Iron-Catalyzed C(sp2)-C(sp3) Cross-Coupling of Chlorobenzenesulfonamides with Alkyl Grignard Reagents: Entry to Alkylated Aromatics

Article abstract of DOI:10.1021/acs.joc.8b02886

Alkylated benzosulfonamides are compounds of high importance in organic synthesis, including the production of pharmaceuticals, agrochemicals, and plasticizers. We report the iron-catalyzed C(sp²)-C(sp³) cross-coupling of chlorobenzosulfonamides with alkyl Grignard reagents under mild and sustainable conditions. Electronically and sterically varied benzosulfonamides as well as challenging alkyl organometallics containing β-hydrogen afford alkylated benzosulfonamides in high to excellent yields. Sulfonamide represents the most reactive activating group for iron-catalyzed cross-coupling. The process affords alkylated benzenesulfonamides poised for medicinal chemistry applications and traceless reductive cleavage.

Full text of DOI:10.1021/acs.joc.8b02886

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Note
Iron-Catalyzed C(sp2)–C(sp3) Cross-Coupling of Chlorobenzenesulfonamides
with Alkyl Grignard Reagents: Entry to Alkylated Aromatics
Elwira Bisz, and Michal Szostak
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02886 • Publication Date (Web): 21 Dec 2018
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The Journal of Organic Chemistry
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Iron-Catalyzed C(sp2)–C(sp3) Cross-Couplingof
Chlorobenzenesulfonamides with Alkyl Grignard
Reagents: Entry to Alkylated Aromatics
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Elwira Bisz,*,‡ and Michal Szostak*,†,‡
‡Department of Chemistry,Opole University, 48 Oleska Street, Opole 45-052, Poland
†Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United
States
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RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
Corresponding author
ebisz@uni.opole.pl
michal.szostak@rutgers.edu
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Abstract
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Alkylated benzosulfonamides are compounds of high importance in organic synthesis, including the
production of pharmaceuticals, agrochemicals and plasticizers. We report the iron-catalyzed C(sp2)–
C(sp3) cross-coupling of chlorobenzosulfonamides with alkyl Grignard reagents under mild and
sustainable conditions. Electronically- and sterically-varied benzosulfonamides as well as challenging
alkyl organometallics containing -hydrogen afford alkylated benzosulfonamides in high to excellent
yields. Sulfonamide represents the most reactive activating group for iron-catalyzed cross-coupling. The
process affords alkylated benzenesulfonamides poised for medicinal chemistry applications and
traceless reductive cleavage.
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The iron-catalyzed cross-coupling has emerged as an increasingly powerful method for organic
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synthesis.1,2 The high interest of the organic community in iron catalysis is driven by the abundance of
iron in the Earth’s crust leading to a sustained catalyst economy.3 Equally importantly, iron-catalysis
allows to execute traditionally challenging cross-coupling disconnections,4 including alkylative cross-
couplings which are notoriously difficult because of the propensity of alkyl organometallic reagents to
undergo -hydride elimination and homo-coupling.5 In recent years, iron-catalyzed cross-couplings
have attracted a major attention of researchers in pharmaceutical industry.6
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Sulfonamides are among the most important molecules in drug discovery.7 In particular, the discovery
of sulfa drugs have led to the construction of the dominant concepts in modern medicinal chemistry,7,8
and resulted in the development of a wide range of antibacterial, hypoglycaemic, diuretic and
antihypertensive drugs (Figure 1). In modern drug discovery alkylated benzenesulfonamides are further
used as lead molecules for the treatment of cancer, as fatty acid amide hydrolase inhibitors, N-myristoyl
transferase inhibitors and calcium-sensing receptor antagonists (Figure 1), among other applications.9
Furthermore, alkylated benzenesulfonamides are prevalent in industries beyond drug discovery,
including as agrochemical agents and plasticizers.10 As a consequence of the key importance of
sulfonamides in organic chemistry, new methods for the synthesis of sulfonamides continue to have a
major impact on organic synthesis and medicinal chemistry.11
Inspired by our interest in amide bonds12 and iron-catalyzed cross-couplings,13 herein, we report the
iron-catalyzed C(sp2)–C(sp3) cross-coupling of chlorobenzenesulfonamides with alkyl Grignard
reagents (Figure 2). The reaction proceeds under exceedingly mild conditions using sustainable iron-
catalysis. We demonstrate that a broad range of electronically- and sterically-varied benzosulfonamides
as well as challenging alkyl organometallics containing -hydrogen are compatible with these
conditions. Mechanistic studies reveal that sulfonamide acts as one of the most reactive activating
groups for iron-catalyzed alkylative cross-coupling with Grignard reagents,14,15 which may have
implications for the future design of iron-catalyzed cross-coupling methods mediated by O-coordinating
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additives. Collectively, the process affords alkylated benzosulfonamides poised for applications in
medicinal chemistry as well as traceless reductive cleavage processes.
