Using Anilines as Masked Cross-Coupling Partners: Design of a Telescoped Three-Step Flow Diazotization, Iododediazotization, Cross-Coupling Process

Article abstract of DOI:10.1002/chem.201603626

The conversion of commercially available anilines into biaryl and biarylacetylene products was realized by using a telescoped, three-reactor flow diazotization/iododediazotization/cross-coupling process. The segmented flow stream created by off-gassing during the Sandmeyer sequence was restored to a continuous column of reaction solution by using a specially designed continuous-flow unit controlled by custom software created in-house. The resultant aryl iodide was then combined with a stream of cross-coupling solution that fed into the final reactor. The system proved versatile as modifications to the diazotization/iododediazotization sequence could be made rapidly to account for any substrate specificity (e.g., solubility problems), leading to a wide substrate scope of Suzuki–Miyaura and Sonogashira cross-coupled products.

Full text of DOI:10.1002/chem.201603626

DOI: 10.1002/chem.201603626
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Organic Chemistry
Using Anilines as Masked Cross-Coupling Partners: Design of
a Telescoped Three-Step Flow Diazotization, Iododediazotization,
Cross-Coupling Process
Matthieu Teci,[a] Michael Tilley,[a] Michael A. McGuire,*[b] and Michael G. Organ*[a, c]
Abstract: The conversion of commercially available anilines
into biaryl and biarylacetylene products was realized by
using a telescoped, three-reactor flow diazotization/iodode-
diazotization/cross-coupling process. The segmented flow
stream created by off-gassing during the Sandmeyer se-
quence was restored to a continuous column of reaction so-
lution by using a specially designed continuous-flow unit
controlled by custom software created in-house. The resul-
tant aryl iodide was then combined with a stream of cross-
coupling solution that fed into the final reactor. The system
proved versatile as modifications to the diazotization/iodo-
dediazotization sequence could be made rapidly to account
for any substrate specificity (e.g., solubility problems), lead-
ing to a wide substrate scope of Suzuki–Miyaura and Sono-
gashira cross-coupled products.
ied,[5] opening up new possibilities in other cross-coupling ap-
plications.[6] Despite these successes, early attempts to extend
the use of diazonium salts in Sonogashira cross-couplings were
unsuccessful.[7] It is now well understood that under conven-
tional conditions, diazonium salts in the presence of copper
tend to form undesired alkyne–alkyne homocoupled products
in preference to the desired arylacetylene derivatives. Conse-
quently, much research has gone into developing alternative
strategies to access these arylacetylene compounds. In 2010,
Sarkar et al. reported a Pd/Au/2,6-di-tert-butyl-4-methylpyridine
(DBMP) catalytic system, where AuI was key to the strategy
[Scheme 1, Eq. (1)].[8] Like CuI, AuI forms actetylide complexes;
however, it is more resistant towards oxidation, resulting in
higher selectivity for the cross-coupled products during the So-
nogashira reaction. Within the same year, Cacchi and co-work-
ers disclosed an interesting iododediazotization/Sonogashira
sequence. Under these more conventional Sonogashira cross-
coupling conditions using CuI, the instability of the arenediazo-
nium salts was circumvented by the in situ generation of the
corresponding aryl iodides prior to the cross-coupling reaction
by using tetrabutylammonium iodide [Scheme 1, Eq. (2)].[9]
In the above-mentioned applications, and as a general
trend, diazonium salts used in cross-coupling reactions are
usually freshly prepared to achieve high yields; however, multi-
component reaction sequences initiated by an aniline diazoti-
zation reaction have also been reported, albeit with lower
yields.[4–5,8,10] From this standpoint, anilines, which are widely
available, can serve as “masked” coupling partners to provide
rapid access to structurally diverse cross-coupling product li-
braries.
Introduction
Anilines are valued building blocks in organic synthesis and
are widely available from commercial sources or upon reduc-
tion of the corresponding nitro compounds.[1] Their acid-cata-
lyzed diazotization with nitrite is facile, straightforward, and af-
fords the corresponding diazonium salts quantitatively after
a few minutes.[2] Conceptually, these reactive species offer
a number of advantages in synthetic chemistry, such as fast re-
action times, working at lower temperatures, and typically
complete and clean transformations meaning that products
can be isolated readily. However, in practice, their propensity
to decompose through uncontrollable and sometimes explo-
sive pathways presents serious safety issues and limits their
use on the industrial scale.
Historically, arenediazonium products were employed as
high-energy intermediates to access a variety of diverse func-
tionalities including aryl halides, cyanides, diazo, or phenol
compounds.[3] Their ability to oxidatively add to Pd0 complexes
and subsequently react with olefins in Heck-type reactions was
first introduced in 1977 by Matsuda and co-workers.[4] Since
then, the Matsuda–Heck reaction has been intensively stud-
[a] M. Teci, M. Tilley, Prof. M. G. Organ
Department of Chemistry, York University
4700 Keele Street, Toronto, Ontario, M3J 1P3 (Canada)
[b] Dr. M. A. McGuire
GlaxoSmithKline Pharmaceuticals Inc., 709 Swedeland Rd.
PO Box 1539, UMW 2810, King of Prussia, PA 19406 (USA)
E-mail: Michael.A.McGuire@gsk.com
[c] Prof. M. G. Organ
Centre for Catalysis Research and Innovation and Department of Chemistry
University of Ottawa, Ottawa, Ontario, K1N 6N5 (Canada)
E-mail: organ@uottawa.ca
Given the usefulness of these compounds and our group’s
experience in continuous-flow organic chemistry proces-
ses,[10c,11] we envisioned a three-step flow diazotization/iodode-
diazotization/cross-coupling sequence as a powerful alternative
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201603626.
