Intramolecular carbene C-H insertion reactions of 2-diazo-2-sulfamoylacetamides

Article abstract of DOI:10.3390/molecules24142628

The intramolecular C-H insertions of carbenes derived from 2-diazo-2-sulfamoylacetamides were studied. 2-Diazo-2-sulfamoylacetamides were first prepared from chloroacetyl chloride and secondary amines through acylation followed by sequential treatments with sodium sulfite, phosphorus oxychloride, secondary amines, and 4-nitrobenzenesulfonyl azide. The results indicate that: (1) 2-diazo-N,N-dimethyl-2-(N,N-diphenylsulfamoyl)acetamide can take the formal aromatic 1,5-C-H insertion in its N-phenylsulfonamide moiety to afford the corresponding 1,3-dihydrobenzo[c]isothiazole-3-carboxamide 2,2-dioxide derivative; (2) no aliphatic C-H insertions occur for 2-diazo-2-(N,N-dialkylsulfamoyl)acetamides; and (3) for 2-diazo-N-phenyl-2-(N-phenylsulfamoyl)acetamides, the formal aromatic 1,5-C-H insertion in the N-phenylacetamide moiety is favorable to afford the corresponding 3-sulfamoylindolin-2-one derivatives as sole or major products. The intramolecular competitive aromatic 1,5-C-H insertion reactions of 2-diazo-2-sulfamoylacetamides with aryl groups on both amide and sulfonamide groups reveal that the N-aryl substituents on acetamide are more active than those on sulfonamide. The chemoselectivity is controlled by electronic effect of the aryl group.

Full text of DOI:10.3390/molecules24142628

molecules
Article
Intramolecular Carbene C-H Insertion Reactions
of 2-Diazo-2-sulfamoylacetamides
†
†
Chuqiang Que , Peipei Huang , Zhanhui Yang , Ning Chen and Jiaxi Xu *
State Key Laboratory of Chemical Resource Engineering, Department of Organic Chemistry, College of
Chemistry, Beijing University of Chemical Technology, Beijing 100029, China
*
Correspondence: jxxu@mail.buct.edu.cn; Tel./Fax: +86-10-6443-5565
†
These authors contributed equally to this work.
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editors: Richard A. Bunce, Philippe Belmont, Wim Dehaen and Eugene Babaev
Received: 1 July 2019; Accepted: 16 July 2019; Published: 19 July 2019
ꢀ
ꢁꢂꢃꢄꢅꢆ
Abstract: The intramolecular C-H insertions of carbenes derived from 2-diazo-2-sulfamoylacetamides
were studied. 2-Diazo-2-sulfamoylacetamides were first prepared from chloroacetyl chloride
and secondary amines through acylation followed by sequential treatments with sodium
sulfite, phosphorus oxychloride, secondary amines, and 4-nitrobenzenesulfonyl azide. The
results indicate that: (1) 2-diazo-N,N-dimethyl-2-(N,N-diphenylsulfamoyl)acetamide can take
the formal aromatic 1,5-C-H insertion in its N-phenylsulfonamide moiety to afford the
corresponding 1,3-dihydrobenzo[c]isothiazole-3-carboxamide 2,2-dioxide derivative; (2) no
aliphatic C-H insertions occur for 2-diazo-2-(N,N-dialkylsulfamoyl)acetamides; and (3) for
2-diazo-N-phenyl-2-(N-phenylsulfamoyl)acetamides, the formal aromatic 1,5-C-H insertion in
the N-phenylacetamide moiety is favorable to afford the corresponding 3-sulfamoylindolin-2-one
derivatives as sole or major products. The intramolecular competitive aromatic 1,5-C-H insertion
reactions of 2-diazo-2-sulfamoylacetamides with aryl groups on both amide and sulfonamide groups
reveal that the N-aryl substituents on acetamide are more active than those on sulfonamide. The
chemoselectivity is controlled by electronic effect of the aryl group.
Keywords: amide; carbene insertion; C-H insertion; competitive reaction; diazo compound;
sulfonamide; sultam
1
. Introduction
The transition-metal-catalyzed intramolecularly aliphatic and aromatic C-H insertions of
diazo amides provide important transformations to efficiently synthesize nitrogen-containing
heterocycles with the new C-C bond formation [
1
],
–
γ
4
]. The reactivity of diazoamides has been
-lactams (II) [ ], indolin-2-ones (III) [10 15],
), and cyclopropanation products
21] (Scheme 1a) and a series of exquisite reactions has been established to construct complex
well studied (Scheme 1a), affording -lactams ( ) [
β
I
5–
9
5
–9
–
1,4-dihydroisoquinolin-3(2H)-ones (IV), Buchner products (
V
(
VI) [16
–
and useful structures, such as biological and natural products [22,23].
Recently, we put much attention to the reactivity of different diazosulfonamides
(Scheme 1b) [24
,
25], and realized the rhodium- and copper-catalyzed intramolecular aromatic
1
2
,5-C-H insertion of N,N-diaryl diazomethanesulfonamides with the ethoxycarbonyl group (ethyl
-(N,N-diarylsulfamoyl)-2-diazoacetates) to prepare ethyl 1-aryl-1,3-dihydrobenzo[c]isothiazole-3-
-sultams) (R = OEt, Scheme 1b) [24]. We
also achieved the copper-catalyzed intramolecularly aromatic 1,5-C-H insertion of N-alkyl-N-aryl
diazomethanesulfonamides with the acetyl and benzoyl groups to synthesize 1-alkyl-3-acetyl/
carboxylate 2,2-dioxides (N-aryl-3-ethoxycarbonyl benzo-
γ
1
benzoyl-2,2-dioxido-1,3-dihydrobenzo[c]isothiazoles (R = Me, Ph, Scheme 1b) [25]. For the
N-alkyldiazomethanesulfonamides with acetyl, benzoyl, and ethoxycarbonyl groups, the aliphatic C-H
Molecules 2019, 24, 2628; doi:10.3390/molecules24142628
www.mdpi.com/journal/molecules

Molecules 2019, 24, 2628
2 of 14
insertions, including 1,4-, 1,5-, and 1,6-insertions, of the N-alkyl groups on the sulfonamide moiety were
not observed [24 25]. Compared with diazoacetamides, only limited investigations on the reactivity
and chemoselectivity on diazosulfonamides were conducted [24 25]. 2-Diazo-2-sulfamoylacetamides
,
,
are also carbamoyl diazomethanesulfonamides from the viewpoint of sulfonamides. They are
diazomethanes with both carbamoyl and sulfamoyl groups. The following is not clear to date:
(1) Do aromatic 1,5-C-H insertions of carbamoyl diazomethanesulfonamides take place on their
N-phenyl group on sulfonamide? (2) Do aliphatic C-H insertions occur in 2-diazo-2-(N,N-
dialkylsulfamoyl)acetamides? (3) If 2-diazo-2-sulfamoylacetamides have two aryl groups on different
nitrogen atoms of their amide and sulfonamide groups, what is the chemoselectivity in their
intramolecular competitive aromatic 1,5-C-H insertion reactions? Herein, we report our results
on the intramolecular carbene C-H insertion reactions of 2-diazo-2-sulfamoylacetamides with different
alkyl and aryl substituents on the nitrogen atoms of the amide and sulfonamide groups.
Scheme 1. Intramolecular carbene C-H insertion reactions of diazoacetamide derivatives and acyl
diazomethanesulfonamides.

