Solvent-free microwave-assisted preparation of n-(2-(pyridin-2-yl)-ethyl) sulfonamides

Article abstract of DOI:10.1080/00397911.2013.819437

Although nitrogen-containing heterocycles and sulfonamides both play crucial roles in the chemical and pharmaceutical industries, surprisingly little research exists that examines the bifunctional N-(2-(pyridin-2-yl)ethyl) sulfonamide scaffold for any potential applications. Retrosynthetic analysis indicates that this skeleton would be well suited for a conjugate addition reaction. However, the ability of 2-vinylpyridine to behave as an acceptor, and of sulfonamides to behave as donors, has very limited literature precedent, and thus required some preliminary investigations into their mutual reactivity. Herein outlines our laboratory's discovery of a novel and efficient solvent-free 1,4-aza-conjugate addition reaction between sulfonamides and 2-vinylpyridines that provides expedient access to various N-(2-(pyridin-2-yl)ethyl)sulfonamide derivatives. The products, possessing multiple sites of Bronsted acidity and basicity in close proximity, could display a wide array of valuable host-guest properties and should thus be investigated for potent pharmaceutical or agrochemical properties.

Full text of DOI:10.1080/00397911.2013.819437

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Solvent-Free Microwave-Assisted
Preparation of N-(2-(Pyridin-2-yl)-
ethyl)sulfonamides
Paul Ghattas a , Joseph W. Carlin a , Steven L. Murkli Jr. a & Danielle
L. Jacobs a
a Department of Chemistry, Biochemistry, and Physics , Rider
University , Lawrenceville , New Jersey , USA
Published online: 27 Dec 2013.
To cite this article: Paul Ghattas , Joseph W. Carlin , Steven L. Murkli Jr. & Danielle L. Jacobs (2014)
Solvent-Free Microwave-Assisted Preparation of N-(2-(Pyridin-2-yl)-ethyl)sulfonamides, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
44:4, 520-529, DOI: 10.1080/00397911.2013.819437
To link to this article: http://dx.doi.org/10.1080/00397911.2013.819437
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Synthetic Communications1, 44: 520–529, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.819437
SOLVENT-FREE MICROWAVE-ASSISTED
PREPARATION OF N-(2-(PYRIDIN-2-
YL)-ETHYL)SULFONAMIDES
Paul Ghattas, Joseph W. Carlin, Steven L. Murkli, Jr., and
Danielle L. Jacobs
Department of Chemistry, Biochemistry, and Physics, Rider University,
Lawrenceville, New Jersey, USA
GRAPHICAL ABSTRACT
Abstract Although nitrogen-containing heterocycles and sulfonamides both play crucial
roles in the chemical and pharmaceutical industries, surprisingly little research exists that
examines the bifunctional N-(2-(pyridin-2-yl)ethyl)sulfonamide scaffold for any potential
applications. Retrosynthetic analysis indicates that this skeleton would be well suited for a
conjugate addition reaction. However, the ability of 2-vinylpyridine to behave as an
acceptor, and of sulfonamides to behave as donors, has very limited literature precedent,
and thus required some preliminary investigations into their mutual reactivity. Herein out-
lines our laboratory’s discovery of a novel and efficient solvent-free 1,4-aza-conjugate
addition reaction between sulfonamides and 2-vinylpyridines that provides expedient access
to various N-(2-(pyridin-2-yl)ethyl)sulfonamide derivatives. The products, possessing mul-
tiple sites of Brønsted acidity and basicity in close proximity, could display a wide array of
valuable host–guest properties and should thus be investigated for potent pharmaceutical or
agrochemical properties.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Conjugate
2-vinylpyridine
addition;
microwave-assisted
synthesis;
sulfonamide;
Received June 14, 2013.
Address correspondence to Danielle L. Jacobs, Department of Chemistry, Biochemistry, and
Physics, Rider University, 2083 Lawrenceville Road, Lawrenceville, NJ 08648, USA. E-mail: djacobs@
rider.edu
520

