Frozen aryldiazonium chlorides in radical reactions with alkenes and arenes

Article abstract of DOI:10.1016/j.tet.2018.05.089

Frozen aryldiazonium chlorides have been investigated in radical alkene and arene functionalizations. Through freezing at – 84 °C, aryldiazonium chlorides, which otherwise show significant decomposition in aqueous solution after several hours at room temp

Full text of DOI:10.1016/j.tet.2018.05.089

Accepted Manuscript
Frozen aryldiazonium chlorides in radical reactions with alkenes and arenes
Daniel Thon, Michael C.D. Fürst, Lisa-Marie Altmann, Markus R. Heinrich
PII:
S0040-4020(18)30669-0
10.1016/j.tet.2018.05.089
TET 29596
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 2 February 2018
Revised Date: 29 May 2018
Accepted Date: 31 May 2018
Please cite this article as: Thon D, Fürst MCD, Altmann L-M, Heinrich MR, Frozen aryldiazonium
chlorides in radical reactions with alkenes and arenes, Tetrahedron (2018), doi: 10.1016/
j.tet.2018.05.089.
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Frozen aryldiazonium chlorides in radical
reactions with alkenes and arenes
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Daniel Thon, Michael C. D. Fürst, Lisa-Marie Altmann, Markus R. Heinrich*
Department of Chemistry and Pharmacy, Pharmaceutical Chemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nikolaus-
Fiebiger-Straße 10, 91058 Erlangen, Germany

1
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Tetrahedron
journal homepage: www.elsevier.com
Frozen aryldiazonium chlorides in radical reactions with alkenes and arenes
Daniel Thon, Michael C. D. Fürst, Lisa-Marie Altmann and Markus R. Heinrich*
aDepartment of Chemistry and Pharmacy, Pharmaceutical Chemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, 91058
Erlangen, Germany
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Frozen aryldiazonium chlorides have been investigated in radical alkene and arene
functionalizations. Through freezing at – 84°C, aryldiazonium chlorides, which otherwise show
significant decomposition in aqueous solution after several hours at room temperature, can be
stored for at least 20 days. In addition, the slow melting of aryldiazonium-containing ice cubes
can serve as an alternative to syringe pumps that are commonly used if a controlled addition of
the diazonium salt to the reaction mixture is required.
Available online
Keywords:
Diazonium
2009 Elsevier Ltd. All rights reserved
.
Radical reaction
Carboamination
Carbohydroxylation
Biaryl
1. Introduction
solutions, in which most diazonium chlorides can be obtained,
the presence of organic co-solvents such as acetonitrile or
dimethylsulfoxide can facilitate undesired hydrogen abstraction
by aryl radicals.3a Regarding the overall context, slow addition of
the diazonium salt by syringe pump is a common measure to
keep the stationary diazonium concentration low. In this way,
undesired homo-coupling reactions, particularly the attack of aryl
radicals onto unconverted diazonium ions, can effectively be
suppressed.8a
Aryldiazonium salts are versatile starting materials for a broad
range of organic transformations, which can roughly be divided
into three major subgroups.1 The first group, namely ionic
reactions, comprises azo couplings and triazene formations, the
Balz-Schiemann and the Japp-Klingemann reaction.2 Radical
reactions of diazonium salts, representing the second subgroup,
include Gomberg-Bachmann- and Pschorr-type aryl-aryl
couplings, Meerwein-type alkene functionalizations, Sandmeyer
reactions and hydrogen atom transfer reactions, and several
others.3 In addition, aryldiazonium salts have been successfully
employed in palladium-catalyzed cross-couplings as well as in
closely related transition-metal mediated reactions, thereby
constituting the third subgroup.4 One major drawback that is
however commonly associated with aryldiazonium salts is their
insufficient stability and the related risk of uncontrolled
reactions, even including explosions.5 For this reason, large scale
reactions and storage should generally be conducted with suitable
precautions.6 In the overall context, aryldiazonium tetrafluoro-
borates probably represent the most useful type of salt, as a
comparably convenient synthesis is then combined with a long
storage life for most substitution patterns, given that the
diazonium salt was previously prepared in sufficiently high
purity.7
Against this general background, it was an interesting question
whether the durability of aqueous aryldiazonium chlorides could
be increased through freezing.9 In this way, the intended radical
reactions could be performed with lower amounts of organic co-
solvents and the slow melting of the frozen diazonium salts might
even render the use of a syringe pump unnecessary.10 In this
article, we now present first results on the use of a frozen
aryldiazonium chloride in radical alkene and arene
functionalizations.