Molecules 2019, 24, 2628
3 of 14
2
. Results and Discussion
2
.1. Synthesis of 2-Diazo-2-sulfamoylacetamides 1
Because the carbene C-H insertion of carbamoyl diazomethanesulfonamides has not been explored
previously, to confirm whether N-aryl-carbamoyl-diazomethanesulfonamides can take the aromatic
,5-C-H insertion in their N-arylsulfonamide moiety, we first prepared N-methyl-N-phenyl and
1
N,N-diphenyl carbamoyl-diazomethanesulfonamides 1a and 1b. The reaction of 2-chloroacetyl chloride
and dimethylammonium chloride (4a·HCl) in the presence of triethylamine in dichloromethane afforded
2
-chloro-N,N-dimethylacetamide (5a) in 90% yield. 2-Chloroacetamide 5a was treated with sodium
sulfite in water three times to give rise to solid sodium carbamoylmethanesulfonate after removal of
water. The mixture of dry crude sodium sulfonate and phosphorus oxychloride was refluxed for 3 h to
afford the corresponding sulfonyl chloride 6a, which further reacted with N-methylaniline (4b) and
diphenylamine (4c), respectively. However, only diphenylamine (4c) gave rise to sulfamoylacetamide
7
b
in a low yield of 16%. It is somewhat strange that N,N-dimethylcarbamoylmethanesulfonyl chloride
(6a) failed to react with N-methylaniline (4b) (Scheme 2). To verify the results, we attempted the
reaction several times, but all failed to afford sulfamoylacetamide 7a (Table 1, entry a).
The reactions of 2-chloroacetyl chloride and secondary amines 4b and 4c produced tertiary
2-chloroacetamides 5c and 5d in excellent yields. 2-Chloroacetamides 5c,d were treated with
sodium sulfite in water three times to give rise to solid sodium carbamoylmethanesulfonates after
removal of water. The mixtures of dry crude sodium sulfonates and phosphorus oxychloride were
refluxed for 3 h to afford the corresponding sulfonyl chlorides 6c
insertions of 2-diazo-2-(N,N-dialkylsulfamoyl)acetamides, sulfonyl chlorides 6c
N-butylbenzylamine (4d) to yield 2-(N-benzyl-N-butylsulfamoyl)-2-diazoacetamides 7c
,
d
. To evaluate aliphatic C-H
were reacted with
in satisfactory
,d
,
d
yields (Table 1, entries c and d). To investigate the intramolecular competitive aromatic 1,5-C-H insertion
of N-aryl-2-(N-arylsulfamoyl)-2-diazoacetamides, sulfonyl chlorides 6c,d were further reacted with
another secondary amines 4b
e–h). Sulfamoylacetamides
transformation reaction with 4-nitrobenzenesulfonyl azide (NsN ) in acetonitrile with DBU as base
,c
to yield sulfamoylacetamides 7e
–h
in 30–88% yields (Table 1, entries
7
were converted into 2-diazosulfamoylacetamides
1
through the diazo
3
(Scheme 2).
Scheme 2. Synthesis of 2-diazo-2-sulfamoylacetamides.
Although the reaction of N,N-diphenylcarbamoylmethanesulfonyl chloride (6d) and diphenylamine
4c) worked well (Table 1, entry h), when we tried to react it with di(4-methoxyphenyl)amine (4e),
(
di(4-methylphenyl)amine (4f), di(4-chlorophenyl)amine (4g), and di(4-bromophenyl)amine (4h) to
prepare different 2-(N,N-diarylsulfamoyl)-2-diazo-N,N- diphenylacetamides 1i with different electron
–l
density phenyl groups on the nitrogen of the sulfonamide group, no reaction occurred or only trace
amounts of the corresponding 2-diazosulfamoylacetamides were observed.

Molecules 2019, 24, 2628
4 of 14
Table 1. Synthesis of 2-diazo-2-sulfamoylacetamides 1.
Yield (%)
Entry
R1
R2
R3
R4
5
7
1
a
b
c
d
e
f
Me
Me
Me
Ph
Me
Me
Ph
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Me
Ph
Bu
Bu
Me
Ph
Me
Ph
Ph
Ph
Bn
Bn
Ph
Ph
Ph
Ph
90
-
-
25
59
28
74
30
88
72
16
45
50
88
26
60
65
90
96
90
g
h
96
Ph
2
.2. Intramolecular Carbene C-H Insertion Reactions of 2-Diazo-2-sulfamoylacetamides 1
The reaction of 2-diazo-N,N-dimethyl-2-(N,N-diphenylsulfamoyl)acetamide (1b) was applied
to optimize the reaction conditions. The results indicate that 2-diazo-2-sulfamoylacetamide 1b in
refluxing toluene under stirring and the catalysis of Cu(acac) for 9 h is the optimal condition, similar to
2
a previous study [25], affording N,N-dimethyl-1-phenyl-1,3-dihydrobenzo[c]isothiazole-3-carboxamide
2
,2-dioxide (2b) in 90% yield (Table 2, entry 1). The results show that N-aryl-diazomethanesulfonamides
with carbamoyl substituents are suitable substrates for the intramolecular aromatic 1,5-C-H insertion
on the aryl group of sulfamide.
To further examine aliphatic C-H insertion of 2-diazo-2-sulfamoylacetamides, both 2-diazo-2-
(N-benzyl-N-butylsulfamoyl)-N- methyl-N-phenylacetamide (1c) and 2-diazo-2-(N-benzyl-N-
butylsulfamoyl)-N,N-diphenylacetamide (1d) were conducted under the optimal reaction
conditions, affording 3-(N-benzyl-N-butylsulfamoyl)-1-methylindolin-2-one (3c) and 3-(N-benzyl-
N-butylsulfamoyl)-1-phenylindolin-2-one (3d) chemospecifically in 76% and 85% yields, respectively
(Table 2, entries 2 and 3). Similar to acyl diazomethanesulfonamides [24,25], aliphatic 1,4-, 1,5-,
and 1,6-C-H insertions in the butyl group; aromatic 1,6-C-H insertion; Buchner reaction; and
cyclopropanation on the benzene ring in the benzyl group did not occur, although diazosulfones and
diazosulfonates favored aliphatic insertions [26–32].
Although the aliphatic carbene 1,4-C-H insertion of diazoamides generally occurred and
was sensitive to the acyl groups [1–15], it appeared quite different in our attempted acyl
diazo-N-methylmethanesulfonamides [25] and 2-diazo-2-(N-benzyl-N-butylsulfamoyl)acetamides 1c,d,
possibly because of the subtle changes in conformation or the bond length of diazomethanesulfonamides,
as Doyle and coworkers mentioned [3].
To investigate the intramolecular competitive aromatic 1,5-C-H insertion reaction, four
representative N-aryl-2-diazo-2-(N-arylsulfamoyl)acetamides 1e–h with two, three, or four N-phenyl
groups, respectively, were conducted under the optimal conditions. The results are presented in
Table 2. 2-Diazo-N-methyl-N-phenyl-2-(N-methyl-N-phenylsulfamoyl)acetamide (1e) gave rise to
chemospecific 1-methyl-3-(N-methyl-N-phenylsulfamoyl)indolin-2-one (3e) only in 53% yield (Table 2,
entry 4). The structure was assigned by comparing the IR absorbing wave number of the C=O group
−
1
−1
−1
in the amide moiety in 1e (1658 cm ), 2b (1656 cm ), and 3e (1720 cm ) (
-diazo-N-methyl-N-phenyl-2-(N,N-diphenylsulfamoyl)acetamide (1f) yielded both N-methyl-N,1-
diphenyl-1,3-dihydrobenzo[c]isothiazole-3-carboxamide 2,2-dioxide (2f) in 15% yield and 1-methyl-
-(N,N-diphenylsulfamoyl)indolin-2-one (3f) in 44% yield, favoring the aromatic 1,5-C-H insertion in
γ-lactam). However,
2
3
the N-phenyl amide moiety (Table 2, entry 5). Both 2-diazo-2-(N-methyl-N-phenylsulfamoyl)-N,N-
diphenylacetamide (1g) and 2-diazo-N,N-diphenyl-2-(N,N-diphenylsulfamoyl)acetamide (1h) gave
rise to chemospecific 3-(N-methyl-N-phenylsulfamoyl)-1-phenylindolin-2-one (3g) and 1-phenyl-3-
(N,N-diphenylsulfamoyl)indolin-2-one (3h) in similar yields of 52% and 48%, respectively (Table 2,
entries 6 and 7). No corresponding 1,3-dihydrobenzo[c]isothiazole-3-carboxamide 2,2-dioxide was
observed in the reaction mixture in each of cases.

