Palladium-Catalyzed One-Pot Synthesis of N -Sulfonyl, N -Phosphoryl, and N -Acyl Guanidines

Article abstract of DOI:10.1055/s-0036-1588576

An efficient palladium-catalyzed cascade reaction of azides with isonitrile and amines is presented; it offers an alternative facile approach toward N -sulfonyl-, N -phosphoryl-, and N -acyl-functionalized guanidines in excellent yield. These series of substituted guanidines exhibit potential biological and pharmacological activities. In addition, the less reactive intermediate benzoyl carbodiimide could be isolated by silica gel column flash chromatography in moderate yield.

Full text of DOI:10.1055/s-0036-1588576

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–K
paper
A
en
G. Qiao et al.
Paper
Synthesis
Palladium-Catalyzed One-Pot Synthesis of N-Sulfonyl,
N-Phosphoryl, and N-Acyl Guanidines
R2
Guanyu Qiao
Zhen Zhang
HN
O
O
S
NR3R4
O
R1
O
N
Baoliang Huang
Liu Zhu
S
R2
R1
O
R2 NC
Pd2(dba)3 (2.5 mol%)
dioxane, r.t.
N3
O
P
HN
+
R1
R1
R1
N3
Fan Xiao
O
R3R4NH
O
N
NHR3
R2
R1
P
R1
N3
Zhenhua Zhang*
N
O
HN
C
t-Bu
Department of Applied Chemistry, China Agricultural University,
West Yuanmingyuan Rd. 2, Beijing 100193, P. R. of China
zhangzhh@cau.edu.cn
N
via
R
R1
N
NHR3
43 examples
the less reactive benzoyl carbodiimides can be isolated
1 = aryl, alkyl, acyl, sulfonyl R2 = aryl, alkyl
R3, R4 = aryl, alkyl
up to >98% yield
R
Received: 06.07.2017
Accepted after revision: 31.08.2017
Published online: 12.10.2017
OH
O
B
O
O
HN
R
CO2H
NH
HO
O
O
DOI: 10.1055/s-0036-1588576; Art ID: ss-2017-h0444-op
OH
AcHN
H2N
S
O
P
CH3
O
NH
H3C
H3C
N
N
H2N
O
BHQ1
Abstract An efficient palladium-catalyzed cascade reaction of azides
with isonitrile and amines is presented; it offers an alternative facile ap-
proach toward N-sulfonyl-, N-phosphoryl-, and N-acyl-functionalized
guanidines in excellent yield. These series of substituted guanidines ex-
hibit potential biological and pharmacological activities. In addition, the
less reactive intermediate benzoyl carbodiimide could be isolated by sil-
ica gel column flash chromatography in moderate yield.
N
NH
O
NH
CH3
Tmg
sulfaguanidine
zanamivir derivatives
Figure 1 Examples of N-sulfonyl, N-phosphoryl, and N-acyl guanidines
in drugs
Key words sulfones, phosphorus, azides, functionalized guanidines,
palladium catalysis
also provided convenient methods to access isocyanates
(from carbon monoxide)9 and carbodiimides (from isoni-
triles)10 as intermediates. Palladium complexes, which are
widely used in synthetic chemistry due to their ease of han-
dling and good functional group tolerance,11 have also been
studied in azide transfer reactions with carbon monoxide9b–e
and isonitriles.10c As a continuation of our work on palladi-
um-catalyzed reactions of azides with σ-donors/π-accep-
tors,10c herein we report a simple Pd2(dba)3-catalyzed cou-
pling of easily accessible and air- and moisture-stable sulfo-
nyl-, acyl-, and phosphoryl azides with isonitriles and
Guanidine, a prominent nitrogen-containing structural
motif, is ubiquitous in agrochemicals and pharmaceuticals.1
N-Sulfonyl-,2 N-phosphoryl-,3 and N-acyl-functionalized4
guanidines exhibit a broad range of biological and pharma-
cological activities. For example, sulfaguanidine has been
used to treat enteritis,5 tetramethyl phosphoryl guanidine
(Tmg) has been used to resist 3′-phosphodiesterase cleav-
age in a new fluorescent oligonucleotide-based assay,3 and
zanamivir derivatives have also been used as neuramini-
dase inhibitors to treat type A and B influenza (Figure 1).6
Guanidines are typically accessed by nucleophilic addition
of amines to N-sulfonyl-, N-acyl-, and N-phosphoryl-func-
tionalized carbodiimides, which are mostly obtained by de-
sulfuration of thioureas (Scheme 1, a).7 However, the prepa-
ration of carbodiimide substrates is tedious, and harsh ad-
ditives are needed. It is highly desirable to develop facile
and practical methods to synthesize these functionalized
guanidines with a broad substrate scope.