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Scheme 1. Batch syntheses of diarylacetylene products from diazonium salts [Eqs. (1) and (2)] versus the flow sequential reaction (telescoped) strategy starting
from anilines [Eq. (3)].
to the more conventional batch chemistry approach
[Scheme 1, Eq. (3)]. In addition to offering a straightforward ap-
proach to larger quantities of product by either flowing longer
or ‘scaling out’ in parallel reactors, safety concerns can be
easily addressed as only small quantities of the hazardous are-
nediazonium species are produced at any one point in time
and are immediately consumed in such telescoped pro-
cess.[3a,5d,g,10c,12] Although attractive, such a strategy comes with
technical challenges that have to be addressed. First, the Sand-
meyer sequence releases nitrogen gas, resulting in a segment-
ed flow, which makes it impossible to balance stoichiometries
with reactants being infused downstream for the subsequent
cross-coupling reaction. Second, salts generated in this se-
quence will lead to reactor plugging, which is the nemesis of
flow chemistry. In this paper, we have developed solutions to
meet these challenges for flow chemistry.
Two different soluble halide sources were assessed for the hal-
odediazotization step, namely tetrabutylammonium bromide
and its iodide counterpart. As expected, when two equivalents
of nBu4NBr were used, no aryl bromide product (3a) was ob-
served after 20 min at room temperature (Table 1, entry 1). On
the other hand, within the same period of time, the more nu-
cleophilic iodide salt was converted quantitatively to 4a
Table 1. Optimization of the halodediazotization step under batch condi-
tions.[a]
Entry
X (equiv)
t [min]
2a [%]
Product
Conv. [%]
Results and Discussion
1
2
3
4
5
Br (2)
I (2)
I (1.2)
I (1.2)
Br (1.2)
20
20
20
20
20
100
trace
41
trace
100
3a
4a
4a
4a
3a
trace
99
We began our study by investigating the diazotization/iodode-
diazotization sequence in batch by using acetonitrile solutions
of 4-methoxy-2-nitroaniline (1a; Table 1).
59
99[b]
trace[b]
The aniline was successively treated with equimolar amounts
of tert-butyl nitrite and methanesulfonic acid to generate di-
azonium salt 2a. At room temperature, the reaction proceeded
cleanly and quantitatively in less than one minute, which can
be followed visually by a change in color from red to yellow.
[a] General conditions: 4-methoxy-2-nitroaniline (0.5 mmol), tBuONO
(0.55 mmol), CH3SO3H (0.55 mmol), nBu4NX, in acetonitrile (4 mL). Percent
conversion to products 3a or 4a was determined by 1H NMR spectro-
scopic analysis of the crude reaction mixture. [b] Reaction performed
using sonication.
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(Table 1, entry 2). Decreasing the equivalents of nBu4NI from 2
to 1.2, while keeping the reaction time the same, lowered con-
version to 59%, leaving 41% of unreacted 2a (Table 1, entry 3).
Rather than increasing the reaction temperature or time, soni-
cation was employed, which significantly accelerated the rate
of iodidediazotization leading to complete conversion to 4a
after just 20 min (Table 1, entry 4). Lastly, the halodediazotiza-
tion step was performed again by using sonication, but this
time in the presence of 1.2 equivalents of nBu4NBr; however,
only trace amounts of 3a were observed (Table 1, entry 5).
With these results in hand, we then subjected the crude aryl
iodide mixture to Sonogashira cross-coupling conditions. 1-
Ethynyl-4-methylbenzene was chosen as the alkyne coupling
partner to make reaction monitoring straightforward by
1H NMR spectroscopy, and diisopropylamine was chosen as
a mild base (Table 2). Initially, the combination of Pd(OAc)2
(5 mol%)/PPh3 (15 mol%) and CuI (10 mol%) was screened as
the catalyst system for this Sonogashira reaction, leading to
80% conversion of the coupled product (5a; Table 2, entry 1).
These results prompted us to assess other Pd sources previous-
ly reported as efficient Sonogashira cross-coupling catalysts.[13]
Under the same conditions, [PdCl2(dppf)] (5 mol%; dppf=1,1’-
bis(diphenylphosphino)ferrocene) led to 60% conversion to 5a
(Table 2, entry 2), whereas [PdCl2(PPh3)2] (5 mol%) was found
to be the most efficient precatalyst, resulting in >97% conver-
sion after 20 min at 708C (Table 2, entry 3). Unfortunately, low-
ering the reaction temperature to room temperature proved
unsuccessful, even under sonication. Further, the reaction pro-
ceeded with concomitant formation of a yellow solid, which is
highly undesirable for flow applications (Table 2, entry 4). Low-
ering the catalyst loading of both the Cu and Pd sources to 5
and 2.5 mol%, respectively, as well as increasing the reaction
time to 40 min led to a maximum conversion of 69% to 5a at
708C (Table 2, entries 5 and 6).
In this study, the Sonogashira cross-coupling reaction is per-
formed by using 10 equivalents of diisopropylamine. In addi-
tion to their decomposition in the presence of copper and ter-
minal alkynes, arenediazonium salts are also well-known to
react with amines to afford triazene compounds. To highlight
the pivotal role of the iododediazotization step within this tele-
scoped sequence, that is, it must be quantitative in order to
obtain any of the desired coupled product in high yields, 2a
was treated with diisopropylamine (10 equiv). After 20 min at
1
708C, complete consumption of 2a was observed by H NMR
analysis and 3,3-diisopropyl-1-(5-methoxy-2-nitrophenyl)triaz-1-
ene was isolated in 75% yield (see the Supporting Informa-
tion). Thus, the middle step in our proposed sequence must
go efficiently to full conversion.
