Synthesis of N-Sulfonyl Amidines and Acyl Sulfonyl Ureas from Sulfonyl Azides, Carbon Monoxide, and Amides

Article abstract of DOI:10.1021/acs.joc.6b02894

A Pd-catalyzed and ligand-free carbonylation/cycloaddition/decarboxylation cascade synthesis of sulfonyl amidines from sulfonyl azides and substituted amides at low CO pressure is reported. The reaction proceeds via an initial Pd-catalyzed carbonylative generation of sulfonyl isocyanates from sulfonyl azides, followed by a [2 + 2] cycloaddition with amides and subsequent decarboxylation, which liberates the desired sulfonyl amidines, generating N₂ and CO₂ as the only reaction byproducts. Using this simple protocol, a diverse range of sulfonyl amidines was obtained in moderate to excellent yields. In addition, the reaction can also be directed through a more conventional amidocarbonylation pathway by employing N-monosubstituted amide nucleophiles to afford acyl sulfonyl ureas in good yields.

Full text of DOI:10.1021/acs.joc.6b02894

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Article
Synthesis of N-Sulfonyl Amidines and Acyl Sulfonyl Ureas
from Sulfonyl Azides, Carbon Monoxide and Amides
Shiao Y. Chow, and Luke R. Odell
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02894 • Publication Date (Web): 02 Feb 2017
Downloaded from http://pubs.acs.org on February 6, 2017
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Synthesis of N-Sulfonyl Amidines and Acyl Sulfonyl Ureas from Sulfonyl Azides,
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Carbon Monoxide and Amides
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Shiao Y. Chow, Luke R. Odell*
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala Biomedical
Center, Uppsala University, P. O. Box 574, SE-751 23 Uppsala, Sweden
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
To whom correspondence should be addressed. Luke Odell, Phone: +46-18-4714297, Fax: +46-18-
4714474. E-mail: luke.odell@orgfarm.uu.se
Graphical Abstract
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Abstract
A Pd-catalyzed and ligand-free carbonylation/cycloaddition/decarboxylation cascade synthesis of
sulfonyl amidines from sulfonyl azides and substituted amides at low CO pressure is reported. The
reaction proceeds via an initial Pd-catalyzed carbonylative generation of sulfonyl isocyanates from
sulfonyl azides, followed by a [2+2] cycloaddition with amides and subsequent decarboxylation
liberates the desired sulfonyl amidines generating N2 and CO2 as the only reaction byproducts.
Using this simple protocol, a diverse range of sulfonyl amidines were obtained in moderate to
excellent yields. In addition, the reaction can also be directed through a more conventional
amidocarbonylation pathway by employing N-monosubstituted amide nucleophiles to afford acyl
sulfonyl ureas in good yields.
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Introduction
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Amidines are one of the most widely exploited moieties in medicinal and synthetic
compounds. Notably, they serve as a highly-conserved motif seen in both substrates and inhibitors
of trypsin-like serine proteases due to their strong ionic interactions with the acidic S1 pockets.1–4 In
addition to being key intermediates in the synthesis of heterocyclic compounds, amidines are also
chelators of transition metals (e.g. ZnII) and have been successfully exploited as inhibitors of
anthrax lethal factor, a zinc metalloenzyme.5,6 The emergence of sulfonyl amidines as bioactive
pharmacophores (Figure 1) with anti-resorptive7, anti-tumour8 and anti-proliferative9 properties has
led to numerous new synthetic developments to access this highly polar, structurally rigid and
hydrogen-bond rich moiety (Scheme 1). These include (a) direct condensation of sulfonamide and
formamide,10 (b) three-component aerobic oxidative coupling of sulfonamides, terminal alkynes,
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and amines catalyzed by Cu(OTf)2, (c) the coupling of primary, secondary or tertiary amines and
sulfonyl azides with terminal alkynes,12 (d) coupling of thioamides and sulfonyl azides,13 and (e)
dehydrogenation of tertiary amines coupled with a tandem reaction with sulfonyl azides14 (Scheme
1).
Amidines
Sulfonyl amidines
Melagatran15
Thrombin Inhibitor
Anti-proliferative9
Anti-tumor8
LB3081216
Thrombin inhibitor
Anti-resorptive7
Figure 1: Biologically active amidines and sulfonyl amidines.
In our previous work on sulfonyl-containing compounds, we reported a versatile Pd-mediated
carbonylative preparation of sulfonyl carbamates and sulfonyl ureas by assembling sulfonyl azides,
carbon monoxide, and alcohol or aromatic amine nucleophiles.17 In contrast, aliphatic amines were
found to under a direct substitution reaction with sulfonyl azides to form substituted sulfonamides.
In an effort to overcome this issue, we sought to develop a telescoped process involving the initial
formation of a sulfonyl isocyanate intermediate followed by the addition of an amine nucleophile.
