Exploring flow procedures for diazonium formation

Article abstract of DOI:10.3390/molecules21070918

The synthesis of diazonium salts is historically an important transformation extensively utilized in dye manufacture. However the highly reactive nature of the diazonium functionality has additionally led to the development of many new reactions including

Full text of DOI:10.3390/molecules21070918

molecules
Article
Exploring Flow Procedures for Diazonium Formation
Te Hu, Ian R. Baxendale * and Marcus Baumann
Department of Chemistry, University of Durham, South Road, Durham DH1 3LE, UK;
te.hu@durham.ac.uk (T.H.); marcus.baumann@durham.ac.uk (M.B.)
* Correspondence: i.r.baxendale@durham.ac.uk; Tel.: +44-191-3342185
Academic Editor: Alessandro Palmieri
Received: 12 June 2016; Accepted: 5 July 2016; Published: 14 July 2016
Abstract: The synthesis of diazonium salts is historically an important transformation extensively
utilized in dye manufacture. However the highly reactive nature of the diazonium functionality
has additionally led to the development of many new reactions including several carbon-carbon
bond forming processes. It is therefore highly desirable to determine optimum conditions for the
formation of diazonium compounds utilizing the latest processing tools such as flow chemistry to
take advantage of the increased safety and continuous manufacturing capabilities. Herein we report
a series of flow-based procedures to prepare diazonium salts for subsequent in-situ consumption.
Keywords: diazonium salts; flow chemistry; meso reactor; processing; supported reagent
1. Introduction
The formation and continuous processing of highly reactive or potentially unstable intermediates
has proven to be a strong driver for the adoption of flow based chemical synthesis [1–3]. Indeed, the
ability to continuously prepare transient species using small volume reactor technology and directly
couple their formation into a subsequent consuming reaction step has significantly enhanced the safety
profile of many chemical sequences [4–7]. For this reason we are currently experiencing a resurgence
of interest in many classical transformations that have historically been relegated to almost obscurity
because of inherent batch based safety concerns and an inability to scale the transformation [8–16].
The improved mixing efficiencies and greater temperature control imparted through the application
of flow based reactor technologies is thus enabling their reinvestigation. From our own repertoire of
studies the diazonium functionality has shown particular versatility as a reactive intermediate [17
–20]
that benefits from being prepared and directly reacted in a continuous flowing process [21 37]. Within
–
this manuscript we describe a number of methods that can be used to conveniently prepare these
species at differing scale and with contrasting processing advantages.
2. Results and Discussion
We initially started our investigations by evaluating the various methods of forming aryl diazonium
salts under flow conditions. These can be broadly classified into three general methods based upon
the phases used, namely: aqueous (Section 2.1); organic (Section 2.2) and solid phase (Section 2.3).
2.1. Formation of Aryl Diazonium Species under Aqueous Conditions
For the development of the aqueous conditions for preparing diazonium salts in flow we evaluated
the classical combination of sodium nitrite and hydrochloric acid. To aid in the rapid optimization of
the transformation we incorporated flow ReactIR analysis into the process [38,39]. The reactor setup
consisted of six paired HPLC pumps used to deliver three variable concentrations of the different
reaction inputs (Figure 1). Stream one contained the sodium nitrite solution, stream two an aqueous
solution of hydrochloric acid and stream three the aniline component as its mono-hydrochloric acid
Molecules 2016, 21, 918; doi:10.3390/molecules21070918
www.mdpi.com/journal/molecules

Molecules 2016, 21, 918
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salt [40], also dissolved in water. The final configuration of T-mixing pieces as shown in Figure 1
was determined through experimental testing. It was found that mixing the hydrochloric acid and
nitrite stream prior to introduction of the aniline gave consistently superior results [41]. It was further
observed that altering the delay time between this initial mixing event and subsequent introduction of
the aniline stream had no detectable effect on the tested reactions (delay range 1.2–40 s). In this regard
the aqueous acid catalyzed decomposition of inorganic nitrite to nitrous acid and further to nitric oxide
is known to be a very rapidly established equilibrium process [42]. The presence of very low levels of
a NO triple bonded species as determined by ReactIR at 2190–2215 cm´1 was noted, but it was not
deemed useful to quantify its formation (generation of calibration curves) under these equilibrium
conditions. Instead monitoring of the subsequent diazonium formation step was examined instead.
Figure 1. Configuration of flow reactors for diazonium formation using aqueous conditions.
To test the range of viable reactant concentrations, 1.0 M stock solutions of the three reagents
were prepared; water was used as the diluent for the three makeup pumps. Serial dilution profiles for
each reagent stream were systematically produced whilst always ensuring the required theoretical
minimum 1:1:1 reagent stoichiometry. It was quickly found that a viable concentration window
of 0.2 + 0.25 M aniline, 1.8 equivalents of HCl and 1.3 equivalents of sodium nitrite worked well
across a representative subset of anilines (Ar = 4-Me, 2-OMe, 2-F, 4-OMe, 4-Br, 3-NO2, 4-NO2 and
3-CF3). In general higher aniline concentration led to precipitation issues and significant by-product
formation (triazine formation with low acid concentration). The use of 1.8 equivalents of hydrochloric
acid gave excellent conversions to the diazonium salt in every case (>93% purity), however, using
a higher ratio for the more electron rich anilines (Ar = 4-OMe {2.2 M} and 2-OMe {2.0 M}) was
found to completely suppress the formation of small quantities of diazo coupled material and other
unidentified side products [43–49]. Importantly, it should be noted that in each instance the first
equivalent of the hydrochloric acid was always present as a part of the aniline stock solution (HCl salt),
facilitating solubility of the aniline substrate in the aqueous media. Therefore only the further excess
(>1 equivalent) is supplied as a separate stream and used in the generation of the reactive nitrosonium
cation prior to its combination with the aniline flow stream (Figure 1). This is important because as
identified earlier it was found that pre-generation of the intermediate NO+ containing solution prior to
its unification with the aniline yielded improved results. This was additionally confirmed by altering
the reaction setup to eliminate the separate acid stream and alternatively supply the same quantity
of hydrochloric acid as a homogeneous mixture with the aniline starting material. The solutions
thus generated although containing only the diazonium intermediate as the primary constituent
(by 1H-NMR, 13C-NMR and HR-MS analysis) were definitively of lower purity [41]. In addition using
these solutions as feeds for the subsequent steps also resulted in lower overall recovery of the desired
addition products (see later description).

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2.1.1. Temperature Dependence
We next evaluated temperature dependence as a parameter of the reaction outcome. Normally
temperatures close to 0 ˝C are employed in batch diazotization reactions to regulate the exothermic
nature of the diazonium salt formation. Our objective was to determine if an operational window
closer to ambient (25 ˝C) could be feasibly used to simplify the chemical processing in flow. It was
initially found difficult to quantify the outcome of this assessment. Ultimately, it was found beneficial
to compare the effect of temperature on the product output when calibrated against an internal
standard. For this purpose we used 2-nitro-5-methoxytoluene (25 mol % wrt aniline) which provided
simple calibration using both NMR and ReactIR analysis (placed in the aniline stock solution
during processing).
To facilitate investigation of the diazonium stability at various temperatures a Polar Bear Plus
flow synthesizer [50] was integrated into the system using pre-cooling incubation loops to regulate
the temperature of the input fluids prior to mixing (set at the reactor temperature). It was rapidly
˝
determined that even at
´
10 C the formation of the diazonium salt occurred rapidly and was complete
for all evaluated substrates in less than 2.5 min residence time (flow rate 2.0 mL/min; 0.35 M aniline
Ar = 4-NO2, 4-MeO and Ph, 1.8 equivalents of HCl and 1.3 equivalents of NaNO2).
˝
An expanded temperature range of
´
10 to 50 C was therefore investigated using the same fixed
flow rate and reagent concentration to assess stability of the diazonium salt (Figure 2). Only a small
decrease in purity of the diazonium adduct was detected between
no aniline starting material was detected). Raising the temperature over the next 15 ˝C gave a small
but incremental increase in the amount of diazonium impurities, measured as a reciprocal decrease in
´
10 and 10 ˝C (Ar = Ph < 0.1%,
the relative quantity of diazonium detected relative to the internal standard (Ar = Ph
heating then resulted in much higher levels of decomposition and identification of the corresponding
phenolic products (as determined by LC-MS). Figure 2 shows the extracted plot of the flow stream as
ď
1.7%). Further
monitored by ReactIR analysis comparing the internal standard against the level of phenyl diazonium
˝
salt during a continuous temperature ramp (0.2 C
¨
min´1; data points generated by the summation of
˝
20 independent temperature stabilized scans). As can be seen, for temperatures up to 20 C only minor
decomposition occurs, however, a significant onset in the rate of decomposition is seen at around
33 ˝C. Therefore a compromise cooling solution for this system would be a working temperature of
8–10 ˝C coupled with a shorter segmentation time before subsequent reaction of the newly formed
diazonium species.
Figure 2. Plot of the percentage decrease in phenyl diazonium output against a change in temperature
for phenyl diazonium.

Molecules 2016, 21, 918
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As expected due to the electronic factors affecting the subsequent formation of the intermediate
carbocation from the 4-NO2 and 4-MeO substituted aryl diazonium these species proved much more
stable to decomposition [43
–
49]. For these substrates the onset of any˝detectable decomposition was
˝
first observed at >25 C and was not significant (>0.5%) until >40 C was attained. Conducting
an investigation of the literature confirmed that ortho- and meta-substitution patterns exert a more
pronounced effect on the rates of diazonium decomposition leading to the corresponding phenolic
derivative. However, conversely such substitution then often retards the subsequent phenol/diazo
coupling process meaning the overall rates of decomposition/consumption of the parent diazonium
approximates the simple phenyl unit albeit the by-product distribution is significantly different [43–49].
In summary, diazonium formation occurred very rapidly, requiring less than 1 min to ensure
˝
complete conversion of the starting aniline in the flow reactor when a reaction temperature of 10 C is
employed. The stability of the diazonium product was deter˝mined to be temperature dependent but
showed acceptable processing stability at temperatures ď10 C over short hold times <5 min.
2.1.2. Flow Rate Analysis
Finally, an investigation into the viable flow rate range was undertaken. The rate determining
step for the sequence is the formation of the N-nitrosoamine, however this is still extremely fast.
Importantly we had already identified that product decomposition was only an issue as the reaction
temperature approached ambient when using long diazonium hold times (see above discussion).
Therefore a processing scenario involving fast throughputs seemed to offer an immediate advantage.
Using a simplified three pump system we established the modified flow reactor setup as depicted
in Figure 3. Initially at high flow rates we experienced poor mixing due to laminar flow resulting in
incomplete conversion of the aniline starting material. This was quickly rectified by replacing the
simple PEEK T-mixers in the system with dedicated mixing chips [51]. A 0.27 mL internal volume chip
was used for the HCl and NaNO2 solution mixing and a larger 2 mL chip for further combining with
the aniline solution at the higher combined flow rate. In addition a 2.75 mL cooling loop was placed
directly after the first mixing chip and a 5 mL cooling coil after the second mixing chip. The entire
mixing (chips) and reaction zone (tubular coils) was maintained at 10 ˝C using a single Polar Bear
Plus flow synthesizer (a copper plate housing the two mixing chips was attached to the top of the
Polar Bear’s central cooling column which also supported the 2.75 and 5 mL cooling coils). Using this
setup even at high flow rates (X = 5 mL/min) at the limits of the HPLC pumping equipment (pump C
operational maximum 10 mL/min) complete conversion to the diazonium salts was achieved across
a spectrum of substrates; Ar = 4-Cl (1), 4-Me, 2-OMe, 4-OMe, 4-Br, 3-NO2 and 3-CF3. Furthermore,
in each case a clean solution of the product as a yellow/orange liquid was produced without evidence
of by-product formation. This was therefore adopted as the reactor setup for all future reactions under
these aqueous conditions.
To exemplify the generation of the diazonium salts and the ability to trap in situ the reactive
species in a linked flow process a small collection of oxamic acid derivatives were prepared through
the reduction of the parent diazonium compound using solutions of ascorbic acid (Figure 4; total
residence time of ~34 min) [52–55]. The final products 1–12 were easily isolated in very high purity
using a batch extraction, involving a simple extraction following determination of the crude conversion
(Table 1). It was also possible for certain substrates to isolate the intermediate ester (42%–62% yield)
prior to hydrolysis (13–18: see Experimental Section), however in each case if the material was left
to stand in the reaction mixture for >15 min the principle product in solution was the oxamic acid
derivative. In practice the reactor output was left to stand for 1 h to ensure complete hydrolysis of the
intermediate before work-up and isolation of the desired oxamic acid product.