Molecules 2019, 24, 2628
5 of 14
Table 2. Intramolecular carbene C-H insertions of diazosulfamoylacetamides 1 a.
a
Reactions were conducted on a 0.5 mmol scale in 10 mL of toluene. The yields were obtained by chromatography
on silica gel.

Molecules 2019, 24, 2628
6 of 14
2
.3. Mechanism on the Aromatic 1,5-C-H Insertion
According to previous publications [
1
–
4,
14], considering the mechanism of the intramolecular
aromatic 1,5-C-H insertion, it is proposed as follows. Diazosulfamoylacetamides
Cu(acac) to generate Cu-carbon ylides , of which the carbocation electrophilically attacks the
benzene ring in the N-phenyl group in the amide moiety (in the sulfonamide moiety only for
-diazo-N,N-dialkyl(N-arylsulfamoyl)acetamides) to yield cyclized intermediates (Frediel–Craft
alkylation). After releasing Cu(acac) catalyst and the proton transfer, the intermediates convert
1 react with
A
2
2
B
B
2
to aromatic 1,5-inserted enolic intermediates
C, which tautomerize into final products
2
and/or
3
(Scheme 3).
Scheme 3.
Proposed mechanism for the intramolecular aromatic 1,5-C-H insertion of
diazosulfamoylacetamides 1.
2
.4. Rationale on the Chemoselectivity in the Aromatic 1,5-C-H Insertions of
N-aryl-2-diazo-2-(N-arylsulfamoyl)acetamides
2-Diazo-N-phenyl-2-(N-phenylsulfamoyl)acetamides 1e
–h
generally predominantly reacted on
the phenyl group of N-phenylacetamides, giving rise to 3-sulfamoylindolin-2-ones 3e
–h as major
or exclusive products. Only 2-diazo-N-methyl-N-phenyl-2-(N,N-diphenylsulfamoyl)acetamide (1f
)
generated 1,3-dihydrobenzo[c]isothiazole-3-carboxamide 2,2-dioxide 2f as a minor product at the
same time.
On the basis of Hammett constants [33], methanesulfonyl (σ = 0.73) is a stronger electron-
withdrawing group than acetyl ( = 0.47). It should be reasonable to rationalize that the phenyl
σ
group of N-phenylamides is generally electron-richer than that of N-phenylsulfonamides, favoring
the electrophilic attack of Cu-carbon ylides to the phenyl group of amides, showing higher
reactivity of N-phenylacetamides. The chemoselectivity is attributed to the different electronic
effects of methanesulfonamido and acetamido groups when amides and sulfonamides possess similar
steric hindrance. For example, the O=C-N(Me)-Ph and (O=) S-N(Me)-Ph conjugative systems in
2
substrate 1e can exist in the same planes or almost same planes. Thus, the electron-withdrawing
conjugative effect of the methanesulfonamido group is stronger than that of the acetamido group,
resulting in lower electron density of the phenyl group on sulfonamide. Thus, the aromatic
1,5-C-H insertion occurs on the phenyl group of acetamide. In N,N-diphenyl derivative 1h, both
O=C-N(Ph)-Ph and O=S-N(Ph)-Ph conjugative systems cannot exist in the same planes due to
steric hindrance of two phenyl groups. The phenyl group of acetamide is electron-richer than that
of sulfonamide as well in 1h. The phenyl group of O=C-N(Ph)-Ph is absolutely electron-richer
than that of (O=) S-N(Me)-Ph in substrate 1g because the former is not in the same plane due
2
to steric hindrance of two phenyl groups, while the latter is in the same plane. Similarly,

Molecules 2019, 24, 2628
7 of 14
the aromatic 1,5-C-H insertion of both substrate 1g and 1h occurs on the electron-rich phenyl
group of acetamide. However, for 2-diazo-N-methyl-N-phenyl-2-(N,N-diphenylsulfamoyl)acetamide
(
1f), the (O=) S-N(Ph)-Ph conjugative system is non-planar, showing weak electron-withdrawing
2
conjugative effect due to steric hindrance of two phenyl groups, while the near planar
O=C-N(Me)-Ph conjugative system shows strong electron-withdrawing conjugative effect to
decrease the electron density of the phenyl group on the N-phenylacetamide, resulting in closer
electron-densities of these two phenyl groups on both acetamide and sulfonamide. This is the reason
2-diazo-N-methyl-N-phenyl-2-(N,N-diphenylsulfamoyl)acetamide (1f) chemoselectively generated
both 3-sulfamoylindolin-2-one 3f as major product and 1,3-dihydrobenzo[c]isothiazole-3-carboxamide
2
,2-dioxide 2f as a minor product.
The intramolecular competitive reactions of 2-diazo-N-phenyl-2-(N-phenylsulfamoyl)acetamides
reveal that the chemoselectivity of the aromatic 1,5-C-H insertion is controlled by the electron density
of the N-phenyl groups on amides and sulfonamides, but impacted by the steric hindrance. The results
also support our proposed reaction mechanism. That is, the electrophilic attack of Cu-carbon ylides on
more electron-rich phenyl group in reactants is the key step, i.e. rate-limiting step, in the aromatic
carbene 1,5-C-H insertion. This result is similar to Maguire’s report that the aliphatic C-H insertion
of carbenes derived from 2-diazo-2-sulfonylacetamides exclusively occurred on the N-alkyl groups
on amides, rather than on the alkyl groups of alkanesulfonyls [31]. These results together reveal that
diazosulfonamides have more inert reactivity than their analogs diazoacetamides
3
. Materials and Methods
3
.1. Materials and Instruments
Toluene was refluxed over Na with diphenyl ketone as an indicator and freshly distilled prior
1
to use. Melting points were obtained on a MP-500 melting point apparatus and are uncorrected. H
and 13C-NMR spectra were recorded on a 400 MHz Bruker spectrometer in CDCl with TMS as an
3
internal standard and the chemical shifts (
δ
) are reported in parts per million (ppm). The IR spectra
−
1
(
KBr pellets, v (cm )) were taken on a FTIR spectrometer. HRMS measurements were carried out on
an Agilent LC/MSD TOF mass spectrometer. TLC separations were performed on silica gel GF254
◦
plates, and the plates were visualized under UV light. Petroleum ether (PE, 30
−
60 C) and ethyl acetate
(EA) were used for column separation.
It is noteworthy that the signal of the carbon attached with diazo group in diazosulfamoylacetamides
cannot be displayed in their 13C-NMR spectra. Similar observations were also reported by Novikov
1
and Du Bios in the synthesis of diazosulfones and diazosulfonates, respectively [27,28].
3
.2. General Procedure for the Preparation of Chloroacetamides 5
Dimethylammonium chloride (4.08 g, 50 mmol) and triethylamine (10.1 g, 100 mmol) were
dissolved in dichloromethane (50 mL). Chloroacetyl chloride (6.78 g, 60 mmol) was added dropwise
◦
◦
under stirring at 0 C. The resulting solution was stirred at 0 C for 4 h. After washing with water
30 mL 3), drying over Na SO , and removing the solvent, the crude N,N-dimethyl-2-chloroacetamide
(
×
2
4
was obtained and used directly in the next step [34].
To a solution of diphenylamine (8.45 g, 50 mmol) or N-methylaniline (5.35 g, 50 mmol) in dry
toluene (30 mL), chloroacetyl chloride (5.65 g, 50 mmol) was added dropwise under stirring. The
resulting solution was refluxed for 4 h. After removal of solvent under reduced pressure, the crude
product was obtained and used directly in the next step [34].
3
.2.1. 2-Chloro-N,N-dimethylacetamide (5a)
1
Yellow oil, 6.10 g, 90% yield. H-NMR (400 MHz, CDCl )
δ
4.07 (s,2H), 3.08(s, 3H), 2.97(s, 3H).
3
13
C-NMR (101 MHz, CDCl ) δ 166.5, 41.2, 37.6, 35.9 [35].
3

