i
4j
4
5
82%
81%
1j
1m
1n
4m
4n
4o
6
7
75%[b]
Standard operating procedure for the synthesis of the Cu-
AAC products (Table 2):
72%[b] [c]
1o
Method A: The following solutions were prepared: Solution
1: the aniline (5 mmol, 0.5 M) and CH3SO3H (355 μL, 5.5
mmol, 0.55 M) in DMSO. Solution 2: t-BuONO (655 μL, 5.5
mmol, 0.55 M) in DMSO. Solution 3: NaN3 (358 mg, 5.5
mmol, 0.55 M) in DMSO. Solution 4: CuI (24 mg, 0.125
mmol, 0.0083 M), i-Pr2NH (500 µL, 3.5 mmol, 0.23 M) and
[a] General conditions for the telescoped diazotization / azidodediazotization /
Huisgen dipolar cycloaddition reaction sequence: solution 1 (aniline, 5 mmol,
0.5 M and CH3SO3H (1.1 equiv.) in DMSO), solution 2 (tꢀBuONO, 1.1 equiv.
in DMSO), solution 3 (NaN3 (1.1 equiv.) in DMSO), solution 4 (malonitrile (2
equiv.) in DMSO) and solution 5 (DBU (2 equiv.) in DMSO) were placed in
their respective syringes (i.e., solution 1 in syringe 1, etc.) and connected to
ACS Paragon Plus Environment

Organic Process Research & Development
Page 6 of 9
1,10-phenanthroline (23 mg, 0,125 mmol, 0.0083 M) in tion (i.e., solution 1 in syringe 1, etc.) were connected to
1
DMSO. Solution 5: the alkyne (6.5 mmol, 0.43 M) in DMSO.
Solution 6: neat DMSO. Each syringe containing their re-
spective solution (i.e., solution 1 in syringe 1, etc.) were
connected to the continuous flow system as described
above, with reactor R2 submerged in a sonicator main-
tained at rt and reactor R3 placed in an oil bath at 60°C.
Solutions 1, 2, and 3 were infused at a flow rate of 33
μL/min (residence time in R1 = 2.7 min; residence time in
R2 = 5 min). Solutions 4 and 5 were infused at a flow rate
of 50 μL/min whereas the continuous flow unit infused the
crude azide at a flow rate of 99 μL/min (residence time in
R3 = 20 min). Solution 6 was not infused. Before collection
of the effluent, the crude reaction mixture was analyzed by
TLC and 1H-NMR to ensure complete conversion of the aryl
azide. After flowing for 90 minutes directly into a vessel
containing water, the crude reaction mixture was extract-
ed with ethyl acetate (2x10 mL), and the combined organic
layers were dried over anhydrous MgSO4. Following filtra-
tion, the solvent was removed under reduced pressure and
the residue purified by flash column chromatography us-
ing the indicated solvent system. Reaction yields are based
on the volume of the aniline solution infused over 90 min
(2.97 mL, 1.49 mmol of the aniline were infused following
methods A or B (16.5 µmol/min).
the continuous flow system as described above, with reac-
tor R2 submerged in a sonicator maintained at rt and reac-
tor R3 kept at rt. Solutions 1, 2, and 3 were infused at a
flow rate of 33 μL/min (residence time in R1 = 2.7 min;
residence time in R2 = 5 min). Solutions 4 and 5 were
infused at a flow rate of 50 μL/min whereas the continu-
ous flow unit infused the crude azide at a flow rate of 99
μL/min (residence time in R3 = 20 min). Before collection
of the effluent, the crude reaction mixture was analyzed by
TLC and 1H-NMR to ensure complete conversion of the aryl
azide. After flowing for 90 minutes directly into a vessel
containing water, the crude reaction mixture was extract-
ed with ethyl acetate (2x10 mL), and the combined organic
layers were dried over anhydrous MgSO4. Following filtra-
tion, the solvent was removed under reduced pressure and
the residue purified by flash column chromatography us-
ing the indicated solvent system. Reaction yields are based
on the volume of the aniline solution infused over 90 min
(2.97 mL, 1.49 mmol of the aniline were infused (16.5
µmol/min).