Molecules 2016, 21, 918
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Figure 3. Flow reactor setup for diazotization at high flow rates.
Figure 4. Flow preparation of masked hydrazine derivatives.
Table 1. Flow in situ formation of hydrazine derivatives from diazonium salts.
Product A
Aniline Substrate
Yield (%)
1
2
3
4
5
6
7
8
9
2-Br
3-Br
4-Br
2-Cl
3-Cl
79
80
94
68
83
90
89
92
90
67
72
77
4-Cl
2-NO2
3-NO2
4-NO2
2-OMe
3-Me
4-Me
10
11
12
A: The products were isolated by basification of the reaction mixture pH ~8 followed by extraction with EtOAc.
The aqueous solution was then acidified to pH ~4 and extracted with EtOAc, the organic phase was dried over
MgSO4, the solvent evaporated and the isolated compound characterized.

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2.2. Formation of Aryl Diazonium Species under Organic Non Aqueous Conditions
We have previously conducted several investigations into the preparation of diazonium salts as
intermediates in organic solvents using alkyl nitrites as the corresponding NO+ source [17 20]. In our
–
previous work we have employed almost exclusively tert-butyl nitrite as the diazotizing reagent due to
its availability and higher safety profile for use in batch mode. However, several other materials exist
which become viable alternatives representing a potential cost saving when employed at scale working
safely within a flow regime. We therefore decided to test some of these other compounds; namely,
n-butyl nitrite (CAS: 544-16-1), isobutyl nitrite (CAS: 542-56-3), isopentyl nitrite (CAS: 110-46-3), pentyl
nitrite (CAS: 463-04-7) and isopropyl nitrite (CAS: 541-42-4); the reactor set-up used is shown in
Figure 5. Conversion of the aniline starting material was determined by 1H-NMR analysis against
an internal standard (2-nitro-5-methoxytoluene). Each of the tested reagents performed equally well
using the general reactor setup as shown in Figure 4, although isopropyl nitrite proved more difficult
to handle practically due to its low boiling point. In general it was found that tert-butyl nitrite could be
directly substituted in this process without any change in observed yield or purity of the flow stream
˝
using 1.1 equivalents of the alkyl nitrite and a reaction temperature of 20 C. It should be noted that a
decreased concentration of the starting materials was needed due to the considerably lower solubility
of several of the diazonium species in acetonitrile to avoid the issue of precipitation and blocking of
the reactor.
Figure 5. Flow reactor for diazonium formation under anhydrous conditions (material not
isolated—anion not determined).
We next considered the use of nitrosyl halides (BrNO and ClNO) which can also be used as
diazotization reagents under anhydrous conditions [56]. These species are gases but can be readily
generated in situ by the reaction of trimethylsilyl halides (Br/Cl) with alkyl nitrites, under essentially
acid free conditions. This was highly desirable as we had experienced difficulties in achieving high
isolated yields of the corresponding diazonium salt when using certain acid sensitive substrates.
We therefore wished to evaluate these conditions for use with a particularly problematic substrate,
namely tert-butyl 4-aminophenylcarbamate. Under our standard aqueous conditions we identified
16% doubly diazotized material and 53% mono-Boc protected diazonium product, the remaining
being unidentified by-products [57]. We found the best reagent combination was 1.15 equivalents of
isobutyl nitrite and trimethylsilyl halide in a 2:1 solvent mixture of dichloroethane and MeCN which
gave good solubility of the diazonium salt (Figure 6). Satisfyingly under these conditions no doubly
diazotized product was detected with only clean and complete conversion to the desired product
being observed. To aid with safe isolation and enable full characterization the intermediate diazonium
salt was converted to the tetrafluoroborate salt 19. Due to the gaseous nature of the intermediate

Molecules 2016, 21, 918
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diazotizing agent we are currently working on their generation for use in other applications through
the adoption of the flow tube-in-tube gas reactor system [58–61].
Figure 6. Flow reactor for diazotization of tert-butyl 4-aminophenylcarbamate.
2.3. Formation of Aryl Diazonium Species Using Solid Phase Techniques
In our previous flow work we have found it extremely beneficial to supplement packed cartridges
of immobilized reagents into the flow streams to simplify the introduction of reagents or help purify
reactions [62,63]. We were therefore interested in the potential of using such an approach to help
generate diazonium salts in flow. The simplest approach we could envisage was to utilize a sulfonic
acid functionalized ion exchange matrix to act as an acid source and to ultimately form a corresponding
aryl-diazonium sulfate species retained by association to the support [64
that a related strategy had already been adopted in batch using a sulfonic acid modified silica [66
In addition we and Filimonov et al. had used a polymer bound nitrite source to assist in the formation
of various arene-diazoniums [68 69]. Encouraged by these previous results we tested three support
,
65]. Interestingly, we found
,67].
,
materials for the promotion of diazotization reactions in flow, namely, MP-TsOH [70], Si-SA (two forms
namely SCX and SCX2) [71], and Nafion NR50 [72]. Glass Omnifit tubes were packed with the different
solid supports and placed within the flow path of a Vapourtec R2+/R4 unit (Figure 7).
Figure 7. Flow reactor for diazonium formation under heterogeneous conditions.
Several loading approaches were contrasted for simplicity and efficiency. It was decided to
pursue a non-aqueous set of reaction conditions because of the variable solubility of the different
aniline starting materials at neutral pH in water. First, a solution of the aniline in an organic solvent
(EtOH, MeCN, DCE or NMP; 1.15 M, flow rate 0.25 mL/min) was passed through the cartridge of
immobilized acid. In general a discernible color change could be observed progressing through the
cartridge as capture of the aniline occurred. To further assist with the determination of the extent of
loading a UV-Vis detector (Gilson 155) was placed in-line to monitor for aniline breakthrough (scanning
mode) [73]. Upon detection of aniline in the output line an automated valve trigger enabled exchange
of the input flow to an alternative pure solvent stream. The column was washed using the pure solvent

Molecules 2016, 21, 918
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to remove any non-captured aniline, which could be collected for calibration of the loading and if
required easily isolated for recycling. Again, this secondary washing process was monitored by UV-Vis
to enable automated assessment and processing. Unfortunately, it was found that the results obtained
were very inconsistent. Ultimately, it was shown that highly UV active impurities in the aniline
starting materials were generating false positive detection signals resulting in premature termination
of the loading sequence. To avoid this we instead repeated the loading but employed direct in-line
MS analysis (Advion Expression CMS) enabling mass directed triggering [74,75]. This alternative
approach allowed us to rapidly calibrate the active chemical loading of the sulfonic acid supports
(Table 2). Beneficially the column washing stage could again be successfully conducted as previously
stated monitoring for completeness using the in-line MS analysis. This therefore allowed us to progress
a strategy of loading and washing in an automated fashion (Figure 8).
Figure 8. Flow reactor loading set-up.
Table 2. Loading results for the supported acids using PhNH2 in MeCN.
Supported Acid
Theoretical Loading (mmol/g)
Measured Loading (mmol/g)
3.55 A/3.84 B
0.61/0.62 C/0.60 D
0.53/0.53 C/0.53 D
0.37 A/0.54 B/0.77 E
0.66
MP-TOSH
Si-SA (SCX)
Si-SA (SCX2)
Nafion NR50
Nafion NR50F
4.45
0.63
0.54
0.80
0.80
A standard 6 g of supported acid was used in a glass column (10 cm length, 6.6 mm i.d. with adjustable length
end pieces), 1 equivalent of aniline was passed through the resin followed by washing by 5 column volumes of
pure solvent, results given for MeCN. A: 0.25 mL/min; B: 0.10 mL/min; C: 0.5 mL/min; D: 1 mL/min; E: 3 h in
batch; F: The material was crushed into a powder and mixed with 20% w/w MgSO4.
Analysis of Table 2. The relative differences between the theoretical and actual loading for the
MP-TsOH and Nafion NR50 resins can be accounted for because of the degree of permeation of
the aniline into the micro beads. The MP-TsOH is supplied as 375–575 micron particles, the silica
supports as 40–63 µm spheres and the Nafion as large pellets (1.7–3 mm). With larger beads channeling
effects can occur as the fluidic flow moves through the packed bed convecting the aniline through the
cartridge and reducing the contact time for effective diffusion. In the case of the silica supports the
smaller particle size and the fact the materials are only surface functionalized gives easy site access
and rapid scavenging. This was shown by first doubling and then quadrupling the tested flow rate
and examining the scavenging process (Table 2 data).
It should also be noted that changing the solvent from MeCN had a large impact on the capture
results for the Nafion resin. Using NMP increased the sequestration rate whereas EtOH gave a
correspondingly decrease. This can be rationalized by the expected swelling properties of the Nafion

