Oligomerization: An Inherent Property of Sulfonimidamides?

Article abstract of DOI:10.1002/ejoc.202000802

The treatment of the TBS-protected p-toluenesulfonimidamide with HCl exclusively affords the deprotected product. However, when HCl was replaced with formic acid, and the reaction mixture was left for an extended time or treated at high temperature, a mixture of oligomers was obtained as main products. The relevant N,N'-capped oligomers were prepared through carbamoylation with p-chlorophenyl isocyanate. The key to dicarbamoylation is to remove formic acid from the reaction mixture. For comparison, methylsulfonimidamide (as the representative of alkyl sulfonimidamides) was tested under similar conditions. Dissimilarly, the oligomerization occurred slowly, and the N,N'-dicarbamoylation is needed for an adequate separation of the oligomeric derivatives by HPLC. Oligomerization is an unexpected but inherent feature of sulfonimidamides, thus it is suggested that sulfonimidamides should be prepared in the HCl form or the TBS-protected derivatives to minimize the risk of formation of oligomers. Additionally, this work provides a simple approach to access oligomeric sulfonimidamides, an unexplored motif.

Full text of DOI:10.1002/ejoc.202000802

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Oligomerization: an Inherent Property of Sulfonimidamides?
Authors: Yantao Chen, Carl-Johan Aurell, and Rebecca Rae
This manuscript has been accepted after peer review and appears as an
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000802
Link to VoR: https://doi.org/10.1002/ejoc.202000802
01/2020

10.1002/ejoc.202000802
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Oligomerization: an Inherent Property of Sulfonimidamides?
Yantao Chen,a,* Carl-Johan Aurell,b and Rebecca Raec
[a]
Dr. Yantao Chen
Medicinal Chemistry Department
Research and Early Development, Cardiovascular, Renal and Metabolism
BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
E-mail: yantao.chen@astrazeneca.com ; yantaochen@yahoo.com
Homepage: https://www.linkedin.com/in/kscp167/
Dr. Carl-Johan Aurell
Early Chemical Development
Pharmaceutical Sciences
BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
Dr. Rebecca Rae
[b]
[c]
Medicinal Chemistry Department
Research and Early Development, Respiratory & Immunology
BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract:
The
treatment
of
the
TBS-protected
p-
toluenesulfonimidamide with HCl exclusively affords the deprotected
product. However, when HCl was replaced with formic acid, and the
reaction mixture was left for extended time or treated at high
temperature, a mixture of oligomers was obtained as main products.
The relevant N,N’-capped oligomers were prepared through
carbamoylation with p-chlorophenyl isocyanate. The key to
dicarbamoylation is to remove formic acid from the reaction mixture.
For comparison, methylsulfonimidamide (as the representative of
alkyl sulfonimidamides) was tested under similar conditions.
Dissimilarly, the oligomerization occurred slowly, and the N,N’-
dicarbamoylation is needed for an adequate separation of the
oligomeric derivatives by HPLC. Oligomerization is an unexpected but
inherent feature of sulfonimidamides, thus it is suggested that
sulfonimidamides should be prepared in the HCl form or the TBS-
protected derivatives to minimize the risk of formation of oligomers.
Additionally, this work provides a simple approach to access
oligomeric sulfonimidamides, an unexplored motif.
Recently, polysulfonamides (PSAs), the third type of sulfur-
containing polymers, have been explored in material sciences[3]
and the research of lithium-ion batteries.[4] In 2007, Bae and Kang
applied oligomeric sulfonamides as a tool for the effective
endosomal release of polyplexes or delivery of nucleic acid.[5]
Figure 1 shows the general structures of the published sulfur-
containing polymers: PSIAs, PSIs, PSAs, and oligomeric
sulfonimidamides (OSIAs) from this work.
Figure 1. General structures of sulfur-containing polymers.
Sulfonimidamides (SIAs) as an isosteric replacement for
sulfonamides (SAs) have attracted significant attention in organic
chemistry, medicinal and agro-chemistry.[6] In our previous work,
the tert-butyl dimethylsilyl (TBS) protected SIAs such as 2
(Scheme 2) were prepared from the corresponding TBS-
protected sulfonamides.[7] As a well-known protecting group for
alcohols or amines in organic synthesis, TBS is usually removed
in an acidic media, such as HCl, formic acid (HCOOH), etc.[8] The
deprotection of the TBS protected SIAs was successfully
conducted using HCl or HCOOH in a short period of reaction time
(30 min).[7]
Introduction
In 1993, Roy reported the synthesis of trimethylsilyl (TMS)
sulfonimidates (1). Taking advantage of the susceptibility of the
Si-N bond to cleavage at high temperature, the author reported
the synthesis of polysulfonimidamides (PSIAs) through
desilylation.[1] (Scheme 1)
The chemistry of OSIAs in this work was unexpectedly discovered
from the HCOOH-mediated deprotection of the TBS-protected p-
toluenesulfonimidamide (2) as shown in Scheme 2. This work
demonstrates that oligomerization of the monomer 3 (Scheme 2)
in the neutral form also occurs in a neutral solvent (such as
MeCN). The results show that oligomerization is an inherent
feature of primary sulfonimidamides.