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Notable features of our findings include: (1) the synthesis of alkylated benzenesulfonamides of
medicinal interest that would be difficult to access by other methods, (2) the discovery of sulfonamide
as the strongest activating group for iron-catalyzed cross-couplings, (3) the potential for using tertiary
sulfonamides as traceless activating groups.
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Figure 1. Biologically-active sulfonamides: (a) Classic sulfa drugs (top), and (b) pharmaceutically-
active alkylated sulfonamides (bottom).
Figure 2. Iron-catalyzed C(sp2)–C(sp3) cross-coupling of chloro-benzosulfonamides with alkyl
Grignard reagents (this study).
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Our studies began with an investigation of the cross-coupling of N,N-dimethyl-4-
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chlorobenzenesulfonamide with n-alkyl Grignard reagent containing -hydrogens (Table 1). An
important precedent in the cross-coupling of sterically-hindered sulfonamides should be noted.14a,b In
contrast to the amide bond, the nitrogen atom in the sulfonamide grouping tends to be pyramidalized,16
which in turn may influence the coordination. Furthermore, the weak N–SO2 bond is prone to reductive
cleavage under cross-coupling conditions.17 Hence, at the outset it was unclear if non-sterically
demanding sulfonamides can be used as cross-coupling partners. Since we are focused on developing
operationally-practical methods of broad synthetic appeal, we selected rapid addition of organometallic
reagent and the use of cheap, readily accessible O-coordinating additives.14a,b As shown, no reaction was
observed in the absence of iron (Table 1, entry 1). The reaction was inefficient in the absence of
additives (entry 2). Pleasingly, we found that the combined use of iron and NMP (NMP = N-methyl-2-
pyrrolidone) afforded the coupling product in excellent yield (Table 1, entries 3-6). Importantly, while
efficient coupling was observed with as little as 50 mol% of NMP (entry 4), the use of excess of NMP
afforded the cleanest reactions. We further note that the use of TMEDA (61% yield) or HMTA
(hexamethylenetetramine) (70% yield) under the optimized conditions is less efficient; however, DMI
(98%) and DMPU (97%) can be used as NMP replacements in this cross-coupling. NMP was selected
for the study to enable comparison with the benchmark method. At present, cross-coupling at lower
catalyst loading is less efficient. Ongoing studies in our laboratories are focused on the development of
iron-catalyzed cross-couplings at low catalyst loadings. Importantly, under these reaction conditions, the
cleavage of SO2–N bond, or side reactions from the Grignard reagents, including -hydride elimination
and homo-coupling were not observed, indicating a significant activating effect of the sulfonamide
moiety.
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Having determined that sterically-non-hindered N,N-dimethyl-4-chlorobenzenesulfonamide serves as
an efficient cross-coupling partner, the substrate scope of this reaction was next explored (Table 2).