Molecules 2019, 24, 2628
8 of 14
3
7
.2.2. 2-Chloro-N-methyl-N-phenylacetamide (5c)
◦
◦
1
Blue crystals, m.p. 76–77 C, Lit [34]. 77–79 C. 8.30 g, 90% yield. H-NMR (400 MHz, CDCl )
δ
3
13
.46–7.29(m, 5H, ArH), 3.86 (s, 2H),3.32 (s, 3H). C-NMR (101 MHz, CDCl3)
27.0, 41.4, 37.9.
δ
166.2, 142.6, 130.0, 128.5,
1
3
.2.3. 2-Chloro-N,N-diphenylacetamide (5d)
◦
◦
1
Colorless crystals, m.p. 124–125 C, Lit [35]. 119–120 C. 11.75 g, 96% yield. H-NMR (400 MHz,
CDCl ) δ 7.39–7.25(m, 10H, ArH), 4.02 (s, 2H).
3
3
.3. General Procedure for the Synthesis of Sulfamoylacetamides 7
Chloroacetamide (25 mmol) was added to a suspension of sodium sulfite (3.94 g, 31.25 mmol)
5
in water (40 mL), and the mixture was stirred for 8 h at room temperature. After removal of water
under reduced pressure, the crude product containing sodium chloride was obtained. To the crude
product 25 mL of toluene was added, which was removed along with water under reduced pressure.
The procedure was repeated three times to give the crude dry sodium sulfonate.
To the crude dry sodium sulfonate, 12.5 mL (ca. 20.5 g, 13.5 mmol) of POCl was added and the
3
mixture was refluxed for 3 h. After being dissolved in DCM (13 mL), to the mixture was added a
secondary amine 4 (25 mmol) dissolved in DCM (13 mL). The resulting solution was stirred at room
temperature for another 3 h. The mixture was transferred to conical flask of 250 mL, and 50 mL of
water and ice mixture was added. After the pH value of the mixture was adjusted to 6–8 with 20%
sodium hydroxide, the organic phase was separated and then dried over anhydrous sodium sulfate.
After removal of solvent under reduced pressure, the residual oil was purified on silica gel column
(EA:PE = 1:10, v/v) to yield the pure 2-sulfamoylacetamide 7.
3
.3.1. 2-(N-Benzyl-N-butylsulfamoyl)-N-methyl-N-phenylacetamide (7c)
Yellow oil, 5.56 g, 59% yield. R = 0.20 (silica gel plate, EA:PE = 1:5, v/v). H-NMR (400 MHz,
1
f
CDCl3)
H), 1.24–1.13 (m, 2H), 0.78 (t, J = 7.3 Hz, 3H). 13C-NMR (101 MHz, CDCl3)
28.6, 128.5, 128.2, 127.6, 127.5, 54.4, 52.9, 48.8, 37.8, 30.4, 19.9, 13.6. IR (CH Cl , cm ): 1662, 1339, 1148.
δ
7.49–7.23 (m, 10H), 4.46 (s, 2H), 3.84 (s, 2H), 3.33 (s, 3H), 3.24 (t, J = 7.6 Hz, 2H), 1.46–1.33 (m,
2
1
δ
162.6, 143.0, 137.1, 130.1,
−
1
2
2
+
+
HRMS (ESI) calcd for C H N O S [M + H ] m/z: 375.1737, found 375.1744.
20
27
2
3
3
.3.2. 2-(N-Benzyl-N-butylsulfamoyl)-N,N-diphenylacetamide (7d)
◦
Yellow crystals, m.p. 111
H-NMR (400 MHz, CDCl3)
−
112 C. 3.02 g, 28% yield. R = 0.17 (silica gel plate, EA:PE = 1:5, v/v).
f
1
δ
7.47–7.22 (m, 15H), 4.51 (s, 2H), 4.03 (s, 2H), 3.27 (t, J = 7.6 Hz, 2H),
.45–1.39 (m, 2H), 1.23–1.17 (m, 2H), 0.80 (t, J = 7.4 Hz, 3H). 13C-NMR (101 MHz, CDCl3)
162.9, 142.0,
41.9, 137.1, 130.1, 129.2, 128.9, 128.7, 128.5, 128.1, 127.6, 127.0, 126.4, 55.4, 53.0, 48.9, 30.3, 19.8, 13.6. IR
1
1
δ
−
CH Cl , cm ): 1671, 1343, 1152. C H N O S [M + H ] m/z: 437.1893, found 437.1902.
2 2 25 29 2 3
1
+
+
(
3
.3.3. N-Methyl-2-(N-methyl-N-phenylsulfamoyl)-N-phenylacetamide (7e)
◦
Colorless crystals, m.p. 86
−
88 C. 6.29 g, 74% yield. R = 0.11 (silica gel plate, EA:PE = 1:5, v/v).
f
1
H-NMR (400 MHz, CDCl )
δ
7.60–7.56 (m, 2H), 7.45–7.32 (m, 5H), 7.31–7.23 (m, 3H), 3.78 (s, 2H), 3.46
162.5, 142.8, 141.0, 130.1, 129.3, 128.6, 127.6, 127.4,
3
(
1
s, 3H), 3.34 (s, 3H). 13C-NMR (101 MHz, CDCl )
δ
3
−
27.4, 52.1, 40.2, 37.8. IR (CH Cl , cm ): 1658, 1382, 1180. HRMS (ESI) calcd for C H N NaO S [M
2 2 16 18 2 3
1
+
+
+
Na ] m/z: 341.0930, found 341.0939.
3
.3.4. N-Methyl-N-phenyl-2-(N,N-diphenylsulfamoyl)acetamide (7f)
◦
Green crystals, m.p. 130
−
131 C, 2.85 g, 30% yield. R = 0.10 (silica gel plate, EA:PE = 1:5, v/v).
f
1
H-NMR (400 MHz, CDCl3)
δ
7.57 (d, J = 7.6 Hz, 4H), 7.42–7.35 (m, 7H), 7.30 (d, J = 6.8 Hz, 2H), 7.26 (d,
161.5, 142.7, 141.0, 130.0, 129.3,
J = 7.2 Hz, 2H), 4.07 (s, 2H), 3.36 (s, 3H). 13C-NMR (101 MHz, CDCl3)
δ