Scheme 1. Synthesis of PSIAs through desilylation of sulfonimidates.
Polysulfoximines (PSIs), another novel class of sulfur-containing
polymers, were firstly reported by Takata and co-workers and
applied for high-performance engineering plastics.[2]
1
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10.1002/ejoc.202000802
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Further study on the unknown peaks in Figure 2 reveals that the
difference of the molecular weights of two neighboring peaks is
identical (153 Da). The solid from the reaction mixture was filtered.
Compared with the commercial material, 1H and 13C NMR results
show that the solid formed in the reaction mixture is ammonium
formate (for the comparison, see Supporting Information). The
melting point (119.4 °C by DSC) is also in good agreement with
the commercial material (119.4 °C by DSC, Fluka). Combining
these results, we assume that oligomerization occurs under the
reaction conditions, i.e., two molecules of 3 are oligomerized to
form the dimer (peak 3), and a higher degree of oligomerization
leads to the formation of the trimer (peak 4), and the 4-mer (peak
5) (Figure 2).
Scheme 2. Unexpected oligomerization of 2 during a long time of deprotection.
(a LCMS peak integration).
Results and Discussion
A possible mechanism is shown in Scheme 3. Formic acid acts
both as an acid and an electrophilic one-carbon reagent. The
acidity of HCOOH facilitates the formation of 3 from the TBS-
protected p-toluenesulfonimidamide 2. In the presence of the
excess HCOOH, the condensation between 3 and HCOOH
affords the formylated intermediate A by the loss of water. The
nucleophilic addition of the amidic NH2 in 3 to the aldehyde
functionality in A forms the intermediate B, which transforms into
the intermediate C through transamidation. In the presence of
HCOOH and water, the N,O-acetal fragment in C is labile. The
nucleophilic addition of the acetal carbon with water forms the
intermediate D. After tautomerization, the conjugated product 4
(dimer) is formed. Meanwhile, the C-N cleavage leads the
formation of the hydrate intermediate E, which transforms to the
solid byproduct ammonium formate F through the loss of water.
The deprotection of 2 in the presence of HCOOH or HCl was
successfully conducted in 30 min at rt. However, when a mixture
of 2 and HCOOH (4 equiv) in acetonitrile (MeCN) was stirred at rt
for 18 h, an unexpected white solid material precipitated. LCMS
of the reaction mixture showed only 5% of the deprotected
product 3 (Peak 2, Figure 2). Surprisingly, at least three unknown
peaks (Peaks 3-5) were found.
In summary, a four-step chemistry occurs from 3 (monomer) to 4
(dimer): 1) formylation of 3 to form A; 2) nucleophilic addition to
afford B; 3) transamidation to create C; 4) C-N cleavage to form
D.
Figure 2. LCMS results after stirring at rt for 18 h (Detector: Total Ion
Chromatogram; Peaks are labeled with retention time (Rt) in minutes during a
2-min run).
Scheme 3. A possible oligomerization mechanism in the presence of HCOOH.
2
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10.1002/ejoc.202000802
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Scheme 3 illustrates two possible approaches to the synthesis of
6 (4-mer), namely, a “2+2” convergent approach and a “3+1”
linear approach. In the former approach, the oligomerization
occurs between two molecules of dimer, while in the latter, the
oligomerization undergoes between a trimer molecule and a
monomer. We assume that, in an extended reaction time or at a
high temperature, highly oligomerized products, such as 7 - 9, can
be formed through these two approaches.
form the intermediate B. The formyl functionality in B reacts with
another formate anion to afford the anhydrate C and the reactive
intermediate D. The latter reacts with 10 to form the urea 11. Thus,
we assume that under the conditions the isocyanate 10 is mainly
consumed by the anhydrate C (coming from HCOOH) rather than
OSIAs.
From the above reaction mixture, we also found LCMS peaks of
the monocarbamoylated products (12), despite at low (<10%)
conversions. We assume that they are formed through the
nucleophilic addition of OSIAs with 10 (Scheme 6).