We wanted our flow process for the three-step diazotiza-
tion/iododediazotization/Sonogashira sequence to be not only
practical, but also versatile within its design. This should facili-
tate the rapid modification of reaction parameters including
solvent, concentrations, etc. In a standard operating procedure
(method A, Scheme 2), syringes 1–4 were filled with acetonitrile
solutions of the aniline (1 equiv, 0.42m), tBuONO (1.1 equiv,
0.46m), methanesulfonic acid (1.1 equiv, 0.46m), and nBu4NI
(1.2 equiv, 0.5m), respectively. Their contents were flowed at
a fixed rate of 22 mLminÀ1 (9.2 mmolminÀ1) and the residence
time in reactor R2 was optimized to 20 min by adjusting the
length of the reactor tubing. R2 was immersed in an ultrasonic
bath at room temperature and the segmented effluent was
temporarily collected in open air in an intermediate reservoir
also placed in the ultrasonic bath. Besides allowing the escape
of nitrogen gas, which ensures the controlled stoichiometric
ratios of reactants in the subsequent cross-coupling reaction,
this strategy allows for the ready sampling of the effluent from
R2 to ensure complete conversion to the iodide. To the best of
our knowledge, only Ley and co-workers have dealt with an in-
termediate off-gassing step within a continuous-flow system.[12]
In that case, rather than restoring a continuous stream, a secon-
dary reactor containing an immobilized reagent on a polymeric
support was used. The segmented flow from the first reactor
was directed to this immobilized reagent column where the
subsequent reaction occurred. Although effective in their ap-
plication, this strategy is quite specific and cannot be readily
extended to other applications.
Table 2. Optimization of the Sonogashira reaction under batch condition-
s.[a]
In our design, the segmented stream was restored to a con-
tinuous one before entering reactor R3 by using a continuous-
flow unit (CFU), a device designed to accommodate a broad
range of fluids at high pressure without pulsation.[11] As depict-
ed in Figure 1, switching the high-pressure four-port valve
from position A to position B allows the two reciprocating sy-
ringe pumps to alternately infuse/refill by connecting/discon-
necting the reagent delivery syringes from the reservoir and
reactor R3. The CFU was set to pump the solution from the re-
servoir and deliver it continuously to reactor R3 at 88 mLminÀ1.
The whole continuous-flow unit, including the valve, pumps,
the refilling/reagent delivery sequence as well as flow rates,
were controlled entirely by software developed by our group.
Owing to the low solubility of [PdCl2(PPh3)2] in organic sol-
vents, the Pd precursor was first suspended in acetonitrile in
Entry
Pd cat. [mol%]
Cu salt
[mol%]
t
T
[8C]
Conv.
[%]
[min]
1
2
3
4
5
6
Pd(OAc)2 (5)/PPh3 (15)
[PdCl2(dppf)] (5)
[PdCl2(PPh3)2] (5)
[PdCl2(PPh3)2] (5)
[PdCl2(PPh3)2] (2.5)
[PdCl2(PPh3)2] (2.5)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (5)
20
20
20
20
20
40
70
70
70
21
70
70
80
60
97
66[b]
63
CuI (5)
69
[a] General conditions: aryl iodide solutions (4 mL) were obtained as de-
scribed in Table 1, entry 4. Fresh acetonitrile (4 mL) was added, followed
by [Pd], CuI (if applicable), the ligand (if applicable), 1-ethynyl-4-methyl-
benzene (1.2 equiv), and iPr2NH (10 equiv). The solution was heated as in-
dicated for the specified period of time. Percent conversion to 5a was
determined by 1H NMR spectroscopic analysis of the crude reaction mix-
ture. [b] The reaction was performed by using sonication.
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Scheme 2. Optimized three-step flow diazotization/iododediazotization/Sonogashira sequence.
Figure 2. 1H NMR spectral analysis (CDCl3, 400 MHz) of the products derived
through the three-reactor diazotization/iododediazotization/Sonogashira se-
quence. (a) 4-Methoxy-2-nitroaniline 1a; (b) crude 1-iodo-4-methoxy-2-nitro-
benzene 4a; (c) crude 4-methoxy-2-nitro-1-(2-p-tolylethynyl)benzene 5a.
system and base solution, were infused into reactor R3 at
a flow rate of 44 mLminÀ1. Combined with the CFU stream, the
total flow rate in R3 was 176 mLminÀ1, consistent with
a 26.5 min residence time, which was purposefully kept longer
to ensure quantitative couplings across a wide variety of sub-
strates.