During our initial studies, we observed the formation of an unexpected side product, identified
herein as a sulfonyl amidine, formed from sulfonyl azides and the reaction solvent, N,N-
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dimethylacetamide (DMA). There are a few sparse literature reports on the ability of sulfonyl
isocyanates to undergo cycloaddition/decarboxylation reactions with tertiary amides18 (Scheme 1)
and we postulated that a similar pathway was operating in this case. Here, the in situ generated
sulfonyl isocyanate intermediate underwent cycloaddition with DMA to form a labile four-
membered ring that subsequently collapsed to release the sulfonyl amidine product. Indeed, during
the completion of this work Huang et al. reported the synthesis of sulfonyl arylaldimines from
sulfonyl isocyanates and aldehydes via a similar cycloaddition/cycloreversion process,19 which
further strengthened our mechanistic hypothesis. Due to the limited commercial availability of
diverse sulfonyl isocyanates and their tendency to undergo hydrolysis to form sulfonyl amides,20 we
devised a one-pot synthesis of sulfonyl amidines from stable sulfonyl azide precursors and
substituted amides via the in situ generation of sulfonyl isocyanate intermediates. In addition, this
method would also complement the existing methods based on sulfonamide and sulfonyl azide
chemistry, by allowing the introduction of small alkyl groups on the amidine carbon without
requiring access to thioamide starting materials.
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Scheme 1: Synthesis routes to access sulfonyl amidines and derivatives
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Herein, we report a simple carbonylation-cycloaddition protocol using a two-chamber reactor
that involves (1) in situ carbonylative sulfonyl isocyanate formation from sulfonyl azides, followed
by (2) [2+2] cycloaddition of the sulfonyl isocyanate intermediate with substituted amides and
finally (3) decarboxylation to produce the desired sulfonyl amidines concomitant with the release of
CO2. Furthermore, this protocol also allows access to acyl sulfonylureas by simply switching the
nucleophile to an N-monosubstituted amide providing an efficient and diverse route to two distinct
product classes from a common intermediate.
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Results and Discussion
We began our investigation by using p-tolyl sulfonyl azide (1a) and N,N-dimethylacetamide
(DMA, 2a) as model substrates in a modified two-chamber reaction vessel17,21,22 originally
developed by Skrydstrup et al. (Table 1).23,24 Sulfonyl azide, PdCl2 (5 mol%) and DMA (2 mL)
were added to chamber 1 and Mo(CO)6 was added to chamber 2 as the ex situ CO generating
source. Gratifyingly, formation of desired sulfonyl amidine 3a was observed and the product was
isolated in 56% yield. The modest yield was attributed to the poor solubility of PdCl2 in the reaction
solvent and a catalyst screen comprising of a series of Pd(II) and Pd(0) catalysts was carried out.
Table 1: Screening of reaction conditionsa
entry
DMA
solvent
catalyst
Yield (%)
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Excess
Excess
Excess
Excess
Excess
Excess
20 equiv
10 equiv
5 equiv
2 equiv
DMA
DMA
DMA
PdCl2
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96
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Pd(OAc)2
Pd(TFA)2
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DMA Pd(cod)Cl2
DMA
DMA
THF
THF
THF
THF
Pd2(dba)3
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
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aReaction conditions. Chamber 1: p-tolyl sulfonyl azide (0.25 mmol), Pd catalyst (5 mol%), DMA (2 equiv – excess),
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solvent (2 mL); Chamber 2: Mo(CO)6 (0.6 equiv), DBU (1.5 equiv). Reaction was heated at 75 C for 20h. All yields
are isolated yields.
In general, the use of Pd(II) salts was beneficial and Pd(OAc)2 was the most optimal returning
an excellent yield of 96%. In contrast, the use of Pd(PPh3)4 returned a significantly lower yield due
to competing consumption of the starting material through a Staudinger reaction with the
triphenylphosphine ligand. To assess the minimal stoichiometry of the amide, the amount of DMA
was progressively decreased and THF was employed as reaction solvent. It was observed that at
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least 5 equiv of DMA was required to maintain optimal yield (>89%) and a drastic decrease in yield
was observed with just 2 equiv DMA. Based on the need for an excess of DMA, we reasoned that
the amide reactant was also functioning as a chelating ligand of the Pd catalyst.
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The requirement for a large excess of amide was considered a significant drawback due to
potential waste, purification and cost issues. In addition, we anticipated further issues when
expanding the protocol beyond DMA, resulting from variation in the chelating efficiency of
different amides. Thus, a ligand survey using Pd(OAc)2 as the catalyst precursor was carried out in
the presence of 2 equiv of DMA (Table 2). The use of bidentate N-based ligands, 1,10-
phenanthroline and 6-methyl-2,2’-pyridyl, was moderately advantageous leading to a slight
improvement in yield and xantphos returned only traces of the desired product. To further simplify
the reaction conditions, we then employed acetonitrile as a dual reaction solvent and Pd-ligand.
Gratifyingly, the reaction proceeded smoothly to afford 3a in an excellent yield of 91%. Moreover,
the temperature could be reduced to 40 oC without affecting the yield (92%), while a slight decrease
in efficiency was observed at room temperature (71%).
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Table 2: Ligand and temperature optimizationa
entry solvent
Pd ligand
T (oC) yield (%)
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MeCN
MeCN
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aReaction conditions. Chamber 1: p-tolyl sulfonyl azide (0.25 mmol), Pd catalyst (5 mol%), DMA (2 equiv), ligand (7.5
mol%), solvent (3 mL); Chamber 2: Mo(CO)6 (0.6 equiv), DBU (1.5 equiv). All yields are isolated yields.