a) Typical routes to functionalized guanidines
R'
S
HN
HNR1R2
N
additives
R
R'
R
N
NR1R2
R
C
R'
N
N
N
H
H
R = sulfonyl, acyl
additives = TBHP, HgCl2, BiI3
b) This work
R'
HN
HNR3R4
Pd
N
R1 N3
+
R2 NC
C
R2
R1
R1
N
NR3R4
N
Organic azide, an efficient nitrene precursor, has been
identified as a convenient nitrogen source in the formation
of N-containing compounds.8 Transition-metal-catalyzed
reactions of azides with σ-donor/π-acceptor ligands have
R = sulfonyl, acyl, phosphoryl, aryl
R' = alkyl, benzyl, aryl
Scheme 1 Synthesis of functionalized guanidines
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

B
G. Qiao et al.
Paper
Synthesis
amines, as a facile access to N-sulfonyl-, N-acyl-, and N-
phosphoryl-functionalized guanidines under mild condi-
tions without any extra ligands (Scheme 1, b). Apart from
the mild room temperature conditions and the use of only
the Pd2(dba)3 catalyst without any extra ligands, sulfonyl,
phosphoryl, and acyl azides and isonitriles are all commer-
cially available and easy to prepare. It is worth mentioning
that under the mild conditions of this reaction, the inciden-
tal Curtius rearrangement of acyl azides could be avoided.12
In addition, benzoyl carbodiimide could be isolated by silica
gel column flash chromatography.
At the outset, TsN3 (1aa), t-BuNC (2a), and aniline (3a)
were selected as reagents to optimize the reaction condi-
tions (Table 1). Firstly, the screening of catalysts revealed
that good results were obtained with the Pd2(dba)3 catalyst.
Then the optimization of solvent demonstrated that 1,4-di-
oxane was superior to other aprotic or protic solvents. On
the basis of this initial study, the optimal reaction condi-
tions for TsN3, t-BuNC, and aniline were determined to be
the reaction in a sealed tube at room temperature for 5
hours with 1,4-dioxane as solvent.
tle effect on the reactivity (4aa–ad), but also nearly all dif-
ferent electron-withdrawing-/electron-donating-substitut-
ed aromatic rings in sulfonyl azides gave >90% isolated
yields (4ad–ah). When the sulfonyl azides were extended to
heteroaromatic (4ai), benzyl (4ak), and alkyl (4aj) sulfonyl
groups, good results were also obtained. The evaluation of
different isonitriles revealed that alkyl isonitriles and sub-
stituted aryl isonitriles all reacted smoothly to give the de-
sired products (4al, 4an–ap) in high yields. Benzyl isonitrile
only gave a moderate yield (4am). Additionally, in addition
to arylamines, morpholine (4as) and cyanamide (4at) were
also well tolerated, giving products difficult to access from
previous methods.
R2
O
O
HN
Pd2(dba)3 (2.5 mol%)
dioxane, r.t., 5 h
O
O
S
R2 NC
R3R4NH
+
+
R1
S
N3
R1
N
NR3R4
1ax
2
3
4ax
t-Bu
4ae R = 4-F
4af R = 4-Br
4ag R = 4-CF3
4ah R = 4-OMe
96%
HN
4aa R = H
>98%
92%
95%
90%
O
O
92%
83%
96%
4ab R = 2-NO2
4ac R = 3-NO2
4ad R = 4-NO2
S
n-Bu
N
N
H
R
Table 1 Optimization of Reaction Conditionsa
t-Bu
t-Bu
t-Bu
HN
O
O
HN
HN
O
O
t-Bu
O
O
S
nBu
HN
S
PMP
S
PMP
catalyst
N
N
H
n-Bu
N
N
Bn
N
N
Ts
Ph
Ts N3
+
t-BuNC
PhNH2
+
H
H
S
N
N
solvent, r.t., 5 h
H
4aj 92%a
4ak 70%
4ai 97%
1aa
2a
3a
4aq
PMP
Bn
NH
Entry
Catalyst (mol%)
Solvent
Yield (%)b
n-Bu
HN
R
HN
Ts
Ts
PMP
N
N
Ts
PMP
N
N
H
1
2
PdCl2 (5)
THF
n.r.
n.r.
n.r.