Pleasingly, the reaction was found to tolerate electronically- and sterically-varied benzosulfonamides as
well as challenging alkyl organometallics containing -hydrogen (Table 2, entries 1-12). Importantly,
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sulfonamides with varied steric hindrance at the nitrogen atom are readily tolerated, including NMe2
(entry 1), NEt2 (entry 2) and N-iPr2 (entry 3) with no deleterious effect on the coupling. Furthermore,
highly medicinally-relevant N-cyclic sulfonamides are readily tolerated (entry 4). The reaction is also
compatible with N-Ar sulfonamides (entry 5), which are used in sulfonamide exchange reactions18 to
increase the diverse modifications of the sulfonamide bond, as well as N-Bn sulfonamides, which are
used as synthetic equivalent of secondary sulfonamides after hydrogenolysis19 (entry 6). Intriguingly,
very high efficiency without any modification of the reaction conditions was observed in the cross-
coupling of a meta-substituted benzosulfonamide (entry 7), indicating that conjugation with the
sulfonamide moiety is not required for the coupling. Furthermore, even the ortho-substituted
benzenesulfonamide afforded the desired coupling product, albeit in a modest yield (entry 8). The two
latter findings sharply contrast with the cross-coupling of the analogous chloro-benzamides,13d which
(1) require extensive optimization for the cross-coupling at the non-conjugated position, (2) are
completely unreactive in cross-coupling at the sterically-hindered ortho-position.
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The scope of the reaction also encompasses challenging secondary alkyl Grignard reagents, such as
cyclohexyl (entry 9) and isopropyl (entry 10). Again, these Grignard reagents afford cross-coupling
products using the analogous chloro-benzamides in significantly lower yields,13d showing the superior
propensity of sulfonamide as the activating group for cross-coupling. Furthermore, isomerization to n-
alkyl product, which is the major side reaction using other iron-catalyst systems20 was not observed
under these mild conditions. Finally, we were pleased to find that other representative Grignard
reagents, such as prone to -hydride elimination phenethyl Grignard reagent (entry 11) and sensitive
dioxolane Grignard (entry 12), which serves as a synthetic carbonyl equivalent are readily tolerated in
the cross-coupling. It is worthwhile to note that Grignard addition to the electrophilic sulfonamide bond
was not observed in any of the tested examples, attesting to the mild conditions and facility of the
coupling. Several of the synthesized products map very well onto the structures of bioactive
alkylbenzenesulfonamides.8,9 Thus, these reactions should find wide application in the preparation of
medicinally-relevant scaffolds.
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Table 1. Optimization of Fe-Catalyzed Cross-Couplinga
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Fe(acac)3
Yield
(%)b
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Entry
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mol%
Time
(mol%)
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-
10 min
10 min
10 min
10 min
10 min
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NMP
NMP
NMP
NMP
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>98
a1 (0.50 mmol), Fe(acac)3 (5 mol%), THF (0.15 M), C2H5MgCl (1.20 equiv, 2.0 M, THF), 0 °C, 10
min. RMgCl added dropwise over 1-2 s. b Determined by 1H NMR and/or GC-MS.
Table 2. Iron-Catalyzed C(sp2)–C(sp3) Cross-Coupling of Sulfonamides with Alkyl Grignard Reagentsa
Yield
(%)
Entry
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Substrate
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Product
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2f
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a1 (0.50 mmol), Fe(acac)3 (5 mol%), THF (0.15 M), NMP, RMgX (1.20 equiv, THF), 0 °C, 10 min. b15
h, 0 °C. c1 h, 0 °C. d15 h, 23 °C, RMgX (3.0 equiv). See the Supporting Information for details.
Intermolecular competition experiments were conducted to gain insight into the unique reactivity of
benzenesulfonamides in the cross-coupling (Schemes 1-2). Intriguingly, we identified sulfonamide as a
significantly more potent activating group than the amide bond (Scheme 1, sulfonamide:amide =
11.5:1).13d The excellent activating profile of sulfonamide was further confirmed in the competition with
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the ester bond (Scheme 2, sulfonamide:ester = 2.1:1). Hence, to our knowledge, sulfonamide has been
identified as the most activating group for iron-catalyzed cross-couplings,1,13d,14 which may find wide
application in future studies of iron-catalyzed cross-coupling methods. Future work is focused on
mechanistic analysis evaluating broad classes of activating groups in iron-catalyzed cross-coupling.
The utility of the sulfonamide bond is not limited to medicinal chemistry applications. For example, a
recent manuscript describes reductive cleavage of n-alkylbenzosulfonamides catalyzed by Ni.21 Thus, in
combination with our facile way of preparing diverse n-alkylbenzenesulfonamides by iron-catalysis, this
method represents a traceless sulfonamide-based approach to n-alkylated aromatics (Scheme 3).