2. Results and discussion
Initial experiments with silicone ice moulds showed that such
devices are suitable for the intended experiments as these moulds
allow freezing of the diazonium chloride solution as well as
simple removal of the resulting ice spheres and or ice cubes from
the mould. An ice sphere (S) and an ice cuboid (C) prepared in
this way are shown, after removal from the respective silicone
moulds, in Figure 1. The sphere (S) and the cuboid (C) both
contain 1.0 mmol of 4-chlorophenyldiazonium chloride in dilute
hydrochloric acid. The diameter of the sphere (S) was
approximately 17 mm, corresponding to a total volume of ca. 2.5
mL and a concentration of the frozen diazonium chloride of 0.4
Our particular interest in the stability of aromatic diazonium
salts arose from the observation that aqueous aryldiazonium
chlorides performed better in a number of radical reactions than
their related storable tetrafluoroborates.8 A plausible explanation
for this trend is the fact that an organic co-solvent is usually
added so that the tetrafluoroborates can be added to the reaction
mixture dropwise by syringe pump. In contrast to purely aqueous

2
Tetrahedron
ACCEPTED MANUSCRIPT
M. The ice cuboid (C) was obtained from a more dilute aqueous
the comparison of the entry pairs 1 and 3, and 2 and 4. On the
solution of 4-chlorophenyl-diazonium chloride (0.17 M), which
resulted in a total volume of ca. 7.0 mL and an approximate
basis of these results, the direct addition of the frozen diazonium
chloride to the reaction mixture was maintained for the next
study, but the melting time in the solution was increased through
the use of a larger ice cuboid containing the diazonium salt in a
more diluted form. The results obtained from the related series of
experiments are summarized in Table 2.
(C)
(S)
cuboid size of 20×20×18 mm.
(C)
(S)
Table 2. Direct addition of ice cuboids to the reaction mixture: effect of
dilution and prolonged melting time.
Cl
Cl
Na2CO3
Cl
N
+
N
CH3CN/H2O 1:1
50 °C, 15 min
OH
N
2 Cl
Figure 1. Ice sphere (S) (Ø ca. 17 mm, 2.5 mL) and ice cuboid (C) (ca.
OH
1
3
20×20×18 mm, 7 mL).
2
frozen diazonium
cuboid (C)
(2.5 - 7.0 mL, 1.0 mmol)
Further preliminary experiments revealed that freezing of the
diazonium chloride solutions could not be achieved at –21°C or –
30°C, even after several days. Under these conditions, freezing
occurred only partially, and a highly concentrated diazonium salt
solutions remained as supernatant above a frozen portion.
Complete and fast freezing was however possible for the sphere
(S) and the cuboid (C) at – 84°C over a time of three hours.
entry
volume of ice
concentration of
1 in ice cuboid
[mol/L]
0.40
melting time
[s]
yield
[%]
cuboida,b
[mL]
2.5
1
2
3
4
5
6
23
55
42
43
38
37
34
3.5
0.29
70
4.0
0.25
100
201
270
403
To study the applicability of ice spheres (S) and cuboids (C) in
radical arylation reactions, a previously developed base-induced
carboamination reaction11 was chosen as a first example. In the
original work, dropwise addition of freshly prepared aqueous 4-
chlorophenyldiazonium chloride (1) to a mixture of 3-methyl-3-
buten-1-ol (2) and sodium carbonate in aqueous acetonitrile at
50°C had provided the carboamination product 3 in a maximum
yield of 62%. This reaction was now modified in the way that the
diazonium chloride 1 was added as an ice sphere (S) or ice
cuboid (C) to the reaction mixture, either directly or via slow
melting in a glass funnel placed above the round-bottom flask
used as reaction vessel. Note that the ice sphere (S) had the same
size and shape as shown in Figure 1, but the ice cuboid (C) had a
decreased thickness so that its size of 20×20×6 mm amounted to
a volume of 2.5 mL.
4.5
0.22
5.0
0.20
7.0
0.14
aIce cuboids (2.5 – 7.0 mL) used after freezing for at least 3 h at -84°C.
bSee experimental section for details.
Again, prolonged melting times (entries 2-6) did not lead to
improved results, although the longest melting periods of 270 s
(4 min 30 sec) and 403 s (6 min 43 s) (entries 5 and 6) were
comparable to the original addition of diazonium salt 1 to the
reaction mixture by syringe pump over 5 minutes.11 A plausible
explanation for the negative effect of increased cuboid size is the
temperature impact, which is now apparently too strong, so that
the cooling of the reaction mixture becomes too intense. Note
that the size and shape of the largest ice cuboid used in entry 6
(Table 2) is exactly identical to the cuboid shown in Figure 1. On
this basis, we evaluated the stability of the frozen diazonium ice
spheres over time. For this purpose, the previously studied
carboamination reaction (Tables 1 and 2) was repeated with ice
spheres (Figure 1, (S)) stored in the freezer at -84 °C for up to 21
days. The related results are summarized in Scheme 1.
Table 1. Comparison of ice shape and addition method in the base-induced
radical carboamination of 3-methyl-3-buten-1-ol (2).
Cl
Cl
Na2CO3
Cl
N
Cl
+
N
CH3CN/H2O 1:1
50 °C, 15 min
OH
N
2 Cl
OH
1
3
2
frozen diazonium
sphere (S) or cuboid (C)
(2.5 mL, 1.0 mmol)
Cl
Na2CO3
Cl
N
+
N
OH CH3CN/H2O 1:1
50 °C, 15 min
N
2 Cl
OH
entry
ice shapea addition methodb melting time
[s]
yield
[%]
55
1
2
3
frozen diazonium
sphere (S)
(2.5 mL, 1.0 mmol)
direct addition of ice
sphere
melting time: 25 s
1
2
3
4
(S)
(S)
(C)
(C)
direct
via funnel
direct
25
600
23
42
54
via funnel
660
40
aIce spheres and cuboids (each 2.5 mL) used after freezing for at least 3 h
at -84°C. bSee experimental section for details.