36
H
N
N
H
4an R = 4-Cl
4ao R = 4-CN
4ap R = 4-OMe
91%
82%
93%
Pd(PPh3)2Cl2 (5)
Pd(NCPh)2Cl2 (5)
Pd(OAc)2 (5)
THF
4al 80%
4am 32%
3
THF
4
THF
t-Bu
t-Bu
t-Bu
t-Bu
HN
5
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
THF
97
HN
HN
HN
N
Ts
Ts
Ts
Ts
Ph
6
MeCN
DMF
DMSO
acetone
DCE
19
N
N
N
N
N
N
N
N
H
H
H
O
7
11
4at 92%b
4aq >98%
4ar 87%
4as 98%
8
n.r.
69
9
Scheme 2 Scope of the reaction giving N-sulfonyl guanidines. Reagents
and conditions: 1ax (0.2 mmol), 2 (0.22 mmol), 3 (0.24 mmol),
Pd2(dba)3 (0.005 mmol), dioxane (2 mL), r.t., 5 h; yield of isolated prod-
uct. a dppp (dppp = 1,3-bis(diphenylphosphine)propane; 0.4 mmol)
was added. b K2CO3 (0.4 mmol) was added.
10
11
54
1,4-dioxane
>98
a Reaction conditions: 1aa (0.1 mmol), 2a (0.11 mmol), 3a (0.12 mmol),
catalyst (0.005 mmol), solvent (2 mL), sealed tube, r.t., 5 h.
b Yield determined by 1H NMR spectroscopy; n.r. = no reaction.
After the preliminary inspection of the reactivity fea-
tures and the optimization of the reaction conditions, we
explored the generality of this method with regard to dif-
ferent substituted N-sulfonyl-, N-acyl-, and N-phosphoryl-
functionalized guanidines. Firstly, N-sulfonyl guanidines
were investigated and the results are summarized in
Scheme 2. To our delight, the reaction showed an excellent
substrate scope. Not only does the steric hindrance have lit-
Because of the slightly poorer efficiency of phosphoryl
azides compared to sulfonyl azides, the installation of N-
phosphoryl guanidines was envisioned to be more highly
desirable. As shown in Scheme 3, regardless of whether al-
kyl- or aryl-substituted phosphoryl azides, different isoni-
triles, or different amines were used, the targeted phos-
phoryl guanidines could be achieved in good yields (4ba–bd).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

C
G. Qiao et al.
Paper
Synthesis
higher temperature.12 In contrast, this protocol successfully
achieved the generation of N-acyl guanidines by utilizing
acyl azides under mild reaction conditions. As shown in
Scheme 4, the scope was insensitive to electronic changes
of the aromatic ring and different types of fused or hetero
rings in the acyl azides, invariably leading to the target
products in high yields (4ca–ch). The scope of isocyanides
was next examined. The results showed that isocyanocyclo-
hexane worked equally well (4ci–cn), whereas benzyl- and
aryl-substituted isocyanides gave moderate yields (70% and
56% yield for 4co and 4cp, respectively). Additionally, when
the nucleophilic reagent was changed to alkylamine (4cq)
and pyridin-2-amine (4cr), the reaction also proceeded
smoothly to give the corresponding guanidines in reason-
able yields. Gratifyingly, unstable 2-phenylacetyl azide is
also amenable to this transformation (4cs).
Functionalized carbodiimides are not only common
precursors of functionalized guanidines, but also important
intermediates to access N-containing heterocycles.13 Al-
though sulfonyl and phosphoryl carbodiimides are difficult
to separate, it is worth mentioning that when benzoyl azide
(1ca) was used, the less reactive intermediate benzoyl car-
bodiimide (5a) existed transiently in 72% isolated yield after
silica gel column chromatography. The subsequent addition
of amine gave N-acyl guanidine (4ca) in 92% yield. Having
obtained this result, we further investigated the generality
of the formation of N-acyl carbodiimides from acyl azides.