Molecules 2016, 21, 918
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resin in these solvents changing the accessibility to the functional sites, NMP being a much better
solvent for swelling the resin. The MP-TsOH being a highly cross-linked macroporous resin would
not be affected to the same extent as the pores are more rigidly defined. This is consistent with the
observed results.
In a further set of experiments it was also determined that the electronic properties of the aniline
played a significant role in the scavenging efficiency of the species onto the solid supports. As expected
weakly basic anilines such as those with nitro substituents required much longer contact times and
often gave lower final loading capacity (Table 3). There was also a pronounced solvent effect with
EtOH and NMP showing better uptake rates than MeCN and DCE or DCM. As the pKa value of the
corresponding parent solution phase p-toluene sulfonic acid is reported to be much higher in MeCN
(8.5) than water (´2.8) or other hydrogen bonding solvents this is again consistent [76–78].
Table 3. Loading results for 6 g of MP-TsOH using different aniline starting materials dissolved in
EtOH @ 0.50 mL/min.
Aniline
Substrate
Loading Time
(min)
Processed Aniline
(mmol) A
Loading
Diazo Dye Formation
mmol, (%) C
Product
Efficiency (%) B
20
21
22
23
24
25
26
27
28
29
30
31
32
32
33
34
35
36
3-F
3-CF3
4-CN
32.0
29.6
20.0
47.0
51.4
26.8
24.4
33.8
33.2
41.8
18.6
14.2
12.8
13.0
25.2
37.2
26.0
48.4
16.0
14.8
10.0
23.5
25.7
13.4
12.2
16.9
16.6
20.9
8.8
7.1
6.4
6.5
12.6
18.6
13.0
24.2
60
55
37
87
95
50
46
63
62
77
33
26
24
25
47
89
58
81
14.2, 89
12.7, 86
9.3, 93
21.3, 91
22.9, 89
11.6, 87
11.0, 90
nd D
14.3, 86
18.1, 87
5.9, 67
5.8, 82
4.4, 69
3-OMe
4-OMe
2-F,4-CN
2,4-F
2-Cl,5-OPh
3-Cl
3-Me
2-Me,5-NO2
2-NO2
4-NO2
4-NO2
4-Br
H
4-Cl
Dioxol-5yl
5.1, 78 E
11.3, 90
16.7, 90
12.2, 94
20.2, 83
A: Amount of aniline processed before breakthrough was detected by in-line MS analysis; B: Calculated as
theoretical loading divided by actual loading multiplied by 100; C: Percentage conversion based on aniline
loading; D: compound crystalized in the column; E: The column was washed for a further 20 min with EtOH to
elute more of the product from the column.
Although as previously shown reducing the flow through rate did increase the sequestering
efficacy this was not general across all the anilines tested. It was found that even using a flow rate of
0.10 mL/min failed to increase the scavenging capacity >55% for weakly basic anilines such as the
2- or 4-NO2 functionalised species.
It was determined that in general this supported acid strategy could only be effectively used with
the more intrinsically basic aniline substrates. It was therefore not possible to determine a generic set
of loading conditions as significant individual optimization was required for each starting material.
Preliminary attempts to establish a predictive model based upon a correlation between pKa of the
substrate and its loading were also not successful. Therefore although the loading sequence could
be performed under automated control and it was possible to establish recycling of the aniline flow
streams to increase loading capacities over time we felt this was not a practical approach to synthesis
in this instance. However, having loaded a set of reagent columns with different anilines we proceeded
to test the subsequent diazotization step as a proof of concept study.
A stock solution of isobutyl nitrite (1 M) was prepared in the corresponding aniline loading
solvent and passed through each reactor cartridge in sequence. It should be noted that solvent

Molecules 2016, 21, 918
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swapping was successfully trialed and gave identical results to reacting in the original solvent, with
the notable exception of the Nafion resin which was again put down to its swelling characteristics.
Having experienced repeated problems with the Nafion resin we excluded this from any additional
testing. Interestingly this capacity to exchange solvents offers an advantage for initially loading highly
insoluble anilines (i.e., in NMP or mixed solvents) with the option of subsequently further processing
them in a different solvent. In total two equivalents of isobutyl nitrite based upon the theoretical
loading of the solid resin was directed through each column at a flow rate of 0.5 mL/min. A further
40 mL (~2.5 column volumes) of pure solvent at a flow rate of 1 mL/min was then used to wash the
columns (wash mixture directed to waste).
To assess the quantity of diazotized species associated with the support we used a very facile
diazo dye formation as mediated by reaction with a solution of 2-naphtholate (Figure 9). To this end
a 0.22 M solution of sodium naphtholate prepared from equimolar quantities of sodium ethoxide
and 2-naphthol was pumped through the reactor cartridge at a flow rate of 0.25 mL/min for 20 min.
The reactor was then washed with EtOH and the output collected for a further 15 min to ensure
complete elution of all the diazo species. From this combined output a 1 mL aliquot was sampled,
evaporated and the residue redissolved in a standardized solution of d6-DMSO doped with a known
concentration of 2-methoxytoluene. Subsequent calculation of the quantity of diazo dye was made by
extrapolation from 1H-NMR assessment of the characteristic 1-naphthyl proton in the coupled product.
The main bulk of output solution was evaporated, neutralized with 1 M HCl and extracted into EtOAc
to allow isolation of the diazo product. Pleasingly the assessed conversions matched well with the
previously determined loadings of the aniline starting materials (Table 3 shows the results for EtOH
based on the use of MP-TsOH). In general a consistent but small decrease in the isolated yields of
the diazo dye was observed verses the monitored loading of the resin (3%–12%). This demonstrated
the high efficiency of the diazotization step on the solid phase. The notable outliers were substrates
possessing strongly electron withdrawing nitro functionality which effects solubility and were notably
difficult to fully elute from the column.
Figure 9. Flow reactor loading set-up.
In summary, we have demonstrated that using a solid phase approach could be successfully
applied to the formation and subsequent reaction of certain diazo species prepared from ionically
immobilized anilines. This method offers certain advantages for direct in-line purification of these
reactive intermediates and could add further value for reactions where solvent exchange or pH
adjustment is required when reacting with the final diazonium species. However, a limiting aspect of
this approach was found to be the initial loading of the anilines which was highly dependent upon
their electronic nature. Although this could be assessed and the loading sequence could be achieved

Molecules 2016, 21, 918
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in an automated fashion this approach was deemed non-ideal for practical diazonium generation.
As a result we would recommend the previously described aqueous and organic protocols as the main
preparative methods moving forward.
3. Experimental Section
3.1. General Information
Unless otherwise stated, all solvents were purchased from Fisher Scientific (Bishop Meadow Rd,
Loughborough, UK) and used without further purification. Substrates and reagents were purchased
from Alfa Aesar (Shore Road, Lancashire, Heysham, UK) or Sigma Aldrich (New Road, Gillingham,
Dorset, UK) and used as received.
1H-NMR spectra were recorded on either Avance-400 (Bruker, Elisabethhof 15, Leiderdorp,
The Netherlands) or VNMRS-700 (Varian Medical Systems, Inc., 3100 Hansen Way, Palo Alto, CA, USA)
instruments and peal positions are reported relative to residual solvent: CHCl3 (
2.50 ppm), MeOH-d4 (
3.31 ppm). 13C-NMR spectra were recorded on the same instruments
and are reported relative to CHCl3 ( 77.1 ppm), DMSO-d6 ( 39.5 ppm) or MeOH-d4 ( 49.0 ppm).
Data for 1H-NMR are reported as follows: chemical shift (
/ppm) (integration, multiplicity, coupling
δ 7.26 ppm), DMSO-d6
(δ
δ
δ
δ
δ
δ
constant (Hz)). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet,
p = pentet, m = multiplet, br. s = broad singlet, app = apparent. Data for 13C-NMR are reported
in terms of chemical shift (δ
/ppm) and multiplicity (C, CH, CH2 or CH3). Data for 19F-NMR were
recorded on a Bruker Avance-400 instrument at a frequency of 376 MHz using CFCl3 as external
standard. DEPT-135, COSY, HSQC, and HMBC experiments were used in the structural assignment.
IR spectra were obtained by use of a RX1 spectrometer (Perkin Elmer, 940 Winter St., Waltham, MA,
USA, neat, ATR sampling) with the intensities of the characteristic signals being reported as weak
(w, <20% of tallest signal), medium (m, 21%–70% of tallest signal) or strong (s, >71% of tallest signal).
Low and high resolution mass spectrometry was performed using the indicated techniques on either
LCT Premier XE or TQD instruments (Waters, Centennial Court, Elstree, Hertfordshire, UK) equipped
with Acquity UPLC and a lock-mass electrospray ion source. For accurate mass measurements the
deviation from the calculated formula is reported in ppm. Melting points were recorded on an Optimelt
automated melting point system (Lambda Photometrics, Lambda House, Hertfordshire, UK) with a
heating rate of 1 ˝C/min and are uncorrected. The flow reactors systems used in this investigation
were the manual control R series: R2+ with R4 heater unit (RS-100 system) available from Vapourtec
Ltd. (https://www.vapourtec.com/) and the Polar Bear Plus system commercially available from
Cambridge Reactor Design Ltd. (http://www.cambridgereactordesign.com/). The Polar Bear Plus
flow reactor unit was modified by our workshop to house a removable copper plate which could be
affixed to the top of the unit and housed two Uniqsis mixing chips [51].
3.2. Reactor Configuration for the Synthesis of Hydrazine Derivatives from Diazonium Salts 1–18
Three stock solutions were prepared and connected to the flow reactor feed lines for Pumps A–C
(see Figure 3 for a pictorial layout). Pump A delivered hydrochloric acid (0.84 M), Pump B a solution of
aqueous sodium nitrite (0.98 M) and pump C delivered an aqueous solution of ascorbic acid (0.35 M).
In addition a further pump was used to provide the solutions of aniline as their HCl salts dissolved in
water (0.35 M). The entire reactor was maintained under positive internal pressure using a 75 psi back
pressure regulator at the exit of the reactor. To initiate the reaction each flow channel was pumped at
0.5 mL/min.
Progressing through the reactor; Channel A and B were mixed in a Uniqsis mixer chip of 0.27 mL
internal volume (16 s residence time) before passing into a 2.75 mL PFA tubular residence coil (165 s
residence time). The combined flow was then further united with the aniline solution mixing in a
second Uniqsis mixer chip of 2 mL internal volume (80 s residence time). The reacting solution then
passed into a 5 mL residence PFA foil coil (150 s residence time, the solution turns pale yellow to