The results summarized in Table 1 indicate that slow melting
in the funnel, resulting in addition times in the range of 600 to
660 seconds (entries 2 and 4), does provide lower yields than fast
melting upon direct addition of ice sphere or ice cuboid to the
reaction mixture (entries 1 and 3). During direct addition (entries
1 and 3), the temperature of the reaction mixture dropped by 6
°C, but reached 50 °C again after 5 minutes. No significant
difference was observed between the two ice shapes, as shown by

3
Scheme 1. Base-induced radical carboamination conducted with ice sphere
(2.5 mL, 0.4 M, 1.0 mmol) frozen at -84°C for at least 3 h up to 21 d. aYield
determined after column chromatography. bYield determined by 1H-NMR
In the next step, the frozen diazonium chloride 1 was applied
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for two radical aryl-aryl coupling reactions (Scheme 3).13,14 As
these reactions are typically carried out at room temperature or
below, we reasoned that the temperature impact of direct addition
should not cause difficulties. Moreover, the more diluted ice
cuboid (Figure 1, (C)) was chosen, since the diazonium chloride
1 is, when using a syringe pump, typically added over a time of
10 to 15 minutess.
using dimethyl terephthalate as internal standard
.
The reactions conducted on the first day revealed that the
addition of the diazonium salt 1 to the reaction mixture in the
form of an ice sphere (S) can even be superior to the established
addition as an aqueous solution by syringe pump. These two
carboamination reactions were carried out using the same
diazonium chloride solution, in one case directly after preparation
(syringe pump) and in the other case after freezing for 3 h at –
84°C via addition of an ice sphere. The fact the yield of the
syringe pump experiment (48%/50%) did not reach the
previously reported value of 62%11 is most probably due to
different batches of chemicals or slight variations in the
preparation of the diazonium salt. Evaluating the results of the
consecutive experiments conducted on days 7, 9, 14, 16 and 21, a
good stability of the frozen diazonium chloride can be assumed.
Cl
Cl
OH
O
N
NH2
6
8
(10 mmol)
(10 mmol)
OH
O
1
N
TiCl3 (2 mmol)
H2O/HCl, r.t.
7 + 25 min
TiCl3 (1 mmol)
H2O/HCl, r.t.
7 + 25 min
frozen
diazonium
cuboid (C)
NH2
b
a
7
9
(69%)
(54%)
direct addition of ice (7.0 mL, 1.0 mmol) direct addition of ice
cuboid
cuboid
melting time: 7 mins
melting time: 7 mins
a
Scheme 3. Biaryl synthesis using frozen diazonium chloride cuboids. Yield
determined after column chromatography. bYield determined by 1H-NMR
using dimethyl terephthalate as internal standard.
To further explore the suitability of the frozen diazonium
chloride 1 for radical alkene functionalizations, a recently
developed carbohydroxylation method was investigated.12 For
this transformation, preliminary experiments showed that an
addition of the frozen diazonium ice sphere (Figure 1, (S)) to the
reaction mixture by slow melting in a funnel is superior to direct
addition to the reaction mixture. This effect is contrary to what
was observed for the carboamination (Table 1), and could be due
to a higher sensitivity of the carbohydroxylation reaction towards
a drop of the reaction temperature. The results of a series of
experiments with diazonium chloride 1 and α-methylstyrene (4)
are summarized in Scheme 2.
After
a few experiments aimed at optimization (see
Supporting Information), the heterobiaryls 7 and 9 could be
prepared from furfurylamine (6) or 3-hydroxypyridine (8) in
reasonable yields using titanium(III) chloride in acidic solution.
In the case of 2-arylpyridine 9, the isolated yield of 69%
compares well with the previously achieved result under syringe
pump addition (74%).14 In contrast to that, the synthesis of the
arylfurfurylamine 7 led to a lower yield of 54% compared to 74%
by syringe pump addition,13 which points to a temperature effect
and a higher sensitivity of this particular arylation reaction
towards cooling.
Cl
OH
Cl
KOAc
+
CH3CN/H2O 5:1
70 °C,15 min
N2 Cl
Finally, the radical arylation of 3-hydroxypyridine (8) was
repeated under variation of the substituent on the diazonium salt
(Scheme 4). Diazonium salts bearing either a strongly electron-
donating (1a, R = OMe), a more or less neutral (1b, R = Me) or a
strongly electron-withdrawing (1c, R = CO2Me) substituent were
included in this study. A comparison of the results with those
previously obtained under syringe pump addition reveals that the
donor-substituted diazonium salt 1a is best suited for the addition
as an ice cuboid in titanium(III)-mediated radical arylations. The
acceptor-substituted salt 1c, on the other hand, led to the lowest
yield and also to the largest difference in yield compared to the
traditional addition by syringe pump.14
1
4
5
frozen diazonium
sphere (S)
(2.5 mL, 1.0 mmol)
addition of ice
sphere via funnel
melting time: 10 min
OH
R
N
OH
R
8 (10 mmol)
Cl
Scheme 2. Carbohydroxylation conducted with ice sphere (2.5 mL, 0.4 M,
1.0 mmol) frozen at -84°C for at least 3 h up to 16 d. aYield determined after
column chromatography. bYield determined by 1H-NMR using dimethyl
terephthalate as internal standard.