As shown in Scheme 5, the reaction could be carried out be-
tween a series of electron-donating/electron-withdrawing-
substituted benzoyl azides and hetero acyl azides and t-BuNC
(2a), affording the corresponding pure N-acyl carbodiimides
R2
Pd2(dba)3
(2.5 mol%)
O
P
HN
O
R1
R1
R1
P
R1
N3
R2 NC
R3NH2
+
+
N
NHR3
dioxane, r.t., 5 h
1bx
2
3
4bx
t-Bu
HN
O
P
HN
O
P
PhO
PhO
PhO
PhO
Ph
Ph
N
N
N
N
H
H
4ba 90%
t-Bu
4bb 82%
O
HN
t-Bu
O
HN
PhO
PhO
P
n-Bu
MeO
MeO
N
N
P
Ph
H
N
N
H
4bc 89%
4bd 63%
Scheme 3 Scope of the reaction giving N-phosphoryl guanidines. Re-
agents and conditions: 1bx (0.2 mmol), 2 (0.22 mmol), 3 (0.24 mmol),
Pd2(dba)3 (0.005 mmol), dioxane (2 mL), r.t., 5 h; yield of isolated prod-
uct.
Acyl azides are known as privileged precursors toward
isocyanates, undergoing a direct Curtius rearrangement,
endowing these compounds with thermal instability at a
R2
O
O
HN
Pd2(dba)3
(2.5 mol%)
R3
R2 NC
R3NH2
N3
N
N
H
+
+
R1
R1
dioxane, r.t., 5 h
1cx
2
3
4cx
t-Bu
O
HN
4ca R = 4-H
4cb R = 4-Me
4cc R = 4-Br
92%
86%
89%
4cd R = 4-OMe
4ce R = 4-CN
96%
91%
Ph
N
N
H
R
t-Bu
t-Bu
t-Bu
O
HN
O
HN
O
O
N
O
HN
Ph
Ph
Ph
N
N
N
N
C
t-Bu
N3
N
N
H
H
N
R
Pd2(dba)3 (2.5 mol%)
dioxane, r.t., 5 h
H
O
R
t-Bu
N
C
+
N
4cf 86%
4cg 93%
4ch 96%
1cx
2a
5
Cy
O
O
O
HN
O
4ci R = 4-H
4cj R = 3-Me
4ck R = 4-Me
75%
93%
90%
4cl R = 4-Cl
4cm R = 4-Br
4cn R = 4-OMe 95%
82%
89%
N
N
N
C
t-Bu
C
t-Bu
Ph
C
t-Bu
N
N
N
N
N
H
R
Me
Cl
5b 69%
5c 56%
5a 72%
Bn
O
HN
O
O
HN
N
N
O
Ph
C
t-Bu
C
t-Bu
Ph
N
N
H
N
N
Ph
Ph
N
N
H
MeO
F3C
4cp 56%a
4co 70%
t-Bu
5e 61%
5d 53%
t-Bu
t-Bu
O
HN
O
HN
O
HN
O
O
Ph
Ph
t-Bu
N
N
C
N
N
Ph
N
N
N
Ph
N
N
C
t-Bu
t-Bu
S
H
H
H
N
N
4cq 82%
4cr 65%
4cs 61%
5g 59%
5f 54%
Scheme 4 Scope of the reaction giving N-acyl guanidines. Reagents
and conditions: 1cx (0.2 mmol), 2 (0.22 mmol) and 3 (0.24 mmol),
Scheme 5 Scope of the reaction giving N-acyl carbodiimides. Reagents
and conditions: 1cx (1 mmol), 2a (1.1 mmol), Pd2(dba)3 (0.025 mmol),
dioxane (4 mL), r.t., 5 h; yield of isolated product.
Pd2(dba)3 (0.005 mmol), dioxane (2 mL), r.t., 5 h; yield of isolated prod-
uct. a Zn(OTf)2 (0.03 mmol) was added.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

D
G. Qiao et al.
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Synthesis
5a–g in moderate isolated yields. Unfortunately, the purifi-
cation of N-acyl carbodiimidies obtained from other isoni-
triles was not successful.
tometer. Mass spectra were obtained on a Waters Auto Purification
LC/MS system. HMRS was carried out on a Bruker Apex IV FTMS spec-
trometer. All catalysts and ligands were purchased from Sigma-Al-
drich. All alkyl isonitriles and benzyl isonitriles are commercially
available, unless stated otherwise.