Furthermore, owing to the utility of SO2NR2 moiety, other methods for manipulation of tertiary
sulfonamides are well-established, further enhancing the utility of our method.22
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Scheme 1. Intermolecular Competition Experiments: Amides
Scheme 2. Intermolecular Competition Experiments: Esters
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Scheme 3. Sulfonamide as Traceless Activating Group
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In conclusion, we have reported the iron-catalyzed C(sp2)–C(sp3) cross-coupling of
chlorobenzenesulfonamides with alkyl Grignard reagents. The method represents a convenient access to
alkylated benzenesulfonamides that are widely used in the synthesis of pharmaceuticals, agrochemicals
and plasticizers. A broad range of electronically- and sterically-varied benzenesulfonamides and
challenging alkyl organometallics containing -hydrogen undergo cross-coupling under exceedingly
mild reaction conditions that tolerate the presence of an electrophilic sulfonamide moiety in the
presence of readily-accessible and cheap Grignard organometallics. Importantly, our study demonstrates
that sulfonamide acts as the one of most reactive activating groups for iron-catalyzed alkylative cross-
couplings, a class of reactions that is broadly used in pharmaceutical settings. Further, the sulfonamide
group is poised for applications as traceless activating group. Studies to facilitate further reaction
development using sustainable iron-catalysis are in progress and will be reported in due course.
Experimental Section
General Methods. All compounds reported in the manuscript are commercially available or have
been previously described in literature unless indicated otherwise. All experiments involving iron were
performed using standard Schlenk techniques under argon or nitrogen atmosphere unless stated
otherwise. All sulfonamides have been prepared by standard methods.23 1H NMR and 13C NMR data are
given for all compounds in the Experimental Section for characterization purposes. 1H NMR, 13C NMR
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and HRMS data are reported for all new compounds. All products have been previously reported, unless
stated otherwise. Spectroscopic data matched literature values. General methods have been published.13a
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General Procedure for Iron-Catalyzed C(sp2)–C(sp3) Cross-Coupling. An oven-dried vial
equipped with a stir bar was charged with an sulfonamide substrate (neat, typically, 0.50 mmol, 1.0
equiv) and Fe(acac)3 (typically, 5 mol%), placed under a positive pressure of argon and subjected to
three evacuation/backfilling cycles under vacuum. Tetrahydrofuran (0.15 M) and NMP were
sequentially added with vigorous stirring at room temperature, the reaction mixture was cooled to 0 °C,
a solution of Grignard reagent (typically, 1.2 equiv) was added dropwise with vigorous stirring and the
reaction mixture was stirred for the indicated time at 0 °C. After the indicated time, the reaction mixture
was diluted with HCl (1.0 N, 1.0 mL) and Et2O (1 x 30 mL), the organic layer was extracted with HCl
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1
(1.0 N, 2 x 10 mL), dried and concentrated. The sample was analyzed by H NMR (CDCl3, 400 MHz)
and GC-MS to obtain conversion, yield and selectivity using internal standard and comparison with
authentic samples. Purification by chromatography on silica gel (EtOAc/hexanes = 1/3) afforded the
title product.
General Procedure for Determination of Relative Reactivity. According to the general procedure,
an oven-dried vial equipped with a stir bar was charged with two chloride substrates (each 0.50 mmol,
1.0 equiv) and Fe(acac)3 (5 mol%), placed under a positive pressure of argon and subjected to three
evacuation/backfilling cycles under vacuum. Tetrahydrofuran (0.15 M) and NMP (neat, 600 mol%)
were sequentially added with vigorous stirring at room temperature, the reaction mixture was cooled to
0 °C, a solution of C2H5MgCl (2.0 M in THF, 0.25 mmol, 0.50 equiv) was added dropwise with
vigorous stirring and the reaction mixture was stirred for 10 min at 0 °C. Following the standard work-
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up, the sample was analyzed by H NMR (CDCl3, 400 MHz) and GC-MS to obtain conversion, yield
and selectivity using internal standard and comparison with authentic samples.