TiCl3 (1 mmol)
H2O/HCl, r.t., 7 + 25 min
N2
N
1a: R = OMe
1b:
1c:
frozen diazonium
cuboid (C)
10: R = OMe, 60%a,[65%]b
direct addition of ice
cuboid
melting time: 7 mins
a
b
11:
12:
R = Me
R = CO2Me
R = Me, 52% ,[64%]
R = CO2Me, 39% ,[55%]
a
b
In the case of the carbohydroxylation, the comparison of
direct addition by syringe pump or, after freezing, as ice sphere
on day 1 gave minimally improved results compared with the
classical syringe pump method. Again, the same diazonium
chloride solution was used for these two experiments, as well as
for the later stability evaluation, to allow unambiguous
conclusions. As evidenced by the reactions carried out on days 3,
6, 8, 13, 14 and 16, the diazonium chloride 1 again displayed a
good stability at -84°C, and comparable yields were obtained for
alcohol 5 over that period of time.
(7.0 mL, 1.0 mmol)
Scheme 4. Biaryl compounds 10-12 prepared from diazonium chlorides 1a-c
(ice cuboids) and 3-hydroxypyridine (8). aYield determined after column
chromatography. bYield reported in literature for the addition of 1a-c by
syringe pump.14
3. Conclusion
In summary, these results demonstrate that the frozen
diazonium chlorides are applicable in radical alkene and arene

4
Tetrahedron
ACCEPTED MANUSCRIPT
functionalizations. The actual time of addition, resulting from
Aliquots of the diazonium chloride (1 and 1a-c) (2.5 mL, 0.40 M,
the melting process of the ice sphere or cuboid, can be tuned
through its dilution and through the method of addition from a
few seconds to several minutes. In the case that the particular
reaction is temperature sensitive, and the cooling impact through
direct addition turns out to be unfavorable, slow melting in a
funnel placed above the reaction vessel can be a useful
alternative. Besides the advantage that frozen diazonium
chlorides are storable without significant decomposition at -84°C
for at least three weeks, the slow release of the diazonium ions by
melting of the ice sphere or cuboid can replace the typically used
syringe pump.
1 mmol, see above) were filled into the cavities of the silicone
tray (cuboid shape, Lurch) using a syringe. Afterwards, water
(4.5 mL) was added to each previously filled cavity. Then, the
silicone tray was placed into the fridge and stored at -84°C for
one day. Right before the respective reaction, the silicone tray
was taken from the fridge and the ice cuboid was easily detached
from the tray using a tweezer.
4.2.2. (E)-4-(4-Chlorophenyl)-((4-chlorophenyl)-diazenyl)-3-
methylbutan-1-ol (3).
4.2.2.1. Synthesis using a syringe pump (reference experiment)
4. Experimental section
4.1. General techniques
To a stirred solution of the 3-methyl-3-buten-1-ol (2) (1.21 mL,
12.0 mmol) and Na2CO3 (477 mg, 4.50 mmol) in
acetonitrile/water (1:1, 5 mL) at 50 °C, an aliquot of the 0.4 M 4-
chlorophenyldiazonium chloride solution (1) (2.5 mL, 1.00
mmol) was added dropwise over 5 minutes via syringe pump.
After stirring for 10 minutes at 50 °C, the reaction mixture was
diluted with water (10 ml) and extracted with MTBE (3 × 30 ml).
The combined organic layers were washed with brine (30 ml) and
dried over Na2SO4. The solvents were removed under reduced
pressure. The yield of 3 (81.0 mg, 0.24 mmol, 48%) was
Solvents and reagents were obtained from commercial sources
and used as received. 1H-NMR and 13C-NMR spectra were
recorded on Bruker Avance 600 (1H: 600 MHz; 13C: 151 MHz)
and Bruker Avance 400 (1H: 400 MHz; 13C: 101 MHz)
1
spectrometers. For H-NMR spectra CDCl3. and CD3OD were
used as solvents. CHCl3 (7.26 ppm), CD3OH (3.31 ppm).
Chemical shifts were reported in parts per million (ppm).
Coupling constants were reported in Hertz (Hz). The following
abbreviations were used for the description of signals: s (singlet),
d (doublet), t (triplet), q (quartet), m (multiplet), bs (broad
singlet). 13C-NMR spectra were recorded in CDCl3, and CD3OD
using CDCl3 (77.16 ppm), and CD3OD (49.05 ppm) as standard.
Chemical shifts were given in parts per million (ppm). Analytical
TLC was carried out on Merck silica gel plates using short wave
(254 nm) UV light to visualize components. Silica gel (Kieselgel
60, 40-63mm, Merck) was used for flash column
chromatography. For preparation of the respective ice cubes and
ice spheres, two commercially available silicone trays (Lurch)
were used.