On the basis of the experimental results, a possible reac-
tion mechanism is proposed as shown in Scheme 6. Initial-
ly, under the catalysis of Pd2(dba)3, 1aa releases a molecule
of nitrogen to produce intermediate A. A reacts with 2a to
form a ternary ring intermediate B. Then, reductive elimi-
nation of intermediate B liberates carbodiimide C; nucleop-
hilic attack of aniline follows, generating product 4a. The
palladium catalyst is released, to continue participating in
the reaction, thus completing the entire catalytic cycle.
N-Sulfonyl Guanidine 4aq; Typical Procedure for the Synthesis of
N-Acyl-, N-Sulfonyl-, and N-Phosphoryl Guanidines 4aa–cs
Pd2(dba)3 (4.6 mg, 0.005 mmol), TsN3 (40 mg, 0.2 mmol), PhNH2 (23
mg, 0.24 mmol), and freshly distilled dioxane (2 mL) were added to a
dry flask equipped with a magnetic stir bar. The flask was sealed,
evacuated, and refilled with N2. Then t-BuNC (18 mg, 0.22 mmol) was
added and the reaction mixture was stirred at r.t. for 5 h. Once the
reaction was completed, the mixture was concentrated under reduced
pressure. The resulting crude residue was purified by column chro-
matography (silica gel); this afforded the desired product 4aq; yield:
67 mg (>98%).
t-Bu
N
C
2a
A
N2
TsN PdLn
Benzoyl Carbodiimide 5a; Typical Procedure
TsN3
Pd2(dba)3 (22.8 mg, 0.025 mmol) and freshly distilled dioxane (5 mL)
were added to a dry flask equipped with a magnetic stir bar. The flask
was sealed, evacuated, and refilled with N2. Then PhCON3 (147 mg, 1
mmol) and t-BuNC (90 mg, 1.1 mmol) were added and the reaction
mixture was stirred at r.t. for 5 h. Once the reaction was completed,
the mixture was concentrated under reduced pressure. The resulting
crude residue was purified by flash column chromatography (silica
gel); this afforded the desired product 5a; yield: 135 mg (72%).
1aa
Ts
N
PdLn
B
C
N
LnPd
t-Bu
t-Bu
N
Ts
Ph
N-[(tert-Butylamino)(butylamino)methylene]benzenesulfon-
amide (4aa)
N
N
H
H
4a
t-Bu
The title compound was prepared according to the typical procedure.
N
C N
NH2
Ts
Yield: 62 mg (99%); colorless sticky liquid.
PdLn
IR (neat): 1597, 1565, 1130, 1082, 747, 691 cm–1
.
C
3a
1H NMR (400 MHz, CDCl3): δ = 7.98–7.72 (m, 2 H), 7.55–7.32 (m, 3 H),
7.18 (s, 1 H), 4.27 (s, 1 H), 3.02 (s, 2 H), 1.53–1.46 (m, 2 H), 1.42–1.15
(m, 11 H), 0.91 (t, J = 7.3 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 154.47, 144.04, 131.11, 128.36,
125.81, 52.76, 41.36, 30.78, 29.53, 19.89, 13.61.
Scheme 6 Possible mechanism
In summary, we have developed a novel, general, and ef-
ficient strategy to access N-sulfonyl-, N-phosphoryl-, and N-
acyl-functionalized guanidines directly from azides, isoni-
triles, and amines in a tandem process, producing products
with high value in the area of agrochemicals and pharma-
ceuticals. This protocol is characterized by needing only a
single Pd2(dba)3 catalyst without any complicated ligand,
proceeding under robust conditions, and showing a broad
substrate scope and good functional-group tolerance. Nota-
bly, acyl azides could generally be applied successfully in
this transformation, and the corresponding N-acyl carbo-
diimides could be isolated in moderate yields.
HRMS (ESI): m/z [M + H]+ calcd for C15H26N3O2S: 312.1746; found:
312.1756.
N-[(tert-Butylamino)(butylamino)methylene]-2-nitrobenzene-
sulfonamide (4ab)
The title compound was prepared according to the typical procedure.