Figure 1. Schematic description of the continuous-flow unit (CFU).
the presence of CuI and iPr2NH. After one hour at room tem-
perature, a suitable dark solution was obtained and transferred
to syringe 6. Syringe 5, containing an acetonitrile solution of 1-
ethynyl-4-methylbenzene, and syringe 6, filled with the catalyst
To prevent any potential degradation of the product during
collection (e.g., Lewis acid catalyzed cyclization of (2-alkynyl)ni-
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trobenzene derivatives),[14] the crude effluent from reactor R3
was poured in a flask containing only water. Recently, our
group has highlighted the crucial role of proper and effective
quenching of product solutions in flow processes.[10c] As Sono-
gashira reactions have also been carried out by using water as
the solvent,[15] it was mandatory to unambiguously establish
Table 3. Scope study for telescoped diazotization/iododediazotization/Sonogashira flow reaction sequence.[a]
Entry
1
Aniline
Product
Method
A
Yield [%][b]
85
1a
1b
5a
5b
2
3
A
A
87
71
1c
5c
4
5
6
7
1d
1e
1 f
5d
5e
5 f
A
A
B
B
79
72
90
70
1g
5g
8
9
1h
1i
5h
5i
C
C
71
72
10
11
12
1j
1k
1l
5j
5k
5l
C
D
E
69
71
78
13
14
1m
1n
5m
5n
F
F
75
76
15
1b
5o
A
78
16
17
1p
1p
5p
5q
F
F
74
70
[a] General conditions for the streamlined diazotization/iododediazotization/Sonogashira flow reaction: Method A: solution 1 (aniline, 5 mmol, in acetoni-
trile, 0.42m), solution 2 (tBuONO, 1.1 equiv in acetonitrile), solution 3 (CH3SO3H, 1.1 equiv in acetonitrile), solution 4 (nBu4NI, 1.2 equiv in acetonitrile), solu-
tion 5 (the alkyne, 1.2 equiv in acetonitrile), and solution 6 ([PdCl2(PPh3)2], 5 mol%, CuI, 10 mol%, and iPr2NH, 10 equiv in acetonitrile) were placed in their
respective syringes (i.e., solution 1 in syringe 1, etc.) and connected to the continuous-flow system as illustrated in Scheme 2. Method B: similar to meth-
od A except the aniline concentration was 0.21m. Method C: similar to method A except solution 3 was comprised of CF3COOH (1.1 equiv, in acetonitrile).
Method D: similar to method A except solution 4 was comprised of nBu4NI (1.4 equiv, 0.54m in acetonitrile) and solution 5 was comprised of 1-ethynyl-4-
methylbenzene (1.4 equiv, 0.29m in acetonitrile). Method E: similar to method A except solution 4 was flowed at 26 mLminÀ1 instead of 22 mLminÀ1 and so-
lution 5 was flowed at 51 mLminÀ1 instead of 44 mLminÀ1. Method F: similar to method A except solutions of the aniline and CH3SO3H in DMSO were used.
[b] Yields are based on the volume of the aniline solution infused over 90 min [1.98 mL, 0.83 mmol of the aniline were infused when following methods A
and C–F (9.2 mmolminÀ1), whereas 0.42 mmol of aniline per run were infused when method B was applied (4.6 mmolminÀ1)].
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the complete conversion of either the aryl iodide or the alkyne
in reactor R3. To this end, TLC and 1H NMR spectroscopic analy-
ses of crude samples of the effluent from R3 were performed
prior to collection for each reaction screened.
high yields (Table 3, entries 2–5). As 4-amino-N,N-dimethylben-
zenesulfonamide (1 f) and 4-amino-2-chlorophenol (1g) are
less soluble starting materials in acetonitrile, method B was
used instead. Compared with method A, method B consisted
of reducing the solution concentrations in syringes 1–6 by half
and the corresponding products 5 f and 5g were obtained in
good yields (Table 3, entries 6 and 7). Remarkably, hydroxyl
groups were nicely tolerated, as were sulfonamides. When 4-
aminoacetophenone (1h), 4-chloroaniline (1i), and 3-chloro-4-
methoxyaniline (1j) were processed by following method A,
the addition of methanesulfonic acid resulted in the precipita-
tion of the corresponding diazonium salts.
Using the flow set-up depicted in Scheme 2, the diazotiza-
tion/iododediazotization/Sonogashira reaction of 4-methoxy-2-
nitroaniline was first processed by using method A. In a typical
procedure, 0.83 mmol of the aniline were infused over
a period of 90 min (9.2 mmolminÀ1). Both the diazotization/io-
dodediazotization and Sonogashira cross-coupling steps were
1
monitored by H NMR spectroscopy (Figure 2). The diazotiza-
tion/iododediazotization sequence was shown to be quantita-
tive (compare spectrum a with b, Figure 2). Although the isola-
tion of 4a was never attempted in this study, the possibility to
achieve the highly efficient flowed syntheses of aryl iodides fol-
lowing this two-step strategy is noteworthy. Full consumption
of 4a in the subsequent Sonogashira cross-coupling reactor
(compare spectrum b with c, Figure 2) yielded 5a in 85% over-
all isolated yield (Table 3, entry 1).
To address this issue, trifluoroacetic acid was used instead
(method C), resulting in homogeneous solutions and good al-
kynylation yields (Table 3, entries 8–10). With the bulkier ortho-
disubstituted 2,3-dimethyl-5-nitroaniline (1k) and the more
electron-rich 2-methoxyaniline (1l), applying method A result-
ed in 61% and 68% yields, respectively, owing to incomplete
iododediazotization and Sonogashira coupling reactions
(Table 3). Increased yield of 5k was achieved by increasing the
flow rate of syringes 4 and 5, without altering the concentra-
tions of the solutions therein (method D, Table 3, entry 11). Al-
ternatively, increased yield of 5l was achieved by increasing
the concentration of the solution in syringes 4 and 5 without
With an efficient, three-reactor flow diazotization/iododedia-
zotization/Sonogashira process in hand, we then evaluated the
scope of this transformation by using a variety of anilines.
Under method A conditions, other nitro-, (alkylthio)-, trifluoro-
methyl-, and chloro-substituted anilines were processed in
Scheme 3. Optimized three-step flow diazotization/iododediazotization/Suzuki–Miyaura sequence.