With the optimal conditions in hand, we proceeded to explore the reaction scope with an array
of sulfonyl azides and amides (Table 3). Sulfonyl azides containing either electron-withdrawing
(3b-c) or electron-donating group (3d) underwent smooth conversion to the corresponding sulfonyl
amidines, giving excellent yields of 81-94%. Similarly, electron-rich heterocyclic (3e) and benzylic
(3f) sulfonyl azides performed well as substrates returning high yields of the desired products (87-
90%). Next, a range of di-, and tri-substituted amides (3g-3p) were employed as substrates to
examine steric tolerance of the cycloaddition reaction. Similar to tri-substituted DMA (3a), di-
substituted dimethylformamide (3g) performed well affording an excellent yield of 91%. The
introduction of bulkier i-propyl-N substituents resulted in lower conversion to 3h and no
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improvement was observed despite the addition of excess amide. Increasing the reaction
temperature to 55 oC was beneficial and a moderate yield of 43% was obtained. In contrast, a cyclic
N-substituent was well-tolerated in which 3i was isolated in a high yield of 86%, likely due to
decreased steric interference by the constrained cyclohexyl ring.
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Table 3: Scope of the carbonylative sulfonyl amidine cascade reactiona
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3d, 84%
3a, 92%
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3c, 94%
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3i, 86%
3f, 90%
3g, 91%
3h, 43%b
3l, 20%b
3j, 48%b
3k, 35%b
3n, 40%
3m, 31%b
Diuretic25
3o, No reaction
3p, 34%
aReaction conditions. Chamber 1: sulfonyl azide (0.25 mmol, 1 equiv), amide (1 mmol, 5 equiv), Pd(OAc)2 (5 mol%);
Chamber 2: Mo(CO)6 (0.15 mmol, 0.6 equiv), DBU (0.35 mmol, 1.5 equiv). Reaction heated and stirred vigorously at
40 oC. bReaction run at 55 oC.
Subsequently, a series of tri-substituted amides (3j-3m) with various groups attached to the
amide carbon were investigated, in which elevated temperatures were used to overcome steric
hindrance. Bulky groups (butyl, tert-butyl and phenyl) were indeed compatible and afforded
modest, albeit decreased yields (20-48%). Notably, the presence of a vinyl group was also
compatible with the reaction conditions (3m), despite the potentially competing side-reaction
between the vinyl group and the sulfonyl isocyanate moiety. The cyclic substrate, N-methyl-2-
pyrrolidone was also tolerated and returned a moderate yield of the diuretic 3n.25 To investigate
functional groups tolerance of the cycloaddition reaction, we also employed amino acids containing
a N,N-dimethylated carboxyl group at either the α-position (Boc-Gly-CON(Me)2, 3o) or γ-position
(Boc-N,N-dimethylGln-COOMe, 3p). No product was observed in 3o likely due to steric
interference by the bulky adjacent Boc-protected α-amino group, while a moderate yield was
obtained for 3p due to the distal position of the reacting γ-amide in relation to the α-carbon of the
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amino acid. Finally, we explored the use of other carbonyl derivatives (ester, ketone and aldehyde)
as the reacting partner and no conversion was observed indicating a possible preference for an
electron-rich rather than electrophilic carbonyl derivative.
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Next, we turned our attention to N-monosubstituted amides as substrates (Table 4).
Surprisingly, when using acetamide was employed as a substrate, the reaction led to the exclusive
formation of an N-acyl sulfonyl urea (4a) and no trace of the expected sulfonyl amidine was
observed (Scheme 2). In this case, the amide acted as an N-nucleophile with the sulfonyl isocyanate
intermediate leading to the formation of the acyl sulfonyl urea, analogous to the carbonylative
preparation of sulfonyl ureas.17 Due to self-catalyzed hydrolysis and stability issues, the compound
was isolated as the triethylamine salt in an excellent yield of 89%.
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Scheme 2: Formation of acyl sulfonyl urea from mono N-substituted amide
We then proceeded to explore the use of N-monosubstituted amides with varying steric and
electronic properties. Introduction of a bulkier aryl group at R3 was well tolerated, returning 4b and
4c in excellent yield (78-87%). The presence of an N-methyl group led to a slight decrease in yield
(4d) and N-benzylacetamide afforded 4e in moderate yield due to sluggish conversion, and
increasing the reaction temperature to 55 oC led to no improvement as a result of thermal instability
of the acyl sulfonylurea product (see supporting information for details). Unfortunately, the use of
N,N-dimethylurea as nucleophile was unsuccessful and only traces of the desired product (4f) were
observed. Gratifyingly, the use of aryl sulfonyl azides containing either electron-withdrawing or -
donating group as substrates proceeded smoothly and 4g and 4h were obtained in high yields of
89% and 84%, respectively.