Oligomers 3 – 5 were firstly isolated after preparative HPLC
(buffer pH 10). However, impurities (10%) were found when the
aqueous fraction was concentrated at reduced pressure. We
reason that each oligomer in the aqueous HPLC fraction
undergoes further oligomerization during evaporation. To achieve
a high purity (>95%) for characterizing the oligomers, we
attempted to convert them into the N,N’-dicarbamoylated
derivatives, in which both the amidic NH2 and the imidic NH are
protected with the carbamoyl group (Scheme 4).
Scheme 4. Initial attempts of N,N’-dicarbamoylation of OSIAs.
Initially, we tried the carbamoylation by adding 4-chlorophenyl
isocyanate (10, 2 equiv) directly to the reaction mixture that
contained OSIAs. Unfortunately, the desired dicarbamoylated
OSIAs were not formed. Instead, the urea 11 was the main
product. Based on the relevant information from the literature,[9]
we propose a possible mechanism of the formation of 11 as
shown in Scheme 5.
Scheme 6. Carbamoylation of OSIAs when HCOOH exists in the reaction
mixture.
HRMS of the reaction mixture was checked, which confirmed that
in addition to 12 (n = 2 - 4), N-monoformylated oligomers (13, n =
2, 3) were also formed in the reaction mixture, although at an
ignorable level. Not surprisingly, the reaction of 12 with C, and/or
the reaction of 13 with 10 leads the formation of 14 (n = 1 - 4),
which were also found in HRMS experiments. Interestingly,
intermediates 15 were not found. We reason that the isocyanate
10 dominates in the nucleophilic addition of 13 because of higher
electrophilicity than anhydrate C.
In summary, the addition of 10 to the reaction mixture containing
HCOOH does not afford the expected dicarbamoylated products.
Instead, 11 is produced as the main product. Side-products 12 –
14, are also formed under the conditions. Therefore, it is crucial
to remove HCOOH from the reaction mixture before the addition
of 10.
Thus, an excess amount (5 equiv) of polymer‐supported trisamine
(Biotage® PS-trisamine) as a base was added to the reaction
mixture to neutralize HCOOH. After the addition of 10, the
relevant dicarbamoylated products were found in LCMS. However,
the byproduct 11 was still formed, which indicates the presence
of HCOOH in the reaction mixture after the treatment by PS-
trisamine. We reason that PS-trisamine only takes the free
HCOOH away from the reaction mixture, while the formate anions
in the salt form with oligomeric amines remain in the mixture after
Scheme 5. A possible mechanism of the formation of 11.
In the presence of an excess base (i-Pr2NEt), HCOOH was
deprotonated and the resulting formate anion preferably reacts
with 10 to form the intermediate A, from which CO2 is excluded to
3
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10.1002/ejoc.202000802
European Journal of Organic Chemistry
FULL PAPER
[g] no other reagents added; [h] nf: LCMS peak not found; [i] 2 (35.3 µmol),
MeCN (1 mL), rt, 2 d.
the treatment. The formate anions undergo the side-reactions as
illustrated in Scheme 5.
The results in Table 1 indicate that the oligomerization of the
neutral 3 occurs in the presence of both organic (Entry 1) and
inorganic bases (Entry 2). Under acidic conditions, the HCl salt is
rather stable, only a trace of dimer is formed (Entry 3) after 2 d.
However, in the presence of HCOOH, the salt is partially
oligomerized (Entry 4), while the neutral 3 completely goes to
oligomerization (Entry 5). The result of Entry 6 indicates that a
solution of the neutral 3 in a neutral solvent (e.g. MeCN) still
undergo oligomerization at room temperature, despite slow
progress.
To completely remove HCOOH from the mixture, a strong acid,
such as HCl, was added to the reaction mixture. Through the acid
exchange, the HCl salts of the oligomers were obtained. The
addition of 10 to the HCl salts under basic conditions (i-Pr2NEt)
afforded the expected dicarbamoylated products. It is worth
noting that the byproduct 11 was not found in LCMS.
As proposed in Scheme 3, an oligomer, such as 3 (monomer), 4
(dimer), and
5 (trimer), can go to a higher degree of
oligomerization. Therefore, we synthesized the relevant the
dicarbamoylated oligomers 16 – 18 from 3 – 5 in one reaction
mixture, and 19 – 22 from 6 – 9 in the other reaction mixture. For
16 – 18, the oligomeric mixture was stirred for 18 h at rt to gain 3
– 5 as the main oligomers, followed by the removal of HCOOH,
and the addition of the isocyanate 10 and i-Pr2NEt to afford the
expected products with the total isolated-yield at 58% (10% + 2 ×
12% + 3 × 8%); 2) for 19 – 22, the oligomerization underwent at
45 ℃ for 10 h, followed by a similar treatment as done for
dicarbamoylation of 3 – 5 to give the desired products at 62% of
total yields (Scheme 7).