Characterization Data for Starting Materials
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4-Chloro-N,N-dimethylbenzenesulfonamide (1a).24 Yield 95% (2.09 g). White solid. 1H NMR (400
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MHz, CDCl3) δ 7.73 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 2.72 (s, 6H). C{1H} NMR (100
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MHz, CDCl3) δ 139.4, 134.1, 129.5, 129.2, 38.9.
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4-Chloro-N,N-diethylbenzenesulfonamide (1b).25 Yield 97% (2.41 g). Colorless oil. H NMR (400
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MHz, CDCl3) δ 7.76 (d, J = 8.7 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 3.24 (q, J = 7.1 Hz, 4H), 1.13 (t, J =
7.1 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3)  138.9, 138.5, 129.2, 128.3, 42.0, 14.1.
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4-Chloro-N,N-diisopropylbenzenesulfonamide (1c).14a Yield 88% (2.44 g). White solid. H NMR
(400 MHz, CDCl3) δ 7.80 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H), 3.76-3.65 (m, 2 H), 1.27 (d, J =
6.8 Hz, 12H). 13C{1H} NMR (100 MHz, CDCl3)  141.4, 138.3, 129.2, 128.8, 48.9, 22.1.
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1-((4-Chlorophenyl)sulfonyl)pyrrolidine (1d).26 Yield 96% (2.35 g). White solid. H NMR (400
MHz, CDCl3) δ 7.78 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 3.24 (ddd, J = 6.8, 4.4, 2.7 Hz, 4H),
1.80-1.76 (m, 4H). 13C{1H} NMR (100 MHz, CDCl3)  139.2, 135.6, 129.5, 129.0, 48.1, 25.4.
1
4-Chloro-N-methyl-N-phenylbenzenesulfonamide (1e).27 Yield 97% (2.73 g). White solid. H
NMR (400 MHz, CDCl3) δ 7.45 (q, J = 8.8 Hz, 4H), 7.35-7.27 (m, 3H), 7.12-7.07 (m, 2H), 3.18 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3)  141.3, 139.5, 135.0, 129.4, 129.2, 129.2, 127.8, 126.8, 38.3.
1
N-Benzyl-4-chloro-N-methylbenzenesulfonamide (1f).28 Yield 95% (2.82 g). White solid. H NMR
(400 MHz, CDCl3) δ 7.78 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H), 7.37-7.27 (m, 5H), 4.14 (s, 2H),
2.60 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3)  139.3, 136.0, 135.4, 129.6, 129.0, 128.8, 128.5,
128.2, 54.2, 34.44.
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3-Chloro-N,N-dimethylbenzenesulfonamide (1g).29 Yield 96% (2.11 g). White solid. H NMR (400
MHz, CDCl3) δ 7.77 (t, J = 1.9 Hz, 1H), 7.69-7.65 (m, 1H), 7.61-7.57 (m, 1H), 7.53-7.48 (m, 1H), 2.74
(s, 6H). 13C{1H} NMR (100 MHz, CDCl3)  137.5, 135.5, 133.0, 130.5, 127.8, 125.9, 38.0.
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2-Chloro-N,N-dimethylbenzenesulfonamide (1h).11b Yield 95% (2.09 g). White solid. H NMR
(400 MHz, CDCl3) δ 8.05 (dd, J = 7.9 Hz, 1H), 7.56-7.47 (m, 2H), 7.44-7.38 (m, 1H), 2.89 (s, 6H).
13C{1H} NMR (100 MHz, CDCl3)  136.1, 133.7, 132.2, 127.1, 37.5.
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Characterization Data for Cross-Coupling Products
4-Ethyl-N,N-dimethylbenzenesulfonamide (Table 2, 2a). New compound. Prepared according to the
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general procedure using 4-chloro-N,N-dimethylbenzenesulfonamide (0.50 mmol), Fe(acac)3 (5 mol%),
NMP (600 mol%), THF (0.15 M), and C2H5MgCl (2.0 M in THF, 1.20 equiv). The reaction mixture
was stirred for 10 min at 0 °C. Yield 97% (103.0 mg). Colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.69
(d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 2.73 (q, J = 7.7 Hz, 2H), 2.69 (s, 6H), 1.27 (t, J = 7.6 Hz,
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3H). C{1H} NMR (100 MHz, CDCl3) δ 149.6, 132.4, 128.5, 127.9, 38.0, 28.8, 15.2. HRMS (ESI/Q-
TOF) m/z: [M + Na]+ calcd for C10H15NO2SNa 236.0721 found 236.0724.