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altering flow rates (method E, Table 3, entry 12). Ester and ni-
trile groups on the aniline were also well tolerated. However,
both the nitrosamine and arenediazonium salt resulting from
4-aminobenzoate (1m) and 4-aminobenzonitrile (1n) showed
a propensity to precipitate. In these cases, the anilines as well
as methanesulfonic acid were dissolved in DMSO (method F)
and the corresponding products 5m and 5n were obtained in
good yields (Table 3, entries 13 and 14). In the last part of this
screening exercise, heterocyclic substituents on either the
alkyne or the aniline were investigated. 3-Ethynylpyridine was
successfully employed with 4-methoxy-2-nitroaniline by apply-
ing method A (Table 3, entry 15). Method F allowed for the
conversion of 3-aminopyridine into 5p and 5q when 1-ethyn-
yl-4-methylbenzene and 3-ethynylthiophene were used, re-
spectively (Table 3, entries 16 and 17). In these last three exam-
ples, a small amount of precipitate was observed in reactor R3,
but no plugging occurred and the couplings proceeded
smoothly.
Table 4. Optimization of flow diazotization/iododediazotization/Suzuki–
Miyaura sequence.[a]
Entry
x
Residence time
[min]
Conv.
[%]
(equiv)
1
2
3
4
2
45
45
90
85
87
65
1.5
1.5
1.25
45 min+24 h
45
[a] General conditions for the telescoped diazotization/iododediazotiza-
tion/Suzuki–Miyaura flow reaction: Method A: solution 1 (aniline, 5 mmol
in acetonitrile, 0.42m), solution 2 (tBuONO, 1.1 equiv in acetonitrile), solu-
tion 3 (CH3SO3H, 1.1 equiv in acetonitrile), solution 4 (nBu4NI, 1.2 or
1.4 equiv in acetonitrile), solution 5 (arylboronic acid, 1.25–2 equiv in
methanol), and solution 6 ([PdCl2(PPh3)2], 5 mol%, CuI, 10 mol%, and
iPr2NH, 10 equiv in acetonitrile) were placed in their respective syringes
(i.e., solution 1 in syringe 1, etc.) and connected to the continuous-flow
system as illustrated in Scheme 3. Reactor R2 (PFA capillary tubing, 1/8
ODꢁ0.06 inch ID, volume=2521 mL) was submerged in an ultrasonic
bath at room temperature and reactor R3 (PFA capillary tubing, 1/8 ODꢁ
0.06 inch ID, 4674 mL) was placed in an oil bath at 608C. Solutions 1, 2, 3,
and 4 were infused at a flow rate of 22 mLminÀ1 (residence time in R1=
2.7 min; residence time in R2=20 min) and the effluent was collected in
an intermediate reservoir placed in the ultrasonic bath. Solutions 5 and 6
were flowed at 44 mLminÀ1 whereas the continuous-flow unit infused the
crude iodide mixture at 88 mLminÀ1 (residence time in reactor R3=
45 min). Percent conversion to product 6a was determined by 1H NMR
spectroscopic analysis of the crude reaction mixture.
With these optimized flow conditions for the synthesis of
aryl iodides from the corresponding anilines developed, the
possibility to quickly assemble a similar diazotization/iodode-
diazotization/Suzuki–Miyaura process became appealing.
Indeed, changing the last cross-coupling step in the reaction
sequence would not only provide straightforward access to
biaryl libraries but would also demonstrate the versatility of
this general strategy. One major challenge associated with
Suzuki–Miyaura cross-coupling reactions under flow conditions
rises from the use of insoluble, inorganic bases such as Cs2CO3
or the use of strong bases that result in rather insoluble boro-
nate complexes. In most cases, these flow reactions are carried
out by using complex solvent mixtures in attempts to keep
the reaction medium homogeneous.[16] Although uncommon,
the use of soluble amines as mild bases for Suzuki–Miyaura re-
actions has also been reported.[17] Consequently, we envisioned
that the three-reactor flow diazotization/iododediazotization/
cross-coupling process described above in Scheme 2 for Sono-
gashira coupling could easily be adapted for telescoped diazo-
tization/iododediazotization/Suzuki–Miyaura reactions by re-
placing the aryl alkyne in syringe 5 with a solution of arylbor-
onic acid (Scheme 3). However, before this process could be
evaluated, optimal conditions for the Suzuki–Miyaura cross-
coupling step needed to be developed.
maining flow conditions the same, led to a further decrease in
the conversion to product 5a (Table 4, entry 4).