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Table 4: Acyl sulfonyl urea reaction scope a
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4a, 89%b
4e, 21%
4d, 69%
4h, 84%
4b, 87%
4f, Trace
4c, 78%
4g, 89%
aReaction conditions: Chamber 1: sulfonyl azide (0.25 mmol, 1 equiv), amide (1 mmol, 2 equiv), Pd(OAc)2 (5 mol%),
MeCN (3 mL); Chamber 2: Mo(CO)6 (0.15 mmol, 0.6 equiv), DBU (0.35 mmol, 1.5 equiv), MeCN (3 mL). Reaction
heated and stirred vigorously at 40 oC.
A plausible mechanism for the cascade formation of sulfonyl amidines is depicted in Scheme
3. Analogous to the in situ generation of sulfonyl isocyanates we reported in the alkoxy- and amino-
carbonylation of sulfonyl azides17, the Pd(OAc)2 pre-catalyst is first reduced by either CO,
acetonitrile and/or amide, to an active Pd(0) species. Addition of the sulfonyl azide precursors to the
Pd(0) species generates the nitrene-palladium complex A via nitrogen extrusion and subsequent
insertion of CO followed by reductive elimination leads to the formation of complex B. The
sulfonyl isocyanate intermediate then undergoes a [2+2] cycloaddition with a di- or tri-substituted
amide and finally, the four-membered ring intermediate collapses releasing the final sulfonyl
amidine product and CO2. In contrast, when the reaction is conducted with a primary or secondary
amide, addition to the sulfonyl isocyanate via the nucleophilic nitrogen center is favored and the
competing amidocarbonylation pathway leads to the formation of the acyl sulfonyl urea products.
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Scheme 3: Plausible mechanism of carbonylation-cycloaddition synthesis of sulfonyl amidines and
formation of acyl sulfonyl ureas.
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To further delineate the mechanism of the carbonylative formation of sulfonyl amidines, a
series of control experiments were carried out (Scheme 4). Removal of either Pd-catalyst or the CO
source led to complete abolishment of conversion and no product was observed, suggesting that the
transformation is indeed palladium-catalyzed and CO-mediated reduction of the Pd(II) precatalyst is
required. The direct addition of DMA or acetamide to p-tolylsulfonyl isocyanate led to formation of
sulfonyl amidine 3a and acyl sulfonyl urea 4a, respectively indicating that both reaction pathways
proceed via the same sulfonyl isocyanate intermediate, generated in situ from a sulfonyl azide
precursor in the present reaction. (Scheme 4) This further was supported by the unsuccessful
generation of 3a and 4a from p-tolylsulfonamide. Finally, we employed p-tolylsulfonyl chloride as
precursor in the presence of sodium azide for the in situ generation of the sulfonyl azide substrate,26
however no product was observed.
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Scheme 4: Control experiments for the synthesis of 3a and 4a
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Conclusion
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In conclusion, we have developed a simple, ligand-free, and versatile one-pot synthesis of
sulfonyl amidines and acyl sulfonyl ureas from readily available sulfonyl azide precursors. Using
acetonitrile as solvent in conjunction with ubiquitous Pd(OAc)2, we have successfully identified a
carbonylation-cycloaddition-decarboxylation cascade process to access a range of sulfonyl amidines
from sulfonyl azides and amides without the requirement for additional ligands. Notably, aside from
the Mo formed during the carbon monoxide releasing step, CO2 and N2 are the only by-products
formed in this reaction. This protocol can also be directed through an amidocarbonylation pathway
by using primary and secondary amide nucleophiles to afford acyl sulfonyl ureas in moderate to
excellent yields. These simple three-component carbonylative reactions represent a robust and
divergent synthetic platform that provide access to two important classes of sulfonyl-containing
compounds with immense pharmaceutical relevance, controlled only by the choice of amide
nucleophile.
Experimental Section
General methods
All reagents and solvents (anhydrous MeCN, EtOAc, hexane, n-pentane, acetone, methanol and
Et3N) were of commercial quality and used without further purification. Yields are for isolated,
homogenous and spectroscopically pure material. Silica gel chromatography was carried out on E.
Merck silica gel (60 Å pore size, particle size 40-63 nm) column. 1H NMR spectra were recorded at
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400 MHz and 13C NMR spectra at 100 MHz. The chemical shifts for H NMR and C NMR were
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referenced to tetramethylsilane via residual solvent signals (1H, CDCl3 at 7.26 ppm; C, CDCl3 at
13
77.16 ppm; 1H, (CD3)2CO at 2.05 ppm; C, (CD3)2CO at 206.26 ppm). LC/MS was performed on
an instrument equipped with a CP-Sil 8 CB capillary column (50 x 3.0 mm, particle size 2.6 μm,
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pore size 100 Å) running at an ionization potential of 70 eV with a CH3CN/H2O gradient (0.05%
HCOOH). Accurate mass values were determined via electrospray ionization with a 7-T hybrid ion
trap and a TOF detector running in positive mode.
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General procedure for the preparation of sulfonyl azide precursors.
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All sulfonyl azides were prepared from the corresponding sulfonyl chloride26 following the
literature procedures. It should be noted that as sulfonyl azides are potentially explosive, all
reactions should be carried out behind blast shields and the use of plastic spatulas for the handling
of solid material is recommended.