Molecules 2019, 24, 2628
9 of 14
−
28.6, 128.5, 127.5, 127.5, 77.3, 77.0, 76.7, 53.6, 37.9. IR (CH Cl , cm ):1659, 1356, 1155. HRMS (ESI)
2 2
1
1
+
+
calcd for C H N O S [M + H ] m/z: 381.1267, found 381.1263.
21
21
2
3
3
.3.5. 2-(N-Methyl-N-phenylsulfamoyl)-N,N-diphenylacetamide (7g)
◦
Yellow crystals, m.p. 165
−
166 C. 8.38 g, 88% yield. R = 0.13 (silica gel plate, EA:PE = 1:5, v/v).
f
1
H-NMR (400 MHz, CDCl3)
δ
7.60 (d, J = 7.7 Hz, 2H), 7.47–7.17 (m, 13H), 3.96 (s, 2H), 3.48 (s, 3H).
13
C-NMR (101 MHz, CDCl3)
δ
162.8, 141.9, 140.9, 130.1, 129.3, 129.2, 128.6, 127.68, 127.5, 127.0, 126.4,
−
7.3, 77.0, 76.7, 52.9, 40.4. IR (CH Cl , cm ): 1668, 1351, 1148. HRMS (ESI) calcd for C H N O S
2 2 21 21 2 3
1
+
7
[
+
M + H ] m/z: 381.1267, found 381.1263.
3
.3.6. N,N-Diphenyl-2-(N,N-diphenylsulfamoyl)acetamide (7h)
◦
Blue crystals, m.p. 199
H-NMR (400 MHz, CDCl3)
C-NMR (101 MHz, CDCl3)
−
200 C. 7.96 g, 72% yield. R = 0.31 (silica gel plate, EA:PE = 1:3, v/v).
δ
f
1
7.59 (d, J = 7.8 Hz, 4H, ArH), 7.40–7.17 (m, 16H, ArH), 4.21 (s, 2H).
13
δ
161.9, 142.0, 141.9, 140.8, 130.0, 129.3, 129.2, 128.9, 128.8, 128.6, 127.7,
−
27.0, 126.5, 54.4. IR (CH Cl , cm ): 1669, 1357, 1159. HRMS (ESI) calcd for C H N O S [M + H ]
2 2 26 23 2 3
1
+
+
1
m/z: 443.1424, found 443.1419.
3
.4. General Procedure for the Synthesis of 2-Diazo-2-sulfamoylacetamides 1
The corresponding 2-sulfamoylacetamide
-nitrobenzenesulfonyl azide (699 mg, 3.06 mmol). The resulting solution was cooled to 0 C. DBU (684
7
(3 mmol) was dissolved in 24 mL of dry MeCN with
◦
4
mg, 0.69 mL, 4.5 mmol) was added, and the reaction mixture was warmed up to room temperature
and stirred for 2 h. After removal of solvent under reduced pressure, the crude product was purified
on silica gel column (EA:PE = 1:10, v/v) to yield the pure 2-diazo-2-sulfamoylacetamides 1.
3
.4.1. 2-Diazo-N,N-dimethyl-2-(N,N-diphenylsulfamoyl)acetamide (1b)
◦
Yellow crystals, m.p. 107
−
108 C. R = 0.16 (silica gel plate, EA:PE = 1:5, v/v). 966 mg, 88% yield.
f
1
H-NMR (400 MHz, CDCl )
δ
7.64 (d, J = 7.6 Hz, 2H), 7.45–7.25 (m, 4H), 7.37–7.27 (m, 4H), 4.00 (s, 3H),
3
3
5
.52 (s, 3H). 13C-NMR (101 MHz, CDCl )
δ
162.8, 141.9, 130.1, 129.3, 128.6, 127.68, 127.5, 127.0, 126.4,
3
−1
+
2.9, 40.4. IR (CH Cl , cm ): 2097, 1641, 1357, 1143. HRMS (ESI) calcd for C H N NaO S [M +
Na ] m/z: 367.0835, found 367.0840.
2
2
16 16
4
3
+
3
.4.2. 2-(N-Benzyl-N-butylsulfamoyl)-2-diazo-N-methyl-N-phenyl acetamide (1c)
◦
Yellow crystals, m.p. 108
−
110 C. 540 mg, 45% yield. R = 0.33 (silica gel plate, EA:PE = 1:5, v/v).
f
1
H-NMR (400 MHz, CDCl3)
δ
7.46–7.21 (m, 10H), 4.59 (s, 2H), 3.35 (s, 3H), 3.32 (t, J = 7.2 Hz, 2H),
.46–1.38 (m, 2H), 1.46–1.38 (m, 2H), 1.26–1.16 (m, 2H), 0.80 (t, J = 7.6 Hz, 3H). 13C-NMR (101 MHz,
1
CDCl3)
δ 159.5, 142.3, 137.0, 130.3, 128.5, 128.5, 128.1, 127.6, 126.5, 53.5, 49.6, 38.3, 30.3, 19.8, 13.6. IR
−
1
+
+
(
CH Cl , cm ): 2093, 1642, 1347, 1149. HRMS (ESI) calcd for C H N O S [M + H ] m/z: 401.1642,
2
2
20 25
4
3
found 401.1654.
3
.4.3. 2-(N-Benzyl-N-butylsulfamoyl)-2-diazo-N,N-diphenyl acetamide (1d)
Yellow oil, R = 0.58 (silica gel plate, EA:PE = 1:5, v/v). 693 mg, 50% yield. H-NMR (400 MHz,
1
f
CDCl )
δ
7.45–7.24 (m, 15H), 4.62 (s, 2H), 3.41 (d, J = 7.6 Hz, 2H), 1.54–1.46 (m, 2H), 1.32–1.23 (m, 2H),
3
.86 (t, J = 7.6 Hz, 3H). 1 C-NMR (101 MHz, CDCl3)
3
δ
C (101 MHz, CDCl ) 160.2, 141.9, 136.9, 129.8,
0
1
3
−
28.5, 128.1, 127.7, 127.5, 126.8, 53.4, 49.6, 30.3, 19.9, 13.7. IR (CH Cl , cm ): 2103, 1612, 1343, 1148.
2 2
1
+
+
HRMS (ESI) calcd for C H N O S [M + H ] m/z: 463.1798, found 463.1796.
25
27
4
3
3
.4.4. 2-Diazo-N-methyl-2-(N-methyl-N-phenylsulfamoyl)-N-phenylacetamide (1e)
◦
Yellow crystals, m.p. 107
v/v). H-NMR (400 MHz, CDCl )
−
108 C. 966 mg, 88% yield. R = 0.16 (silica gel plate, EA:PE = 1:5,
f
1
δ
7.50–7.44 (m, 2H), 7.43–7.36 (m, 2H), 7.37–7.27 (m, 4H), 7.08–7.02
3