As a comparison to 3, the TBS-protected sulfonimidamide 2 was
tested under neutral and basic conditions (Entry 7, Entry 8). The
results indicate that the TBS derivative is very stable in MeCN.
Under the neutral or basic conditions (i-Pr2NEt), no TBS-
deprotection or oligomerization was observed.
From Table 1, we learn that: 1) the neutral sulfonimidamide 3 or
its HCl salt is fairly stable in a neutral solvent (MeCN) (Entry 3,
Entry 6); 2) the TBS protected sulfonimidamide 2 is very stable in
a neutral or basic media (Entry 7, Entry 8). Therefore, we
recommend that an SIA-featured final product should be prepared
and stored in its HCl salt form, while for an SIA-containing
intermediate, in addition to the HCl salt form, the TBS-protected
derivative is also a good option. Practically, the HCOOH-
containing aqueous buffer should not be used in preparative
HPLC.
In contrast to Scheme 3, in which HCOOH plays an important role
for oligomerization, we propose another possible mechanism of
oligomerization to form the dimer (4) in the presence of organic or
inorganic bases, as shown in Scheme 8.
Scheme 7. N,N’-dicarbamoylation of OSIAs in the absence of HCOOH.
Next, we studied oligomerization of 3 in its neutral form under six
conditions (Table 1). The integration in the percentage of the
LCMS peak of each oligomer in each reaction mixture is
summarized in Table 1.
Table 1. Oligomerization of 3 under different conditions.[a]
Entry
monomer
dimer
trimer
4-mer
5-mer
(3)
(4)
(5)
(6)
(7)
1[b]
2[c]
3[d]
4[e]
5[g]
6[g]
7[i]
77
62
93
76
nf
8
8
nf[h]
nf
28
7
3
nf
nf
nf
33
nf
nf
nf
nf
20
nf
nf
23
3
nf
Scheme 8. A possible oligomerization mechanism in the presence of bases
(Entry 1 and Entry 2 in Table 1).
36
93
4
<2
The pKa value of p-toluenesulfonamide in MeCN is 26.9.[10]
However, the pKa value of 3 is not available in the literature. We
assume that 3, acting as a weak Brønsted acid under basic
conditions, is deprotonated to create the intermediates A, which
tautomerizes to form B. The nucleophilic reaction of A/B with
another molecule of 3, which acts as an electrophile, forms the
labile intermediates C/D, which contain the triaminesulfur (SON3)
fragment. Through the exclusion of one NH3 molecule, the dimer
2 (100%)
2 (100%)
8[i,b]
[a] conditions: 3 (35.3 µmol), MeCN (1 mL), rt, 2 d; [b] i-Pr2NEt (4 equiv); [c] aq.
K3PO4 (48 µL, 4 equiv) and MeOH (0.1 mL); [d] HCl (2 equiv) in MeOH (0.1 mL);
[e] HCl (2 equiv) in MeOH (0.1 mL) and HCOOH (4 equiv); [f] HCOOH (4 equiv);
4
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10.1002/ejoc.202000802
European Journal of Organic Chemistry
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product E and/or its tautomeric form (4) is formed. In summary,
under basic conditions, the nucleophilic addition between two
monomeric molecules, followed by NH3 exclusion, affords the
dimeric product 4. Similarly, oligomer 5, the trimer is formed from
the mixture of the monomer (3) and the dimer (4).
In summary, we present the oligomerization of sulfonimidamides
through transamidation under basic, acidic, and neutral conditions,
and conclude that oligomerization is an inherent property of a
sulfonimidamide. In light of the increasing application of
sulfonimidamides in organic chemistry, medicinal and agro-
chemistry,[6] we think our work is useful for chemists who work
with sulfonimidamides. A practical way to avoid the side-reaction
is to keep the substance in its HCl form or the TBS-protected
derivative.
Encouraged by the success oligomerization of 3, we used 23 as
the representative substrate of alkyl sulfonimidamides for the
oligomerization study. It is noteworthy that compared with the
oligomerization of 3, the oligomerization of 23 underwent slowly
at room temperature. After 3 days, the monomer as the major
product, dimer, and trimer as minor products were found in LCMS.
Moreover, the oligomers are extremely polar, and hard to
separate by normal phase HPLC. To our delight, the relevant
dicarbamoylated products (24 – 26) were isolated by HPLC.
