Building a sulfonamide library by eco-friendly flow synthesis

Article abstract of DOI:10.1021/co400012m

A rapid and eco-friendly synthesis of a sulfonamide library under flow conditions is described. The study illustrates an efficient, safe, and easily scalable preparation of sulfonamides by use of a meso-reactor apparatus, thus demonstrating the impact of flow technologies within drug discovery. Waste minimization, employment of green media, and nontoxic reactants are achieved by the optimization of the flow setup and experimental protocol designed to sequentially synthesize primary, secondary, and tertiary sulfonamides. Isolation of the products involves only extraction and precipitation affording pure compounds in good to high yields without further purification for biological evaluation.

Full text of DOI:10.1021/co400012m

Letter
pubs.acs.org/acscombsci
Building a Sulfonamide Library by Eco-Friendly Flow Synthesis
Antimo Gioiello,* Emiliano Rosatelli, Michela Teofrasti, Paolo Filipponi, and Roberto Pellicciari
̀
Dipartimento di Chimica e Tecnologia del Farmaco, Universita di Perugia, Via del Liceo, 1, 06123 Perugia, Italy.
S
* Supporting Information
ABSTRACT: A rapid and eco-friendly synthesis of a
sulfonamide library under flow conditions is described. The
study illustrates an efficient, safe, and easily scalable
preparation of sulfonamides by use of a meso-reactor
apparatus, thus demonstrating the impact of flow technologies
within drug discovery. Waste minimization, employment of
green media, and nontoxic reactants are achieved by the
optimization of the flow setup and experimental protocol
designed to sequentially synthesize primary, secondary, and
tertiary sulfonamides. Isolation of the products involves only
extraction and precipitation affording pure compounds in good
to high yields without further purification for biological evaluation.
KEYWORDS: sulfonamide, flow chemistry, eco-friendly synthesis, compound library
Chart 1. Examples of Sulfonamide-Containing Therapeutic
n recent years, medicinal chemistry has faced a significant
Drugs
I
evolution in both approaches and methodologies because of
the advent of new and innovative technologies. In this context,
flow chemistry has rapidly turned into one of the techniques
that may revolutionize the synthetic sector of drug discovery
from a quality and safety standpoint, as well as in terms of cost-
effectiveness and environmental impact.1−4 The main potential
advantages of the flow approach include the following: high
control of reaction parameters, possibility to conduct reactions
at high temperature and pressure (process intensification),
rapid and automated compound library preparation, telescoping
reactions, in-line purification, easy reproducibility, and scale-up.
As part of our medicinal chemistry efforts, we needed to
develop a facile and rapid synthesis of sulfonamides that was
suitable for preparing a wide variety of compounds. To
accomplish this task, we sought to explore the possibility to
employ flow synthesis and eco-friendly protocols, which could
be also useful for large scale preparations.
Sulfonamides represent a very important class of compounds
in medicinal and synthetic chemistry.5−7 Indeed, sulfonamide
functionality constitutes the structural motif of a variety of
drugs (Chart 1) and bioactive compounds endowed with
antibacterial, antitumor, anti-inflammatory, hypoglycemic, and
protease inhibitory activity among others.6,7 Therefore, the
search for a new and efficient preparation of sulfonamides is
still of great interest.