N,N,4-Triethylbenzenesulfonamide (Table 2, 2b).25 Prepared according to the general procedure
using N,N,4-triethylbenzenesulfonamide (0.50 mmol), Fe(acac)3 (5 mol%), NMP (600 mol%), THF
(0.15 M), and C2H5MgCl (2.0 M in THF, 1.20 equiv). The reaction mixture was stirred for 10 min at 0
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°C. Yield 96% (115.6 mg). Colorless oil. H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.4 Hz, 2H), 7.31
(d, J = 8.5 Hz, 2H), 3.23 (q, J = 7.1 Hz, 4H), 2.71(q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H), 1.13 (t, J
= 7.2 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 149.1, 137.4, 128.5, 127.1, 42.1, 28.8, 15.2, 14.2.
4-Ethyl-N,N-diisopropylbenzenesulfonamide (Table 2, 2c). New compound. Prepared according to
the general procedure using 4-chloro-N,N-diisopropylbenzenesulfonamide (0.50 mmol), Fe(acac)3 (5
mol%), NMP (600 mol%), THF (0.15 M), and C2H5MgCl (2.0 M in THF, 1.20 equiv). The reaction
1
mixture was stirred for 10 min at 0 °C. Yield 97% (130.4 mg). White solid. Mp = 63-64 °C. H NMR
(400 MHz, CDCl3) δ 7.77 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H), 3.75-3.64 (m, 2H), 2.70 (q, J =
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7.6 Hz, 2H), 1.26 (d, J = 6.8 Hz, 12H), 1.25 (t, J = 7.7 Hz, 3H). C{1H} NMR (100 MHz, CDCl3) δ
148.7, 139.9, 128.3, 127.3, 48.6, 28.8, 22.0, 15.2. HRMS (ESI/Q-TOF) m/z: [M + Na]+ calcd for
C14H23NO2SNa 292.1347 found 292.1344.
1-((4-Ethylphenyl)sulfonyl)pyrrolidine (Table 2, 2d). New compound. Prepared according to the
general procedure using 1-((4-chlorophenyl)sulfonyl)pyrrolidine (0.50 mmol), Fe(acac)3 (5 mol%),
NMP (600 mol%), THF (0.15 M), and C2H5MgCl (2.0 M in THF, 1.20 equiv). The reaction mixture
was stirred for 10 min at 0 °C. Yield 95% (113.8 mg). White solid. Mp = 73-74 °C. 1H NMR (400 MHz,
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CDCl3) δ 7.74 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 3.23 (t, J = 6.6 Hz, 4H), 2.73 (q, J = 7.6 Hz,
2H), 1.75 (t, J = 6.6 Hz, 4H), 1.27 (t, J = 7.6 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 149.5,
134.0, 128.5, 127.7, 47.9, 28.8, 25.2, 15.1. HRMS (ESI/Q-TOF) m/z: [M + Na]+ calcd for
C12H17NO2SNa 262.0878 found 262.0876.
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4-Ethyl-N-methyl-N-phenylbenzenesulfonamide (Table 2, 2e). New compound. Prepared according
to the general procedure using 4-chloro-N-methyl-N-phenylbenzenesulfonamide (0.50 mmol), Fe(acac)3
(5 mol%), NMP (600 mol%), THF (0.15 M), and C2H5MgCl (2.0 M in THF, 1.20 equiv). The reaction
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mixture was stirred for 10 min at 0 °C. Yield 98% (134.5 mg). White solid. Mp = 78-79 °C. H NMR
(400 MHz, CDCl3) δ 7.44 (d, J = 8.3 Hz, 2H), 7.32-7.21 (m, 5H), 7.12-7.07 (m, 2H), 3.15 (s, 3H), 2.70
(q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 149.7, 141.6, 133.6,
128.9, 128.2, 128.0, 127.3, 126.6, 38.1, 28.8, 15.1. HRMS (ESI/Q-TOF) m/z: [M + Na]+ calcd for
C15H17NO2SNa 298.0878 found 298.0876.