Yield: 66 mg (92%); colorless sticky liquid.
IR (neat): 1567, 1531, 1350, 1177, 1081, 879, 676 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.70 (s, 1 H), 8.34 (d, J = 8.1 Hz, 1 H),
8.22 (d, J = 7.7 Hz, 1 H), 7.71–7.67 (m, 1 H), 7.19 (s, 1 H), 4.54 (s, 1 H),
3.10 (s, 2 H), 1.55 (s, 2 H), 1.45–1.16 (m, 11 H), 0.91 (t, J = 6.4 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 154.60, 147.87, 146.20, 131.69,
129.97, 125.75, 121.05, 52.45, 41.49, 30.75, 29.52, 19.92, 13.63.
HRMS (ESI): m/z [M + H]+ calcd for C15H25N4O4S: 357.1597; found:
357.1615.
All reactions were performed in a glass vial under a nitrogen atmo-
sphere. Anhydrous solvents were distilled on small scale with CaH2 or
sodium and stored under N2.The boiling point of petroleum ether is
between 60 °C and 90 °C. For chromatography, 200–300 mesh silica
gel (Qingdao, China) was employed. 1H and 13C NMR spectra were re-
corded on Varian 300 or Varian Mercury 400 spectrometer. Chemical
shifts are reported in ppm relative to TMS (1H, δ = 0), residual chloro-
form solvent (13C, δ = 77.00), or DMSO (1H, δ = 2.50; 13C, δ = 39.52). IR
spectra were recorded on a Nicolet AVATAR 330 FT-IR spectropho-
N-[(tert-Butylamino)(butylamino)methylene]-3-nitrobenzene-
sulfonamide (4ac)
The title compound was prepared according to the typical procedure.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

E
G. Qiao et al.
Paper
Synthesis
Yield: 68 mg (95%); yellow sticky liquid.
IR (neat): 1593, 1567, 1323, 1130, 1062, 713, 653 cm–1
.
IR (neat): 1568, 1541, 1367, 1180, 1107, 744, 664 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 7.94 (d, J = 8.6 Hz, 2 H), 7.90 (d, J =
8.7 Hz, 2 H), 6.80 (s, 1 H), 3.14 (dd, J = 12.6, 6.6 Hz, 2 H), 1.34–1.28 (m,
2 H), 1.26 (s, 9 H), 1.14–1.07 (m, 2 H), 0.77 (t, J = 7.3 Hz, 3 H).
13C NMR (101 MHz, DMSO-d6): δ = 154.34, 147.92, 131.14 (q, J = 31.9
Hz), 126.44, 125.93 (q, J = 3.6 Hz), 123.66 (q, J = 272.5 Hz), 51.56,
40.76, 30.89, 28.95, 19.12, 13.50.
1H NMR (400 MHz, CDCl3): δ = 8.70 (s, 1 H), 8.34 (d, J = 8.1 Hz, 1 H),
8.22 (d, J = 7.7 Hz, 1 H), 7.71–7.67 (m, 1 H), 7.19 (s, 1 H), 4.54 (s, 1 H),
3.10 (s, 2 H), 1.55 (s, 2 H), 1.45–1.16 (m, 11 H), 0.91 (t, J = 6.4 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 154.63, 147.44, 137.50, 132.06,
131.80, 129.67, 123.81, 52.31, 41.67, 30.84, 29.54, 19.97, 13.71.
HRMS (ESI): m/z [M + H]+ C16H25F3N3O2S: 380.1620; found: 380.1627.
HRMS (ESI): m/z [M + H]+ calcd for C15H25N4O4S: 357.1597; found:
357.1586.
N-[(tert-Butylamino)(butylamino)methylene]-4-methoxyben-
zenesulfonamide (4ah)
N-[(tert-Butylamino)(butylamino)methylene]-4-nitrobenzene-
The title compound was prepared according to the typical procedure.
sulfonamide (4ad)
The title compound was prepared according to the typical procedure.
Yield: 65 mg (96%); white solid; mp 98–100 °C.
Yield: 60 mg (90%); white solid; mp 105–106 °C.
IR (neat): 1595, 1564, 1254, 1172, 1128, 1082, 831, 678 cm–1
.