With the optimization of the Suzuki–Miyaura cross-coupling
step complete, attention was then focused on the application
of this protocol to the production of biphenyl compounds
(Table 5). Conversion to the corresponding aryl iodides was ac-
complished by following methods A–F, after which the resul-
tant iodide was then subjected to the optimal Suzuki–Miyaura
cross-coupling conditions (Table 4, entry 2). The substrate
scope for this sequence was then investigated and each run
was carried out over a period of 90 min [a total of 0.83 mmol
of the aniline were infused when following methods A and C–
F (9.2 mmolminÀ1), whereas 0.42 mmol of aniline per run were
infused when method B was applied (4.6 mmolminÀ1)]. 2-Me-
thoxy-4-nitroaniline was successfully converted into products
6a and 6b in good yields (Table 5, entries 1 and 2), by using 4-
methoxyphenylboronic acid or phenylboronic acid, respective-
ly. The presence of a thiopropyl substituent on the aniline ring
was also well tolerated (Table 5, entry 3). Under diluted condi-
tions (method B), 4-amino-N,N-dimethylbenzenesulfonamide
afforded the expected coupled product 6 f in 87% yield
(Table 5, entry 4). 4-Acetyl- and 4-chloro-substituted anilines
were processed to the corresponding biphenyl products 6h
and 6j in satisfactory yields by using method C (Table 5, en-
By using 2-methoxy-4-nitroaniline and 4-methoxyphenylbor-
onic acid as model substrates, the operating procedure out-
lined in Scheme 3 was first investigated and the results from
these experiments are summarized in Table 4. Increasing the
residence time in reactor R3 to 45 min and flowing two equiva-
lents of the boronic acid at 608C resulted in 90% conversion
(Table 4, entry 1). Remarkably, no precipitate was observed
during the course of this experiment. Lowering the amount of
4-methoxyphenylboronic acid to 1.5 equivalents resulted in
85% conversion with respect to the aniline (Table 4, entry 2),
the remaining 15% being unreacted intermediate aryl iodide.
Interestingly, keeping a sample of the effluent at room temper-
ature for 24 h did not significantly increase the conversion to
product (Table 4, entry 3). Lastly, further lowering the amount
of arylboronic acid to 1.25 equivalents while keeping the re-
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Table 5. Scope study for telescoped diazotization/iododediazotization/Suzuki–Miyaura flow reaction.[a]
Entry
1
Aniline
Product
Method
Yield [%][b]
1b
1b
6a
6b
A
A
82
78
2
3
1c
6c
A
61
4
5
6
1 f
1h
1j
6 f
6h
6j
B
C
C
87
76
65
7
1k
6k
D
38 (61)[c]
8
9
1m
1p
6m
6p
F
F
69
70
[a] General conditions for the streamlined diazotization/iododediazotization/Suzuki–Miyaura flow reaction: Method A: solution 1 (aniline, 5 mmol in aceto-
nitrile, 0.42m), solution 2 (tBuONO, 1.1 equiv in acetonitrile), solution 3 (CH3SO3H, 1.1 equiv in acetonitrile), solution 4 (nBu4NI, 1.2 or 1.4 equiv in acetoni-
trile), solution 5 (arylboronic acid, 1.5 equiv in methanol), and solution 6 ([PdCl2(PPh3)2], 5 mol%, CuI, 10 mol%, and iPr2NH, 10 equiv in acetonitrile) were
placed in their respective syringes (i.e., solution 1 in syringe 1, etc.) and connected to the continuous-flow system as illustrated in Scheme 3. Method B:
similar to method A except the aniline concentration was 0.21m. Method C: similar to method A except solution 3 was comprised of CF3COOH (1.1 equiv
in acetonitrile). Method D: similar to method A except solution 4 was comprised of nBu4NI (1.4 equiv, 0.54m in acetonitrile). Method F: similar to method A
except solutions of the aniline and CH3SO3H in DMSO were used. [b] Yields are based on the volume of the aniline solution infused over 90 min [1.98 mL,
0.83 mmol of the aniline were infused when following methods A and C–F (9.2 mmolminÀ1), whereas 0.42 mmol of aniline per run were infused when
method B was applied (4.6 mmolminÀ1)]. [c] Syringe 4 was filled with nBu4NI (1.4 equiv, 0.5m in acetonitrile at 22 mLminÀ1), syringe 5 was filled with PEPPSI-
IPr (4 mol%) and 4-methoxyphenylboronic acid (1.5 equiv) in methanol, syringe 6 was filled with tBuOK (1.5 equiv in methanol).
tries 5 and 6). Coupling bulky 2,3-dimethyl-5-nitroaniline by
of the anilines under the reaction conditions and their full con-
version to the corresponding aryl iodides was reached with
the aid of an ultrasonic bath, thus demonstrating the versatility
of the platform. The segmented streams were collected into an
intermediate reservoir, and continuously sent to cross-coupling
reactors by using an automated continuous-flow unit fully con-
trolled by software developed by our group, thus ensuring
known stoichiometric ratios of reactants for the subsequent
coupling reaction. In this final step, straightforward modifica-
tions of the process were applied to either achieve Sonoga-
shira or Suzuki–Miyaura cross-coupling reactions.
using method A led to only 38% yield for 6k (Table 5, entry 7).
However, using
a
more active catalyst, Pd-PEPPSI-IPr[18]
(4 mol%; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-
chloropyridyl)palladium(II) dichloride) and stronger base,
tBuOK (1.5 equiv), significantly increased the yield from 31% to
61%. Finally, methyl 4-aminobenzoate and 3-aminopyridine
were successfully flowed to afford 6m and 6p in good yields
(Table 5, entries 8 and 9). Although a small amount of solid ap-
peared in reactor R3 when 3-aminopyridine was used, the
system did not plug during the 90 min the effluent was col-
lected.
Acknowledgments
Conclusions
The authors thank NSERC Canada for support of this research.
In this study, we have described a versatile, high-yielding, flow
process for the conversion of a wide variety of commercially
available anilines into biaryl and biarylacetylene products. For
the first crucial diazotization/iododediazotization sequence,
several methods were developed to ensure complete solubility
Keywords: anilines · diazotization · cross-coupling · flow
conditions · sustainable chemistry
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[1] a) A. S. Kende, J. S. Mendoza, Tetrahedron Lett. 1991, 32, 1699–1702;
b) A. M. Tafesh, J. Weiguny, Chem. Rev. 1996, 96, 2035–2052; c) R. J.