N-(2-(PYRIDIN-2-YL)-ETHYL)SULFONAMIDES
521
INTRODUCTION
Pyridine rings are linchpins of the pharmaceutical and chemical industries.[1]
Like their phenyl cousins, these heterocycles are rigid and planar, allowing for
hydrophobic interactions within enzyme binding pockets; however, the addition of
an electron-rich heteroatom concomitantly provides sites for hydrogen bonding,
improving solvation properties[2] while encouraging interactions with more polar
substrates.
Similarly, perhaps no medicinal pharmacophore has enjoyed as much success
in pharmaceuticals as the sulfonamide. The dual proximal functionalities of (a) a
strong hydrogen bond donor that can also be ionized at physiological pH and (b)
a weakly basic sulfonyl hydrogen bond acceptor allows for myriad electrostatic inter-
actions with biological targets,[3–6] while the tetrahedral geometry of the sulfur atom
provides for a high degree of conformational flexibility.[6]
The marriage of these two functionalities into an N-(2-(pyridin-2-yl)ethyl)sul-
fonamide (1) scaffold promises much more than merely imparting the well-known
chemical and pharmacokinetic properties of the individual pharmacophores. The
ideal proximal placement of two basic nitrogen heteroatoms should welcome strong
substrate–metal host–guest chelation interactions. Such metal ligation has repeatedly
demonstrated significance in a number of chemical processes,[7,8] and the presence of
at least two nitrogen atoms should give N-(2-(pyridin-2-yl)ethyl)sulfonamide scaf-
folds a strong chelation affinity for metal cations.[9,10] This potential for tight chela-
tion elucidates molecules containing this unique scaffold as good candidates for
water[11,12] and environmental purification and analysis,[13,14] medical diagnostics
and therapies,[12,15–26,10,27–30] and organocatalysis.[8]
Despite this vast potential, surprisingly little research exists that examines a
straightforward synthetic approach to the N-(2-(pyridin-2-yl)ethyl)sulfonamide (1)
scaffold. Our laboratory envisions this target as an opportunity to investigate the
viability of an aza-conjugate addition between 2-vinylpyridines (2) as electron accep-
tors and sulfonamides (3) as electron donors. 1,4-Conjugate additions are remarkably
efficient reactions used ubiquitously in organic synthesis for the construction of diver-
sified molecular skeletons, particularly those with ethylene connectors between two
functionalities. However, the innately poor behavior of sulfonamides as electron
donors and 2-vinylpyridines as acceptors poses a significant challenge. Conjugate
addition with weakly nucleophilic sulfonamides has been severely limited to activated
acrylate substrates with electron-withdrawing substituents, and further activation of
either the nucleophile[31–37] or electrophile[38–41] is required. Alternatively, although
not widespread within the synthetic literature, 2-vinylpyridine has demonstrated lim-
ited success as an acceptor in conjugate addition reactions,[42] most recently using
sodium methanesulfinate as a nucleophile.[43] In most of these examples, however,
the success of the reaction is reliant on activation of 2-vinylpyridine via Brønsted
acid,[43–47] Lewis acid,[48,49] or Morita–Baylis–Hillman-type activation.[50]
Despite these inherent limitations, our laboratory has recently discovered a
facile and efficient aza-conjugate addition for the synthesis of the N-(2-(pyridin-2-
yl)ethyl)sulfonamide (1) scaffold (Scheme 1). We herein describe the development
of the solvent-free protocol, demonstrate its utility in the synthesis of various deri-
vatives, and propose a rational mechanism based on our studies.