Among the many strategies reported for the synthesis of
sulfonamide derivatives,8−13 the classical approach from amino
compounds and sulfonyl chlorides has attracted considerable
attention thanks to the good reactivity and simplicity of the
experimental protocols.14−19 The main drawbacks of this
methodology include the use of organic amine bases to
scavenge the acid (HCl) that is generated during the reaction,
high temperatures needed for the less reactive substrates, as
well as laborious purifications often required when competing
side reactions occur.20 Recently, a sulfonamide synthesis has
been described in aqueous media and under dynamic control.21
The method avoided the use of organic bases and chromato-
graphic purifications and was applied to a variety of arylsulfonyl
chlorides and amines. Noteworthy, the reactions were carried
out after the pH adjustment of the solution, they took several
hours for completion and can be employed mainly to primary
aryl amino derivatives partially soluble in water. A fully
Received: January 23, 2013
Revised: March 18, 2013
Published: March 20, 2013
© 2013 American Chemical Society
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ACS Combinatorial Science
Letter
automated two-step flow process was reported for the
preparation of a 48-member library of secondary sulfona-
mides.22 It included the N-monoalkylation of primary
sulfonamides through a resin catch and release strategy
followed by removal of the Boc-protecting group. More
recently, a combination of flow and batch chemistries was
applied for the synthesis of trisubstituted pyrrolidines.23 In this
case, the sulfonylation reaction was conducted in batch
modality by treatment of the pyrrolidine intermediates with a
set of sulfonyl chlorides in the presence of Hunig’s base in
DMF.
In continuation of our recent interest in the development of
novel flow methodologies for the synthesis of medicinally
relevant compounds,24 we demonstrate how to perform a
green, scalable, one-pot flow preparation of primary, secondary,
and tertiary sulfonamides capable of delivering pure products
without the use of tedious work-ups and purifications. Starting
with classical laboratory batch-screen, we decided to study the
reaction between p-anisidine (1){1} and tosyl chloride (2){1}
under Schotten−Baumann conditions (Scheme 1) as a model
system for the fine-tuning of the experimental parameters and
the implementation of the flow setup.
use of water and acetone as the solvent system at different
ratios did not fit for a flow process due to the formation of
precipitates. The addition of phase transfer agents, such as
Bu4NBr,21 can give satisfactory results only when the reactions
were performed with liquid reagents. The problem was resolved
by using polyethylene glycol 400 (PEG 400) as an additional
organic cosolvent for the reaction. PEGs have been widely used
as powerful and eco-friendly reaction medium for several
synthetic transformations.25−29 In particular, PEG 400 is
relatively cheap, readily recyclable, biodegradable and water-
soluble making it easily removable by simple workup
operations. Moreover, PEG 400 is endowed with a viscosity
value of 90 cP thus ensuring the flow system to operate
properly. The best result in terms of solubility was obtained
with a solution of H2O/acetone/PEG 400 1:2:1 (v/v/v).
Having established the optimal solvent system, the reactions
were then carried out in a flow meso-reactor equipped with a
two-loop injection system, two pumps devoted to the acetone
and H2O reservoir of solvent, a 10 mL reactor, a back pressure
regulator (BPR), a UV detector and a fraction collector (Figure
1). With the aim to find the experimental conditions that would
Scheme 1. Reaction of Amines with Sulfonyl Chlorides in
Flow Conditions
Figure 1. Flow setup used during the optimization of the reaction
conditions. BPR = back pressure regulator; cmpds = compounds; h =
hour.
guarantee the highest productivity and rapidity, a series of
experiments were performed varying the residence time (flow
rate) (Table 1). Temperature was fixed at 25 °C, and the
reactions were performed by loop injection of two stock
solutions: the first one was constituted with p-anisidine (1a)
(0.22 mol) and NaHCO3 (0.40 mol) dissolved in water/PEG
400 (2 mL, 1:1, v/v), and the second one with an acetone
solution (2 mL) of tosyl chloride (2a) (0.20 mol). Two
equivalents of NaHCO3 were sufficient to ensure HCl trapping
a
Table 1. Flow Rate Effect
b
c
entry
flow rate (mL min−1
)
yield (%)
1
2
3
4
5
6
7
8
0.2
0.3
0.4
0.5
0.75
1
91
100
100
100
98
The initial attempts were not very encouraging. As expected,
the reaction conducted in acetone−aqueous, basic (Na2CO3 or
NaOH) solution gave poor yields because of hydrolysis of the
p-toluensulfonyl chloride (data not shown). In this respect, it
has been reported that the optimal pH for minimizing the
occurrence of hydrolysis is between 8 and 9.21 We thus
considered the use of NaHCO3 as the base being endowed with
a pKa and pH value of 10.3 and 8.4, respectively. However, the
94
1.5
2.0
76
74
a
1{1}/2{1}/NaHCO3 = 1/0.9/2; T = 25 °C; BPR = 100 psi.
b
c
Combined flow rate (pump A + pump B). Determined by 1H NMR
analysis of the crude reaction mixture.