N-Benzyl-4-ethyl-N-methylbenzenesulfonamide (Table 2, 2f). New compound. Prepared according
to the general procedure using N-benzyl-4-chloro-N-methylbenzenesulfonamide (0.50 mmol), Fe(acac)3
(5 mol%), NMP (600 mol%), THF (0.15 M), and C2H5MgCl (2.0 M in THF, 1.20 equiv). The reaction
mixture was stirred for 10 min at 0 °C. Yield 98% (141.0 mg). White solid. Mp = 71-72 °C. 1H NMR
(400 MHz, CDCl3) δ 7.75 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 7.33-7.24 (m, 5H), 4.12 (s, 2H),
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2.73 (q, J = 7.6 Hz, 2H), 2.57 (s, 3H), 1.27 (t, J = 7.6 Hz, 3H). C{1H} NMR (100 MHz, CDCl3) δ
149.6, 135.7, 134.4, 128.6, 128.6, 128.4, 127.8, 127.6, 54.1, 34.4, 28.8, 15.1. HRMS (ESI/Q-TOF) m/z:
[M + Na]+ calcd for C16H19NO2SNa 312.1034 found 312.1035.
3-Ethyl-N,N-dimethylbenzenesulfonamide (Table 2, 2g). New compound. Prepared according to the
general procedure using 3-chloro-N,N-dimethylbenzenesulfonamide (0.50 mmol), Fe(acac)3 (5 mol%),
NMP (600 mol%), THF (0.15 M), and C2H5MgCl (2.0 M in THF, 1.20 equiv). The reaction mixture
was stirred for 10 min at 0 °C. Yield 93% (99.4 mg). Colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.62-
7.57 (m, 2H), 7.49-7.43 (m, 2H), 2.74 (q, J = 7.7 Hz, 2H), 2.71 (s, 6H), 1.27 (t, J = 7.6 Hz, 3H).
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13C{1H} NMR (100 MHz, CDCl3) δ 145.6, 135.3, 132.5, 129.1, 127.0, 125.2, 38.1, 28.8, 15.5. HRMS
(ESI/Q-TOF) m/z: [M + Na]+ calcd for C10H15NO2SNa 236.0721 found 236.0720.
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2-Ethyl-N,N-dimethylbenzenesulfonamide (Table 2, 2h). New compound. Prepared according to
the general procedure using 2-chloro-N,N-dimethylbenzenesulfonamide (0.50 mmol), Fe(acac)3 (5
mol%), NMP (600 mol%), THF (0.15 M), and C2H5MgCl (2.0 M in THF, 1.20 equiv). The reaction
mixture was stirred for 15 h at 0 °C. Yield 50% (53.0 mg). Colorless oil. 1H NMR (400 MHz, CDCl3) δ
7.86 (dd, J = 8.0, 1.3 Hz, 1H), 7.51 (td, J = 7.5, 1.4 Hz, 1H), 7.39 (dd, J = 7.7, 0.9 Hz, 1H), 7.31 (td, J =
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7.9, 1.4 Hz, 1H), 3.04 (q, J = 7.5 Hz, 2H), 2.80 (s, 6H), 1.28 (t, J = 7.5 Hz, 3H). C{1H} NMR (100
MHz, CDCl3) δ 144.4, 135.5, 133.0, 131.3, 130.1, 126.0, 37.2, 26.3, 15.8. HRMS (ESI/Q-TOF) m/z: [M
+ Na]+ calcd for C10H15NO2SNa 236.0721 found 236.0717.
4-Cyclohexyl-N,N-dimethylbenzenesulfonamide (Table 2, 2i). New compound. Prepared according
to the general procedure using 4-chloro-N,N-dimethylbenzenesulfonamide (0.50 mmol), Fe(acac)3 (5
mol%), NMP (600 mol%), THF (0.15 M), and c-C6H11MgCl (1.0 M in THF, 1.20 equiv). The reaction
mixture was stirred for 60 min at 0 °C. Yield 84% (112.4 mg). White solid. Mp = 102-103 °C. 1H NMR
(400 MHz, CDCl3) δ 7.69 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 2.70 (s, 6H), 2.64-2.53 (m, 1H),
1.92-1.82 (m, 4H), 1.81-1.73 (m, 1H), 1.48-1.35 (m, 4H), 1.31-1.21 (m, 1H). 13C{1H} NMR (100 MHz,
CDCl3) δ 153.4, 132.7, 128.0, 127.6, 44.6, 38.1, 34.2, 26.8, 26.1. HRMS (ESI/Q-TOF) m/z: [M + Na]+
calcd for C14H21NO2SNa 290.1191 found 290.1187.