Rahaim, R. E. Maleczka, Org. Lett. 2005, 7, 5087–5090; d) G. S. Vanier,
Synlett 2007, 2007, 0131–0135; e) S. Chandrappa, K. Vinaya, T. Ramak-
rishnappa, K. S. Rangappa, Synlett 2010, 3019–3022; f) G. Wienhçfer, I.
Sorribes, A. Boddien, F. Westerhaus, K. Junge, H. Junge, R. Llusar, M.
Beller, J. Am. Chem. Soc. 2011, 133, 12875–12879; g) S. Sharma, M.
Kumar, V. Kumar, N. Kumar, J. Org. Chem. 2014, 79, 9433–9439.
[2] a) M. P. Doyle, B. Siegfried, J. F. Dellaria, J. Org. Chem. 1977, 42, 2426–
2431; b) M. P. Doyle, J. F. Dellaria, B. Siegfried, S. W. Bishop, J. Org. Chem.
1977, 42, 3494–3498; c) P. Griefs, Just. Liebigs Ann. Chem. 1858, 106,
123–125.
[3] a) R. Fortt, R. C. R. Wootton, A. J. de Mello, Org. Process Res. Dev. 2003, 7,
762–768; b) G. Balz, G. Schiemann, Ber. Dtsch. Chem. Ges. 1927, 60,
1186–1190; c) T. Sandmeyer, Ber. Dtsch. Chem. Ges. 1884, 17, 2650–
2653; d) T. Sandmeyer, Ber. Dtsch. Chem. Ges. 1884, 17, 1633–1635.
[4] a) K. Kikukawa, K. Nagira, F. Wada, T. Matsuda, Tetrahedron 1981, 37, 31–
36; b) K. Kikukawa, K. Maemura, Y. Kiseki, F. Wada, T. Matsuda, C. S.
Giam, J. Org. Chem. 1981, 46, 4885–4888; c) K. Kikukawa, K. Maemura,
K. Nagira, F. Wada, T. Matsuda, Chem. Lett. 1980, 9, 551–552; d) F. Akiya-
ma, H. Miyazaki, K. Kaneda, S. Teranishi, Y. Fujiwara, M. Abe, H. Tanigu-
chi, J. Org. Chem. 1980, 45, 2359–2361; e) T. M. Kiyoshi Kikukawa, Chem.
Lett. 1977, 6, 159–162.
[11] a) E. Comer, M. G. Organ, Chem. Eur. J. 2005, 11, 7223–7227; b) E.
Comer, M. G. Organ, J. Am. Chem. Soc. 2005, 127, 8160–8167; c) G.
Shore, S. Morin, M. G. Organ, Angew. Chem. Int. Ed. 2006, 45, 2761–
2766; Angew. Chem. 2006, 118, 2827–2832; d) W. S. Bremner, M. G.
Organ, J. Comb. Chem. 2007, 9, 14–16; e) G. Shore, M. G. Organ, Chem.
Commun. 2008, 838–840; f) G. Shore, M. Tsimerman, M. G. Organ, Beil-
stein J. Org. Chem. 2009, 5, 35; g) S. Achanta, V. Liautard, R. Paugh, M. G.
Organ, Chem. Eur. J. 2010, 16, 12797–12800; h) F. Ullah, T. Samarakoon,
A. Rolfe, R. D. Kurtz, P. R. Hanson, M. G. Organ, Chem. Eur. J. 2010, 16,
10959–10962; i) T. O. Painter, P. D. Thornton, M. Orestano, C. Santini,
M. G. Organ, J. Aube, Chem. Eur. J. 2011, 17, 9595–9598; j) Q. Zang, S.
Javed, F. Ullah, A. Zhou, C. A. Knudtson, D. Bi, F. Z. Basha, M. G. Organ,
P. R. Hanson, Synthesis 2011, 2743–2750; k) S. Faisal, F. Ullah, P. K. Maity,
A. Rolfe, T. B. Samarakoon, P. Porubsky, B. Neuenswander, G. H. Lushing-
ton, F. Z. Basha, M. G. Organ, P. R. Hanson, ACS Comb. Sci. 2012, 14,
268–272; l) F. Ullah, Q. Zang, S. Javed, P. Porubsky, B. Neuenswander,
G. H. Lushington, P. R. Hanson, M. G. Organ, Synthesis 2012, 44, 2547–
2554; m) Q. Zang, S. Javed, D. Hill, F. Ullah, D. Bi, P. Porubsky, B. Neuens-
wander, G. H. Lushington, C. Santini, M. G. Organ, P. R. Hanson, ACS
Comb. Sci. 2012, 14, 456–459; n) G. A. Price, A. R. Bogdan, A. L. Aguirre,
T. Iwai, S. W. Djuric, M. G. Organ, Catal. Sci. Technol. 2016, 6, 4733–4742;
o) M. Tilley, G. Li, P. Savel, D. Mallik, M. G. Organ, Org. Process Res. Dev.
2016, 20, 517–524.
[5] a) B. Ahmed-Omer, D. A. Barrow, T. Wirth, Tetrahedron Lett. 2009, 50,
3352–3355; b) F.-X. Felpin, L. Nassar-Hardy, F. Le Callonnec, E. Fouquet,
Tetrahedron 2011, 67, 2815–2831; c) J. G. Taylor, A. V. Moro, C. R. D. Cor-
reia, Eur. J. Org. Chem. 2011, 1403–1428; d) N. Chernyak, S. L. Buchwald,
J. Am. Chem. Soc. 2012, 134, 12466–12469; e) N. Oger, E. Le Grognec,
F.-X. Felpin, J. Org. Chem. 2014, 79, 8255–8262; f) B. J. Deadman, S. G.