1
determined by H-NMR using dimethyl terephthalate as internal
standard.
4.2.2.2. Synthesis via direct addition of ice sphere
To a vigorously stirred solution of the 3-methyl-3-buten-1-ol (2)
(1.21 mL, 12.0 mmol) and Na2CO3 (477 mg, 4.50 mmol) in
acetonitrile/water (1:1, 5 mL) in a 50 ml wide-neck (NS 29/32)
round-bottom flask at 50 °C was added a frozen ice sphere (-84
°C, 3.0 h freezing time) of 4-chlorophenyldiazonium chloride (1)
(2.5 mL, 0.4
M, 1.00 mmol) (see preparation 4.2.1.1). After the
melting process (ca. 25 s), the reaction mixture was stirred for a
further 15 minutes at 50 °C.Afterwards, the reaction mixture was
diluted with water (10 mL) and extracted with MTBE (3 × 30
mL). The combined organic layers were washed with brine (30
mL) and dried over Na2SO4. The solvents were removed under
reduced pressure. The yield was determined by by 1H-NMR
using dimethyl terephthalate as internal standard (55%). Then the
product was purified by column chromatography on silica gel
(hexane/EtOAc = 4:1) and gave 3 (97.9 mg, 0.29 mmol, 57%) as
orange oil.
4.2. Compounds
4.2.1. 4-Chlorophenyldiazonium chloride (1), 4-methoxyphenyl-
diazonium chloride (1a), 4-methylphenyldiazonium chloride
(1b), 4-(methoxycarbonyl)phenyldiazonium chloride (1c)
To an ice-cooled degassed solution of the respective
aniline (10.0 mmol) in HCl (3 N, 10 mL) and water (10 mL), a
degassed solution of sodium nitrite (0.69 g, 10.0 mmol) in water
(5 mL) was added dropwise by syringe pump over a period of
10 minutes. After stirring for an additional 20 minutes at 0 °C,
4.2.2.3. Synthesis through addition of ice sphere via funnel
the 0.4
M solution of the diazonium chloride (1, 1a-c) (10 mmol/
25 mL) was used for preparation of various ice spheres (S) and
ice cubes (C), or was directly added to the reaction mixtures in
the case of reference experiments.
Onto a vigorously stirred solution of the 3-methyl-3-buten-1-ol
(2) (12.0 mmol, 1,21 mL) and Na2CO3 (477 mg, 4.50 mmol) in
acetonitrile/water (1:1, 5 mL) in a 25 ml narrow-neck round-
bottom flask at 50 °C was placed a glass funnel with a drop
opening of around 6 mm. Then, a frozen ice sphere (-84 °C, 3.0 h
freezing time) of 4-chlorophenyldiazonium chloride (1) (2.5 mL,
4.2.1.1. Preparation of ice cuboids (C) and ice spheres (S) for
carboamination and carbohydroxylation:
Aliquots of the 4-chlorophenyldiazonium chloride (1) (2.5 mL,
0.40 M, 1 mmol, see above) were filled into the cavities of the
silicone tray (cuboid shape or spherical shape, both from Lurch)
using a syringe. The silicone tray was then placed into the fridge
and stored at -84°C for at least three hours. Right before the
respective reaction, the silicone tray was taken from the fridge
and the ice cuboid or sphere was easily detached from the tray
using a tweezer.
0.4
M, 1.00 mmol) (see preparation 4.2.1.1) was placed into the
funnel. When melting of the sphere and thus the addition was
completed after ca. 10 minutes, the reaction mixture was stirred
for another 15. The reaction mixture was diluted with water (10
mL) and extracted with MTBE (3 × 30 mL). The combined
organic layers were washed with brine (30 mL) and dried over
Na2SO4. The solvents were removed under reduced pressure. The
yield of 3 (42%) was determined by 1H-NMR of the crude
product with internal standard.
4.2.1.2. Preparation of diluted ice cuboids (C) for biaryl
synthesis:
Rf = 0.2 (hexane/EtOAc = 4:1) [UV]. 1H-NMR (600 MHz,
CDCl3): δ (ppm) = 1.23 (s, 3 H), 1.96 (bs, 1 H), 1.96 (td, J = 6.3

5
Hz, J = 14.1 Hz, 1 H), 2.19 (td, J = 6.2 Hz, J = 14.1 Hz, 1 H),
>12 using an aqueous 2 N NaOH solution. After extraction with
ACCEPTED MANUSCRIPT
3.04 (d, J = 13.2 Hz, 1 H), 3.14 (d, J = 13.1 Hz, 1 H), 3.77 (td, J
= 6.3 Hz, J = 11.0 Hz, 1 H), 3.85 (td, J = 6.2 Hz, J = 11.0 Hz, 1
H), 6.99 (d, J = 8.4 Hz, 2 H), 7.18 (d, J = 8.4 Hz, 2 H), 7.44 (d, J
= 8.7 Hz, 2 H), 7.59 (d, J = 8.7 Hz, 2 H). 13C-NMR (300 MHz,
CDCl3): δ (ppm) = 21.9, 41.3, 44.8, 59.1, 73.4, 123.4, 128.0,
129.3, 132.0, 132.3, 135.6, 136.7, 149.9. The analytical data
obtained is in agreement with the data reported in literature.11
ethyl acetate (3 × 150 mL), the combined organic phases were
washed with saturated aqueous sodium chloride (100 mL) and
dried over anhydrous sodium sulfate. Concentration under
reduced pressure gave the desired crude product 7. The yield of 7
(54%) was determined by H-NMR using dimethyl terephthalate
as internal standard. Purification by chromatography
1
(CHCl3/MeOH = 20:1) gave a pure sample of 7.