4-Isopropyl-N,N-dimethylbenzenesulfonamide (Table 2, 2j). New compound. Prepared according
to the general procedure using 4-chloro-N,N-dimethylbenzenesulfonamide (0.50 mmol), Fe(acac)3 (5
mol%), NMP (600 mol%), THF (0.15 M), and i-PrMgBr (1.0 M in THF, 1.20 equiv). The reaction
mixture was stirred for 60 min at 0 °C. Yield 74% (84.3 mg). Colorless oil. 1H NMR (400 MHz, CDCl3)
δ 7.70 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 3.05-2.94 (m, 1H), 2.70 (s, 6H), 1.28 (d, J = 6.9 Hz,
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6H). C{1H} NMR (100 MHz, CDCl3) δ 154.2, 132.8, 128.0, 127.2, 38.1, 34.3, 23.8. HRMS (ESI/Q-
TOF) m/z: [M + Na]+ calcd for C11H17NO2SNa 250.0878 found 250.0880.
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N,N-Dimethyl-4-phenethylbenzenesulfonamide (Table 2, 2k).30 Prepared according to the general
procedure using 4-chloro-N,N-dimethylbenzenesulfonamide (0.50 mmol), Fe(acac)3 (5 mol%), NMP
(600 mol%), THF (0.15 M), and PhCH2CH2MgCl (1.0 M in THF, 1.20 equiv). The reaction mixture
was stirred for 60 min at 0 °C. Yield 83% (119.8 mg). White solid. 1H NMR (400 MHz, CDCl3) δ 7.67
(d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 7.5 Hz, 2H), 7.23-7.18 (m, 1H), 7.15-7.12 (m,
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2H), 3.03-2.97 (m, 2H), 2.96-2.91 (m, 2H), 2.68 (s, 6H). C{1H} NMR (100 MHz, CDCl3) δ 147.2,
140.9, 132.9, 129.3, 128.6, 128.0, 126.4, 38.1, 37.9, 37.5.
4-(2-(1,3-Dioxan-2-yl)ethyl)-N,N-dimethylbenzenesulfonamide (Table 2, 2l). New compound.
Prepared according to the general procedure using 4-chloro-N,N-dimethylbenzenesulfonamide (0.50
mmol), Fe(acac)3 (5 mol%), NMP (600 mol%), THF (0.15 M), and (2-(1,3-dioxan-2-
yl)ethyl)magnesium bromide (0.5 M in THF, 3.00 equiv). The reaction mixture was stirred for 15 h at
23 °C. Yield 96% (143.7 mg). White solid. Mp = 112-113 °C 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J =
8.3 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 4.52 (t, J = 5.1 Hz, 1H), 4.12 (dd, J = 10.7, 5.0 Hz, 2H), 3.80-3.72
(m, 2H), 2.84-2.78 (m, 2H), 2.70 (s, 6H), 2.15-2.02 (m, 1H), 1.96-1.89 (m, 2H), 1.40-1.33 (m, 1H).
13C{1H} NMR (100 MHz, CDCl3) δ 147.4, 132.9, 129.1, 128.0, 101.0, 66.9, 38.0, 36.2, 30.0, 25.8.
HRMS (ESI/Q-TOF) m/z: [M + Na]+ calcd for C14H21NO4SNa 322.1089 found 322.1085.
Acknowledgements. We gratefully acknowledge Narodowe Centrum Nauki (grant no.
2014/15/D/ST5/02731), Rutgers University and the NSF (CAREER CHE-1650766) for generous
financial support.
1
Supporting Information Available. H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
Author Information. Corresponding author: ebisz@uni.opole.pl; michal.szostak@rutgers.edu
References
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