Molecules 2016, 21, 918
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˝
orange). The whole initial stage mixing unit was temperature regulated (10 C) using a Polar Bear Plus
flow reactor unit.
In the second stage reactor the freshly prepared diazonium mixture (combined flow rate
2 mL/min) was united at an Upchurch peek T-mixer with a solution of ascorbic acid delivered
from Pump C set at 0.5 mL/min. The flow stream was then progressed into a 52 mL PFA flow coil
(20.8 min residence time).
The isolation of certain intermediate hydroxamic esters, namely 13
immediate extraction of the reactor output with ethyl acetate (5 volumes) and washing the organic
phase with sodium hydrogen carbonate (2 M; 2 ). The organic solution was dried over MgSO4, filtered
–18, could be achieved by
ˆ
and concentrated in vacuo to provide a pale yellow solid which was triturated with a 1:1 mixture of
hexane and acetone to furnishing the desired product.
Alternatively, the output solution was collected and left to stir for 1 h to ensure complete hydrolysis
to the corresponding oxamic acid, 1–12, had occurred. The products were isolated by basification of
the reaction mixture pH ~9 followed by extraction with EtOAc (3 volumes). The aqueous solution
was then acidified to pH ~4 and extracted with EtOAc (3 volumes), the organic phase was dried over
MgSO4, the solvent evaporated to yield compounds 1–12. Note: for compounds 1–12 a proton signal
sites under the residual DMSO signal.
3.3. Product Characterization
1
2-(2-(2-Bromophenyl)hydrazinyl)-2-oxoacetic acid (
DMSO-d6)
(m, 2H). 13C-NMR (101 MHz, DMSO-d6)
(CH), 113.6 (CH), 107.5 (C). FT-IR
1
): 10 mmol scale, 2.05 g, 79%. H-NMR (400 MHz,
δ
10.78 (br. s, 1H), 8.25 (s, 1H), 7.51–7.35 (m, 2H), 7.22 (td, J = 7.7, 1.4 Hz, 1H), 6.78–6.63
162.0 (C), 159.1 (C), 145.3 (C), 132.9 (CH), 128.8 (CH), 120.9
max 3329 (w), 3230 (w), 2900 (w), 1729 (m), 1670 (s), 1593 (m), 1451
(m), 1215 (s), 747 (s), 634 (m) cm´1. LC-MS (ESI) Rt = 1.98 min, m/z 258.9 (M + H), HR-MS (ES+)
δ
ν
calculated for C8H7BrN2O3 258.9718, found 258.9729 (∆ = 4.2 ppm).
1
2-(2-(3-Bromophenyl)hydrazinyl)-2-oxoacetic acid (
DMSO-d6)
J = 8.2, 2.2, 0.9 Hz, 1H). 13C-NMR (101 MHz, DMSO-d6)
122.5 (C), 121.7 (CH), 114.9 (CH), 111.8 (CH). FT-IR
2
): 10 mmol scale, 2.07 g, 80%. H-NMR (400 MHz,
δ
10.70 (br. s, 1H), 8.22 (s, 1H), 7.11 (t, J = 8.0 Hz, 1H), 6.89 (m, 1H), 6.82 (m, 1H), 6.71 (ddd,
162.1 (C), 159.1 (C), 150.6 (C), 131.2 (CH),
max 3339 (w), 3207 (w), 1730 (m), 1663 (s), 1594
δ
ν
(s), 1219 (s), 1036 (m), 867 (m), 748 (s), 486 (m) cm´1. LC-MS (ESI) Rt = 1.74 min, m/z 258.9 (M + H),
HR-MS (ES+) calculated for C8H7BrN2O3 258.9718, found 258.9728 (∆ = 3.9 ppm).
1
2-(2-(4-Bromophenyl)hydrazinyl)-2-oxoacetic acid (
DMSO-d6)
13C-NMR (101 MHz, MeOD-d4)
(C). FT-IR
3
): 20 mmol scale, 4.86 g, 94%. H-NMR (400 MHz,
δ
10.68 (br. s, 1H), 8.12 (br. s, 1H), 7.31 (d, J = 8.7 Hz, 2H), 6.72–6.62 (d, J = 8.7 Hz, 2H).
160.7 (C), 158.7 (C), 147.2 (C), 131.4 (2 CH), 114.6 (2 CH), 111.52
3295 (m), 3028 (w), 1730 (m), 1700 (s), 1482 (s), 1399 (m), 1199 (s), 1176 (m), 824 (s),
704 (m), 477 (s) cm´1. LC-MS (ESI) Rt = 1.77 min, m/z 258.97 (M + H), HR-MS (ES+) calculated for
C8H7BrN2O3 258.9718, found 258.9719 (∆ = 0.4 ppm).
δ
ˆ
ˆ
ν
max
1
2-(2-(2-Chlorophenyl)hydrazinyl)-2-oxoacetic acid (
DMSO-d6)
1H), 6.75 (d, J = 7.6 Hz, 1H). 13C-NMR (101 MHz, DMSO-d6)
128.2 (CH), 120.3 (CH), 117.8 (CH), 113.4 (CH). FT-IR
4
): 20 mmol scale, 2.91 g, 68%. H-NMR (400 MHz,
δ
10.74 (s, 1H), 7.64 (s, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 6.78 (d, J = 7.6 Hz,
162.1 (C), 159.2 (C), 144.3 (C), 129.7 (C),
3339 (w), 3207 (w), 1730 (m), 1663 (s), 1490
δ
ν
max
(m), 1257 (m), 1220 (s), 1037 (m), 748 (s), 486 (s) cm´1. LC-MS (ESI) Rt = 1.69 min, m/z 215.0 (M + H),
HR-MS (ES+) calculated for C8H7ClN2O3 215.0223, found 215.0231 (∆ = 3.7 ppm).
1
2-(2-(3-Chlorophenyl)hydrazinyl)-2-oxoacetic acid (
DMSO-d6)
(101 MHz, DMSO-d6)
111.4 (CH). FT-IR
5
): 10 mmol scale, 1.78 g, 83%. H-NMR (400 MHz,
δ
10.71 (br. s, 1H), 8.23 (br. s, 1H), 7.17 (t, J = 8.0 Hz, 1H), 6.81–6.61 (m, 3H). 13C-NMR
δ
162.1 (C), 159.1 (C), 150.4 (C), 134.0 (C), 130.9 (CH), 118.8 (CH), 112.0 (CH),
3351 (w), 3291 (w), 1747 (s), 1674 (m), 1560 (s), 1473 (m), 1249 (m), 1206 (s),
ν
max

Molecules 2016, 21, 918
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792 (m), 479 (s) cm´1. LC-MS (ESI) Rt = 1.72 min, m/z 215.0 (M + H), HR-MS (ES+) calculated for
C8H7ClN2O3 215.0223, found 215.0224 (∆ = 0.5 ppm).
1
2-(2-(4-Chlorophenyl)hydrazinyl)-2-oxoacetic acid (
DMSO-d6)
(101 MHz, DMSO-d ) δ 162.1 (C), 159.0 (C), 147.8 (C), 129.0 (2CH), 122.7 (C), 114.3 (2 CH). FT-IR ν
6
): 10 mmol scale, 1.93 g, 90%. H- NMR (400 MHz,
δ
10.69 (br. s, 1H), 8.11 (br. s, 1H), 7.20 (d, J = 9.0 Hz, 2H), 6.92 (d, J = 9.0 Hz, 2H). 13C-NMR
max
6
3288 (w), 2991 (w), 1735 (w), 1696 (s), 1596 (w), 1489 (s), 1202 (w), 1175 (m), 827 (s), 481 (s) cm´1
.
LC-MS (ESI) Rt = 1.75 min, m/z 215.0 (M + H), HR-MS (ES+) calculated for C8H7ClN2O3 215.0223,
found 215.0230 (∆ = 3.3 ppm).
2-(2-(2-Nitrophenyl)hydrazinyl)-2-oxoacetic acid (
DMSO-d6) 11.08 (br. s, 1H), 9.36 (br. s, 1H), 8.11 (dd, J = 8.5, 1.5 Hz, 1H), 7.60 (ddd, J = 8.5, 6.9, 1.5 Hz,
1H), 7.09 (dd, J = 8.6, 1.2 Hz, 1H), 6.90 (ddd, J = 8.4, 7.0, 1.3 Hz, 1H). 13C-NMR (101 MHz, DMSO-d6)
7
): 30 mmol scale, 6.01 g, 89%. 1H-NMR (400 MHz,
δ
δ
161.6 (C), 158.6 (C), 144.8 (C), 136.9 (CH), 132.3 (C), 126.3 (CH), 118.6 (CH), 115.2 (CH). FT-IR νmax 3228
(w), 1757 (m), 1672 (m), 1612 (m), 1319 (s), 1261 (s), 1153 (s), 951 (m), 737 (s), 490(s) cm´1. LC-MS (ESI)
Rt = 1.44 min, m/z 226.1 (M + H), HR-MS (ES+) calculated for C8H7N3O5 226.0464, found 226.0473
(∆ = 4.0 ppm).
2-(2-(3-Nitrophenyl)hydrazinyl)-2-oxoacetic acid (
DMSO-d6) 10.88 (s, 1H), 8.61 (s, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 6.8 Hz, 1H), 7.44 (d, J = 8.1 Hz,
1H), 7.15 (d, J = 6.9 Hz, 1H). 13C-NMR (101 MHz, DMSO-d6)
162.0 (C), 159.0 (C), 150.1 (C), 149.0 (C),
130.7 (CH), 119.0 (CH), 113.7 (CH), 106.2 (CH). FT-IR 3361 (w), 3270 (w), 1757 (m), 1664 (m), 1526
8
): 28 mmol scale, 5.80 g, 92%. 1H-NMR (400 MHz,
δ
δ
ν
max
(s), 1489 (m), 1349 (s), 1205 (m), 732 (s), 494 (s) cm´1. LC-MS (ESI) Rt = 1.34 min, m/z 226.1 (M + H),
HR-MS (ES+) calculated for C8H7N3O5 226.0464, found 226.0469 (∆ = 2.2 ppm).
2-(2-(4-Nitrophenyl)hydrazinyl)-2-oxoacetic acid (
DMSO-d6)
10.97 (s, 1H), 9.22 (s, 1H), 8.08 (d, J = 9.1 Hz, 2H), 6.78 (d, J = 9.1 Hz, 2H). 13C-NMR
(101 MHz, DMSO-d6) 161.7 (C), 158.8 (C), 154.4 (C), 138.8 (2 CH), 126.3 (C), 111.3 (2 CH). FT-IR
max 3300 (w), 1699 (m), 1592 (s), 1499 (s), 1526 (s), 1309 (s), 1215 (m), 1109 (s), 732 (s), 840 (m) cm´1
9
): 12 mmol scale, 2.43 g, 90%. 1H-NMR (400 MHz,
δ
δ
ν
.
LC-MS (ESI) Rt = 1.29 min, m/z 226.1 (M + H), HR-MS (ES+) calculated for C8H7N3O5 226.0464, found
226.0470 (∆ = 2.7 ppm).
1
2-(2-(2-Methoxyphenyl)hydrazinyl)-2-oxoacetic acid (10): 30 mmol scale, 4.22 g, 67%. H-NMR (400 MHz,
DMSO-d6)
162.2 (C), 158.7 (C), 146.9 (C), 137.6 (C), 121.1 (CH), 119.8 (CH), 112.0 (CH), 110.9 (CH), 55.9 (CH3). FT-IR
δ δ
10.69 (br. s, 1H), 7.11 (br. m, 1H), 6.78 (m, 4H), 3.81 (s, 3H). 13C-NMR (101 MHz, DMSO)
´1
.
ν
3325 (w), 3209 (w), 3049 (w), 1709 (m), 1679 (s), 1499 (s), 1346 (s), 1211 (s), 1028 (m), 733 (s) cm
max
LC-MS (ESI) Rt = 1.70 min, m/z 211.1 (M + H), HR-MS (ES+) calculated for C9H10N2O4 211.0719,
found 211.0719 (∆ = 0 ppm).
1
2-Oxo-2-(2-(m-tolyl)hydrazinyl)acetic acid (11): 30 mmol scale, 4.19 g, 72%. H-NMR (400 MHz, DMSO-d6)
δ
10.63 (br. s, 1H), 7.93 (br. s, 1H), 7.06 (m, 1H), 6.57 (m, 3H), 2.23 (s, 3H). 13C-NMR (101 MHz, DMSO-d6)
δ
162.3 (C), 159.1 (C), 148.8 (C), 138.3 (C), 129.1 (CH), 120.2 (CH), 113.3 (CH), 110.1 (CH), 21.7 (CH3).
FT-IR
ν
3283 (m), 2916 (w), 3049 (w), 1758 (m), 1683 (s), 1612 (m), 1346 (m), 1169 (s), 1956 (m),
max
689 (s) cm´1. LC-MS (ESI) Rt = 1.48 min, m/z 195.1 (M + H), HR-MS (ES+) calculated for C9H10N2O3
195.0770, found 195.0773 (∆ = 1.5 ppm).
1
2-Oxo-2-(2-(p-tolyl)hydrazinyl)acetic acid (12): 25 mmol scale, 3.73 g, 77%. H-NMR (400 MHz, DMSO-d6)
δ
10.61 (br. s, 1H), 7.80 (br. s, 1H), 6.97 (d, J = 8.2 Hz, 2H), 6.64 (d, J = 8.2 Hz, 2H), 2.18 (s, 3H). 13C-NMR
(101 MHz, DMSO-d6)
(CH3). FT-IR
δ
162.4 (C), 159.0 (C), 146.5 (C), 129.6 (2CH), 128.0 (C), 113.1 (2
ˆ
CH), 20.6
ν
max 3326 (w), 3177 (w), 1755 (m), 1683 (s), 1511 (m), 11354 (s), 1280 (m), 940 (m), 807(s),
477(s) cm´1. LC-MS (ESI) Rt = 1.82 min, m/z 195.08 (M + H), HR-MS (ES+) calculated for C9H11N2O3
195.0770, found 195.0775 (∆ = 2.6 ppm).
(3R,4S)-4-Hydroxy-2-oxotetrahydrofuran-3-yl-2-(2-(4-bromophenyl)hydrazinyl)-2-oxoacetate (13): 5 mmol
1
scale, 687 mg, 53%. H-NMR (700 MHz, DMSO-d6)
δ 11.00 (d, J = 2.5 Hz, 1H), 8.22 (d, J = 2.7 Hz, 1H),