General procedure for the synthesis of sulfonyl amidines, exemplified by N,N-dimethyl-N’-
tosylacetimidamide18 (CAS 93958-32-8) (3a). Chamber 1 of a two-vial reactor17 was charged with
toluene sulfonyl azide (50 mg, 0.25 mmol), N,N-dimethylacetamide (47 μL, 0.50 mmol, 2 equiv)
and Pd(OAc)2 (3 mg, 5 mol%) and chamber 2 was charged with Mo(CO)6 (40 mg, 0.15 mmol, 0.6
equiv). Both chambers were capped and anhydrous MeCN (2 mL) was added through the septum to
each chamber and the reaction vessel was purged with N2 for 5 min. DBU (57 μL, 0.38 mmol, 1.5
equiv) was added through the septum to Chamber 2 to induce to release of CO and the assembly
was stirred vigorously for 20 h at 40 ºC. The reaction mixture from chamber 1 was concentrated in
vacuo and loaded directly onto a silica gel column. The sulfonyl amidine compound was obtained
as a white solid (56 mg, 92%), eluting with 30% EtOAc in n-pentane. 1H NMR (400 MHz, CDCl3)
δ 7.80 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H), 3.07 (s, 3H), 3.05 (s, 3H), 2.47 (s, 3H), 2.38 (s,
13
3H). C NMR (100 MHz, CDCl3) δ 166.0, 141.9, 141.3, 129.2, 126.4, 38.9, 21.5, 18.1. MS m/z:
[M + H]+ calcd. for C11H17N2O2S 241.1, found. 241.3.
General procedure for the synthesis of acyl sulfonyl ureas, exemplified by N-
(tosylcarbamoyl)acetamide.TEA salt18 (CAS 34543-10-7) (4a). Chamber 1 of a two-vial reactor17
was charged with toluene sulfonyl azide (50 mg, 0.25 mmol), acetamide (30 mg, 0.50 mmol, 2
equiv) and Pd(OAc)2 (3 mg, 5 mol%) and chamber 2 was charged with Mo(CO)6 (40 mg, 0.15
mmol, 0.6 equiv) Both chambers were capped and anhydrous MeCN (2 mL) was added through the
septum to each chamber and the reaction vessel was purged with N2 for 5 min. DBU (57 μL, 0.38
mmol, 1.5 equiv) was added through the septum to Chamber 2 to induce to release of CO and the
assembly was stirred vigorously for 20 h at 40 ºC. The reaction mixture from chamber 1 was
concentrated in vacuo and loaded directly onto a silica gel column, eluting with 1% MeOH and 2%
TEA in acetone. The acyl sulfonyl urea compound was obtained as a colorless oil (76 mg, 89%). 1H
NMR (400 MHz, (CD3)2CO) δ 7.80 (d, J = 8.2 Hz, 2H), 7.33 – 7.16 (m, 2H), 3.09 (m, 6H), 2.35 (s,
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3H), 2.03 (s, 3H), 1.89 (s, 1H), 1.18 (t, J = 7.3 Hz, 9H). ; 13C NMR (101 MHz, (CD3)2CO) δ 173.1,
172.8, 157.2, 143.1, 141.7, 129.4, 127.7, 46.7, 24.5, 22.6, 21.3, 9.1. MS m/z: [M + H]+ calcd. for
C10H13N2O4S 257.1, found. 257.1.
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3b, N,N-Dimethyl-N'-((4-nitrophenyl)sulfonyl)acetimidamide. Purification by column
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chromatography (30% EtOAc in n-pentane) afforded 3b as a white solid (55 mg, 81% yield). H
NMR (400 MHz, (CD3)2CO) δ 8.37 (d, J = 9.0 Hz, 2H), 8.14 (d, J = 9.0 Hz, 2H), 3.23 (s, 3H), 3.08
(s, 3H), 2.51 (s, 3H).; 13C NMR (101 MHz, (CD3)2CO) δ 166.3, 150.6, 149.3, 127.4, 123.9, 38.4,
38.1, 17.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd. for C10H14N3O4S 272.0700, found. 272.0696.
3c, N’-((4-Bromophenyl)sulfonyl)-N,N-dimethylacetimidamide. Purification by column
1
chromatography (30% EtOAc in n-pentane) afforded 3c as a white solid (72 mg, 94% yield). H
NMR (400 MHz, (CDCl3) δ7.82 – 7.76 (m, 2H), 7.60 – 7.52 (m, 2H), 3.09 (s, 3H), 3.05 (s, 3H) 2.49
(s, 3H).; 13C NMR (101 MHz, CDCl3) δ 166.1, 143.1, 132.2, 131.8, 130.0, 128.0, 126.2, 39.1, 39.1,
18.3. HRMS (ESI-TOF) m/z: [M + H]+ calcd. for C10H14BrN2O2S 304.9954, found 304.9959
3d, N’-((4-Methoxyphenyl)sulfonyl)-N,N-dimethylacetimidamide. Purification by column
1
chromatography (30% EtOAc in n-pentane) afforded 3d as a white solid (64 mg, 84% yield). H
NMR (400 MHz, (CD3)2CO) δ7.79 (d, J = 8.9 Hz, 2H), 7.01 (d, J = 8.9 Hz, 2H), 3.86 (s, 3H), 3.17
(s, 3H), 3.02 (s, 3H), 2.44 (s, 3H). ; 13C NMR (101 MHz, (CD3)2CO) δ 165.8, 161.8, 137.4, 127.9,
113.5, 55.0, 38.1, 37.7, 16.9. HRMS (ESI-TOF) m/z: [M + H]+ calcd. for C11H17N2O3S 257.0955,
found 257.0959
3e,
N,N-Dimethyl-N’-(thiophen-2-ylsulfonyl)acetimidamide.