Rf = 0.4 (CHCl3/MeOH = 5:1) [UV]. 1H-NMR (400 MHz,
CDCl3) δ 1.66 (bs, 2H), 3.89 (bs, 2H), 6.23 (d, J = 3.3 Hz, 1H),
6.56 (d, J = 3.3 Hz, 1H), 7.34 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 8.7
Hz, 2H). 13C-NMR (151 MHz, CDCl3) δ 39.5, 106.1, 107.4,
124.8, 128.8, 129.4, 132.7, 152.0, 156.7. The analytical data
obtained is in agreement with the data reported in literature.13
4.2.3. 1-(4-Chlorophenyl)-2-phenylpropan-2-ol (5)
4.2.3.1. Synthesis using a syringe pump (reference experiment)
To a stirred solution of α-methylstyrene (4) (0.78 mL, 6.00
mmol) and KOAc (442 mg, 4.50 mmol) in acetonitrile/water
(5:1, 6 mL) at 70 °C, a solution of 4-chlorophenyldiazonium
chloride (1) (2.5 mL, 0.4
M, 1.00 mmol) was added dropwise
4.2.5. 2-(4-Chlorophenyl)pyridin-3-ol (9)
over 5 minutes via syringe pump. After stirring for 10 minutes at
70 °C, the reaction mixture was diluted with water (10 mL),
cooled to room temperature and extracted with MTBE (3 × 30
mL). The combined organic layers were washed with brine (30
ml) and dried over Na2SO4. The solvents were removed under
reduced pressure. The yield of 5 (155 mg, 0.63 mmol, 63%) was
The diluted 4-chlorophenyldiazonium chloride (1) ice cuboid (C)
(7.0 mL, 1.0 mmol) (see preparation 4.2.1.2) was added to a
vigorously stirring solution of 3-hydroxypyridine (8) (951 mg,
10 mmol) in 2 mL 6
N HCl and TiCl3 (ca. 1 M solution in 3 N
HCl, 1 mL, 1 mmol) under nitrogen atmosphere at room
temperature. After melting of the ice cuboid (ca. 7 minutes), the
resulting mixture was stirred for a further 25 minutes. Then,
water (100 mL) was added and the pH-value was adjusted to pH
9-10 using saturated sodium carbonate solution. After extraction
with ethyl acetate (3 × 150 mL), the combined organic phases
were washed with saturated aqueous sodium chloride (100 mL)
and dried over anhydrous sodium sulfate. Concentration under
reduced pressure gave the desired crude product. Purification by
column chromatography (chloroform/diethyl ether 10:1 to 1:1)
gave 9 (142 mg, 0.69 mmol, 69%) as a white solid.
Rf = 0.4 (5:1 chloroform/diethyl ether). 1H-NMR (400 MHz,
CD3OD) 7.23 (dd, J = 8.2, 4.6 Hz, 1H), 7.33 (dd, J = 8.2, 1.4 Hz,
1H), 7.43 (d, J = 8.8 Hz, 2H), 7.87 (d, J = 8.8 Hz, 2H), δ 8.10
(dd, J = 4.6, 1.4 Hz, 1H). 13C-NMR (151 MHz, CD3OD) δ 125.1,
125.3, 129.1, 131.9, 135.1, 137.5, 141.2, 146.0, 153.4. The
analytical data obtained is in agreement with the data reported in
literature.14
1
determined by H-NMR using dimethyl terephthalate as internal
standard.
4.2.3.2. Synthesis through addition of ice sphere via funnel
Onto a stirred solution of α-methylstyrene (4) (0.78 mL, 6.00
mmol) and KOAc (442 mg, 4.50 mmol) in acetonitrile/water
(5:1, 6 mL) in a 25 ml narrow-neck round-bottom flask at 70 °C
was placed a glass funnel with a drop opening of around 6 mm.
Then, a frozen ice sphere (-84 °C, 3.0 h freezing time) of 4-
chlorophenyldiazonium chloride (1) (0.4
M, 2.5 mL, 1.0 mmol)
(see preparation 4.2.1.1) was placed into the funnel. After
melting of the sphere was completed (ca. 10 minutes), the
reaction mixture was stirred for another 15 minutes at 70 °C. The
reaction mixture was diluted with water (10 mL) and extracted
with MTBE (3 × 30 mL). The combined organic layers were
washed with brine (30 mL) and dried over Na2SO4. The solvents
were removed under reduced pressure. The yield was determined
by by 1H-NMR using dimethyl terephthalate as internal standard
(59%). Then the product was purified by column
chromatography on silica gel (hexane/EtOAc = 6:1) and gave
pure 5 (153 mg, 0.62 mmol, 62%) as yellow oil.