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ACS Combinatorial Science
Letter
a
Table 2. Overview of Synthesized Library Compounds and Purity Data
b
c
entry
amine 1{1−19}
sulfonyl chloride 2{1−5}
sulfonamide (%)
isolated yield (%)
1
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{2}
{2}
{2}
{2}
{2}
{2}
{3}
{3}
{3}
{3}
{3}
{4}
{4}
{4}
{4}
{4}
{5}
{5}
{5}
{5}
{5}
{5}
{5}
{5}
3 (98)
3 (90)
3 (100)
3 (86)
3 (98)
3 (100)
3 (100)
3 (98)
3 (92)
3 (100)
3 (98)
3 (95)
3 (100)
3 (96)
3 (100)
4 (98)
4 (89)
4 (93)
4 (100)
4 (97)
4 (93)
5 (100)
5 (91)
5 (98)
5 (100)
5 (93)
6 (100)
6 (85)
6 (100)
6 (100)
6 (90)
7 (85)
7 (95)
7 (100)
7 (100)
7 (98)
7 (88)
7 (86)
7 (90)
92
62
97
70
89
98
94
86
77
97
87
85
93
90
95
88
60
84
97
90
82
96
68
82
98
78
96
58
96
97
80
76
82
83
87
72
81
71
76
2
{2}
3
{3}
4
{4}
5
{6}
6
{7}
7
{8}
8
{9}
9
{11}
{13}
{14}
{15}
{16}
{17}
{18}
{3}
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
{4}
{5}
{8}
{10}
{14}
{1}
{2}
{3}
{8}
{10}
{3}
{4}
{5}
{8}
{12}
{13}
{16}
{3}
{1}
{2}
{17}
{18}
{19}
a
b
1/2/NaHCO3 = 1/0.9/2; T = 25 °C; BPR = 100 psi; combined flow rate = 0.5 mL min−1. Determined by 1H NMR analysis of the crude reaction
c
mixture. Determined after extraction.
and the correct value of pH at the end of the reaction (pH 8).
After the injection into the flow stream and the switching of the
valves through the loops, the two solutions were mixed in a T-
junction, pumped through the coil reactor, and the output
collected using a UV detector and a fraction collector (Figure
1). The conversion of the substrate and the relative reaction
yields were determined by NMR analysis of the crude mixtures.
As illustrated in Table 1, a high efficiency was maintained
with a flow rate ranging from 0.2 to 1.0 mL min−1, obtaining a
quantitative conversion with a total flow rate of 0.5 mL min−1.
The collected product was quenched with 3 N HCl and
extracted with Et2O to give the desired sulfonamide 3 with high
purity (>95%) without further purifications.
products spanning different structural and physicochemical
properties. Thus, reagent solutions were injected in sequence
via loops and pumped at equal flow rates (0.25 mL min−1) to
meet at a T-piece mixer. After it passed the reactor heater, the
flow stream went through the UV detector useful to indicate
the volume of reaction mixture to be collected. In this way a
large number of compounds were prepared in a single run
consisting of amine variations.
The analysis of the results showed that sulfonamides were
formed in good to high yields (Table 2) and clearly
demonstrated the efficiency of the method to prepare arrays
of sulfonamides in a sequential flow-through process. In
particular, the reactions of primary aryl amines having both
electron-donating and electron-withdrawing groups proceeded
with excellent and good yields, respectively (Table 2). These
results were particularly interesting because under classical
batch conditions, electron-withdrawing substituted amines
1{1−2,4} gave moderate and low yields and required several
Using the optimized experimental conditions, the reaction
was applied to a variety of amines and sulfonyl chlorides
(Scheme 1) according to the flow setup depicted in Figure 1.