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
1-(4-Nitrophenyl)-1,5,6,7-tetrahydro-4
H-
benzo[ ][1,2,3]triazol-4-one (4n) (Table 3, entry 6):
d
Following the standard operating
procedure described above with
4-nitroaniline (1n) and 1,3-
cyclohexanedione, after purifica-
Method B: This method was similar to Method A except all
concentrations were diluted down to half: [aniline] = 0.33
M; [CH3SO3H] = 0.36 M; [t-BuONO] = 0.36 M; [NaN3] =
0.36 M; [Cu] = 0.0054 M; [1,10-phenanthroline] = 0.0054
M, [i-Pr2NH] = 0.15 M, [alkyne] = 0.39 M. The neat DMSO
in syringe 6 was infused at 400 µL/min.
tion by flash column chromatography (75% AcOEt / Hex-
anes, Rf = 0.40), 287 mg of 4n (75%) were obtained as a
white solid. Mp > 190 °C; 1H-NMR (300 MHz, CDCl3)
δ
8.46
= 6.1
= 6.6 Hz, 2H)
190.2, 144.4, 142.5,
(d,
Hz, 2H), 2.69 (t,
ppm; 13C{1H} NMR (75 MHz, CDCl3)
J
= 9.0 Hz, 2H), 7,86 (d,
J = 9.0 Hz, 2H), 3.05 (t, J
1-(2-Methoxy-4-nitrophenyl)-4-phenyl-1H-1,2,3-triazole
J
= 6.6 Hz, 2H), 2.27 (q, J
(3n) (Table 2, entry 14):
δ
134.7, 133.2, 125.0, 123.9, 38.3, 23.2, 21.9 ppm Spectral
data were in accordance with those described in the litera-
ture.9
Using method A described above
with 2-methoxy-4-nitroaniline
(1a) and ethynylbenzene. The
flow process was run for 8 hours.
After purification by flash column
O
N
N
O2N
N
5-Amino-1-(4-chloro-3-(trifluoromethyl)phenyl)-1H-1,2,3-
triazole-4-carbonitrile (4c) (Table 3,
entry 1):
chromatography
(50%
AcO-
Et/hexanes, Rf = 0.36), 1.872 g of 3n (80%) were obtained
Following the standard operating
procedure described above with 4-
1
as a white solid. Mp = 186 °C; H-NMR (300 MHz, CDCl3)
δ
8.51 (s, 1H), 8.21 (d,
Hz, 1H), 8.01 (d, = 2.3 Hz, 1H), 7.93 (d,
7.48 (t, = 7.4 Hz, 2H), 7.40 (d, = 7.5 Hz, 1H), 4.10 (s, 3H)
ppm; 13C{1H} NMR (75 MHz, CDCl3)
150.7, 148.1, 148.0,
J
= 8.7 Hz, 1H), 8.06 (dd,
J = 8.7, 2.3
chloro-3-(trifluoro)methylaniline (1c) and malonitrile,
after purification by flash column chromatography (25%
AcOEt/hexanes, Rf = 0.32), 353 mg of 4c (83%) were ob-
J
J
= 7.4 Hz, 2H),
J
J
δ
1
tained as a white solid. Mp = 150 °C; H-NMR (300 MHz,
131.1, 130.1, 129.1, 128.7, 126.0, 125.2, 121.5, 116.9,
108.0, 57.0 ppm; HRMS (EI) calcd. for C15H12N4O3 296.0909
[M+]; found 296.0913.
d6-dmso)
7.93 (dd,
NMR (100 MHz, d6-dmso)
131.0, 128.0 (q,
δ
J
8.09 (d,
= 2.5, 8.6 Hz, 1H), 7.38 (s, 2H) ppm; 13C{1H}
148.4, 133.2, 133.1, 132.0,
= 32.4 Hz), 125.2 (q, = 5.6 Hz), 122.2 (q,
J = 2.5 Hz, 1H), 7.99 (d, J = 8.6, 1H),
δ
J
j
J
= 273.5 Hz), 113.3, 101.3 ppm; HRMS (EI) calcd. for
Standard operating procedure for the synthesis of the Cu-
AAC products (Table 2):
C10H5ClF3N5 287.0186 [M+]; found 287.0178.
