Continuous flow synthesis of secondary amides by tandem azidation-amidation of anilines

Article abstract of DOI:10.1055/s-0031-1291013

The continuous flow synthesis of a variety of secondary amides by tandem azidation-amidation of anilines is described. This new procedure benefits from the improved safety feature of generating aromatic azides in flow, thus ensuring low concentrations of any potentially hazardous intermediates. The protocol was amenable to the production of multi-gram quantities of the amide product. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1291013

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LETTER
lCettoerntinuous Flow Synthesis of Secondary Amides by Tandem Azidation–
Amidation of Anilines
Continuous Flow Synthesis of Secondary Amides
Christian Spiteri, John E. Moses*
School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
Fax +44(115)9513533; E-mail: john.moses@nottingham.ac.uk
Received: 20.02.2012; Accepted after revision: 23.03.2012
acid,5 often employing coupling additives such Castro’s
Abstract: The continuous flow synthesis of a variety of secondary
reagent,6 dicyclohexylcarbodiimide,7 3-(diethylphosphor-
amides by tandem azidation–amidation of anilines is described.
yloxy)-1,2,3-benzotriazin-4(3H)-one,8 or O-(benzotri-
This new procedure benefits from the improved safety feature of
generating aromatic azides in flow, thus ensuring low concentra-
azol-1-yl)-N,N,N′,N′-tetramethyluronium
hexafluoro-
tions of any potentially hazardous intermediates. The protocol was phosphate,9 amongst others.4,5 Although very important,
amenable to the production of multi-gram quantities of the amide
product.
such reagents add extra cost and also generate undesirable
by-products that can be difficult to remove from the final
product.8 Thus, the development of new amide bond
Key words: flow chemistry, amide synthesis, aromatic azides, azi-
dation–amidation, synthetic methods
forming reactions that circumvent such problems are de-
sirable; ideally, such reactions would attain ‘click’10 status
in terms of selectivity and operational simplicity.
Increased efficiency, reduction of turnaround time, and
We recently reported a microwave-enhanced tandem azi-
many other practical factors influence the pursuit of new
dation–amidation of anilines11 involving in situ genera-
technology development in chemistry. Over the past few
tion of an aromatic azide, followed by immediate reaction
years, flow chemistry has evolved as a valuable alterna-
with a thioacid derivative.12,13
tive to traditional batch-processing methods,1 with many
Given the potential hazards associated with some organic
significant advances in unattended automation, resin-teth-
azides, we envisaged that a continuous flow version of
ered reagents, and extensive library production having
this method would offer added safety advantages, permit-
ting the synthesis of the azide intermediates in relatively
low concentrations.14,15
been reported.2 New methodologies and instrumentation
of flow systems are constantly evolving and adapting to
the changes and demands of the modern research environ-
ment.3 Here, we report the development of a continuous
flow method for the synthesis of a number of secondary
amides, employing a tandem azidation–amidation of ani-
lines.
Experiments were performed with a Vapourtec flow de-
vice equipped with an R4 reactor module, a standard PFA
10 mL coil tube reactor and three pumps, coupled to a
CEM Discovery microwave reactor with 10 mL flow cell
unit (Figure 1). Substrates 4-nitroaniline (1) and thioacetic
acid (2) were selected for initial screening studies.11
Amide bond formation is one of the most common trans-
formations in organic chemistry, and particularly useful
for applications in medicinal chemistry and drug discov-
ery programs.4 Typically, amide synthesis involves addi-
tion of a nucleophilic amine to an activated carboxylic
Thus, a system was engineered in which the in situ azida-
tion of 1, using our previously reported conditions14
(TMSN3, t-BuONO, MeCN) was carried out in a 10 mL
Figure 1 Flow reactor set-up with a three-pump system, connected to a microwave reactor. Acronyms: HP for high pressure, BPR for back
pressure regulator and T1 and T2 for T-junctions.
SYNLETT 2012, 23, 1546–1548
Advanced online publication: 29.05.2012
0
9
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6
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2
1
4
1
4
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DOI: 10.1055/s-0031-1291013; Art ID: ST-2012-D0154-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Continuous Flow Synthesis of Secondary Amides
1547
The optimized flow conditions proved to be useful for the
syntheses of a range of secondary amides. The results pre-
sented in Table 2 show that a range of functional groups
were well-tolerated, including; methoxy, nitrile, nitro-,
halo-, ester, carboxylic acids and heterocyclic functional-
ity (Table 2, 5–13). Electron-poor anilines were found to
give superior conversions over electron-rich (6–12 vs. 5).
In fact, anilines with strong deactivating groups (e.g., CF3
or F), gave nearly quantitative yields of 7 and 11 (92 and
100%, respectively). On the other hand, other deactivating
groups (e.g., CN, CO2Et, Cl, and CO2H) afforded the cor-
responding products 6, 8 and acid 1016 in lower yields (Ta-
ble 2).
Table 1 Screening and Optimization
O
O
N3
NH2
HS
HN
(2)
t-BuONO
TMSN3
2,6-lutidine
MeCN,
50 min,
60 °C
solvent,
addition rate,
μW, 80 °C
NO2
NO2
NO2
1
3
4
Entrya
Solvent
Rate of addition Yield
(mL/min)
(%)b
1
2
3
4
5
6
7
8
9
MeOH
0.07
0.1
0.2
0.1
0.18
0.2
0.2
0.2
0.2
60
56
68
72
56
88
88
31
72
MeOH
Table 2 Substrate Scopea,b
MeOH
O
O
H2O
HN
NH2
N3
HS
(2)
t-BuONO
H2O
TMSN3
2,6-lutidine
MeCN,
50 min,
60 °C
MeCN–H2O
(1:1)
μW, 80 °C
H2O
R1
R1
R1
H2O–MeCN (1:1)
H2O–MeCN (1:4)
H2O–MeCN (1:4)
O
O
O
HN
HN
HN
a Reaction conditions: 1 (0.25 mmol), t-BuONO (1.0 equiv), TMSN3
(1.0 equiv), 2 (1.3 equiv), 2,6-lutidine (1.3 equiv).
b Isolated yield.
CF3
OMe
CN
5 (<5%)
6 (56%)
7 (92%)
coil tube reactor, heated at 60 °C with a residence time of
50 min.15b,15c The solution of azide 3 was then pumped to
a T-junction where it was mixed with a solution of thio-
acetic acid 2 and 2,6-lutidine in polar-protic solvent (see
Table 1). The resulting mixture was then directed to the
microwave reactor chamber and irradiated at 80 °C
(150 W), followed by collection of the product 4 in a
closed flask over a period of approximately two hours.
The volatile components were then removed under re-
duced pressure and the product 4 was collected by filtra-
tion.
O
HN
O
O
HN
HN
COOH
Cl
O
OEt
8 (58%)
9 (30%)
10 (25%)
O
O
O
HN
HN
Using this instrumentation configuration, a number of re-
action conditions were investigated with several different
solvent systems for the amidation step, and varying rates
of addition of 2 and 2,6-lutidine (pump C, Figure 1) into
the flow system. Table 1 summarizes the conditions
screened, which afforded the amide product 4 in moderate
to good overall yield.
CN
HN
N
NO2
S
F
11 (100%)
12 (25%)c
13 (20%)
a Reaction conditions: aniline derivative (0.25 mmol), t-BuONO (1.0
equiv), TMSN3 (1.0 equiv), 2 (1.3 equiv), 2,6-lutidine (1.3 equiv).
b Isolated yields.
The flow rate of pump C and solvent choice were found to
have a significant effect on the reaction outcome. Optimal
conditions were found with a pump C flow rate of 0.2
mL/min, and water as the solvent system (Table 1, entry
6). Unfortunately, use of water also resulted in the product
4 precipitating, causing blockages in the flow piping sys-
tem after several runs. This problem could be avoided by
using a mixture of acetonitrile and water (1:1) as solvent
without affecting the yield (Table 1, entry 7).
c 2-Cyano-4-nitroaniline precipitated out within the injection loop.
Thus, not all the starting material was injected into the flow reactor.
The solubility of the corresponding aniline derivative was
found to be a crucial factor for the overall yield. For ex-
ample, 2-cyano-4-nitroaniline tended to precipitate in the
reaction loop, affording 12 in only 25% yield. Further-
more, 2-(4-aminophenyl)acetic acid and 2,6-diiodo-4-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1546–1548