Purification
by
column
1
chromatography (30% EtOAc in n-pentane) afforded 3e as a white solid (51 mg, 87% yield). H
NMR (400 MHz, (CD3)2CO) δ 7.69 (dd, J = 5.0, 1.4 Hz, 1H), 7.51 (dd, J = 3.7, 1.3 Hz, 1H), 7.07
(dd, J = 5.0, 3.6 Hz, 1H), 3.21 (s, 3H), 3.09 (s, 3H), 2.47 (s, 3H).; 13C NMR (101 MHz, (CD3)2CO)
δ 166.1, 147.2, 129.9, 129.0, 126.6, 38.3, 37.9, 16.9. HRMS (ESI-TOF) m/z: [M + H]+ calcd. for
C8H13N2O2S2 233.0413, found 233.0419
3f, N’-(Benzylsulfonyl)-N,N-dimethylacetimidamide. Purification by column chromatography
1
(30% EtOAc in n-pentane) afforded 3f as a white solid (54mg, 90% yield). H NMR (400 MHz,
(CD3)2CO) δ7.44-7.42 (m, 2H), 7.35 – 7.28 (m, 3H), 4.17 (s, 2H), 3.10 (s, 3H), 2.98 (s, 3H), 2.27 (s,
3H). ; 13C NMR (101 MHz, (CD3)2CO) δ165.7, 132.0, 131.1, 127.9, 127.5, 60.6, 37.9, 37.7, 17.1.
HRMS (ESI-TOF) m/z: [M + H]+ calcd. for C11H17N2O2S 241.1005, found 241.1010
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3g, N,N-Dimethyl-N’-tosylformimidamide18 (CAS 25770-53-0). Purification by column
1
chromatography (30% EtOAc in n-pentane) afforded 3g as a white solid (52 mg, 91% yield). H
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NMR (400 MHz, (CDCl3) δ 8.13 (s, br, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.28 – 7.24 (m, 2H,), 3.12 (s,
3H), 3.01 (s, 3H), 2.40 (s, 3H). 13C NMR (101 MHz, (CDCl3) δ 159.2, 142.6, 139.7, 129.4, 126.7,
41.6, 35.6, 21.6. MS m/z: [M + H]+ calcd. for C10H15N2O2S 227.1, found. 227.2.
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3h, N,N-Diisopropyl-N’-tosylformimidamide27 (CAS 1304779-03-0). Purification by column
1
chromatography (30% EtOAc in n-pentane) afforded 3h as a white solid (31 mg, 43% yield). H
NMR (400 MHz, (CD3)2CO) δ 8.24 (s, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.34 – 7.27 (m, 2H), 4.36 (p, J
= 6.8 Hz, 1H), 3.90 (p, J = 6.8 Hz, 1H), 2.38 (s, 3H), 1.34 (d, J = 6.8 Hz, 6H), 1.25 (d, J = 6.8 Hz,
6H); 13C NMR (101 MHz, (CD3)2CO) δ 156.9, 141.8, 129.3, 129.1, 126.1, 49.8, 47.7, 22.3, 20.4,
18.7. MS m/z: [M + H]+ calcd. for C14H23N2O2S 283.1, found. 283.2.
3i, N-Cyclohexyl-N’-tosylacetimidamide28 (CAS 101354-34-1). Purification by column
1
chromatography (30% EtOAc in n-pentane) afforded 3i as a white solid (65 mg, 86% yield). H
NMR (400 MHz, (CD3)2CO) δ 7.75 (d, J = 8.2 Hz, 2H), 7.61 – 7.48 (s, br, 1H), 7.32 (d, J = 8.0 Hz,
2H), 3.78 (dq, J = 6.9, 3.6 Hz, 1H), 2.39 (s, 3H), 2.28 (s, 3H), 1.97 – 1.83 (m, 2H), 1.70 (m, 2H),
1.61 – 1.51 (m, 1H), 1.45 – 1.04 (m, 5H).; 13C NMR (101 MHz, (CD3)2CO) δ 165.6, 143.1, 142.5,
129.9, 127.1, 51.3, 32.5, 26.2, 25.5, 21.4, 20.8. MS m/z: [M + H]+ calcd. for C15H23N2O2S 295.1,
found. 295.2.
3j, N,N-Dimethyl-N’-tosylpentanimidamide. Purification by column chromatography (30%
1
EtOAc in n-pentane) afforded 3j as a white solid (33 mg, 48% yield). H NMR (400 MHz,
(CD3)2CO) δ7.76 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 3.20 (s, 2H), 3.00 (s, 3H), 2.38 (s,
3H), 1.70 – 1.58 (m, 2H), 1.29 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H).; 13C NMR (101 MHz, (CD3)2CO) δ
168.5, 142.8, 141.3, 128.9, 126.0, 37.8, 32.4, 20.4, 19.8, 13.6. HRMS (ESI-TOF) m/z: [M + H]+
calcd. for C14H23N2O2S 283.1475, found 283.1484.