The following solutions were prepared: Solution 1: the
aniline (5 mmol, 0.5 M) and CH3SO3H (355 μL, 5.5 mmol,
0.55 M) in DMSO. Solution 2: t-BuONO (655 μL, 5.5 mmol,
0.55 M) in DMSO. Solution 3: NaN3 (358 mg, 5.5 mmol, 0.55
M) in DMSO. Solution 4: 1,5-diazabicyclo(4.3.0)non-5-ene
(2 equiv, 0.67 M) in DMSO. Solution 5: malonitrile (2
equiv., 0.67 M), or 1,3-cyclohexane-dione (2 equiv., 0.67
M) in DMSO. Each syringe containing their respective solu-
ASSOCIATED CONTENT
Supporting Information
It includes detailed experimental procedures, their optimiza-
tion, pictures of the flow process, a description of the continu-
ous flow unit, and a full characterization for all compounds
prepared.
ACS Paragon Plus Environment

Page 7 of 9
Organic Process Research & Development
Chem., 2014, 85, 65ꢀ76; (n) Solum, E. J.; Vik, A.; Hansen, T. V.,
Steroids, 2014, 87, 46ꢀ53.
AUTHOR INFORMATION
1
2
Corresponding Author
6.
7.
Chen, M.; Buchwald, S. L., Ang. Chem. Int. Ed., 2013, 52, 4247ꢀ4250.
3
4
5
* M. G. Organ, Director, Centre for Catalysis Research and
Innovation (CCRI) and Department of Chemistry, University of
Ottawa, Ottawa, Ontario, K1N6N5 (Canada)
(a) Bogdan, A. R.; Wang, Y., RSC Adv., 2015, 5, 79264ꢀ79269; (b)
Baumann, M.; Rodriguez Garcia, A. M.; Baxendale, I. R., Org. Biomol.
Chem., 2015, 13, 4231ꢀ4239.
6
7
8
9
Email: organ@uottawa.ca
8.
(a) Borukhova, S.; Seeger, A. D.; Noël, T.; Wang, Q.; Busch, M.;
Hessel, V., ChemSusChem, 2015, 8, 504ꢀ512; (b) Ötvös, S. B.;
Mándity, I. M.; Kiss, L.; Fülöp, F., Chem. Asian J., 2013, 8, 800ꢀ808;
(c) Smith, C. D.; Baxendale, I. R.; Lanners, S.; Hayward, J. J.; Smith,
S. C.; Ley, S. V., Org. Biomol. Chem., 2007, 5, 1559ꢀ1561; (d) Varas,
A. C.; Noël, T.; Wang, Q.; Hessel, V., ChemSusChem, 2012, 5, 1703ꢀ
1707; (e) Bédard, A.ꢀC.; Collins, S. K., Org. Lett., 2014, 16, 5286ꢀ
5289; (f) Bogdan, A. R.; James, K., Chem. Eur. J., 2010, 16, 14506ꢀ
14512; (g) Bogdan, A. R.; James, K., Org. Lett., 2011, 13, 4060ꢀ4063;
(h) Borukhova, S.; Noël, T.; Metten, B.; de Vos, E.; Hessel, V.,
ChemSusChem, 2013, 6, 2220ꢀ2225; (i) Fuchs, M.; Goessler, W.;
Pilger, C.; Kappe, C. O., Adv. Synth. Catal., 2010, 352, 323ꢀ328; (j)
Jumde, R. P.; Evangelisti, C.; Mandoli, A.; Scotti, N.; Psaro, R., J.
Catal., 2015, 324, 25ꢀ31; (k) Kupracz, L.; Hartwig, J.; Wegner, J.;
Ceylan, S.; Kirschning, A., Beilstein J. Org. Chem, 2011, 7, 1441ꢀ
1448; (l) Ötvös, S. B.; Georgiádes, Á.; ÁdokꢀSipiczki, M.; Mészáros,
R.; Pálinkó, I.; Sipos, P.; Fülöp, F., 2015, 501, 63ꢀ73; (m) Ötvös, S. B.;
Georgiádes, Á.; Mándity, I. M.; Kiss, L.; Fülöp, F., Beilstein J. Org.