Additionally, we also obtained byproducts 27 – 29, which are
analogous to the intermediate 14 (Scheme 9).
We expect that as an unexplored chemical motif, the oligomeric
sulfonimidamides may find applications in the chemistry
community in the future.
Experimental Section
General
Unless otherwise noted all materials and reagents were obtained from
commercial sources and used without further purification. All solvents used
in moisture sensitive reactions were of the commercial anhydrous grade.
The decomposition temperature was measured on a Mettler Toledo
DSC3+. The sample was heated at a rate of one degree per minute. The
onset value was used as decomposition temperature. Nuclear magnetic
resonance (NMR) spectra were recorded on a Bruker 500 MHz Avance III
system using a 5mm cryo QNP (1H, 19F, 13C, 15N) probe. Chemical shifts
(δ) are reported in parts per million (ppm) and are referenced to the
residual solvent signal set to 3.30 ppm (CD3OD) and 2.50 ppm (DMSO-d6)
for 1H; 49.10 ppm (CD3OD) and 39.5 ppm (DMSO-d6) for 13C. Multiplicities
are reported using the following abbreviations: s = singlet, d = doublet, m
Scheme 9. Synthesis of the dicarbamoylated products 24 – 26, and the
intermediates 27 – 29.
1
= multiplet. Some H spectra show the presence of acetamide, which is
Scheme 7 illustrates the formation of monomer (3), dimer (4), and
trimer (5) when the mixture was stirred at rt for 10 h, and the
formation of 4-mer (6), 5-mer (7), 6-mer (8), and 7-mer (9) when
the mixture was stirred at 45 ℃ for 10 h. We were curious about
what will happen if the mixture was stirred at a higher temperature.
Figure 3 shows the LCMS results of the reaction mixture which
was stirred at 70 ℃ for 30 min. Mass fragmentation indicates the
formation of monomer (Rt = 0.40), dimer (Rt = 0.64), trimer (Rt =
0.83), 4-mer (Rt = 0.96), 5-mer (Rt = 1.06), 6-mer (Rt = 1.14), 7-
mer (Rt = 1.20), and highly oligomerized components.
formed during the evaporation of the basic buffer (a mixture of MeCN-
NH4OH in water), at approximate shifts of 1.93 ppm for 1H and 22.1, 176.5
ppm for 13C. The base (i-Pr2NEt) are also presented in some 1H spectra.
Exchangeable protons (NH) are missing in the 1H spectra due to chemical
exchange with water signal. For the racemic products 16 and 24, which
are the mixture of two enantiomers, the NMR is reported as a pure
substance. For other products, which are the mixture of diastereomers, a
range of chemical shifts is usually reported in this work. A Waters
XBridge™ column with C18 packing material has been used for high-
resolution mass spectra (HRMS) experiments. HRMS results were
recorded for all final products, on a Waters Xevo QTof mass spectrometer
fitted with an electrospray (ESI) ion source.
Because of the chirality of the sulfur atom in each oligomer, each
dicarbamoylated product is racemic, i.e. a mixture of enantiomers or
diastereomers, which are practically difficult to be isolated by chiral HPLC.
We do not intend to isolate each isomer, rather than to communicate this
unexpected chemistry. In fact, when the oligomerization number n > 3,
both the 1H and 13C NMR spectra of an oligomeric derivative look
complicated.
General Method for Oligomerization
A mixture of an N-TBS protected sulfonimidamide) (2 mmol), formic acid
(8 mmol) in MeCN (9 mL) was stirred under appropriate conditions in three
vials.
Vial A: the mixture was stirred at rt for 10 h for the preparation of the
oligomer 3 – 5; Vial B: the mixture was stirred at 45 ℃ for 10 h for the
synthesis of the oligomers 6 – 9; and Vial C: the mixture was stirred at rt
for 3 d when 23 was used as the substrate.
Figure 3. LCMS results after stirring at 70 ℃ for 30 min (Detector: UV 254 nm,
peaks are labeled with retention time (Rt) in minutes during a 2-min run).