Collins, A. R. Maguire, Chem. Eur. J. 2015, 21, 2298–2308; g) N. Oger, E.
Le Grognec, F.-X. Felpin, Org. Chem. Front. 2015, 2, 590–614.
[6] a) S. Darses, T. Jeffery, J.-P. GenÞt, J.-L. Brayer, J.-P. Demoute, Tetrahedron
Lett. 1996, 37, 3857–3860; b) A. Roglans, A. Pla-Quintana, M. Moreno-
MaÇas, Chem. Rev. 2006, 106, 4622–4643; c) S. Sengupta, S. K. Sadhu-
khan, Tetrahedron Lett. 1998, 39, 715–718; d) S. Cacchi, G. Fabrizi, A.
Goggiamani, A. Sferrazza, Synlett 2009, 973–977; e) S. Sengupta, S.
Bhattacharyya, J. Org. Chem. 1997, 62, 3405–3406; f) F. Mo, G. Dong, Y.
Zhang, J. Wang, Org. Biomol. Chem. 2013, 11, 1582–1593; g) Y. Qin, W.
Wei, M. Luo, Synlett 2007, 2410–2414; h) R. H. Taylor, F.-X. Felpin, Org.
Lett. 2007, 9, 2911–2914.
[12] C. J. Smith, N. Nikbin, S. V. Ley, H. Lange, I. R. Baxendale, Org. Biomol.
Chem. 2011, 9, 1938–1947.
[13] R. Chinchilla, C. Nꢂjera, Chem. Rev. 2007, 107, 874–922.
[14] a) F. Nepveu, S. Kim, J. Boyer, O. Chatriant, H. Ibrahim, K. Reybier, M.-C.
Monje, S. Chevalley, P. Perio, B. H. Lajoie, J. Bouajila, E. Deharo, M. Sau-
vain, R. Tahar, L. Basco, A. Pantaleo, F. Turini, P. Arese, A. Valentin, E.
Thompson, L. Vivas, S. Petit, J.-P. Nallet, J. Med. Chem. 2010, 53, 699–
714; b) N. Asao, K. Sato, Y. Yamamoto, Tetrahedron Lett. 2003, 44, 5675–
5677.
[15] a) B. Liang, M. Dai, J. Chen, Z. Yang, J. Org. Chem. 2005, 70, 391–393;
b) B. H. Lipshutz, D. W. Chung, B. Rich, Org. Lett. 2008, 10, 3793–3796.
[16] a) K. Mennecke, A. Kirschning, Synthesis 2008, 3267–3272; b) T. Noꢃl, S.
Kuhn, A. J. Musacchio, K. F. Jensen, S. L. Buchwald, Angew. Chem. Int. Ed.
2011, 50, 5943–5946; Angew. Chem. 2011, 123, 6065–6068; c) T. Noꢃl,
A. J. Musacchio, Org. Lett. 2011, 13, 5180–5183; d) C. Mateos, J. A.
Rincꢄn, B. Martꢅn-Hidalgo, J. Villanueva, Tetrahedron Lett. 2014, 55,
3701–3705.
[7] S. Darses, G. Michaud, J.-P. GenÞt, Eur. J. Org. Chem. 1999, 1875–1883.
[8] B. Panda, T. K. Sarkar, Chem. Commun. 2010, 46, 3131–3133.
[9] G. Fabrizi, A. Goggiamani, A. Sferrazza, S. Cacchi, Angew. Chem. Int. Ed.
2010, 49, 4067–4070; Angew. Chem. 2010, 122, 4161–4164.
[17] a) K. R. Buszek, N. Brown, Org. Lett. 2007, 9, 707–710; b) B. H. Lipshutz,
T. B. Petersen, A. R. Abela, Org. Lett. 2008, 10, 1333–1336.
[18] M. G. Organ, S. C¸alimsiz, M. Sayah, K. H. Hoi, A. J. Lough, Angew. Chem.
Int. Ed. 2009, 48, 2383–2387; Angew. Chem. 2009, 121, 2419–2423.
[10] a) M. B. Andrus, C. Song, Org. Lett. 2001, 3, 3761–3764; b) S. Cacchi, G.
Fabrizi, A. Goggiamani, A. Sferrazza, Synlett 2009, 1277–1280; c) K. S.
Nalivela, M. Tilley, M. A. McGuire, M. G. Organ, Chem. Eur. J. 2014, 20,
6603–6607; d) N. Oger, M. d’Halluin, E. Le Grognec, F.-X. Felpin, Org.
Process Res. Dev. 2014, 18, 1786–1801.
Received: July 29, 2016
Published online on && &&, 0000
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FULL PAPER
&
Organic Chemistry
M. Teci, M. Tilley, M. A. McGuire,*
M. G. Organ*
&& – &&
Using Anilines as Masked Cross-
Coupling Partners: Design of
a Telescoped Three-Step Flow
Diazotization, Iododediazotization,
Cross-Coupling Process
Coupling under continuous flow: A
versatile, high-yielding, flow process for
the conversion of a wide variety of com-
mercially available anilines into biaryl
and biarylacetylene products is de-
scribed. The system proved versatile as
modifications to the diazotization/iodo-
dediazotization sequence could be
made rapidly to account for any sub-
strate specificity (e.g., solubility prob-
lems), leading to a wide substrate scope
of Suzuki–Miyaura and Sonogashira
cross-coupled products.
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Chem. Eur. J. 2016, 22, 1 – 10
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