Chem, 2013, 9, 1508ꢀ1516; (n) Otvos, S. B.; Hatoss, G.; Georgiades,
A.; Kovacs, S.; Mandity, I. M.; Novak, Z.; Fulop, F., RSC Adv., 2014,
4, 46666ꢀ46674; (o) Tahir, M. N.; Qamar, R.ꢀu.; Adnan, A.; Cho, E.;
Jung, S., Tetrahedron Lett., 2013, 54, 3268ꢀ3273; (p) Tinder, R.; Farr,
R.; Heid, R.; Zhao, R.; Rarig, R. S.; Storz, T., Org. Process Res. Dev.,
2009, 13, 1401ꢀ1406.
Funding Sources
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 work was supported by NSERC (Canada)
Notes
The authors declare no competing financial interest.
REFERENCES
1.
(a) Ullah, F.; Samarakoon, T.; Rolfe, A.; Kurtz, R. D.; Hanson, P. R.;
Organ, M. G., Chem. Eur. J., 2010, 16, 10959ꢀ10962; (b) Glasnov, T.
N.; Kappe, C. O., Chem. Eur. J., 2011, 17, 11956ꢀ11968; (c) Hessel,
V.; Cortese, B.; de Croon, M. H. J. M., Chem. Eng. Sci., 2011, 66,
1426ꢀ1448; (d) Hessel, V.; Kralisch, D.; Kockmann, N.; Noël, T.;
Wang, Q., ChemSusChem, 2013, 6, 746ꢀ789; (e) Gutmann, B.;
Cantillo, D.; Kappe, C. O., Ang. Chem. Int. Ed., 2015, 54, 6688ꢀ6728.
2.
3.
(a) Hartman, R. L.; McMullen, J. P.; Jensen, K. F., Ang. Chem. Int.
Ed., 2011, 50, 7502ꢀ7519; (b) Wegner, J.; Ceylan, S.; Kirschning, A.,
Chem. Commun., 2011, 47, 4583ꢀ4592; (c) Yoshida, J.ꢀi.; Kim, H.;
Nagaki, A., ChemSusChem, 2011, 4, 331ꢀ340; (d) Yoshida, J.ꢀi.;
Takahashi, Y.; Nagaki, A., Chem. Commun., 2013, 49, 9896ꢀ9904.
9.
(a) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.;
Sharpless, K. B.; Fokin, V. V., J. Am. Chem. Soc., 2005, 127, 210ꢀ
216; (b) Shao, C.; Wang, X.; Zhang, Q.; Luo, S.; Zhao, J.; Hu, Y., J.
Org. Chem., 2011, 76, 6832ꢀ6836; (c) Shi, F.; Waldo, J. P.; Chen, Y.;
Larock, R. C., Org. Lett., 2008, 10, 2409ꢀ2412; (d) Wu, L.ꢀY.; Xie, Y.ꢀ
X.; Chen, Z.ꢀS.; Niu, Y.ꢀN.; Liang, Y.ꢀM., Synlett, 2009, 2009, 1453ꢀ
1456; (e) Yamada, Y. M. A.; Sarkar, S. M.; Uozumi, Y., J. Am. Chem.
Soc., 2012, 134, 9285ꢀ9290; (f) Ali, A.; Correa, A. G.; Alves, D.;
ZukermanꢀSchpector, J.; Westermann, B.; Ferreira, M. A. B.; Paixao,
M. W., Chem. Commun., 2014, 50, 11926ꢀ11929; (g) Jiang, Y.;
Kuang, C.; Yang, Q., Synlett, 2009, 2009, 3163ꢀ3166; (h) Kwok, S.
W.; Fotsing, J. R.; Fraser, R. J.; Rodionov, V. O.; Fokin, V. V., Org.