The scope was not to obtain a full combinatorial library with all
possible combinations but, rather, to prepare a diverse set of
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ACS Combinatorial Science
Letter
hours to reach completation. Notably, less reactive secondary
1{15−19} and alkyl amines 1{11−14} and various arylsulfonyl
chlorides 2{1−5} also worked well in the reaction. All the
products 3−7 were isolated by simple extraction and then
analyzed by GC-MS and NMR spectroscopy. In all cases, the
desired compounds were obtained in excess of 95% purity
without further purification. No cross-contamination was
detected in any instance.
Scale Up. One of the main advantages of flow synthesis is
the easy scaling-up either by continuous running or by the
numbering up of flow reactors. As an example, we have applied
our method for the large preparation of probenecid (10), a
prototypical uricosuric drug also used to treat patients with
renal impairment as an adjunct to antibacterial therapy. The in-
flask patented synthesis of this compound has been reported to
proceed in one or two steps with an overall yield ranging from
41% to 65%.30−32 Thus, 4.4 g of 4-(chlorosulfonyl)benzoic acid
(8) were dissolved in 200 mL of acetone and processed with
5.6 mL of dipropylamine (9) and 3.4 g of NaHCO3 in 200 mL
of a water/PEG 400 solution (Figure 2). The crude flow stream
material ready for biological screenings. Importantly, the
method can be easily automated through the use of an
appropriate software and autosampler. Second, since this
method works efficiently with both primary and secondary
amines and various sulfonyl chlorides, it provides a convenient
route for a wide variety of sulfonamides. Finally, we have
demonstrated the utility of this method for large scale
preparation of probenecid (9) obtained in a single step in
78% yield and purified by precipitation with a purity of 95%.
Moreover, the solvents used can be easily recovered and reused
for further reactions reducing waste, pollution and costs (E-
factor = 0.66).33
ASSOCIATED CONTENT
■
S
* Supporting Information
Description of the experimental procedures, analytical proto-
cols, NMR spectra, and MS data. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Address: Laboratory of Medicinal and Advanced Synthetic
Chemistry (Lab MASC), Dipartimento di Chimica e
̀
Tecnologia del Farmaco, Universita di Perugia, Via del Liceo,
1, 06123 Perugia, Italy. E-mail: antimo@chimfarm.unipg.it. Fax:
+39.075.5855160. Tel: +39.075.5852318.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ABBREVIATIONS
■
Figure 2. Flow scale up of probenecib.
PEG, polyethylene glycol; BPR, back pressure regulator
was dropped into an aqueous solution of HCl 3 N (pH< 2)
providing 9 in 78% yield and with a purity greater than 95% by
simple precipitation. The filtered solution was then washed
with diethyl ether, distilled to recycle acetone, and water used
for the reaction, and treated with a solution of NaOH and
Amberlist A15 for the recovery of PEG 400 and of the excess of
amine. Additionally, the ether used in the workup was also
recovered and used in following reactions.
In conclusion, we have developed the synthesis of
sulfonamides by employing flow-based technology to aid the
preparation of a wide variety of compounds and to facilitate the
scale-up operations. This work could therefore support
medicinal chemistry programs at various stages as the hit-to-
lead, lead-optimization and lead candidate scale-up.
Several aspects of this continuous flow process are
noteworthy. First, so far this is the only example of an eco-
benign synthesis of sulfonamide library in a single continuous
step. Reactions were performed at room temperature using an
acetone solution of sulfonyl chlorides along with an aqueous
solution of the amines and NaHCO3, a reagent flow rate of 0.5
mL min−1 and a residence time of approximately 15 min. PEG
400 was essential to achieve the complete solubilization of
organic and inorganic reactants. As previously noted, the
isolation of the desired products was achieved without the use
of column purifications, in high yield and affording quality
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