Molecules 2019, 24, 2628
10 of 14
(
1
m, 2H), 3.60 (s, 3H), 3.34 (s, 3H). 13C-NMR (101 MHz, CDCl )
δ
159.4, 142.2, 140.8, 130.2, 129.3,
3
−
28.3, 127.6, 126.3, 126.3, 40.4, 38.3. IR (CH Cl , cm ): 2097, 1641, 1357, 1143. HRMS (ESI) calcd for
2 2
1
+
+
C H N NaO S [M + Na ] m/z: 367.0835, found 367.0840.
16
16
4
3
3
.4.5. 2-Diazo-N-methyl-N-phenyl-2-(N,N-diphenylsulfamoyl)acetamide (1f)
◦
Yellow crystals, m.p. 127
−
128 C. 316 mg, 26% yield. R = 0.30 (silica gel plate, EA:PE = 1:5, v/v).
f
1
H-NMR (400 MHz, CDCl )
δ
7.41 (d, J = 7.2 Hz, 4H), 7.38–7.29 (m, 9H), 6.89–6.86 (m, 2H), 3.33 (s,
3
13
3
(
H). C-NMR (101 MHz, CDCl ) δ 158.3, 142.2, 140.9, 130.3, 129.4, 128.4, 128.2, 127.5, 126.2, 38.4. IR
3
−
CH Cl , cm ): 2102, 1642, 1355, 1162. HRMS (ESI) calcd for C H N O S [M + H ] m/z: 407.1172,
2 2 21 19 4 3
1
+
+
found 407.1165.
3
.4.6. 2-Diazo-2-(N-methyl-N-phenylsulfamoyl)-N,N-diphenylacetamide (1g)
◦
Yellow crystals, m.p. 127
−
128 C. 731 mg, 60% yield. R = 0.26 (silica gel plate, EA:PE = 1:5, v/v).
f
1
H-NMR (400 MHz, CDCl3)
δ
7.51 (d, J = 7.8 Hz, 2H), 7.45 (t, J = 7.7 Hz, 2H), 7.40–7.29 (m, 5H), 7.25
160.0, 141.7,
40.8, 129.8, 129.4, 127.6, 127.4, 126.7, 126.1, 40.4. IR (CH Cl , cm ): 2099, 1650, 1354, 1144. HRMS
(
1
(
d, J = 7.5 Hz, 2H), 7.06 (d, J = 7.5 Hz, 4H), 3.57 (s, 3H). 13C-NMR (101 MHz, CDCl )
δ
3
−1
2
2
+
+
ESI) calcd for C H N O S [M + H ] m/z: 407.1172, found 407.1174.
21 19 4 3
3
.4.7. 2-Diazo-N,N-diphenyl-2-(N,N-diphenylsulfamoyl)acetamide (1h)
◦
Yellow crystals, m.p. 178
−
180 C. 913 mg, 65% yield. R = 0.60 (silica gel plate, EA:PE = 1:3, v/v).
f
1
H-NMR (400 MHz, CDCl3)
δ
7.64 (d, J = 8.0 Hz, 4H, ArH), 7.39 (t, J = 7.6 Hz, 4H, ArH), 7.35–7.20
158.7, 141.8, 140.7, 129.8,
29.4, 128.4, 127.6, 127.3, 126.6. IR (CH Cl , cm ): 2104, 1656, 1350, 1155. HRMS (ESI) calcd for
(
1
m, 8H, ArH), 6.93 (d, J = 7.6 Hz, 4H, ArH). 13C-NMR (101 MHz, CDCl )
δ
3
−1
2
2
+
+
C H N O S [M + H ] m/z: 469.1329, found 469.1329.
26
21
4
3
3
.5. General Procedure for the Reaction of 2-Diazo-2-sulfamoylacetamides 1
To a suspension of Cu(acac) (2 mol%, 13 mg, 0.01 mmol) in 10 mL of toluene, the corresponding
2
diazosulfamoylacetamide
of solvent under reduced pressure, the crude reaction mixture was purified on silica gel column (PE:EA
10:1, v/v) to afford the desired product 2 and/or 3.
1 (0.5 mmol) was added, and the mixture was refluxed for 9 h. After removal
=
3
.5.1. N,N-Dimethyl-2,2-dioxido-1-phenyl-1,3-dihydrobenzo[c]isothiazole-3-carboxamide (2b)
◦
Colorless crystals, 142 mg, 90% yield, m.p. 86
H-NMR (400 MHz, CDCl3)
−
88 C, R = 0.10 (silica gel plate, EA:PE = 1:5, v/v).
f
1
δ
: 7.54–7.40 (m, 5H), 7.34–7.21 (m, 2H), 7.09 (td, J = 7.6, 1.1 Hz, 1H), 6.65 (d,
: 161.8, 141.8, 133.6,
30.0, 129.1, 128.4, 126.8, 123.0, 119.8, 111.9, 63.2, 37.9, 36.7. IR (KBr, cm ): 1656, 1332, 1160. HRMS
J = 8.0 Hz, 1H), 5.53 (s, 1H), 3.34 (s, 3H), 3.10 (s, 3H). 13C-NMR (101 MHz, CDCl )
δ
3
−
1
1
+
+
(
ESI) calcd for C H N O S [M + H ] m/z: 317.0954, found 317.0953.
16 17 2 3
3
.5.2. N-Benzyl-N-butyl-2-oxo-1-methylindoline-3-sulfonamide (3c)
Yellow oil, 142 mg, 76% yield, R = 0.18 (silica gel plate, EA:PE = 1:5, v/v). H-NMR (400 MHz,
1
f
CDCl3)
δ
7.65 (d, J = 7.5 Hz, 1H), 7.41–7.27 (m, 6H), 7.13 (t, J = 7.6 Hz, 1H), 6.86 (d, J = 7.9 Hz, 1H), 4.84
(
s, 1H), 4.63 (d, J = 15.6 Hz, 1H), 4.39 (d, J = 15.6 Hz, 1H), 3.47–3.34 (m, 1H), 3.23 (s, 3H), 3.20–3.10 (m,
H), 1.44–1.32 (m, 2H), 1.19–1.09 (m, 2H), 0.79 (t, J = 7.3 Hz, 3H). 1 C-NMR (101 MHz, CDCl3)
3
δ 167.7,
1
1
1
3
44.8, 138.3, 136.6, 130.2, 128.5, 128.2, 127.7, 126.7, 123.2, 119.6, 108.5, 65.5, 52.8, 48.7, 30.3, 26.6, 19.8,
−
1
+
+
3.6. IR (CH Cl , cm ): 1721, 1372, 1343, 1148. HRMS (ESI) calcd for C H N O S [M + H ] m/z:
2
2
20 25
2
3
73.1580, found 373.1584.

Molecules 2019, 24, 2628
11 of 14
3
.5.3. N-Benzyl-N-butyl-2-oxo-1-phenylindoline-3-sulfonamide (3d)
Yellow oil, R = 0.18 (silica gel plate, EA:PE = 1:5, v/v). 184 mg, 85% yield. H-NMR (400 MHz,
1
f
CDCl3)
δ
7.74 (d, J = 7.5 Hz, 1H), 7.57 (t, J = 7.6 Hz, 2H), 7.51–7.39 (m, 5H), 7.39–7.27 (m, 4H), 7.20
(t, J = 7.6 Hz, 1H), 6.84 (d, J = 7.9 Hz, 1H), 5.02 (s, 1H), 4.74 (d, J = 15.6 Hz, 1H), 4.46 (d, J = 15.6 Hz,
1
H), 3.54–3.44 (m, 1H), 3.30–3.19 (m, 1H), 1.57–1.39 (m, 2H), 1.34–1.13 (m, 2H), 0.82 (t, J = 7.3 Hz, 3H).
13
C-NMR (101 MHz, CDCl3)
26.6, 123.7, 119.5, 109.8, 65.7, 53.1, 48.8, 30.3, 19.8, 13.6. IR (CH Cl , cm ): 1724, 1372, 1346, 1148.
δ 167.4, 145.0, 136.6, 133.7, 130.1, 129.8, 128.6, 128.6, 128.2, 127.7, 127.0,
−1
1
2
2
+
+
HRMS (ESI) calcd for C H N O S [M + H ] m/z: 435.1737, found 435.1740.
25
27
2
3
3
.5.4. N,1-Dimethyl-2-oxo-N-phenylindoline-3-sulfonamide (3e)
◦
Colorless crystals, m.p. 127
−
128 C. 84 mg, 53% yield. R = 0.14 (silica gel plate, EA:PE = 1:5,
δ
f
1
v/v). H-NMR (400 MHz, CDCl )
7.69–7.63 (m, 2H), 7.50 (d, J = 7.5 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H),
3
7
.38–7.31 (m, 2H), 7.07 (t, J = 7.6 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 4.88 (s, 1H), 3.52 (s, 3H), 3.25 (s, 3H).
13
C-NMR (101 MHz, CDCl3) δ 167.8, 144.9, 140.8, 130.2, 129.5, 128.0, 127.9, 126.7, 123.3, 119.1, 108.5,
−
3.3, 41.5, 26.6. IR (CH Cl , cm ): 1720, 1372, 1348, 1146. HRMS (ESI) calcd for C H N O S [M +
2 2 16 17 2 3
1
+
6
+
H ] m/z: 317.0954, found 317.0959.
The reaction of 2-diazo-2-sulfamoylacetamide 1a gave rise to inseparable isomeric products 2f
and 3f with very similar polarity under the same reaction conditions. Their yields were obtained on
the basis of 1H NMR analysis. Their melting point is the melting point of the isomeric mixture.
3
.5.5. N-Methyl-2,2-dioxido-N,1-diphenyl-1,3-dihydrobenzo[c]isothiazole-3-carboxamide (2f)
◦
Colorless crystals, 28 mg, 15% yield, m.p. 115
H-NMR (400 MHz, CDCl3)
−
117 C, R = 0.18 (silica gel plate, EA:PE = 1:5, v/v).
f
1
δ
: 7.63–7.62 (m, 2H), 7.50–7.48 (m, 4H), 7.34–7.21 (m, 2H), 7.09 (td, J = 7.6
Hz, 2H), 7.01 (d, J = 7.6 Hz, 1H), 6.82 (d, J = 7.6 Hz, 3H), 6.72 (d, J = 8.0 Hz, 1H), 4.72 (s, 1H), 3.05 (s,
+
+
3
H). HRMS (ESI) calcd for C H N O S [M + H ] m/z: 379.1111, found 379.1107.
21 19 2 3
3
.5.6. 1-Methyl-2-oxo-N,N-diphenylindoline-3-sulfonamide (3f)
◦
Colorless crystals, 83 mg, 44% yield, m.p. 115
H-NMR (400 MHz, CDCl )
7
−
117 C. R = 0.18 (silica gel plate, EA:PE = 1:5, v/v).
f
1
δ
7.58 (d, J = 7.6 Hz, 1H), 7.52 – 7.46 (m, 1H), 7.43–7.21 (m, 10H), 7.09 (t, J =
.6 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 5.05 (s, 1H), 3.21 (s, 3H). 13C-NMR (101 MHz, CDCl3)
166.7, 144.9,
40.9, 130.4, 129.8, 129.3, 129.2, 129.1, 128.4, 127.8, 127.1, 123.2, 123.1, 118.9, 108.5, 63.6, 26.7. IR (CH Cl ,
3
δ
1
2
2
−1
+
+
cm ): 1722, 1369, 1144. HRMS (ESI) calcd for C H N O S [M + H ] m/z: 379.1111, found 379.1107.
21
19
2
3
3
.5.7. N-Methyl-2-oxo-N,1-diphenylindoline-3-sulfonamide (3g)
◦
Colorless crystals, m.p. 127
H-NMR (400 MHz, CDCl3)
H), 7.32–7.22 (m, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 5.03 (s, 1H), 3.55 (s, 3H). C NMR
101 MHz, CDCl3) 167.5, 145.2, 140.8, 133.7, 130.1, 129.8, 129.6, 128.7, 128.1, 128.1, 127.0, 126.6, 123.7,
−
129 C. 98 mg, 52% yield. R = 0.26 (silica gel plate, EA:PE = 1:5, v/v).
f
1
δ
7.71 (d, J = 8.0 Hz, 2H), 7.61–7.51 (m, 3H), 7.50–7.40 (m, 5H), 7.40–7.32 (m,
13
1
(
δ
−
19.0, 109.8, 63.5, 41.7. IR (CH Cl , cm ): 1724, 1348, 1146. HRMS (ESI) calcd for C H N O S [M +
2 2 21 19 2 3
1
+
1
+
H ] m/z: 379.1111, found 379.1107.
3
.5.8. 2-Oxo-N,N,1-triphenylindoline-3-sulfonamide (3h)
◦
Colorless crystals, m.p. 68–70 C. 106 mg, 48% yield. R = 0.24 (silica gel plate, EA:PE = 1:5, v/v).
f
1
H-NMR (400 MHz, CDCl )
δ
7.81 (d, J = 7.5, 1H), 7.51–7.40 (m, 4H), 7.40–7.27 (m, 4H), 7.21–7.04 (m,
H), 6.84 (d, J = 8.0 Hz, 2H), 6.62 (d, J = 8.0 Hz, 1H), 6.26 (s, 1H), 5.03 (s, 1H). 13C-NMR (101 MHz,
CDCl3) 166.5, 149.7, 145.0, 139.7, 133.6, 131.7, 130.4, 129.7, 129.6, 128.6, 127.5, 126.4, 124.8, 124.2,
23.5, 121.4, 118.7, 113.8, 109.6, 69.0. IR (CH Cl , cm ): 1722, 1372, 1369, 1140. HRMS (ESI) calcd for
3
6
δ
−1
1
2
2
+
+
C H N O S [M + H ] m/z: 441.1267, found 441.1266.
26
21
2
3