Lett., 2010, 12, 4217ꢀ4219; (i) Smith, C. D.; Greaney, M. F., Org. Lett.,
2013, 15, 4826ꢀ4829.
(a) Wiles, C.; Watts, P., Exp. Op. Drug Disc., 2007, 2, 1487ꢀ1503; (b)
Painter, T. O.; Thornton, P. D.; Orestano, M.; Santini, C.; Organ, M.
G.; Aubé, J., Chem. Eur. J., 2011, 17, 9595ꢀ9598; (c) Wiles, C.; Watts,
P., Green Chem., 2012, 14, 38ꢀ54; (d) Newman, S. G.; Jensen, K. F.,
Green Chem., 2013, 15, 1456ꢀ1472; (e) Nalivela, K. S.; Tilley, M.;
McGuire, M. A.; Organ, M. G., Chem. Eur. J., 2014, 20, 6603ꢀ6607; (f)
Wiles, C.; Watts, P., Green Chem., 2014, 16, 55ꢀ62; (g) Deadman, B.
J.; Collins, S. G.; Maguire, A. R., Chem. Eur. J., 2015, 21, 2298ꢀ2308;
(h) Müller, S. T. R.; Wirth, T., ChemSusChem, 2015, 8, 245ꢀ250.
4.
5.
(a) Webb, D.; Jamison, T. F., Chem. Sci., 2010, 1, 675ꢀ680; (b)
Wegner, J.; Ceylan, S.; Kirschning, A., Adv. Synth. Catal., 2012, 354,
17ꢀ57; (c) McQuade, D. T.; Seeberger, P. H., J. Org. Chem., 2013, 78,
6384ꢀ6389; (d) Pastre, J. C.; Browne, D. L.; Ley, S. V., Chem. Soc.
Rev., 2013, 42, 8849ꢀ8869.
10.
11.
(a) Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M., Adv. Synth. Catal.,
2010, 352, 3208ꢀ3214; (b) Alonso, F.; Moglie, Y.; Radivoy, G.; Yus,
M., J. Org. Chem., 2011, 76, 8394ꢀ8405; (c) Jiang, Y.; Kuang, C.;
Yang, Q., Synlett, 2010, 2010, 4256ꢀ4260; (d) Lal, S.; DíezꢀGonzález,
S., J. Org. Chem., 2011, 76, 2367ꢀ2373; (e) Liu, M.; Reiser, O., Org.
Lett., 2011, 13, 1102ꢀ1105; (f) Barral, K.; Moorhouse, A. D.; Moses, J.
E., Org. Lett., 2007, 9, 1809ꢀ1811.
(a) Almstead, N.; Karp, G. M.; Wilde, R.; Welch, E.; Campbell, J. A.;
Ren, H.; Chen, G., Pyrazole or triazole compounds and their use for
the manufacture of a medicament for treating somatic mutationꢀrelated
diseases. Google Patents: 2006; (b) Agalave, S. G.; Maujan, S. R.;
Pore, V. S., Chem. Asian J., 2011, 6, 2696ꢀ2718; (c) Baumann, M.;
Baxendale, I. R.; Ley, S. V.; Nikbin, N., Beilstein J. Org. Chem, 2011,
7, 442ꢀ495; (d) Baxter, C. A.; Cleator, E.; Brands, K. M. J.; Edwards,
J. S.; Reamer, R. A.; Sheen, F. J.; Stewart, G. W.; Strotman, N. A.;
Wallace, D. J., Org. Process Res. Dev., 2011, 15, 367ꢀ375; (e) Kharb,
R.; Sharma, P. C.; Yar, M. S., J. Enzyme Inhib. Med. Chem., 2011,
26, 1ꢀ21; (f) Pedersen, D. S.; Abell, A., Eur. J. Org. Chem., 2011,
2011, 2399ꢀ2411; (g) Poulain, A.; CansecoꢀGonzalez, D.; Hynesꢀ