Rf = 0.5 (hexane/EtOAc = 4:1) [UV]. 1H-NMR (600 MHz,
CDCl3): δ (ppm) = 1.56 (s, 3 H), 1.78 (bs, 1 H), 2.99 (d, J = 13.1
Hz, 1 H), 3.06 (d, J = 13.2 Hz, 1 H), 6.88 (d, J = 8.4 Hz, 2 H),
7.15 (d, J = 8.4 Hz, 2 H), 7.22-7.25 (m, 1 H), 7.29-7.33 (m, 2 H),
7.33-7.36 (m, 2 H). 13C-NMR (300 MHz, CDCl3): δ (ppm) =
29.3, 49.8, 74.5, 124.9, 126.8, 128.1, 128.1, 131.8, 132.5, 135.3,
147.1. The analytical data obtained is in agreement with the data
reported in literature.12
4.2.6. 2-(4-Methoxyphenyl)pyridin-3-ol (10)
Biaryl 10 was prepared from diazonium salt 1a analogously to
the procedure described for biaryl 9. The product was purified by
column chromatography on silica gel (CHCl3/MTBE = 6:1 to
1:1) and gave pure 10 (120 mg, 0.60 mmol, 60%) as light brown
solid.
Rf = 0.3 (CHCl3/MTBE = 5:1) [UV]. 1H-NMR (400 MHz,
CD3OD) δ 3.80 (s, 3H), 6.94-7.00 (m, 2H), 7.14 (dd,, J = 8.2, 4.7
Hz, 1H), 7.28 (dd,, J = 8.2, 1.4 Hz, 1H), 7.80-7.83 (m, 2H), 8.04
(dd,, J = 4.7, 1.4 Hz, 1H). 13C-NMR (101 MHz, CD3OD) δ 55.7,
114.3, 124.1, 125.0, 131.0, 131.6, 140.6, 147.2, 153.0, 161.2. The
analytical data obtained is in agreement with the data reported in
literature.14
4.2.4. (5-(4-Chlorophenyl)furan-2-yl)methanamine (7)
The diluted 4-chlorophenyldiazonium chloride (1) ice cuboid (C)
(7.0 mL, 1.0 mmol) (see preparation 4.2.1.2) was added to a
vigorously stirring solution of furfurylamine (6) (925 µL,
4.2.7. 2-(p-Tolyl)pyridin-3-ol (11)
Biaryl 11 was prepared from diazonium salt 1b analogously to
the procedure described for biaryl 9. The product was purified by
column chromatography on silica gel (CHCl3/MTBE = 8:1 to
1:1) and gave pure 11 (97 mg, 0.52 mmol, 52%) as light brown
solid.
10 mmol) in 2 mL 6
N HCl and TiCl3 (ca. 1 M solution in 3 N
HCl, 2 mL, 2 mmol) under nitrogen atmosphere at room
temperature. After melting of the ice cuboid (ca. 7 minutes), the
resulting mixture was stirred for a further 25 minutes. Then,
water (100 mL) was added and the pH-value was adjusted to pH

6
Tetrahedron
ACCEPTED MANUSCRIPT
Rf = 0.3 (CHCl3/MTBE = 5:1) [UV]. 1H-NMR (400 MHz,
Kochi, J. K. J. Am. Chem. Soc. 1997, 119, 4846; (i) Fürst, M. C.
D.; Gans, E.; Böck, M. J.; Heinrich, M. R. Chem. Eur. J. 2017, 23,
15312; (j) Hari, D. P.; Schroll, P.; König, B. J. Am. Chem. Soc.
2012, 134, 2958. (k) Crespi, C.; Jäger, S.; König, B.; Fagnoni, M.
Eur. J. Org. Chem. 2017, 2147.
CD3OD) δ 2.38 (s, 3H), 7.18 (dd, J = 8.2, 4.7 Hz, 1H), 7.24 (d, J
= 8.0 Hz, 2H), 7.30 (dd,, J = 8.2, 1.3 Hz, 1H), 7.72 (d, J = 8.2
Hz, 2H), 8.06 (dd,, J = 4.7, 1.3 Hz, 1H). 13C-NMR (101 MHz,
CD3OD) δ 21.3, 124.4, 125.1, 129.6, 130.2, 135.8, 139.2, 140.7,
147.5, 153.2. The analytical data obtained is in agreement with
the data reported in literature.14
4. (a) Roglans, A.; Pla-Quintana, A.; Moreno-Manas, M. Chem. Rev.
2006, 106, 4622. (b) Bonin, H.; Fouquet, E.; Felpin, F. X., Adv.