Molecules 2016, 21, 918
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7.30 (d, J = 7.2 Hz, 2H), 6.67 (d, J = 7.2 Hz, 2H), 6.15 (d, J = 4.7 Hz, 1H), 5.66 (d, J = 7.9 Hz, 1H), 4.67 (qd,
J = 7.9, 4.7 Hz, 1H), 4.49 (dd, J = 8.5, 7.5 Hz, 1H), 4.04 (t, J = 8.3 Hz, 1H). 13C-NMR (176 MHz, DMSO-d6)
δ
170.6 (C), 159.1 (C), 156.3 (C), 147.8 (C), 131.9 (2
ˆ
CH), 114.8 (2
δ 7.29 (d, J = 7.4 Hz, 2H), 6.74 (d, J = 7.4 Hz, 2H),
ˆ
CH), 110.5 (C), 76.4 (CH), 70.0
1
(CH), 69.8 (CH2). H-NMR (700 MHz, methanol-d4)
4.40 (dd, J = 9.0, 7.0 Hz, 1H), 4.27 (q, J = 7.0 Hz, 1H), 4.17 (d, J = 7.0 Hz, 1H), 3.92 (dd, J = 9.0, 7.0 Hz,
1H). 13C-NMR (176 MHz, methanol-d4)
175.9 (C), 160.0 (C), 157.6 (C), 147.1 (C), 131.4 (2 CH), 114.6
(2 3457 (w), 3355 (w), 3224 (w),
δ
ˆ
ˆ
CH), 111.6 (C), 73.36 (CH), 72.68 (CH), 69.80 (CH2). FT-IR ν
max
1782 (m), 1759 (s), 1690 (m), 1478 (m), 1204 (m), 812 (s), 504 (s) cm´1. LC-MS (ESI) 1.91 Rt m/z 359.3
and 719.3. LC-MS (ESI) Rt = 2.56 min, m/z 359 (M + H), HR-MS (ES+) calculated for C12H11BrN2O6
358.9879, found 358.9891 (
c = 29.1832(16); α = 90 , β = 90 , γ = 90 .
∆
=˝3.3 ppm˝). X-ray CCDC 1485241; P2ac2ab; a = 5.3554(3), b = 8.6070(5),
˝
(3R,4S)-4-Hydroxy-2-oxotetrahydrofuran-3-yl-2-(2-(4-chlorophenyl)hydrazinyl)-2-oxoacetate (14): 5 mmol
1
scale, 644 mg, 60%. H-NMR (700 MHz, DMSO-d6)
δ 11.00 (d, J = 2.6 Hz, 1H), 8.21 (d, J = 2.8 Hz, 1H),
7.19 (d, J = 7.2 Hz, 2H), 6.72 (d, J = 7.2 Hz, 2H), 6.15 (d, J = 4.9 Hz, 1H), 5.66 (d, J = 7.9 Hz, 1H), 4.66
(td, J = 7.7, 4.8 Hz, 1H), 4.49 (dd, J = 8.5, 7.7 Hz, 1H), 4.04 (t, J = 8.5 Hz, 1H). 13C-NMR (176 MHz,
DMSO-d6)
69.9 (CH2), 69.8 (CH). 1H-NMR (400 MHz, methanol-d4)
2H), 5.71 (d, J = 7.7 Hz, 1H), 4.78 (q, J = 7.7 Hz, 1H), 4.58 (dd, J = 8.9, 7.7 Hz, 1H), 4.13 (dd, J = 8.9,
8.0 Hz, 1H). 13C-NMR (176 MHz, methanol-d4)
170.6 (C), 159.2 (C), 156.3 (C), 147.4 (C), 129.1 (2CH),
122.9 (C), 114.3 (2CH), 76.4 (CH), 69.9 (CH), 69.8 (CH2). FT-IR max 3448 (w), 3362 (w), 3227 (w), 1785
(m), 1761 (s), 1692 (m),1508 (m), 1029 (s), 821 (m), 506 (s) cm´1. LC-MS (ESI) Rt = 2.35 min, m/z 315.0
(M + H), HR-MS (ES+) calculated for C12H11ClN2O6 314.0384, found 314.0386 ( = 0.6 ppm). X-ray
δ
170.6 (C), 159.2 (C), 156.3 (C), 147.4 (C), 129.1 (2CH), 122.9 (C), 114.3 (2CH), 76.4 (CH),
δ
7.20 (d, J = 7.3 Hz, 2H), 6.85 (d, J = 7.3 Hz,
δ
ν
∆
˝
˝
˝
CCDC 1485245; P2ac2ab; a = 5.3548(3), b = 8.5893(5), c = 28.7810(16); α = 90 , β = 90 , γ = 90 .
(3R,4S)-4-Hydroxy-2-oxotetrahydrofuran-3-yl-2-(2-(2-nitrophenyl)hydrazinyl)-2-oxoacetate (15): 10 mmol
1
scale, 878 mg, 78%. H-NMR (400 MHz, DMSO-d6)
δ 11.41 (br. s, 1H), 9.46 (br. s, 1H), 8.13 (dd, J = 8.6,
1.6 Hz, 1H), 7.63 (ddd, J = 8.6, 7.0, 1.6 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 6.93 (ddd, J = 8.6, 7.0, 1.6 Hz,
1H), 6.20 (d, J = 5.0 Hz, 1H), 5.73 (d, J = 7.7 Hz, 1H), 4.72 (qd, J = 7.7, 3.4 Hz, 1H), 4.53 (dd, J = 8.5,
7.7 Hz, 1H), 4.09 (t, J = 8.5 Hz, 1H). 13C-NMR (101 MHz, DMSO-d6)
δ
170.6 (C), 158.8 (C), 155.9 (C),
144.4 (C), 136.9 (C), 132.5 (CH), 126.4 (CH), 118.9 (CH), 115.1 (CH), 76.5 (CH), 70.2 (CH2), 69.8 (CH).
FT-IR
ν
3366 (w), 3321 (w), 3271 (w), 1790 (s), 1721 (s), 1701 (s), 1611 (m), 1494 (s), 1350 (m), 1153 (s),
max
752 (s) cm´1. LC-MS (ESI) Rt = 2.06 min, m/z 326.1 (M + H), HR-MS (ES+) calculated for C12H12N3O8
326.0624, found 326.0629 (∆ = 1.5 ppm).
(3R,4S)-4-Hydroxy-2-oxotetrahydrofuran-3-yl-2-(2-(2-methoxyphenyl)hydrazinyl)-2-oxoacetate (16): 5 mmol
1
scale, 441 mg, 42%. HNMR (400 MHz, DMSO-d6)
δ
11.02 (br. s, 1H), 7.33 (br. s, 1H), 6.92 (dd, J = 7.7,
1.7 Hz, 1H), 6.85–6.73 (m, 2H), 6.66 (dd, J = 7.5, 1.9 Hz, 1H), 6.21 (d, J = 4.9 Hz, 1H), 5.70 (d, J = 8.0 Hz,
1H), 4.71 (qd, J = 8.0, 4.9 Hz, 1H), 4.52 (dd, J = 8.5, 7.5 Hz, 1H), 4.07 (t, J = 8.5 Hz, 1H), 3.83 (s, 3H).
13CNMR (101 MHz, DMSO-d6)
(CH), 111.9 (CH), 111.1 (CH), 76.4 (CH), 70.0 (CH2), 69.8 (CH), 55.9 (CH3). FT-IR
(w), 3225 (w), 1784 (m), 1761 (s), 1702 (m), 1499 (s), 1133 (m), 1019 (s), 734 (s), 493 (s) cm´1. LC-MS (ESI)
Rt = 2.03 min, m/z 311.1 (M + H), HR-MS (ES+) calculated for C13H15N2O7 311.0879, found 311.0879
(∆ = 0.0 ppm).
δ
170.7 (C), 159.2 (C), 156.1 (C), 147.0 (C), 137.2 (C), 121.1 (CH), 112.0
max 3432 (w), 3363
ν
(3R,4S)-4-hydroxy-2-oxotetrahydrofuran-3-yl-2-(2-(4-methoxyphenyl)hydrazinyl)-2-oxoacetate (17): 5 mmol
1
scale, 525 mg, 50%. H-NMR (400 MHz, DMSO-d6)
δ
10.98 (br. s, 1H), 7.75 (br. s, 1H), 6.80 (d, J = 8.9 Hz,
2H), 6.72 (d, J = 8.9 Hz, 2H), 6.19 (d, J = 4.9 Hz, 1H), 5.69 (d, J = 7.9 Hz, 1H), 4.70 (qd, J = 7.6, 4.9 Hz,
1H), 4.52 (dd, J = 8.5, 7.6 Hz, 1H), 4.07 (t, J = 8.5 Hz, 1H), 3.68 (s, 3H). 13C-NMR (101 MHz, DMSO-d6)
170.7 (C), 159.4 (C), 156.3 (C), 153.6 (C), 142.2 (C), 115.5 (2 CH), 114.8 (2 CH), 76.3 (CH), 70.0 (CH2),
69.8 (CH), 55.7 (CH3). FT-IR max 3445 (w), 3363 (w), 3224 (w), 1785 (m), 1760 (s), 1700 (m), 1508 (s),
δ
ˆ
ˆ
ν