Roche, R.; MüllerꢀBunz, H.; Schuster, O.; StoeckliꢀEvans, H.; Neels,
A.; Albrecht, M., Organometallics, 2011, 30, 1021ꢀ1029; (h) Yan, W.;
Wang, Q.; Lin, Q.; Li, M.; Petersen, J. L.; Shi, X., Chem. Eur. J., 2011,
17, 5011ꢀ5018; (i) Hsieh, H.ꢀY.; Lee, W.ꢀC.; Senadi, G. C.; Hu, W.ꢀP.;
Liang, J.ꢀJ.; Tsai, T.ꢀR.; Chou, Y.ꢀW.; Kuo, K.ꢀK.; Chen, C.ꢀY.; Wang,
J.ꢀJ., J. Med. Chem., 2013, 56, 5422ꢀ5435; (j) He, Y.ꢀW.; Dong, C.ꢀZ.;
Zhao, J.ꢀY.; Ma, L.ꢀL.; Li, Y.ꢀH.; Aisa, H. A., Eur. J. Med. Chem., 2014,
76, 245ꢀ255; (k) Massarotti, A.; Aprile, S.; Mercalli, V.; Del Grosso, E.;
Grosa, G.; Sorba, G.; Tron, G. C., ChemMedChem, 2014, 9, 2497ꢀ
2508; (l) Pala, N.; Micheletto, L.; Sechi, M.; Aggarwal, M.; Carta, F.;
McKenna, R.; Supuran, C. T., ACS Med. Chem. Lett., 2014, 5, 927ꢀ
930; (m) Pingaew, R.; Saekee, A.; Mandi, P.; Nantasenamat, C.;
Prachayasittikul, S.; Ruchirawat, S.; Prachayasittikul, V., Eur. J. Med.
(a) Sadler S., S. M. M., Kern N. L., Bell D. E., Laverack C. A., Wilkins
D. J., Moeller A. R., NicolaysenB. C., Kozlowski P. N., Wiles C.,Tinder
R. J. and Jones G. B. M., J. Flow Chem., 2014, 4, 140ꢀ147; (b)
Baxendale, I. R.; Ley, S. V.; Mansfield, A. C.; Smith, C. D., Ang.
Chem. Int. Ed., 2009, 48, 4017ꢀ4021; (c) Bogdan, A. R.; Sach, N. W.,
Adv. Synth. Catal., 2009, 351, 849ꢀ854; (d) Ceylan, S.; Klande, T.;
Vogt, C.; Friese, C.; Kirschning, A., Synlett, 2010, 2010, 2009ꢀ2013;
(e) Tu, N. P.; Sarris, K.; Djuric, S. W., RSC Adv., 2015, 5, 4754ꢀ4757;
(f) Zhang, P.; Russell, M. G.; Jamison, T. F., Org. Process Res. Dev.,
2014, 18, 1567ꢀ1570.
12.
13.
14.
(a) Smith, C. J.; Nikbin, N.; Ley, S. V.; Lange, H.; Baxendale, I. R.,
Org. Biomol. Chem., 2011, 9, 1938ꢀ1947; (b) Stazi, F.; Cancogni, D.;
Turco, L.; Westerduin, P.; Bacchi, S., Tetrahedron Lett., 2010, 51,
5385ꢀ5387.
(a) Bräse, S.; Gil, C.; Knepper, K.; Zimmermann, V., Ang. Chem. Int.
Ed., 2005, 44, 5188ꢀ5240; (b) Spiteri, C.; Moses, J. E., Synlett, 2012,
23, 1546ꢀ1548; (c) Scriven, E. F. V.; Turnbull, K., Chem. Rev., 1988,
88, 297ꢀ368.
(a) Price, G. A.; Bogdan, A. R.; Aguirre, A. L.; Iwai, T.; Djuric, S. W.;
Organ, M. G., Catal. Sci. Technol., 2016; (b) Tilley, M.; Li, G.; Savel,
ACS Paragon Plus Environment

Organic Process Research & Development
Page 8 of 9
P.; Mallik, D.; Organ, M. G., Org. Process Res. Dev., 2016, 20, 517ꢀ
524; (c) Achanta, S.; Liautard, V.; Paugh, R.; Organ, M. G., Chem.