IR (neat): 1567, 1528, 1348, 1178, 1130, 1083, 745, 689 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 7.65 (dd, J = 8.8, 1.9 Hz, 2 H), 7.02
(dd, J = 8.8, 2.0 Hz, 2 H), 6.73 (s, 1 H), 3.79 (s, 3 H), 3.12 (dd, J = 11.8,
5.6 Hz, 2 H), 1.35 (m, 2 H), 1.25 (s, 9 H), 1.20–1.13 (m, 2 H), 0.82 (t, J =
6.6 Hz, 3 H).
13C NMR (101 MHz, DMSO-d6): δ = 161.68, 154.31, 136.79, 127.92,
114.18, 55.96, 51.87, 41.18, 31.40, 29.52, 19.71, 14.11.
1H NMR (400 MHz, CDCl3): δ = 8.43–8.19 (m, 2 H), 8.13–7.92 (m, 2 H),
7.17 (s, 1 H), 4.52 (s, 1 H), 3.09 (dd, J = 12.5, 6.8 Hz, 2 H), 1.55 (s, 2 H),
1.45–1.22 (m, 11 H), 0.92 (t, J = 7.2 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 154.58, 150.00, 149.19, 127.09,
123.85, 52.46, 41.50, 30.86, 29.52, 19.90, 13.60.
HRMS (ESI): m/z [M + H]+ calcd for C16H28N3O3S: 342.1851; found:
342.1858.
HRMS (ESI): m/z [M + H]+ calcd for C15H25N4O4S: 357.1597; found:
357.1603.
N-[(tert-Butylamino)(butylamino)methylene]thiophene-2-sul-
fonamide (4ai)
N-[(tert-Butylamino)(butylamino)methylene]-4-fluorobenzene-
sulfonamide (4ae)
The title compound was prepared according to the typical procedure.
The title compound was prepared according to the typical procedure.
Yield: 61 mg (97%); white solid; mp 82–83 °C.
IR (neat): 2966, 1593, 1567, 1406, 1223, 1053, 679 cm–1
Yield: 63 mg (96%); white solid; mp 93–94 °C.
IR (neat): 1592, 1565, 1364, 1225, 1130, 1081, 835, 681 cm–1
.
.
1H NMR (400 MHz, CDCl3): δ = 7.52–7.50 (m, 1 H), 7.43–7.41 (m, 1 H),
7.09 (s, 1 H), 7.00–6.97 (m, 1 H), 3.06 (s, 2 H), 1.56–1.49 (m, 2 H),
1.45–1.23 (m, 11 H), 0.90 (t, J = 7.3 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 154.34, 145.53, 128.95, 128.76,
126.15, 51.98, 41.10, 30.57, 29.21, 19.50, 13.28.
1H NMR (400 MHz, DMSO-d6): δ = 7.80–7.76 (m, 2 H), 7.37–7.32 (m, 2
H), 6.76 (s, 1 H), 3.13 (dd, J = 12.7, 6.6 Hz, 2 H), 1.37–1.30 (m, 2 H),
1.25 (s, 9 H), 1.20–1.10 (m, 2 H), 0.81 (t, J = 7.3 Hz, 3 H).
13C NMR (101 MHz, DMSO-d6): δ = 163.37 (d, J = 248.7 Hz), 154.32,
140.62 (d, J = 3.1 Hz), 128.27 (d, J = 9.2 Hz), 115.65 (d, J = 22.4 Hz),
51.43, 40.70, 30.88, 28.98, 19.17, 13.58.
HRMS (ESI): m/z [M + H]+ calcd for C13H24N3O2S2: 318.1310; found:
318.1305.
HRMS (ESI): m/z [M + H]+ calcd for C15H25FN3O2S: 330.1652; found:
330.1658.
N-{(tert-Butylamino)[(4-methoxyphenyl)amino]methylene}bu-
tane-1-sulfonamide (4aj)
4-Bromo-N-[(tert-butylamino)(butylamino)methylene]benzene-
The title compound was prepared according to the typical procedure.
sulfonamide (4af)
The title compound was prepared according to the typical procedure.
Yield: 63 mg (92%); white solid; mp 77–78 °C.
Yield: 72 mg (92%); white solid; mp 130–131 °C.
IR (neat): 1600, 1511, 1366, 1250, 1131, 1086, 820 cm–1
.