Molecules 2016, 21, 918
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1122 (m), 1030 (s), 820 (s), 493 (s) cm´1. LC-MS (ESI) Rt = 1.81 min, m/z 311.09 (M + H), HR-MS (ES+)
calculated for C13H15N2O7 311.0879, found 311.0891 (∆ = 3.9 ppm).
(3R,4S)-4-Hydroxy-2-oxotetrahydrofuran-3-yl 2-oxo-2-(2-(p-tolyl)hydrazinyl)acetate (18): 5 mmol scale,
1
602 mg, 62%. H-NMR (400 MHz, DMSO-d6)
δ 10.96 (br. s, 1H), 7.89 (br. s, 1H), 6.99 (d, J = 8.2 Hz,
2H), 6.66 (d, J = 8.2 Hz, 2H), 6.19 (d, J = 4.9 Hz, 1H), 5.69 (d, J = 7.9 Hz, 1H), 4.75–4.64 (m, 1H), 4.52
(t, J = 8.2 Hz, 1H), 4.07 (t, J = 8.2 Hz, 1H), 2.19 (s, 3H). 13C-NMR (101 MHz, DMSO-d6)
170.7 (C),
159.3 (C), 156.3 (C), 146.1 (C), 129.7 (2CH), 128.4 (C), 113.1 (2CH), 76.3 (CH), 70.0 (CH2), 69.8 (CH), 20.6
δ
(CH3). FT-IR νmax 3429 (w), 3310 (w), 3260 (w), 1765 (s), 1511 (m), 1193 (s), 1014 (m), 805 (s), 643 (m),
506 (s) cm´1. LC-MS (ESI) Rt = 2.17 min, m/z 295.09 (M + H), HR-MS (ES+) calculated for C13H15N2O7
295.0930, found 295.0928 (∆ = 1.7 ppm).
4-[[(1, 1’-Dimethylethoxy)carbonyl]amino]benzenediazonium tetrafluoroborate (19) [79]: Stock solutions of
isobutyl nitrite (0.345 M) trimethylsilyl chloride (0.345 M) and tert-butyl-4-aminophenylcarbamate
(0.30 M) in 2:1 solvent mixture of dichloroethane and MeCN were prepared. At flow rates of
0.25 mL/min the solutions of trimethylsilyl chloride and isobutyl nitrite were pumped and united
at a Upchurch PEEK T-mixer then immediately combined at a second T-mixer the solution of aniline.
The combined flow stream was progressed into a PFA tubular reactor (internal volume 20 mL, residence
time 26.7 min) maintained at 20 ˝C. Samples of the reactor output were taken every 10 min for direct
1H-NMR analysis to assess conversion (which was consistent at 98% after the first 15 min). The bulk
reactor output was collected (for 2 h) into a stirred round bottom flask containing a suspension of
sodium tetrafluoroborate (1.087 g, 1.1 equiv.) in EtOH (20 mL). The suspension was evaporated and
triturated with a 3:1 mixture of diethyl ether and MeCN to give a pale off white solid 2.266 g, 82%.
1H-NMR (400 MHz, DMSO-d6)
2H), 1.51 (s, 9 H). 13C-NMR (101 MHz, DMSO-d6)
(2 CH), 103.5 (C), 82.2 (C), 28.2 (3
CH3). 19F-NMR (376 MHz, DMSO-d6)
(neat)
δ
/ppm: 10.97 (s, 1H), 8.58 (d, J = 8.0 Hz, 2Hz), 7.95 (d, J = 8.0 Hz,
/ppm: 152.3 (C), 151.5 (C), 135.5 (2 CH), 119.2
/ppm: 148.3 (s). IR
δ
ˆ
ˆ
ˆ
δ
´
ν
3308 (w), 2975 (w), 2246 (m), 1741 (m), 1579 (s), 1527 (s), 1433 (m), 1232 (s), 1154 (s), 1090
(s), 1056 (s), 1006 (s), 839 (s), 519 (s) cm´1. LC-MS (ESI) 220.2 (M+). HR-MS (ESI) calculated for
C11H14N3O2 220.1086, found 220.1099 (∆ = 5.9 ppm).
(E)-1-((3-Fluorophenyl)diazenyl)naphthalene-2-ol (20): Assessed loading 14.2 mmol, 89%; Isolated yield
1
3.44 g, 81%. H-NMR (400 MHz, CDCl3)
δ/ppm: 16.07 (1H, s), 8.53–8.45 (1H, m), 7.70 (1H, d, J = 9.5 Hz),
7.62–7.52 (2H, m), 7.52–7.46 (1H, m), 7.45–7.33 (3H, m), 7.02–6.91 (1H, m), 6.81 (1H, d, J = 9.5 Hz).
13C-NMR (101 MHz, CDCl3)
δ/ppm: 173.5 (C), 163.8 (CF, d, J = 247 Hz), 146.2, (C, d, J = 9 Hz), 141.0
(CH), 133.4 (C), 130.8 (CH, d, J = 9 Hz), 130.4 (C), 129.1 (CH), 128.7 (CH), 128.2 (C), 126.2 (CH), 125.0
(CH), 121.9 (CH), 114.7 (CH, d, J = 3 Hz), 113.7 (CH, d, J = 22 Hz), 104.7 (CH, d, J = 26 Hz). 19F-NMR
(376 MHz, CDCl3)
δ
/ppm:
´
110.87 (s). IR (neat) ν 1611.1 (m), 1596.0 (m), 1495.7 (m), 1251.2 (m),
1213.2 (m), 1109.8 (m), 987.9 (m), 865.8 (m), 834.3 (s), 768.9 (s), 746.0 (s), 675.1 (s), 514.0 (s) 454.6 (m)
cm´1. LC-MS (ESI) 267.1 (M + H). HR-MS (ESI) calculated for C16H12N2OF 267.0934, found 267.0928
(∆ = ´2.2 ppm). Melting range: 136.9–139.7 C.
˝
(E)-1-((3-(Trifluoromethyl)phenyl)diazenyl)naphthalene-2-ol (21) [80]: Assessed loading 12.7 mmol, 86%;
1
Isolated 3.45 g, 74%. H-NMR (400 MHz, CDCl3)
δ/ppm: 16.07 (1H, s), 8.48 (1H, d, J = 7.6 Hz), 7.94
(1H, s), 7.81 (1H, d, J = 8.0 Hz), 7.70 (1H, d, J = 9.5 Hz), 7.63–7.53 (3H, m), 7.51 (1H, d, J = 7.6 Hz), 7.40
(1H, ddd, J = 8.0, 7.2, 1.2 Hz), 6.81 (1H, d, J = 9.5 Hz). 13C-NMR (101 MHz, CDCl3)
δ/ppm: 173.6
(C), 145.0 (C), 141.2 (CH), 133.3 (C), 132.2 (C, q, J = 33 Hz), 130.6 (C), 130.1 (CH), 129.2 (CH), 128.8
(CH), 128.3 (C), 126.4 (CH), 125.0 (CH), 123.8 (CF3, q, J = 274 Hz), 123.2 (CH, q, J = 4 Hz), 121.9 (CH),
121.3 (CH), 114.8 (CH, q, J = 4 Hz). 19F-NMR (376 MHz, CDCl3)
δ/ppm: -62.83 (s). IR (neat) ν 1739.4
(m), 1617.1 (m), 1496.7 (m), 1448.5 (m), 1313.7 (m), 1246.8 (s), 1203.7 (s), 1116.7 (s), 833.9 (s), 795.2 (s),
754.9 (s), 690.4 (s), 663.2 (s), 504.8 (s) cm´1. LC-MS (ESI) 317.5 (M + H). HR-MS (ESI) calculated for
˝
C17H12N2OF3 317.0902, found 317.0901 (∆ = ´0.3 ppm). Melting range: 164.8–167.5 C.

Molecules 2016, 21, 918
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(E)-4-((2-Hydroxynaphthalen-1-yl)diazenyl)benzonitrile (22) [81
,
82]: Assessed loading 9.3 mmol, 93%;
Isolated 2.27 g, 83%.1H-NMR (400 MHz, CDCl3)
δ
/ppm 16.10 (1H, s), 8.40 (1H, d, J = 8.0 Hz), 7.71
(2H, d, J = 9.0 Hz), 7.66 (2H, d, J = 9.0 Hz), 7.65–7.75 (2H, m), 7.53 (1H, m), 7.42 (1H, m), 6.71 (1H, d,
J = 9.6 Hz). 13C-NMR (101 MHz, CDCl3)
/ppm: 179.1 (C), 146.5 (C), 143.0 (CH), 133.8 (2CH), 133.1
(C), 131.5 (C), 129.7 (CH), 129.1 (CH), 128.5 (C), 127.3 (CH), 126.1 (CH), 122.3 (CH), 118.8 (C), 117.3
(2CH), 108.4 (C). IR (neat) 3066.9 (w), 2219.6 (m), 1738.7 (w), 1604.2 (m), 1496.0 (s), 1450.0 (s), 1395.8
(s), 1253.8 (s), 1205.6 (s), 1148.4 (s), 1093.4 (m), 983.1 (m), 837.0 (s), 757.6 (s), 513.5 (s) cm´1. LC-MS
δ
ν
(ESI) 274.0 (M + H). HR-MS (ESI) calculated for C17H12N3O 274.0980, found 274.0980 (
Melting range: 141.6–143.3 C.
∆
= 0.0 ppm).
˝
(E)-1-((3-Methoxyphenyl)diazenyl)naphthalene-2-ol (23) [83
,
84]: Assessed loading 21.3 mmol, 91%; Isolated
1
5.72 g, 88%. H-NMR (400 MHz, DMSO-d6)
δ/ppm: 15.76 (s, 1H), 8.52 (dd, J = 1.1, 8.3 Hz, 1H), 7.95
(d, J = 9.4 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.62 (ddd, J = 1.4, 7.1, 8.3 Hz, 1H), 7.50–7.40 (m, 4H), 6.95 (dt,
J = 2.2, 7.1 Hz, 1H), 6.91 (d, J = 9.4 Hz, 1H), 3.87 (s, 3H). 13C-NMR (101 MHz, DMSO-d6)
/ppm: 170.2
(C), 160.9 (C), 146.6 (C), 140.7 (CH), 133.2 (C), 131.1 (CH), 129.7 (C), 129.6 (CH), 129.4 (CH), 128.3 (C),
126.4 (CH), 124.6 (CH), 121.8 (CH), 114.5 (CH), 111.9 (CH), 104.0 (CH), 55.9 (CH3). IR (neat) 2966 (w),
δ
ν
2838 (w), 1602 (w), 1558 (m), 1487 (s), 1439 (m), 1247 (s), 1115 (s), 1041 (s), 987 (m), 863 (s), 839 (s), 766
(s), 755 (s), 676 (s), 517 (m) cm´1. LC-MS (ESI) 279.2 (M + H). HR-MS (ESI) calculated for C17H15N2O2
˝
279.1134, found 279.1137 (∆ = 1.1 ppm). Melting range: 138.7–140.9 C.
(E)-1-((4-Methoxyphenyl)diazenyl)naphthalene-2-ol (24) [36
,
85]: Assessed loading 22.9 mmol, 89%; Isolated
1
5.80 g, 81%. H-NMR (400 MHz, CDCl3)
δ/ppm: 15.71 (1H, s), 8.71 (1H, d, J = 8.4 Hz), 7.80 (2H, d,
J = 9.0 Hz), 7.74 (1H, d, J = 9.2 Hz), 7.67 (1H, d, J = 7.6 Hz), 7.57 (1H, ddd, J = 8.4, 7.7, 1.2 Hz), 7.39
(1H, ddd, J = 8.4, 7.8, 1.2 Hz), 7.04 (1H, d, J = 9.0 Hz), 7.00 (2H, d, J = 9.1 Hz), 3.86 (3H, s). 13C-NMR
(101 MHz, CDCl3)
δ/ppm: 161.4 (C), 160.6 (C), 141.8 (C), 136.7 (CH), 133.3 (C), 129.5 (C), 128.3 (CH),
128.1 (C+CH), 124.8 (CH), 122.2 (CH), 122.0 (2CH), 121.6 (CH), 114.8 (2CH), 55.6 (CH3). IR (neat)
ν
2836.6 (w), 1601.0 (m), 1502.1 (s), 1299.7 (m), 1158.5 (m), 1031.2 (m), 826.5 (m), 754.2 (m), 512.7 (m)
cm´1. LC-MS (ESI) 279.1 (M + H). HR-MS˝(ESI) calculated for C17H15N2O2 279.1134, found 279.1135
(∆ = 0.4 ppm). Melting range: 133.8–136.2 C.
(E)-3-Fluoro-4-((2-hydroxynaphthalen-1-yl)diazenyl)benzonitrile (25): Assessed loading 11.6 mmol, 87%;
1
Isolated 3.08 g, 79%. H-NMR (400 MHz, CDCl3)
δ/ppm: 16.00 (1H, s), 8.35 (1H, d, J = 8.0 Hz), 8.06
(1H, t, J = 8.0 Hz), 7.66 (1H, d, J = 9.7 Hz), 7.50–7.60 (3H, m), 7.45–7.37 (m, 2H), 6.67 (1H, d, J = 9.7 Hz).
13C-NMR (101 MHz, CDCl3)
δ/ppm: 180.4 (C), 151.2 (CF, d, J = 251 Hz), 143.6 (CH), 135.7 (C, d,
J = 9 Hz), 132.8 (C), 132.7 (C), 129.8 (CH), 129.6 (CH, d, J = 4 Hz), 129.2 (CH), 128.7 (C), 127.8 (CH), 126.4
(CH), 122.6 (CH), 119.6 (CH, d, J = 21 Hz), 117.8 (C, d, J = 3 Hz), 117.0 (CH, d, J = 2 Hz), 107.7 (C, d,
J = 9 Hz). 19F-NMR (376 MHz, CDCl3)
δ
/ppm:
(m), 1452.2 (m), 1266.6 (m), 1202.9 (s), 1106.0 (m), 831.3 (s), 760.5 (s), 613.9 (m), 517.6 (s) cm´1. LC-MS
(ESI) 292.1 (M + H). HR-MS (ESI) calculated for C17H11N3OF 292.0886, found 292.0894 ( = 2.7 ppm).
´
128.16 (s). IR (neat) ν 2225.6 (m), 1613.5 (m), 1512.8
∆
˝
Melting range: 227.4–229.2 C.
(E)-1-((2,4-Difluorophenyl)diazenyl)naphthalene-2-ol (26): Assessed loading 11.0 mmol, 90%; Isolated
1
2.91 g, 84%. H-NMR (400 MHz, CDCl3)
δ/ppm 15.77 (1H, s), 8.53 (1H, d, J = 8.4 Hz), 8.00 (1H, td,
J = 8.9, 6.0 Hz), 7.72 (1H, d, J = 9.4 Hz), 7.61 (1H, m), 7.54 (1H, ddd, J = 8.3, 7.1, 1.3 Hz), 7.40 (1H, ddd,
J = 8.0, 7.1, 1.2 Hz), 7.05–6.94 (2H, m), 6.91 (1H, d, J = 9.4 Hz). 13C-NMR (101 MHz, CDCl3)
δ/ppm:
168.2 (C), 161.8 (CF, dd, J = 251, 11 Hz), 155.1 (CF, dd, J = 255, 12 Hz), 139.6 (CH), 133.2 (C), 131.2 (C, dd,
J = 8, 4 Hz), 130.9 (C), 128.8 (CH), 128.6 (CH), 128.2 (C), 125.8 (CH), 123.7 (CH), 121.7 (CH), 118.1 (CH,
dd, J = 10, 2 Hz), 112.4 (CH, dd, J = 23, 4 Hz), 104.7 (CH, dd, J = 27, 22 Hz). 19F-NMR (376 MHz, CDCl3)
δ
/ppm:
(m), 1271.6 (m), 1203.1 (s), 1132.8 (s), 957.6 (s), 834.0 (s), 801.2 (m), 747.6 (s), 718.9 (m) cm´1. LC-MS
(ESI) 285.0 (M + H). HR-MS (ESI) calculated for C16H11N2OF2 285.0839, found 285.0840 ( = 0.4 ppm).
´
109.81 (d, J = 6 Hz), -123.56 (d, J = 6 Hz). IR (neat) ν 1620.2 (m), 1599.7 (m), 1507.3 (s), 1440.3
∆
˝
Melting range: 140.3–143.1 C.