Eur. J., 2010, 16, 12797ꢀ800; (d) Bremner, W. S.; Organ, M. G., J.
Comb. Chem., 2007, 9, 14ꢀ6; (e) Comer, E.; Organ, M. G., J. Am.
Chem. Soc., 2005, 127, 8160ꢀ7; (f) Comer, E.; Organ, M. G., Chem.
Eur. J., 2005, 11, 7223ꢀ7; (g) Faisal, S.; Ullah, F.; Maity, P. K.; Rolfe,
A.; Samarakoon, T. B.; Porubsky, P.; Neuenswander, B.; Lushington,
G. H.; Basha, F. Z.; Organ, M. G.; Hanson, P. R., ACS Comb. Sci.,
2012, 14, 268ꢀ72; (h) Nalivela, K. S.; Tilley, M.; McGuire, M. A.;
Organ, M. G., Chem. Eur. J., 2014, 20, 6603ꢀ7; (i) Painter, T. O.;
Thornton, P. D.; Orestano, M.; Santini, C.; Organ, M. G.; Aube, J.,
Chem. Eur. J., 2011, 17, 9595ꢀ8; (j) Shore, G.; Morin, S.; Organ, M.
G., Ang. Chem. Int. Ed., 2006, 45, 2761ꢀ6; (k) Shore, G.; Organ, M.
G., Chem. Commun., 2008, 838ꢀ40; (l) Shore, G.; Tsimerman, M.;
Organ, M. G., Beilstein J. Org. Chem., 2009, 5, 35; (m) Ullah, F.;
Samarakoon, T.; Rolfe, A.; Kurtz, R. D.; Hanson, P. R.; Organ, M. G.,
Chem. Eur. J., 2010, 16, 10959ꢀ62; (n) Ullah, F.; Zang, Q.; Javed, S.;
Porubsky, P.; Neuenswander, B.; Lushington, G. H.; Hanson, P. R.;
Organ, M. G., Synthesis, 2012, 44; (o) Zang, Q.; Javed, S.; Hill, D.;
Ullah, F.; Bi, D.; Porubsky, P.; Neuenswander, B.; Lushington, G. H.;
Santini, C.; Organ, M. G.; Hanson, P. R., ACS Comb. Sci., 2012, 14,
456ꢀ9; (p) Zang, Q.; Javed, S.; Ullah, F.; Zhou, A.; Knudtson, C. A.; Bi,
D.; Basha, F. Z.; Organ, M. G.; Hanson, P. R., Synthesis, 2011, 2011,
2743ꢀ2750.
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
15.
16.
Teci M., Tilley M., M. A. McGuire, M. G. Organ, Chem. Eur. J., 2016,
accepted for publication
(a) Berg, R.; Straub, B. F., Beilstein J. Org. Chem, 2013, 9, 2715ꢀ
2750; (b) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V., Org.
Lett., 2004, 6, 2853ꢀ2855; (c) Chassaing, S.; Beneteau, V.; Pale, P.,
Catal. Sci. Technol., 2016, 6, 923ꢀ957; (d) GonzálezꢀOlvera, R.;
EspinozaꢀVázquez, A.; NegrónꢀSilva, G.; PalomarꢀPardavé, M.;
RomeroꢀRomo, M.; Santillan, R., Molecules, 2013, 18, 15064; (e)
Lewis, W. G.; Magallon, F. G.; Fokin, V. V.; Finn, M. G., J. Am. Chem.
Soc., 2004, 126, 9152ꢀ9153; (f) Özçubukçu, S.; Ozkal, E.; Jimeno, C.;
Pericàs, M. A., Org. Lett., 2009, 11, 4680ꢀ4683; (g) Presolski, S. I.;
Hong, V.; Cho, S.ꢀH.; Finn, M. G., J. Am. Chem. Soc., 2010, 132,
14570ꢀ14576; (h) Meldal, M.; Tornøe, C. W., Chem. Rev., 2008, 108,
2952ꢀ3015.
ACS Paragon Plus Environment

Page 9 of 9
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
Table of Contents Graphic
153x60mm (72 x 72 DPI)
ACS Paragon Plus Environment