1548
C. Spiteri, J. E. Moses
LETTER
nitroaniline were insoluble in acetonitrile and, thus, it was
not possible to inject them within the reagent loop A.
Acknowledgment
We thank Vapourtec Ltd, for the loan of an R1Plus pump module.
We are grateful to the EPSRC and GSK for funding (C.S.).
We then progressed to thiobenzoic acid (14), which could
be manually injected into the flow reactor by using
pump C with 2,6-lutidine and methanol as solvent.17
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
Table 3 Substrate Scopea,b
O
O
References
NH2
N3
HN
Ph
HS
Ph
(14)
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t-BuONO
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(1:1)
μW, 80 °C
R1
R1
R1
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O
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HN
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NO2
NO2
15 (90%)
16 (64%)
17 (10%)
18 (5%)
a Reaction conditions: aniline derivative (0.25 mmol), t-BuONO (1.0
equiv), TMSN3 (1.0 equiv), 14 (1.3 equiv), 2,6-lutidine (1.3 equiv).
b Isolated yields.
(7) Sheehan, J. C.; Hess, G. P. J. Am. Chem. Soc. 1955, 77,
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(16) Interestingly, the synthesis of 10 by this method offers an
orthogonal strategy towards divergent amide synthesis
without the need for protecting groups.
As observed with thioacetic acid (2), the reaction worked
best with electron-poor anilines (Table 3). In fact, 4-ni-
troaniline (1) afforded the desired amide 15 in an impres-
sive 90% yield, although the meta-substituted amide 16
was less efficient (64%). However, anilines substituted
with electron-releasing alkyne or methyl groups gave the
corresponding amide products 17 and 18 in much lower
yields (10 and 5%, respectively).
Although yields varied, it is noteworthy that electron-de-
ficient anilines were superior substrates for the transfor-
mation. This is in contrast to conventional amide
syntheses in which electron-deficient nucleophiles can
sometimes be problematic. Thus, the azidation–amidation
protocol offers a complementary route towards electron-
deficient aromatic amides.
To determine if our continuous flow process was amena-
ble to scale-up, we investigated the synthesis of amide 15.
Gratifyingly, scaling the reaction from 0.25 mmol to 7.5
mmol (1.0 g of 1), gave the target amide product 15 in
86% yield (1.5 g), over 18 h under continuous flow.
In conclusion, we have successfully developed a micro-
wave-enhanced azidation–amidation protocol under con-
tinuous flow process. The protocol is straightforward to
perform and is tolerant of a wide variety of substrates.
Furthermore, the flow chemistry enabled gram-scale
quantities of product to be produced. This technology has
the potential to find wide application in industry and of-
fers improved safety features over the batch process.
(17) Compound 14 and 2,6-lutidine in MeCN–H2O (1:1) formed
a white precipitate that could not be manually loaded into the
flow reactor.
Synlett 2012, 23, 1546–1548
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