General Method for Removal of HCOOH
Conclusion
5
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N-((4-Chlorophenyl)carbamoyl)-N'-(N-(N-((4-
The mixture in each vial was filtered to remove the insoluble material
(Ammonium Formate). To the filtrate was added HCl (4 M in dioxane, 1
mL) in each vial. The resulting suspension was concentrated to a dry
residue. The crude was treated with MeCN (6 mL) and HCl (1 mL, 4 M in
dioxane), and the mixture was concentrated to a dry residue, and further
dried in the vacuum for 2 h.
chlorophenyl)carbamoyl)-4-methylphenylsulfonimidoyl)-4-
methylphenylsulfonimidoyl)-4-methylbenzenesulfonimidamide (18)
(The product contains 0.8 eq of i-Pr2NEt)
A white solid (126 mg, 8%). Decomposition temperature 237.9 °C. 1H NMR
(500 MHz, CD3OD) δ 6.91 – 7.82 (m, 20H), 2.15 – 2.38 (m, 9H). 13C NMR
(126 MHz, CD3OD) δ 157.98 – 158.42 (m), 142.66 – 142.78 (m), 142.05 –
142.2 (m), 140.68, 140.63, 140.34, 140.28, 139.94, 139.29, 138.95 –
139.08 (m), 128.29 – 128.6 (m), 128.00, 127.16 – 127.33 (m), 126.91 –
127.09 (m), 126.13 – 126.28 (m), 19.92 – 20.18 (m). HRMS (ESI) m/z
calculated for C35H32Cl2N6O5S3 [M + H]+: 783.1052, found 783.1037.
General Method for Dicarbamoylation
To the crude in each vial were added MeCN (9 mL) and i-Pr2NEt (5 equiv)
mmol). To the resulting mixture was added 1-chloro-4-isocyanatobenzene
(10, 2.2 equiv*), and the resulting mixture was stirred at rt for 30 min.
N-((4-Chlorophenyl)carbamoyl)-N'-(N-(N-(N-((4-
chlorophenyl)carbamoyl)-4-methylphenylsulfonimidoyl)-4-
methylphenylsulfonimidoyl)-4-methylphenylsulfonimidoyl)-4-
methylbenzenesulfonimidamide (19) (The product contains 0.7 eq of i-
Pr2NEt)
*: relative to the sum of the LCMS peak percentage of each oligomer. For
example, the LCMS peak integration of oligomers 3 – 5 is 26%, 32%
(dimer), and 36% (trimer). Thus, when 2 mmol of the sulfonimidamide is
used, the 2.2 equiv of the isocyanate should be: 2.2 × 2 × (0.26 + 0.32/2 +
0.36/3) = 2.4 mmol.
A white solid (61 mg, 3%). Decomposition temperature 239.7 °C. 1H NMR
(500 MHz, CD3OD) δ 6.89 – 7.86 (m, 24H), 2.18 – 2.4 (m, 12H). 13C NMR
(126 MHz, CD3OD) δ 159.29 – 159.76 (m), 144.29 – 144.63 (m), 143.44 –
143.9 (m), 139.87 – 142.21 (m), 129.81 – 130.35 (m), 129.27 – 129.7 (m),
128.32 – 128.97 (m), 127.4 – 128.01 (m), 124.07, 120.86 – 121.83 (m),
21.44 – 21.69 (m). HRMS (ESI) m/z calculated for C42H39Cl2N7O6S4 [M +
H]+: 936.1300, found 936.1310.
General Separation of Final products
After N,N’-dicarbamoylation, the crude mixture was concentrated to a dry
residue. The crudes were purified by preparative HPLC.
Products 16 – 18 were isolated from the crude mixture (Vial A). The
compound was purified by preparative HPLC on an XBridge C18 column
(10 μm 250x50 ID mm) using a gradient of 20-70% acetonitrile in
H2O/MeCN/NH3 95/5/0.2 buffer over 30 min with a flow of 100 mL/min. The
compounds were detected by UV at 240 nm.
N-((4-Chlorophenyl)carbamoyl)-N'-(N-(N-(N-(N-((4-
chlorophenyl)carbamoyl)-4-methylphenylsulfonimidoyl)-4-
methylphenylsulfonimidoyl)-4-methylphenylsulfonimidoyl)-4-
methylphenylsulfonimidoyl)-4-methylbenzenesulfonimidamide (20)
(The product contains 0.5 eq of i-Pr2NEt)
Products 19 – 22 were obtained from the crude mixture (Vial B). The
compound was purified by preparative HPLC on an XBridge C18 column
(10 μm 250x50 ID mm) using a gradient of 50-100% acetonitrile in
H2O/MeCN/NH3 95/5/0.2 buffer over 40 min with a flow of 100 mL/min. The
compounds were detected by UV at 240 nm.
A white solid (106 mg, 5%). Decomposition temperature 244.3 °C. 1H NMR
(500 MHz, CD3OD) δ 6.88 – 7.78 (m, 28H), 2.15 – 2.38 (m, 15H). 13C NMR
(126 MHz, CD3OD) δ 159.29 – 159.69 (m), 144.4 – 144.8 (m), 143.56 –
143.99 (m), 140.21 – 142.05 (m), 127.47 – 130.54 (m), 21.49 – 21.71 (m).