Molecules 2016, 21, 918
17 of 23
1
(E)-1-((5-Chloro-2-phenoxyphenyl)diazenyl)naphthalene-2-ol (27): Isolated 360 mg. H-NMR (400 MHz,
CDCl3) /ppm: 8.51 (1H, d, J = 8.4 Hz), 8.08 (1H, d, J = 2.5 Hz), 7.64 (1H, d, J = 9.6 Hz), 7.60–7.50 (2H,
m), 7.43–7.34 (3H, m), 7.20–7.07 (5H, m), 6.90 (1H, d, J = 8.7 Hz), 6.71 (1H, d, J = 9.6 Hz). 13C-NMR
(101 MHz, CDCl3) /ppm 177.5 (C), 156.1 (C), 145.5 (C), 141.8 (CH), 135.7 (C), 133.4 (C), 131.4 (C),
130.0 (2CH), 129.9 (C), 129.3 (CH), 128.8 (CH), 128.2 (C), 126.6 (CH), 126.1 (CH), 126.0 (CH), 124.2 (CH),
122.1 (CH), 119.8 (CH), 118.8 (2CH), 116.5 (CH). IR (neat) 1617.3 (w), 1585.8 (w), 1473.9 (s), 1238.7
(m), 1197.8 (s), 1114.6 (m), 868.0 (m), 837.3 (s), 764.9 (s), 750.0 (s), 694.4 (s), 516.8 (m) cm´1. LC-MS
δ
δ
ν
(ESI) 375.0 (M + H). HR-MS (ESI) calculated for C22H16N2O2Cl 375.0900, found 375.0902 (
Melting range: 163.8-166.5 C.
∆
= 0.5 ppm).
˝
(E)-1-((3-Chlorophenyl)diazenyl)naphthalene-2-ol (28) [83
,
84]: Assessed loading 14.3 mmol, 86%; Isolated
1
3.89 g, 83%. H-NMR (400 MHz, CDCl3)
δ
/ppm: 16.02 (1H, s), 8.48 (1H, d, J = 8.0 Hz), 7.72 (1H, t,
J = 2.0 Hz), 7.68 (1H, d, J = 9.5 Hz), 7.52–7.56 (2H, m), 7.48 (1H, ddd, J = 8.1, 2.0, 1.0 Hz), 7.39 (1H, ddd,
J = 7.6, 6.6, 1.2 Hz), 7.35 (1H, d, J = 8.0 Hz), 7.22 (1H, ddd, J = 7.9, 2.0, 1.0 Hz), 6.80 (1H, d, J = 9.5 Hz).
13C-NMR (101 MHz, CDCl3)
δ
/ppm: 173.3 (C), 145.6 (C), 141.0 (CH), 135.6 (C), 133.3 (C), 130.5 (CH),
130.4 (C), 129.1 (CH), 128.7 (CH), 128.2 (C), 126.8 (CH), 126.2 (CH), 124.9 (CH), 121.9 (CH), 117.8 (CH),
116.9 (CH). IR (neat) 1617.2 (m), 1550.4 (m), 1499.3 (s), 1437.2 (m), 1252.3 (s), 1204.1 (s), 1068.8 (m),
862.3 (s), 833.9 (s), 779.9 (s), 752.5 (s), 672.8 (s), 510.1 (s) cm´1. LC-MS (ESI) 283.0 (M + H). HR-MS (ESI)
ν
˝
calculated for C16H12N2OCl 283.0683, found 283.0645 (∆ = 2.5 ppm). Melting range: 152.6–155.0 C.
(E)-1-((3-Methylphenyl)diazenyl)naphthalene-2-ol (29) [83 86]: Assessed loading 18.1 mmol, 87%; Isolated
4.47 g, 82%. 1H-NMR (400 MHz, DMSO-d6)
/ppm: 15.83 (s, 1H), 8.55 (d, J = 7.8 Hz, 1H), 7.95
(d, J = 9.4 Hz, 1H), 7.79 (dd, J = 1.3, 7.8 Hz, 1H), 7.69 (s, 1H), 7.60-7.66 (m, 2H), 7.40–7.50 (m, 2H), 7.20
(d, J = 7.8 Hz, 1H), 6.93 (d, J = 9.4 Hz, 1H), 2.42 (s, 3H). 13C-NMR (101 MHz, DMSO-d6)
/ppm: 169.2
(C), 145.5 (C), 140.3 (CH), 139.9 (C), 133.2 (C), 130.1 (CH), 129.6 (C), 129.5 (CH), 129.4 (CH), 129.3 (CH),
128.3 (C), 126.2 (CH), 124.4 (CH), 121.8 (CH), 119.6 (CH), 116.8 (CH), 21.5 (CH3). IR (neat) 3030 (w),
,
δ
δ
ν
2920 (w), 1616 (m), 1505 (s), 1447 (s), 1271 (m), 1236 (s), 1209 (s), 1126 (s), 986 (m), 864 (s), 835 (s), 780
(s), 748 (s), 682 (s), 513 (s) cm´1. LC-MS (ESI) 263.1 (M + H). HR-MS (ESI) calculated for C17H15N2O
˝
263.1184, found 263.1183 (∆ = 0.4 ppm). Melting range: 138.1–139.0 C.
(E)-1-((2-Methyl-5-nitrophenyl)diazenyl)naphthalene-2-ol (30) [87]: Assessed loading 5.9 mmol, 67%;
Isolated 1.98 g, 60%. 1H-NMR (400 MHz, CDCl3)
δ/ppm: 8.76 (1H, d, J = 2.4 Hz), 8.50 (1H, d,
J = 8.1 Hz), 7.95 (1H, dd, J = 8.2, 2.4 Hz), 7.69 (1H, d, J = 9.5 Hz), 7.59 (1H, d, J = 8.0 Hz), 7.54 (1H,
d, J = 7.8 Hz), 7.44 (1H, t, J = 7.2 Hz), 7.38 (1H, d, J = 8.0 Hz), 6.75 (1H, d, J = 9.5 Hz), 2.56 (3H, s).
13C-NMR (101 MHz, CDCl3)
δ
/ppm: 176.5 (C), 147.8 (C), 142.8 (C), 142.3 (CH), 134.1 (C), 133.0 (C),
131.7 (CH+C), 129.7 (CH), 128.9 (CH), 128.3 (C), 126.9 (CH), 125.4 (CH), 122.2 (CH), 120.0 (CH), 110.2
(CH), 17.8 (CH3). IR (neat) 1611.2 (m), 1523.2 (s), 1498.9 (s), 1448.4 (m), 1342.9 (s), 1274.3 (m), 1194.9
(s), 1154.7 (m), 1135.0 (m), 841.2 (s), 795.6 (s), 759.7 (s), 736.5 (s), 507.0 (m) cm´1. LC-MS (ESI) 375.0
(M + H). HR-MS (ESI) calculated for C17H14N3O3 308.1035, found 308.1041 ( 1.3 ppm). Melting
ν
∆
=
´
˝
range: 208.3–210.6 C.
(E)-1-((2-Nitrophenyl)diazenyl)naphthalene-2-ol (31) [88]: Assessed loading 5.8 mmol, 82%; Isolated 1.60 g,
1
77%. H-NMR (400 MHz, CDCl3)
δ/ppm: 8.42 (1H, dd, J = 8.6, 1.3 Hz), 8.38 (1H, d, J = 8.0 Hz), 8.29
(1H, dd, J = 8.5, 1.5 Hz), 7.73 (1H, dddd, J = 8.6, 7.2, 1.5, 0.7 Hz), 7.63 (1H, d, J = 9.7 Hz), 7.52 (1H, ddd,
J = 8.2, 7.1, 1.5 Hz), 7.48 (1H, dd, J = 7.7, 1.5 Hz), 7.41 (1H, ddd, J = 7.7, 7.1, 1.2 Hz,), 7.23 (1H, ddd,
J = 8.5, 7.1, 1.3 Hz), 6.68 (1H, d, J = 9.7 Hz). 13C-NMR (101 MHz, CDCl3)
δ
/ppm: 181.2 (C), 143.4 (CH),
139.3 (C), 135.6 (CH), 133.2 (C), 133.0 (C), 129.6 (CH), 129.2 (CH), 129.0 (C), 127.9 (CH), 127.2 (CH),
126.1 (CH), 123.6 (CH), 123.0 (CH), 117.8 (CH), 100.0 (C). IR (neat) 1737.1 (w), 1603.7 (m), 1570.2 (m),
1476.9 (s), 1448.5 (m), 1187.1 (m), 1130.1 (m), 843.5 (m), 738.7 (s), 505.8 (s) cm´1. LC-MS (ESI) 294.1
(M + H). HR-MS (ESI) calculated for C16H12N3O3 294.0879, found 294.0883 ( = 1.4 ppm). Melting
ν
∆
˝
range: 207.0–209.3 C.