Molecules 2019, 24, 2628
12 of 14
1H-NMR and 13C-NMR spectra of unknown compounds
Supplementary Materials.
1,
2,
3
, and
7
are included in The
4
. Conclusions
The intramolecular C-H insertions of carbenes derived from different diazosulfamoylacetamides were
studied. The results reveal that the aromatic 1,5-C-H insertion can occur on the N-phenylsulfonamides only
when they have no N-phenyl group on their acetamide. No aliphatic C-H insertions were observed for
diazo(N,N-dialkylsulfamoyl)acetamides. The intramolecular competitive aromatic 1,5-C-H insertion
of N-aryl-2-(N-arylsulfamoyl)-2-diazoacetamides occurs on the N-phenylacetamides predominantly
rather than the phenyl group of N-phenylsulfonamides. The chemoselectivity is controlled by the
electron density of the phenyl group and affected by the steric hindrance. The aromatic 1,5-C-H
insertion occurs on the more electron-rich N-phenyl group because the key step (i.e, rate-determining
step) is electrophilic attack (Frediel–Craft alkylation).
Supplementary Materials: Copies of H-NMR and 13C-NMR spectra of unknown compounds
1
1,
2
,
3, and
7
are
included in the Supporting Information
Author Contributions: Conceptualization, J.X.; methodology, Z.Y.; validation, C.Q., P.H, Z.Y, N.C. and J.X.;
formal analysis, N.C.; investigation, C.Q. and P.H.; data curation, N.C.; writing—original draft preparation,
Z.Y.; writing—review and editing, J.X.; visualization, J.X.; supervision, J.X.; project administration, J.X.; funding
acquisition, J.X.
Funding: This research was funded by the National Natural Science Foundation of China, grant number 21572017,
2
1772010, and 21911530099 and the Fundamental Research Funds for the Central Universities, grant number
XK1802-6, and The APC was funded by MDPI.
Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design of the
study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to
publish the results.
References
1.
2.
3.
4.
5.
Padwa, A.; Krunpe, K.E. Application of Intramolecular Carbenoid Reactions in Organic Synthesis. Tetrahedron
992, 48, 5385–5453. [CrossRef]
Doyle, M.P.; McKervey, M.A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds;
1
John Willey and Sons: New York, NY, USA, 2008.
Doyle, M.P.; Duffy, R.; Ratnikov, M.; Zhou, L. Catalytic Carbene Insertion into C
10, 704–724. [CrossRef] [PubMed]
−
H Bonds. Chem. Rev. 2010,
1
Allen, S.E.; Walvoord, R.R.; Padilla-Salinas, R.; Kozlowski, M.C. Aerobic Copper-Catalyzed Organic Reactions.
Chem. Rev. 2013, 113, 6234–6258. [CrossRef] [PubMed]
Doyle, M.P.; Hu, W.; Wee, A.G.H.; Wang, Z.; Duncan, S.C. Influences of Catalyst Configuration and Catalyst
Loading on Selectivities in Reactions of Diazoacetamides. Barrier to Equilibrium between Diastereomeric
Conformations. Org. Lett. 2003, 5, 407–410. [CrossRef] [PubMed]
6
7
.
.
Yoon, C.H.; Niagle, A.; Chen, C.; Gandhi, D.; Jung, K.W.
of N-Benzyl Protecting Groups for High Regioselectivity toward the Total Synthesis of Rolipram. Org. Lett.
003, 5, 2259–2262. [CrossRef] [PubMed]
Choi, M.K.W.; Yu, W.Y.; Che, C.M. Ruthenium-Catalyzed Stereoselective Intramolecular Carbenoid C
Insertion for - and -Lactam Formations by Decomposition of -Diazoacetamides. Org. Lett. 2005, 7,
081–1084. [CrossRef] [PubMed]
Candeias, N.R.; Gois, P.M.P.; Afonso, C.A.M. Rh(II)-Catalyzed Intramolecular C
Substrates in Water: Scope and Limitations. J. Org. Chem. 2006, 71, 5489–5497. [CrossRef] [PubMed]
Bachmann, D.G.; Schmidt, P.J.; Geigle, S.N.; Chougnet, A.; Woggon, W.-D.; Gillingham, D.G. Modular
Ligands for Dirhodium Complexes Facilitate Catalyst Customization. Adv. Synth. Catal. 2015, 357, 2033–2038.
γ
-Lactam Synthesis via C
−
H Insertion: Elaboration
2
−H
β
γ
α
1
8
.
.
−
H Insertion of Diazo
9
[CrossRef]
1
0. Etkin, N.; Babu, S.D.; Fooks, C.J.; Durst, T. Preparation of 3-acetyl-2-hydroxyindoles via rhodium carbenoid
aromatic carbon-hydrogen insertion. J. Org. Chem. 1990, 55, 1093–1096. [CrossRef]