HRMS (ESI) m/z calculated for C49H46Cl2N8O7S5 [M + H]+: 1089.1548,
found 1089.1564.
Product 24 – 29 were obtained from the crude mixture (Vial C). The
compound was purified by preparative HPLC on an XBridge C18 column
(10 μm 250x50 ID mm) using a gradient of 10-50% acetonitrile in
H2O/MeCN/NH3 95/5/0.2 buffer over 20 min with a flow of 100 mL/min. The
compounds were detected by UV at 240 nm.
N-((4-chlorophenyl)carbamoyl)-N'-(N-(N-(N-(N-(N-((4-
chlorophenyl)carbamoyl)-4-methylphenylsulfonimidoyl)-4-
methylphenylsulfonimidoyl)-4-methylphenylsulfonimidoyl)-4-
methylphenylsulfonimidoyl)-4-methylphenylsulfonimidoyl)-4-
methylbenzenesulfonimidamide (21) (The product contains 0.25 eq of i-
Pr2NEt)
All desired HPLC fractions were freezing-dried. The solid samples are
subjected for DSC experiments. No re-crystallization was carried out for
the oil samples. All final samples were also confirmed by HRMS.
A white solid (82 mg, 3%). Decomposition temperature 248.0 °C. 1H NMR
(500 MHz, CD3OD) δ 6.83 – 7.86 (m, 32H), 2.17 – 2.37 (m, 18H). 13C NMR
(126 MHz, CD3OD) δ 159.58 (m), 159.37 – 159.82 (m), 143.57 – 145.28
(m), 139.97 – 142.18 (m), 128.14 – 130.51 (m), 121.02 – 121.75 (m), 21.49
– 21.77 (m). HRMS (ESI) m/z calculated for C56H53Cl2N9O8S6 [M + H]+:
1242.1797, found 1242.1776.
N,N'-Bis((4-chlorophenyl)carbamoyl)-4-
methylbenzenesulfonimidamide (16)
A white solid (91 mg, 10%). Decomposition temperature 142.9 °C. 1H NMR
(500 MHz, CD3OD) δ 7.96 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.7 Hz, 4H),
7.30 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.7 Hz, 4H), 2.37 (s, 3H). 13C NMR
(126 MHz, CD3OD) δ 158.36, 144.38, 140.32, 139.87, 130.29, 129.61,
129.02, 128.37, 121.58, 21.55. HRMS (ESI) m/z calculated for
C21H18Cl2N4O3S [M + H]+: 477.0555, found 477.0554.
N-((4-chlorophenyl)carbamoyl)-N'-(N-(N-(N-(N-(N-(N-((4-
chlorophenyl)carbamoyl)-4-methylphenylsulfonimidoyl)-4-
methylphenylsulfonimidoyl)-4-methylphenylsulfonimidoyl)-4-
methylphenylsulfonimidoyl)-4-methylphenylsulfonimidoyl)-4-
methylphenylsulfonimidoyl)-4-methylbenzenesulfonimidamide (22)
N-((4-Chlorophenyl)carbamoyl)-N'-(N-((4-chlorophenyl)carbamoyl)-4-
methylphenylsulfonimidoyl)-4-methylbenzenesulfonimidamide (17)
(The product contains 0.22 eq of i-Pr2NEt)
A white solid (30 mg, 1%). Decomposition temperature 237.3 °C. 1H NMR
(500 MHz, CD3OD) δ 6.78 – 7.77 (m, 38H), 2.18 – 2.46 (m, 21H). 13C NMR
(126 MHz, CD3OD) δ 144.41 – 145 (m), 142.98 – 143.99 (m), 140.04 –
141.24 (m), 129.75 – 130.48 (m), 129.49, 128.16 – 128.95 (m), 127.47 –
127.99 (m), 121.79, 120.72 – 121.65 (m), 21.45 – 21.78 (m). HRMS (ESI)
A white solid (154 mg, 12%). Decomposition temperature 126.0 °C. 1H
NMR (500 MHz, CD3OD) δ 7.58 – 7.85 (m, 4H), 7.26 – 7.38 (m, 4H), 7.03
– 7.17 (m, 8H), 2.29 (s, 3H), 2.27 (s, 3H). 13C NMR (126 MHz, CD3OD) δ
159.69, 159.50, 143.80, 143.67, 141.61, 141.07, 140.35, 140.26, 129.99,
129.97, 129.47, 129.45, 128.57, 128.53, 127.87, 127.82, 121.40, 21.47 –
21.54 (m). HRMS (ESI) m/z calculated for C28H25Cl2N5O4S2 [M + H]+:
630.0803, found 630.0806.
m/z calculated for C63H60Cl2N10O9S7 [M
1395.2009.