Molecules 2016, 21, 918
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(E)-1-((4-Nitrophenyl)diazenyl)naphthalene-2-ol (32) [89]: Assessed loading 5.1 mmol, 78%; Isolated 1.30 g,
1
68%. H-NMR (400 MHz, CDCl3)
δ/ppm:
δ
16.12 (1H, s), 8.40 (1H, d, J = 8.1 Hz), 8.31 (2H, d, J = 9.1 Hz),
7.69 (1H, d, J = 9.6 Hz), 7.68 (2H, d, J = 9.4 Hz,), 7.59–7.50 (2H, m), 7.46–7.39 (1H, m), 6.69 (1H, d,
J = 9.7 Hz). 13C-NMR (101 MHz, CDCl3)
/ppm: 180.3 (C), 147.9 (C), 144.5 (C), 143.5 (CH), 133.0 (C),
132.0 (C), 129.8 (CH), 129.2 (CH), 128.6 (C), 127.6 (CH), 126.4 (CH), 125.7 (2CH), 122.5 (CH), 116.6
(2CH). IR (neat) 1739.7 (w), 1591.7 (m), 1498.7 (s), 1329.9 (s), 1226.2 (m), 1202.4 (s), 1153.6 (m), 1106.2
(s), 859.6 (m), 835.4 (s), 747.7 (s), 488.9 (s) cm´1. LC-MS (ESI) 294.1 (M + H). HR-MS (ESI) calculated for
δ
ν
˝
C16H12N3O3 294.0879, found 294.0881 (∆ = 0.7 ppm). Melting range: 250.3–253.1 C.
(E)-1-((4-Bromophenyl)diazenyl)naphthalene-2-ol (33) [90
–
92]: Assessed loading 11.3 mmol, 90%; Isolated
1
3.52 g, 86%. H-NMR (400 MHz, CDCl3)
δ/ppm: 16.06 (1H, s), 8.56–8.50 (1H, d, J = 8.4 Hz), 7.73 (1H,
d, J = 9.5 Hz), 7.60–7.68 (1H, m,), 7.60 (4H, m), 7.56 (1H, ddd, J = 8.3, 7.3, 1.5 Hz), 7.44–7.37 (1H, m),
6.86 (1H, d, J = 9.4 Hz,). 13C-NMR (101 MHz, CDCl3)
/ppm: 171.4 (C), 144.1 (C), 140.3 (CH), 133.4
(C), 132.7 (2CH), 130.3 (C), 129.0 (CH), 128.7 (CH), 128.2 (C), 126.0 (CH), 124.5 (CH), 121.8 (CH), 120.8
δ
(C), 120.0 (2CH). IR (neat)
ν 1737.5 (w), 1617.3 (w), 1476.9 (m), 1252.3 (m), 1209.2 (m), 1071.8 (m),
1004.8 (m), 817.7 (s), 748.8 (s), 494.9 (s) cm´1. LC-MS (ESI) 327.0 (M + H). HR-MS (ESI) calculated for
˝
C16H12N2OBr 327.0133, found 327.0126 (∆ = ´2.1 ppm). Melting range: 157.8–160.3 C.
(E)-1-(Phenyldiazenyl)naphthalene-2-ol (34) [93
,
94]: Assessed loading 16.7 mmol, 90%; Isolated 3.86 g,
1
83%. H-NMR (400 MHz, DMSO-d6) δ/ppm: 15.76 (s, 1H), 8.52 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 9.4 Hz,
1H), 7.84 (d, J = 8.2 Hz, 2H), 7.76 (d, J = 8.2 Hz, 1H), 7.60 (ddd, J = 1.4, 7.0, 8.4 Hz, 1H), 7.54 (t, J = 8.2 Hz,
2H), 7.44 (ddd, J = 1.0, 1.2, 7.1 Hz, 1H), 7.38 (t, J = 8.2 Hz, 1H), 6.90 (d, J = 9.4 Hz, 1H). 13C-NMR
(101 MHz, DMSO-d6)
δ/ppm: 169.3 (C), 145.5 (C), 140.4 (CH), 133.2 (C), 130.2 (2CH), 129.6 (C), 129.5
(CH), 129.3 (CH), 128.5 (CH), 128.3 (C), 126.3 (CH), 124.3 (CH), 121.7 (CH), 119.4 (2CH). IR (neat)
ν
3035 (w), 1616 (m), 1496 (s), 1447 (s), 1387 (m), 1254 (s), 1205 (s), 1135 (s), 984 (s), 841 (s), 749 (s), 682
(s), 493 (s) cm´1. LC-MS (ESI) 249.2 (M + H). HR-MS (ESI) calculated for C16H13N2O 249.1028, found
˝
249.1032 (∆ = 1.6 ppm). Melting range: 127.9–130.2 C.
(E)-1-((4-Chlorophenyl)diazenyl)naphthalene-2-ol (35): Assessed loading 12.2 mmol, 94%; Isolated 3.11 g,
85%. 1H-NMR (400 MHz, CDCl3)
δ
/ppm 16.04 (1H, s), 8.54 (1H, dd, J = 8.2, 1.2 Hz), 7.73 (1H, d,
J = 9.4 Hz), 7.67 (2H, d, J = 8.8 Hz), 7.61 (1H, d, J = 8.0 Hz), 7.56 (1H, ddd, J = 8.4, 7.1, 1.3 Hz), 7.47–7.36
(3H, m), 6.88 (1H, d, J = 9.4 Hz). 13C-NMR (101 MHz, CDCl3)
/ppm: 170.7 (C), 143.8 (C), 140.1 (CH),
133.4 (C), 133.0 (C), 130.2 (C), 129.7 (2CH), 128.9 (CH), 128.7 (CH), 128.2 (C), 125.9 (CH), 124.3 (CH),
121.7 (CH), 119.9 (2CH). IR (neat) 1617.3 (w), 1483.9 (m), 1253.5 (m), 1210.7 (m), 1089.8 (m), 820.3
δ
ν
(s), 748.7 (s), 497.1 (s) cm´1. LC-MS (ESI) 283.0 (M + H). HR-MS (ESI) calculated for C16H12N2OCl
283.0638, found 283.0644 (∆ = 2.1 ppm). Melting range: 153.2–156.0 C.
˝
(E)-1-(Benzo[d][1,3]dioxol-5-yldiazenyl)naphthalene-2-ol (36): Assessed loading 20.2 mmol, 83%; Isolated
1
5.40 g, 76%. H-NMR (400 MHz, CDCl3)
δ/ppm: 15.50 (1H, s), 8.70 (1H, d, J = 8.4 Hz), 7.77 (1H, dt,
J = 9.1, 0.6 Hz), 7.70 (1H, d, J = 8.0 Hz,), 7.58 (1H, ddd, J = 8.4, 7.0, 1.3 Hz), 7.51 (1H, d, J = 2.0 Hz),
7.41 (1H, ddd, J = 8.1, 7.0, 1.3 Hz), 7.32 (1H, dd, J = 8.2, 2.0 Hz), 7.06 (1H, d, J = 9.2 Hz), 6.92 (1H, d,
J = 8.2 Hz), 6.07 (2H, s). 13C-NMR (101 MHz, CDCl3) δ/ppm: 160.4 (C), 149.2 (C), 149.0 (C), 143.8 (C),
136.7 (CH), 133.2 (C), 129.5 (C), 128.3 (CH), 128.21 (C), 128.2 (CH), 124.9 (CH), 121.9 (CH), 121.6 (CH),
118.7 (CH), 108.4 (CH), 102.0 (CH2), 98.6 (CH). IR (neat)
ν 2899.5 (w), 1621.2 (m), 1499.6 (m), 1476.8 (s),
1457.3 (s), 1036.9 (s), 820.6 (m), 750.0 (m) cm´1. LC-MS (ESI) 293.0 (M + H). HR-MS (ESI) calculated for
˝
C17H13N2O3 293.0926, found 293.0934 (∆ = 2.7 ppm). Melting range: 143.7–146.2 C.
4. Conclusions
We have evaluated a series of diazonium forming reactions performed using flow chemistry to
aid in the production of these important and synthetically versatile salts. The use of solid supported
acids in flow was shown as a viable approach should small quantities of isolated material be required
(~50 mg
´1 g). Importantly the electronics of the parent aniline played an important role in the

Molecules 2016, 21, 918
19 of 23
efficiency of the methodology and indicated its preferential use for more electron rich aniline starting
materials. For the generation of larger quantities of material expedience intrinsically directs the
synthetic methodology to more solution phase and continuous production operation. In such cases
the use of aqueous conditions may be hindered by solubility limitations of both the starting anilines
and resultant diazonium intermediates, a general working range of 0.3 + 0.26 M was determined for
flow. Beneficially flow proved advantageous for exerting control over mixing and to easily regulate
temperature to inhibit deleterious side reactions such as phenol formation, a temperature operational
working window was defined. Alternatively organic nitrite donors were shown be useful in organic
solvents to easily prepare diazonium intermediates. Of note no additional acid activator was required
for these transformations although trimethyl silyl halides could be added to produce in situ nitrosyl
halides as that can be used as diazonium forming species.
In general a wide range of preparation conditions and the use of several diazotising agents
have been successfully demonstrated in flow. We believe the production of these valuable diazonium
intermediates as a continuous stream which as shown can be intercepted to create additional derivatives
adds significant value. The elimination of intermediate isolation and handling of diazonium species
improves both the overall safety of the process and reduces potential risks due to health hazards
associated with such compounds. In addition, once optimised scale up or repeated access to quantities
of these species can be automated saving valuable synthesis time which can be employed on more
challenging endeavours.
Acknowledgments: We would like to thank the Royal Society URF scheme for support for I.R.B. and M.B. and
the China Scholarship Council (CSC) for support to T.H. We are grateful to A. Batsanov (Durham University,
Department of Chemistry) for solving the X-ray structures.
Author Contributions: All authors contributed equally to the preparation of this manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 1–12, 20–21, 23–35 are available from the authors.
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