Molecules 2019, 24, 2628
13 of 14
1
1
1
1. Wee, A.G.H.; Liu, B.; Zhang, L. Dirhodium tetraacetate catalyzed carbon-hydrogen insertion reaction in
N-substituted .alpha.-carbomethoxy-.alpha.-diazoacetanilides and structural analogs. Substituent and
conformational effects. J. Org. Chem. 1992, 57, 4404–4414. [CrossRef]
2. Wang, H.L.; Li, Z.; Wang, G.W.; Yang, S.D. Silver catalyzed intramolecular cyclization for synthesis of
3-alkylideneoxindoles via C–H functionalization. Chem. Commun. 2011, 47, 11336–11338. [CrossRef]
[PubMed]
3. Brown, D.S.; Elliott, M.C.; Moody, C.J.; Mowlem, T.J.; Marino, J.P., Jr.; Padwa, A. Ligand Effects in the
Rhodium(II)-Catalyzed Reactions of .alpha.-Diazoamides. Oxindole Formation is Promoted by the Use of
Rhodium(II) Perfluorocarboxamide Catalysts. J. Org. Chem. 1994, 59, 2447–2455. [CrossRef]
4. Mo, S.Y.; Yang, Z.H.; Xu, J.X. Aqueous copper nitrate catalyzed synthesis of 3-alkylideneoxindoles from
α-diazo-β-ketoanilides. Eur. J. Org. Chem. 2014, 18, 3923–3929. [CrossRef]
1
1
1
1
5. Mo, S.Y.; Tu, J.Z.; Xu, J.X. Chemospecific synthesis of 2-acetoxyindole-3-carbonitriles catalyzed by Cu(acac)2.
Russ. Chem. Bull. 2016, 65, 1773–1778. [CrossRef]
6. Merlic, C.A.; Zechman, A.L.; Miller, M.M. Reactivity of (
Carbenoids: Arene Activation or Protection? J. Am. Chem. Soc. 2001, 123, 11101–11102. [CrossRef] [PubMed]
7. Park, C.P.; Nagle, A.; Yoon, C.H.; Chen, C.L.; Jung, K.W. Formal Aromatic C H Insertion for Stereoselective
Isoquinolinone Synthesis and Studies on Mechanistic Insights into the C C Bond Formation. J. Org. Chem.
009, 74, 6231–6236. [CrossRef] [PubMed]
η
6-Arene)tricarbonylchromium Complexes with
−
−
2
1
1
8. Wang, J.X.; Stefane, B.; Jaber, D.; Smith, J.A.I.; Vickery, C.; Diop, M.; Sintim, H.O. Remote C-H Functionalization:
Using the N-O Moiety as an Atom-Economical Tether to Obtain 1,5-and the Rare 1,7-C-H Insertions.
Angew. Chem. Int. Ed. 2010, 49, 3964–3968. [CrossRef] [PubMed]
9. Lo, V.K.Y.; Guo, Z.; Choi, M.K.W.; Yu, W.Y.; Huang, J.S.; Che, C.-M. Highly Selective Intramolecular Carbene
Insertion into Primary C–H Bond of α-Diazoacetamides Mediated by a (p-Cymene) ruthenium(II) Carboxylate
Complex. J. Am. Chem. Soc. 2012, 134, 7588–7591. [CrossRef]
2
2
2
2
2
2
2
0. Mo, S.Y.; Xu, J.X. Chemospecific intramolecular Büchner reaction catalyzed by copper(II) acetylacetonate.
ChemCatChem 2014, 6, 1679–1683. [CrossRef]
1. Mo, S.Y.; Li, X.H.; Xu, J.X. In situ generated iodonium ylides as safe carbene precursors for the chemoselective
intramolecular Buchner reaction. J. Org. Chem. 2014, 79, 9186–9195. [CrossRef]
2. Dai, M.; Danishefsky, S.J. The Total Synthesis of Spirotenuipesines A and B. J. Am. Chem. Soc. 2007, 129,
3
498–3499. [CrossRef] [PubMed]
3. Zhang, Y.; Danishefsky, S.J. Total Synthesis of (
J. Am. Chem. Soc. 2010, 132, 9567–9569. [CrossRef] [PubMed]
4. Yang, Z.H.; Xu, J.X. Synthesis of benzo- -sultams via the Rh-catalyzed aromatic C-H functionalization of
diazosulfonamides. Chem. Commun. 2014, 50, 3616–3618. [CrossRef] [PubMed]
±)-Aplykurodinone-1: Traceless Stereochemical Guidance.
γ
5. Huang, P.P.; Yang, Z.H.; Xu, J.X. Specific intramolecular aromatic C H insertion of diazosulfonamides.
−
Tetrahedron 2017, 73, 3255–3265. [CrossRef]
6. Hrytsak, M.; Etkin, N.; Durst, T. Intramolecular rhodium carbenoid insertions into aromatic C-H bonds.
Preparation of 1-carboalkoxy-1,3-dihydrobenzo[c]thiophene 2,2-dioxides. Tetrahedron Lett. 1986, 27,
5
679–5682. [CrossRef]
2
2
2
7. John, J.P.; Novikov, A.V. Selective Formation of Six-Membered Cyclic Sulfones and Sulfonates by C H
−
Insertion. Org. Lett. 2007, 9, 61–63. [CrossRef] [PubMed]
8. Wolckenhauer, S.A.; Devlin, A.S.; Du Bois, J.
Org. Lett. 2007, 9, 4363–4366. [CrossRef] [PubMed]
9. Flynn, C.J.; Elcoate, C.J.; Lawrence, S.E.; Maguire, A.R. Highly Enantioselective Intramolecular Copper
Catalyzed C H Insertion Reactions of -Diazosulfones. J. Am. Chem. Soc. 2010, 132, 1184–1185. [CrossRef]
PubMed]
δ
-Sultone Formation Through Rh-Catalyzed C H Insertion.
−
−
α
[
3
0. Jungon, C.S.; Novikov, A.V. Asymmetric intramolecular C–H insertion of sulfonyldiazoacetates catalyzed by
Rh(II). Tetrahedron Asymmetry 2013, 24, 151–155. [CrossRef]
3
1. Clarke, L.A.; Ring, A.; Ford, A.; Sinha, A.S.; Lawrence, S.E.; Maguire, A.R. Enantioselective copper catalysed
C–H insertion reaction of 2-sulfonyl-2-diazoacetamides to form
612–7628. [CrossRef] [PubMed]
γ-lactams. Org. Biomol. Chem. 2014, 12,
7

Molecules 2019, 24, 2628
14 of 14
3
2. Cui, X.; Xu, X.; Jin, L.-M.; Wojtas, L.; Zhang, X.P. Stereoselective radical C–H alkylation with acceptor/acceptor-
substituted diazo reagents via Co(II)-based metalloradical catalysis. Chem. Sci. 2015, 6, 1219–1224. [CrossRef]
PubMed]
[
3
3
3. Smith, M.B.; March, J. Advanced Organic Chemistry, 5th ed.; John Wiley: New York, NY, USA, 2004; p. 370.
4. Pasquinucci, L.; Prezzavento, O.; Marrazzo, A.; Amata, E.; Ronsisvalle, S.; Georgoussi, Z.; Fourla, D.D.;
Scoto, G.M.; Parenti, C.; Arico, G.; et al. Evaluation of N-substitution in 6,7-benzomorphan compounds.
Bioor Med. Chem. 2010, 18, 4975–4982. [CrossRef] [PubMed]
3
5. Hennessy, E.J.; Buchwald, S.L. Synthesis of Substituted Oxindoles from
Palladium-Catalyzed C H Functionalization. J. Am. Chem. Soc. 2003, 125, 12084–12085. [CrossRef]
PubMed]
α-Chloroacetanilides via
−
[
Sample Availability: Samples of the compounds 2 and 3 are available from the authors.
©
2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).