3k, N,N-Dimethyl-N’-tosylpivalimidamide. Purification by column chromatography (30% EtOAc
1
in n-pentane) afforded 3k as a white solid (25 mg, 35% yield). H NMR (400 MHz, (CD3)2CO) δ
7.73 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 3.39 (s, 6H), 2.38 (s, 3H), 1.22 (s, 9H).; 13C NMR
(101 MHz, (CD3)2CO) δ 172.9, 145.0, 141.5, 129.5, 126.3, 44.3 41.3, 29.1, 21.2. HRMS (ESI-TOF)
m/z: [M + H]+ calcd. for C14H23N2O2S 283.1475, found 283.1480.
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3l, N,N-Dimethyl-N’-tosylbenzimidamide29 (CAS 4115-23-5). Purification by column
1
chromatography (30% EtOAc in n-pentane) afforded 3l as a white solid (15 mg, 20% yield). H
NMR (400 MHz, (CD3)2CO) δ 7.46 – 7.40 (m, 3H), 7.38 – 7.32 (m, 2H), 7.21 – 7.08 (m, 4H), 3.19
(s, 3H), 2.80 (s, 3H), 2.35 (s, 3H)..; 13C NMR (101 MHz, (CD3)2CO) δ 161.5, 143.1, 142.0, 130.2,
129.5, 128.7, 128.4, 127.1, 40.1, 38.1, 21.3. MS m/z: [M + H]+ calcd. for C16H19N2O2S 303.1,
found. 303.2.
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3m, N,N-Dimethyl-N'-tosylacrylimidamide. Purification by column chromatography (30% EtOAc
1
in n-pentane) afforded 3m as a white solid (20 mg, 31% yield). H NMR (400 MHz, (CD3)2CO) δ
7.71 (d, J = 8.1Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 6.60 (ddt, J = 18.1, 12.1, 0.4 Hz, 1H), 5.66 (dd, J
= 12.1, 1.1 Hz, 1H), 5.47 (dd, J = 18.1, 1.1 Hz, 1H), 3.16 (s, 3H), 3.04 (s, 3H), 2.38 (s, 3H).; 13C
NMR (101 MHz, (CD3)2CO) δ 13C NMR (101 MHz, Acetone-d6) δ 164.6, 142.5, 141.3, 129.2,
128.3, 126.3, 126.0, 123.7, 39.3, 37.2 20.4. HRMS (ESI-TOF) m/z: [M + H]+ calcd. for
C12H17N2O2S 253.1005, found 253.1015.
3n, 4-Methyl-N-(1-methylpyrrolidin-2-ylidene)benzenesulfonamide18 (CAS 19734-35-1).
Purification by column chromatography (30% EtOAc in n-pentane) afforded 3n as a white solid (26
1
mg, 40% yield). H NMR (400 MHz, (CD3)2CO) δ 7.73 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz,
2H), 3.56 – 3.46 (m, 2H), 2.92 (m, 5H), 2.39 (s, 3H), 2.12 – 1.94 (m, 2H).; 13C NMR (101 MHz,
(CD3)2CO) δ 169.8, 141.9, 123.0, 128.1, 126.3, 51.2, 31.0, 30.5, 20.4, 18.8. MS m/z: [M + H]+
calcd. for C12H17N2O2S 253.1, found. 253.2.
3p, Methyl 2-((tert-butoxycarbonyl)amino)-5-(dimethylamino)-5-(tosylimino)pentanoate.
Purification by column chromatography (30% EtOAc in n-pentane) afforded 3p as a white solid (37
1
mg, 34% yield). H NMR (400 MHz, (CD3)2CO) δ 7.77 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.0 Hz,
2H), 6.33 (br, 1h), 4.22 (m, 1H), 3.71 (s, 3H), 3.23 (s, 3H), 3.02 (m, 5H), 2.39 (s, 3H), 2.19 (m, 2H),
1.42 (s, 8H); 13C NMR (101 MHz, (CD3)2CO) δ 172.1, 167.6, 142.4, 141.6, 129.0, 126.0, 78.6, 53.4,
51.5, 38.0, 37.7, 28.0, 27.7, 27.2, 20,4. HRMS (ESI-TOF) m/z: [M + H]+ calcd. for C20H32N3O6S
442.2007, found 442.2019.
4b, N-(Tosylcarbamoyl)benzamide.TEA salt (CAS 100970-19-2)30. Purification by column
chromatography (1% MeOH and 2% TEA in Acetone) afforded 4b as a white solid (82 mg, 87%
yield). 1H NMR (400 MHz, (CD3)2CO) δ 7.95 (d, J = 7.8 Hz, 2H), 7.82 (d, J = 7.9 Hz, 2H), 7.56 (d,
J = 7.4 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 2.95 (q, J = 7.2 Hz, 6H), 2.28 (s,
3H), 1.13 (t, J = 7.2 Hz, 9H); 13C NMR (101 MHz, (CD3)2CO) δ 167.6, 156.8, 143.3, 141.3, 134.6,
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133.0, 129.1, 128.5, 127.7, 46.6, 21.1, 9.8. HRMS (ESI-TOF) m/z: [M + H]+ calcd. for
C15H15N2O4S 319.0747, found 319.0768.