522
P. GHATTAS ET AL.
Scheme 1. 1,4-Conjugate addition of sulfonamides 3 to 2-vinylpyridines 2.
DISCUSSION
The aza-conjugate addition of benzensulfonamide 3a to 2-vinylpyridine 2a was
initially employed as a model system. Surprisingly, a clean reaction was observed
when the reagents were heated neat in a sealed tube (Table 1). However, this initial
protocol suffered from (a) the necessity for very high temperatures, wherein no reac-
tion would occur below 120 ꢀC, and (b) extended reaction times longer than 24 h,
after which (c) equilibration would occur between the individual starting materials,
products, and a by-product, presumably bis-alkylated sulfonamide 4a (Fig. 1) result-
ing from a second conjugate addition on unreacted 2-vinylpyridine (Table 1, entries
1–4).
The high temperature and solventless conditions suggested that this novel
1,4-conjugate addition reaction would be a perfect candidate for microwave-assisted
synthesis. Conjugate additions of sulfonamides in particular have been significantly
enabled by microwave radiation, often yielding products in good yields in no longer
Table 1. Impact of various additives, reaction temperatures, heat sources, reaction lengths, and reagent
stoichiometries, on progress of aza-conjugate addition reactions between 2a and 3a
Product ratiosa
Ex.
Heat
Temp. (ꢀC)
Additives (eqv)
3a:2a
Time (h)
1a:2a
1a:4a
1
2
Oil
Oil
125
140
—
—
1:1
1:1
24
24
24
40
.75
.75
1
1.7:1
2.9:1
25:1
2.8:1
6.7:1
10:1
7.7:1
17:1
33:1
—
3
Oil
Oil
165
165
—
—
1:1
1:1
4
6.3:1
5.9:1
17:1
5
MW
MW
MW
MW
MW
MW
MW
MW
Oil
170
170
—
—
1:1
6
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1:1
7
170
170
TBAI (50–100 mg)
TBAB (100 mg)
BnEt3NCl (100 mg)
KF (0.25)
6.7:1
4.5:1
3.4:1
5.0:1
.05:1
8
.75
.75
.75
.5
—
—
9
170
170
10
11
12
13
14
15
16
17:1
—
170
170
Cs2CO3 (0.25)
Cs2CO3 (0.75–2)
HOAc (5) in EtOH
TFA (5) in CH2Cl2
TiCl4 (1–5) in CH2Cl2
AlCl3 (1–5) in CH2Cl2
1:1
5:1
.75
2
No addition
60
60
No addition
No addition
No addition
No addition
Oil
—
5:1
5:1
2
ꢁ78 to rt
2
—
ꢁ78 to 40
5:1
2
aRatios of 1a:2a and 1a:4a determined by 1H NMR integration analysis.

N-(2-(PYRIDIN-2-YL)-ETHYL)SULFONAMIDES
523
Figure 1. Proposed structure of by-product observed in conjugate addition reactions between
sulfonamides (3) and 2-vinylpyridines (2).
than 0.5 h.[31,34,37,51] Encouraged by this literature precedent, microwave heating was
introduced to our conjugate addition reactions. Gratifyingly, 60 W of power allows
the systems to reach and maintain a temperature of 170 ꢀC, and after 30–45 min the
mixtures achieve their maximum conversion, as opposed to days using conventional
heating. This vastly truncated reaction time not only increases the overall attraction
and utility of this reaction in the laboratory, but it is inherently responsible for the
reaction’s success: reaction times of 30–45 min allow for interception of products 1a,
with excellent purities, prior to the long-term equilibration described previously
(Table 1, entries 5 and 6).
Next, we examined the effect of various additives on the reaction progression
(Table 1, entries 7–18). The extent of reaction (1a:2a) and by-product formation
1
(1a:4a) were facilely monitored by comparing the normalized H NMR integrations
between 2-vinylpyridine 2a (three distinct vinyl peaks at 5.41, 6.13, and 6.77 pm), the
desired product 1a (two ethylene peaks at 3.32 and 2.86 ppm), and by-product 4a
(two ethylene peaks directly downfield from the ethylene peaks of 1a). Surprisingly,
adjuvants that typically promote thermally controlled reactions do not improve the
reaction outcome. It was originally theorized that an ionic salt[34,51] would be
required to solubilize the solid sulfonamide reactant, help promote conjugate
addition via participation in a Morita–Baylis–Hillman-type fashion, or even behave
as a highly efficient microwave absorber. However, parallel rate experiments with
various ionic salts demonstrate no impact on the reaction rate or extent of com-
pletion (Table 1, entries 7–9), and inherently increase the complexity of product
isolation.
We also initially proposed that the addition of an inorganic base would
enhance the nucleophilicity of the poorly reactive sulfonamide.[31–34,36,37,51,52] How-
ever, increasing amounts of base are surprisingly detrimental to the reaction pro-
gression (Table 1, entries 10–12). Alternatively, additional Brønsted and Lewis
acids do not appear to activate the pyridine electrophile either, as no trace of
addition product is observed under these conditions (Table 1, entries 13–16).
Since the optimal microwave protocol merely requires the neat mixing of the
two starting materials, with greatest rates of completion observed when the sulfona-
mide is in excess (Table 1, entry 6), the reaction workup is also simplified, obviating
the need for any chromatography or extractions. The crude mixture can be merely
triturated with hot chloroform and hexanes, wherein excess sulfonamide starting