+
H]+: 1395.2045, found
6
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10.1002/ejoc.202000802
European Journal of Organic Chemistry
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N,N'-Bis((4-chlorophenyl)carbamoyl)methanesulfonimidamide (24)
A white solid (153 mg, 19%). Decomposition temperature 190.1 °C. 1H
NMR (500 MHz, DMSO-d6) δ 9.36 (s, 2H), 7.51 (d, J = 8.9 Hz, 4H), 7.32
(d, J = 8.9 Hz, 4H), 3.55 (s, 4H). 13C NMR (126 MHz, DMSO-d6) δ 138.21,
128.69, 126.23, 120.18, 42.49. HRMS (ESI) m/z calculated for
C15H14Cl2N4O3S [M + H]+: 401.0242, found 401.0252.
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A sticky colorless oil (123 mg, 13%). 1H NMR (500 MHz, CD3OD) δ 7.39
– 7.48 (m, 4H), 7.12 – 7.21 (m, 4H), 3.39 (s, 6H). 13C NMR (126 MHz,
CD3OD) δ 160.74, 140.31, 129.49, 127.95, 121.60, 44.45. HRMS (ESI)
m/z calculated for C16H17Cl2N5O4S2 [M + H]+: 478.0177, found 478.0179.
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1
A sticky colorless oil (68 mg, 6%). H NMR (500 MHz, CD3OD) δ 7.38 –
7.48 (m, 4H), 7.12 – 7.23 (m, 4H), 3.36 – 3.48 (m, 9H). 13C NMR (126 MHz,
CD3OD) δ 160.40, 140.27, 129.52, 128.02, 121.61, 46.99, 46.79, 46.43,
44.89, 44.81, 44.76. HRMS (ESI) m/z calculated for C17H20Cl2N6O5S3 [M
+ H]+: 555.0112, found 555.0109.
N-(N-((4-chlorophenyl)carbamoyl)-S-methylsulfonimidoyl)formamide
(27)
1
A sticky colorless oil (32 mg, 6%). H NMR (500 MHz, CD3OD) δ 7.39 –
7.49 (m, 2H), 7.15 – 7.24 (m, 2H), 3.23 (s, 3H). 13C NMR (126 MHz,
CD3OD) δ 173.23, 161.11, 140.54, 129.53, 127.83, 121.40, 43.84. HRMS
(ESI) m/z calculated for C9H10ClN3O3S [M + H]+: 276.0204, found
276.0209.
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N-(N-(N-((4-chlorophenyl)carbamoyl)-S-methylsulfonimidoyl)-S-
methylsulfonimidoyl)formamide (28)
A a sticky colorless oil (12 mg, 2%). 1H NMR (500 MHz, CD3OD) δ 7.41 –
7.48 (m, 2H), 7.16 – 7.24 (m, 2H), 3.27 – 3.38 (m, 6H). 13C NMR (126 MHz,
CD3OD) δ 172.12, 160.56, 140.52, 129.55, 128.00, 121.56, 46.13, 45.85,
45.08, 44.89. HRMS (ESI) m/z calculated for C10H13ClN4O4S2 [M + H]+:
353.0145, found 353.0140.
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A sticky colorless oil (8 mg, 1%). 1H NMR (500 MHz, CD3OD) δ 7.41 – 7.48
(m, 2H), 7.17 – 7.23 (m, 2H), 3.26 – 3.48 (m, 9H). 13C NMR (126 MHz,
CD3OD) δ 171.57, 159.87, 140.90, 129.17, 128.01, 121.53, 44.83-47.21
(m). HRMS (ESI) m/z calculated for C11H16ClN5O5S3 [M + H]+: 430.0080,
found 430.0087.
Acknowledgments
The authors thank Johan Söderlund for his attempts to isolate the
final products.
Keywords: Sulfonimidamides • Deprotection • Formic acid •
Transamidation • Oligomerization
7
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Entry for the Table of Contents
Key Topic: Sulfonimidamides Oligomerization
Deprotection of sulfonimidamides with formic acid in a long period of reaction time (hrs to days) leads to the formation of the
unexpected oligomeric sulfonimidamides. This work demonstrates that an unprotected sulfonimidamide can also undergo a similar
oligomerization in a neutral solvent. The results indicate that oligomerization is an inherent property of sulfonimidamides.
8
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