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4c, 4-Methoxy-N-(tosylcarbamoyl)benzamide.TEA salt. Purification by column chromatography
1
(1% MeOH and 2% TEA in Acetone) afforded 4c as a white solid (88 mg, 78% yield). H NMR
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(400 MHz, (CD3)2CO) δ 7.89 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 8.3 Hz, 1H), 7.60 – 7.50 (m, 2H),
7.40 (t, J = 7.9 Hz, 1H), 7.27 (dd, J = 14.8, 8.0 Hz, 2H), 7.19 – 7.14 (m, 1H), 3.84 (s, 3H), 2.35 (s,
3H), 1.19 (t, J = 7.2 Hz, 9H).; 13C NMR (101 MHz, (CD3)2CO) δ 160.5, 135.3, 130.3, 129.4, 129.33,
128.1, 127.7, 120.9, 119.7, 113.2, 55.6, 46.6, 21.2, 9.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd. for
C16H17N2O5S 349.0853, found 349.0849.
4d, N-Methyl-N-(tosylcarbamoyl)acetamide.TEA salt. Purification by column chromatography
1
(1% MeOH and 2% TEA in Acetone) afforded 4d as a white solid (64 mg, 69% yield). H NMR
(400 MHz, (CD3)2CO) δ 7.84 (d, J = 8.3 Hz, 2H), 7.35 – 7.22 (d, J = 8.2 Hz, 2H), 3.29 (q, J = 7.3
Hz, 6H), 3.13 (s, 3H), 2.39 (s, 3H), 2.34 (s, 3H), 1.32 (t, J = 7.3 Hz, 9H). 13C NMR (101 MHz,
(CD3)2CO) δ 174.3, 142.0, 129.5, 129.0, 127.6, 126.3, 46.2, 31.4, 20.5, 8.1. HRMS (ESI-TOF) m/z:
[M - H]- calcd. for C11H13N2O4S 269.0591, found 269.0606.
4e, N-Benzyl-N-(tosylcarbamoyl)acetamide. Purification by column chromatography (1% MeOH
in Acetone) afforded 4e as a white solid (17 mg, 21% yield). 1H NMR (400 MHz, (CD3)2CO) δ 8.02
– 7.96 (m, 2H), 7.49 (d, J = 8.1 Hz, 2H), 7.39 – 7.28 (m, 3H), 7.18 (m, 2H), 5.06 (s, 2H), 2.49 (s,
3H), 2.35 (s, 2H).; 13C NMR (101 MHz, (CD3)2CO) δ 178.0, 151.3, 146.0, 137.8, 137.3, 130.5,
129.8, 129.5, 128.4, 127.1, 48.5, 25.5, 21.7. HRMS (ESI-TOF) m/z: [M + H]+ calcd. for
C17H19N2O4S 347.1066, found. 347.1065
4g, N-(((4-Nitrophenyl)sulfonyl)carbamoyl)acetamide.TEA salt. Purification by column
chromatography (1% MeOH and 2% TEA in Acetone) afforded 4g as a white solid (86 mg, 89%
yield). 1H NMR (400 MHz, (CD3)2CO) δ 8.24 (d, J = 8.8 Hz, 2H), 8.13 (d, J = 8.8 Hz, 2H), 3.28 (q,
J = 7.3 Hz, 6H), 2.00 (s, 3H), 1.30 (t, J = 7.3 Hz, 9H);13C NMR (101 MHz, (CD3)2CO) δ 171.8,
157.5, 150.4, 149.0, 128.5, 128.1, 123.4, 46.4, 21.6. HRMS (ESI-TOF) m/z: [M - H]- calcd. for
C9H8N3O6S 286.0132, found 286.0124.
4h, N-(((4-Methoxyphenyl)sulfonyl)carbamoyl)acetamide.TEA salt.31 (CAS 99069-29-1)
Purification by column chromatography (1% MeOH and 2% TEA in Acetone) afforded 4h as a
white solid (78 mg, 84% yield). 1H NMR (400 MHz, (CD3)2CO) δ 7.87 (d, J = 8.9 Hz, 2H), 6.97 (d,
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J = 8.9 Hz, 2H), 3.84 (s, 3H), 2.91 (t, J = 7.2 Hz, 6H), 2.08 (s, 3H), 1.15 (t, J = 7.2 Hz, 9H).; C
NMR (101 MHz, (CD3)2CO) δ 172.7, 162.1, 129.1, 128.6, 113.3, 55.0, 46.0, 23.4. HRMS (ESI-
TOF) m/z: [M - H]- calcd. for C10H11N2O5S 271.0387, found 271.0380.
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Acknowledgements
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This work was supported by the Carl Tryggers Foundation for Scientific Research (CTS13:333,
CTS14:356) and Uppsala University. The authors thank Dr. Lisa D. Haigh (Imperial College
London, U.K.) for her assistance with high resolution mass determination.
Associated Content
Supporting information
1H and 13C spectra for all products. This material is available free of charge via the Internet at
http://pubs.acs.org/.
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