524
P. GHATTAS ET AL.
Table 2. Substrate scope for aza-conjugate addition reactions between various vinylpyridines (2) and
sulfonamides (3)a
Sulfonamide
R1
Yieldc (%)
(brsm)d
Ex.
1
Pyridine
Product
1:2b
2a
Ph (3a)
17:1
63 (100)
71 (100)
2
3
2a
2a
Tol (3b)
20:1
Me (3c)
5.0:1
53 (100)
34 (75)
13 (100)
15 (35)
32 (71)
4
5
3a
20:1
3.2:1
5.8:1
6.3:1
3a
6
3b
7e
3a
8
3a
No addition
(Continued )

N-(2-(PYRIDIN-2-YL)-ETHYL)SULFONAMIDES
525
Table 2. Continued
Sulfonamide
R1
Yieldc (%)
(brsm)d
Ex.
9
Pyridine
Product
1:2b
3a
No addition
10
3a
No addition
aAll reactions displayed minimal, if any, by-product via 1H NMR integration analysis.
bRatios of 1:2 determined by 1H NMR integration analysis.
cIsolated product yield.
dYield based on recovered sulfonamide 3.
e0.25 equivalents of Cs2CO3 was added.
material cleanly crashes out and can be recovered. Next, upon cooling the filtrate,
the desired N-(2-(pyridin-2-yl)ethyl)sulfonamide typically crystallizes out, separating
the stable product from any remaining 2-vinylpyridine. This streamlined workup
procedure was only made possible by the elimination of by-product formation:
mono- and bis-alkylated products 1 and 4 co-crystallize and can only be separated
by careful chromatography.
With the conditions for the conjugate addition reaction significantly optimized,
we have had the opportunity to explore the substrate scope and synthesize other N-
(2-(pyridin-2-yl)ethyl)sulfonamide derivatives (Table 2). First the microwave proto-
col has been expanded to include reactions with methane- and toluene sulfonamide
(3b and 3c) nucleophiles, providing products in excellent purity and yields based on
recovered starting material (Table 2, entries 2 and 3). Moreover, we have recently
focused our efforts on employing differentially substituted 2-vinylpyridine electro-
philes and have demonstrated the successful coupling of sulfonamides with alkyl-
and aryl-substituted 2-vinylpyridines (Table 2, entries 4 and 6).
The mechanistic assumption that this reaction does indeed take place via
conjugate addition has been validated by the successful coupling of benzene
sulfonamide 3a with 4-vinylpyridine 2c (albeit with poor yield of the corresponding
1,6-addition product) while 3-vinylpyridine 2h fails to react under the same con-
ditions (Table 2, entries 5 and 10). On this account, it was reasonably predicted that
the attachment of an electron-withdrawing group to the 6-position of 2-vinylpyridine
would improve its electrophilicity and thus hasten the reaction, while an
electron-donating substituent would inherently diminish the reactivity of the pyri-
dine acceptor. In the event, however, it was observed that both withdrawing and
donating substituents deter any conjugate addition from occurring. Surprisingly,
6-trifluoromethyl-2-vinylpyridine 2e can be prompted to react with the addition of