Synth. Catal. 2011, 353, 3063; (c) Taylor, J. G.; Moro, A. V.;
Correia, C. R. D. Eur. J. Org. Chem. 2011, 1403; (d) Felpin, F.-
X.; Nassar-Hardy, L.; Le Callonnec, F.; Fouquet, E. Tetrahedron
2011, 67, 2815; (e) Cortes-Borda, D.; Kutonova, K. V.; Jamet, C.;
Trusova, M. E.; Zammattio, F.; Truchet, C.; Rodriguez-Zubiri, M.;
Felpin, F.-X. Org. Process Res. Dev. 2016, 20, 1979; (f) Rossy,
C.; Fouquet, E.; Felpin, F.-X. Synthesis 2012, 44, 37. (g) Schmidt,
B.; Elizarov, N.; Berger, R.; Hölter, F. Org. Biomol. Chem. 2013,
11, 3674.
5. (a) Ullrich, R.; Grewer, T. Thermochimica Acta 1993, 225, 201.
(b) Sheng, M.; Frurip, D.; Gorman, D J. Loss Prev. Process Ind.
2015, 38, 114. (c) Deadman, B. J.; Collins, S. G.; Maguire, A. R.
Chem. Eur. J. 2015, 21, 2298.
6. Molinaro, C.; Mowat, J.; Gosselin, F.; O’Shea, P. D.; Marcoux, J.-
F.; Angelaud, R.; Davies, I. W. J. Org. Chem. 2007, 72, 1856.
7. For counterion effects on the stability of diazonium ions: (a)
Flood, D. T. Org. Synth. 1943, 2, 295. (b) Filimonov, V. D.;
Trusova, M.; Postnikov, P.; Krasnokutskaya, E. A.; Lee, Y. M.;
Hwang, H. Y.; Kim, H.; Chi, K.-W. Org. Lett. 2008, 10, 3961. (c)
Barbero, M.; Crisma, M.; Degani, I.; Fochi, R.; Perracino, P.
Synthesis 1998, 1171; (d) Kachanov, A. V.; Slabko, O. Y.;
Kaminskii, V. A. Tetrahedron Lett. 2012, 53, 5807.
4.2.8. Methyl 4-(3-hydroxypyridin-2-yl)benzoate (12)
Biaryl 12 was prepared from diazonium salt 1c analogously to
the procedure described for biaryl 9. The product was purified by
column chromatography on silica gel (CHCl3/MTBE = 7:1 to
1:1) and gave pure 12 (90 mg, 0.39 mmol, 39%) as light
yellowish-brown solid.
Rf = 0.3 (CHCl3/MTBE = 5:1) [UV]. 1H-NMR (400 MHz,
CD3OD) δ 3.93 (s, 3H), 7.27 (dd, J = 8.3, 4.6 Hz, 1H), 7.36 (dd,,
J = 8.3, 1.4 Hz, 1H), 8.00 (d, J = 8.8 Hz, 2H), 8.08 (d, J = 8.8 Hz,
2H), 8.14 (dd, J = 4.6, 1.4 Hz, 1H). 13C-NMR (101 MHz,
CD3OD) δ 52.7, 125.4, 125.5, 130.1, 130.4, 130.6, 141.4, 143.6,
145.8, 153.6, 168.4. The analytical data obtained is in agreement
with the data reported in literature.14
8. (a) Wetzel, A.; Ehrhardt, V.; Heinrich, M. R. Angew. Chem. Int.
Ed. 2008, 47, 9130; (b) Pratsch, G.; Anger, C. A.; Ritter, K.;
Heinrich, M. R. Chem. Eur. J. 2011, 17, 4104 (c) Pratsch, G.;
Wallaschkowski, T.; Heinrich, M. R. Chem. Eur. J. 2012, 18,
11555; (d) Hammer, S. G.; Heinrich, M. R. Tetrahedron 2014, 70,
8114; (e) Fehler, S. K.; Pratsch, G.; Östreicher, C.; Fürst, M. C.
D.; Pischetsrieder, M.; Heinrich, M. R. Tetrahedron 2016, 72,
7888; (f) Hofmann, J.; Gans, E.; Clark, T.; Heinrich, M. R. Chem.
Eur. J. 2017, 23, 9647.
Acknowledgments
The authors are grateful for the financial support of M. C. D.
F. by the Studienstiftung des Deutschen Volkes und the Graduate
School Molecular Science (GSMS).
References and notes
9. For a method for reducing the rate of light emission from
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reagents, see: Kricka, L. J.; Ogden, S.; Williams, T. M.; Kant, J. J.
Biolumin. Chemilumin. 1989, 3, 155.
10. For an inexpensive programmable dual-syringe pump for the
chemistry laboratory, see: Cubberley, M. S.; Hess, W. A. J. Chem.
Educ. 2017, 94, 72.
11. Kindt, S.; Wicht, K.; Heinrich, M. R. Org. Lett. 2015, 17, 6122.
12. Kindt, S.; Wicht, K.; Heinrich, M.R. Angew. Chem. Int. Ed. 2016,
55, 8744.
13. Wetzel, A.; Pratsch, G.; Kolb, R.; Heinrich, M. R. Chem. Eur. J.
2010, 16, 2547.
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1597; (e) Hofmann, J.; Heinrich, M. R. Tetrahedron Lett. 2016,
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Supplementary Material
Supplementary data (1H NMR and 13C NMR spectra of
compounds 3, 5, 7 and 9-12; optimization for radical arylation of
6 and 8) associated with this article can be found in the online
version……