526
P. GHATTAS ET AL.
Figure 2. Proposal for initial mutual activation between sulfonamides (3) and 2-vinylpyridines (2) that
occurs prior to conjugate addition.
a substoichiometric quantity of base, while 6-methoxy- and 6-chloro-2-vinylpyridine
(2f and 2g) fail to react neat or in the presence of any adjuvants (Table 2, entries 7–9).
These results strongly suggest that (a) resonance donors disable the overall electro-
philicity of 2-vinylpyridines, but even more intriguingly (b) the conjugate addition
must initially involve mutual activation, likely via hydrogen bonding, between the
pyridine nitrogen and sulfonamide proton (Fig. 2).[53,54] This mechanistic feature
accounts for the observation that pyridine substituents that withdraw electrons
inhibit the nitrogen’s ability to protonate and become an activated conjugate
acceptor, although this inactivity can be overcome by instead increasing the sulfona-
mide’s nucleophilicity via deprotonation. The nature of this mechanism is currently
under investigation in our laboratory.
In summary, our laboratory has developed a novel, generalized method for the
synthesis of N-(2-(pyridin-2-yl)ethyl)sulfonamides (1), via the aza-conjugate addition
of sulfonamides (3) to 2-vinylpyridine derivatives (2). The inherent success of this
microwave-assisted reaction without any adjuvant reagents or solvents, as well as
the ease of product workup and isolation, makes this protocol highly advantageous
and viable, despite the unavoidable thermodynamic equilibration.
EXPERIMENTAL
Benzenesulfonamide (219 mg, 1.39 mmol, 1.5 eqv) and 2-vinylpyridine (0.1 mL,
0.93 mmol, 1.0 eqv) were added to a microwave vial equipped with stir bar. The vial
was irradiated in the microwave for 45 min (170 ꢀC at a maximum of 60 W), after
which the crude reaction mixture was dissolved in acetone, transferred to a
round-bottom flask, and concentrated via rotary evaporation. The resultant brown
residue was dissolved in a minimal amount of hot chloroform and cooled in an ice
bath. The excess sulfonamide precipitate was removed via vacuum filtration, and
the filtrate was concentrated under vacuum. Subsequently, the residue was redis-
solved in a minimal amount of hot chloroform and then triturated with cold hexanes
until a sticky residue formed and the mother liquor became clear. The mother liquor
containing excess 2-vinylpyridine was decanted, whereas the sticky residue was
recrystallized from ethyl acetate=hexanes to afford 150 mg (63% yield, 100% brsm)
of 1aa as a light brown solid: IR (neat) n 3082, 2854, 1595, 1441, 1314, 1144,

N-(2-(PYRIDIN-2-YL)-ETHYL)SULFONAMIDES
527
1
1100 cmꢁ1; H NMR (300 MHz, CDCl3) d 8.45 (1H, d, J ¼ 2.4 Hz), 7.83 (2H, m),
7.59–7.42 (4H, m), 7.15–7.09 (1H, m), 7.04 (1H, d, J ¼ 8.1 Hz), 6.16 (1H, t,
J ¼ 5.1 Hz), 3.36 (2H, q, J ¼ 6 Hz), 2.91 (2H, t, J ¼ 6 Hz); 13C NMR (75 MHz,
CDCl3) d 149.1, 136.7, 132.4, 129.0, 127.0, 123.5, 121.8, 42.1, 35.9. HRMS (TOF)
calculated for C13H15N2O2S [M þ H]þ: 262.07760; found: 262.07786.
SUPPORTING INFORMATION
The following material can be found via the Supplementary Content section of
1
this article’s webpage: (1) example of H NMR used in determining extent of reac-
tion completion; (2) general procedure for syntheses and characterization data for
1
compounds 1aa, 1ab, 1ac, 1ba, 1ca, 1db, and 1ea; and (3) H and 13C NMR spectra
for all N-(2-(pyridinyl)ethyl)sulfonamide products.
ACKNOWLEDGMENTS
We thank Gregory Schaaf (Seachaid Pharmaceuticals) and Matthias McIntosh
(University of Arkansas) for their helpful discussions throughout this project, and
CEM Corporation for their temporary loan of a Discover microwave system. This
project was significantly funded via Rider University Faculty Development Grants.
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