IR (neat): 1594, 1566, 1262, 1128, 1081, 756, 661 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.58 (s, 1 H), 7.08 (d, J = 8.5 Hz, 2 H),
6.90 (d, J = 8.6 Hz, 2 H), 4.43 (s, 1 H), 3.80 (s, 3 H), 3.10–3.03 (m, 2 H),
1.91–1.81 (m, 2 H), 1.50–1.43 (m, 2 H), 1.31 (s, 9 H), 0.94 (t, J = 7.3 Hz,
3 H).
1H NMR (400 MHz, DMSO-d6): δ = 7.72 (d, J = 8.4 Hz, 2 H), 7.66 (d, J =
7.6 Hz, 2 H), 6.76 (s, 1 H), 3.13 (dd, J = 12.6, 6.2 Hz, 2 H), 1.32 (dd, J =
14.6, 7.1 Hz, 2 H), 1.26 (s, 9 H), 1.13 (dd, J = 14.8, 7.4 Hz, 2 H), 0.80 (t, J
= 7.2 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 158.88, 153.88, 128.08, 115.31, 55.58,
54.66, 52.35, 29.26, 25.91, 21.74, 13.81.
HRMS (ESI): m/z [M + H]+ calcd for C16H28N3O3S: 342.1851; found:
13C NMR (101 MHz, DMSO-d6): δ = 154.33, 143.45, 131.72, 127.60,
124.77, 51.52, 40.76, 30.89, 29.01, 19.20, 13.60.
342.1843.
HRMS (ESI): m/z [M + H]+ calcd for C15H25BrN3O2S: 390.0845; found:
390.0840.
N-{(tert-Butylamino)[(4-methoxyphenyl)amino]methylene}-1-
phenylmethanesulfonamide (4ak)
N-[(tert-Butylamino)(butylamino)methylene]-4-(trifluorometh-
The title compound was prepared according to the typical procedure.
yl)benzenesulfonamide (4ag)
The title compound was prepared according to the typical procedure.
Yield: 63 mg (83%); white solid; mp 106–107 °C.
Yield: 53 mg (70%); white solid; mp 154–155 °C.
IR (neat): 1595, 1511, 1362, 1248, 1145, 1089, 792, 704 cm–1
.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 8.35 (s, 1 H), 7.52–7.42 (m, 2 H), 7.41–
7.31 (m, 3 H), 6.83 (d, J = 8.8 Hz, 2 H), 6.74 (d, J = 7.8 Hz, 2 H), 4.32 (s,
2 H), 4.23 (s, 1 H), 3.79 (s, 3 H), 1.29 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 158.90, 154.39, 131.16, 130.91,
128.48, 128.24, 127.71, 115.15, 60.86, 55.59, 52.40, 29.37.
1H NMR (400 MHz, CDCl3): δ = 9.05 (s, 1 H), 7.84 (d, J = 7.9 Hz, 2 H),
7.50 (d, J = 8.2 Hz, 2 H), 7.39 (d, J = 8.1 Hz, 2 H), 7.30 (d, J = 8.1 Hz, 2 H),
7.18 (d, J = 8.5 Hz, 2 H), 6.97 (d, J = 8.2 Hz, 2 H), 6.63 (s, 1 H), 3.83 (d, J
= 0.9 Hz, 3 H), 2.43 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 159.75, 151.60, 142.90, 140.83,
140.08, 133.05, 129.56, 128.47, 126.55, 126.15, 121.50, 118.64,
115.71, 107.68, 55.70, 21.64.
HRMS (ESI): m/z [M + H]+ calcd for C19H26N3O3S: 376.1695; found:
376.1720.
HRMS (ESI): m/z [M + H]+ calcd for C22H21N4O3S: 421.1334; found:
421.1331.
N-{(Butylamino)[(4-methoxyphenyl)amino]methylene}toluene-
sulfonamide (4al)10f
N-{Bis[(4-methoxyphenyl)amino]methylene}toluenesulfon-
amide (4ap)
The title compound was prepared according to the typical procedure.
Yield: 60 mg (80%); yellow sticky liquid.
The title compound was prepared according to the typical procedure.
1H NMR (400 MHz, CDCl3): δ = 8.79 (s, 1 H), 7.83 (d, J = 8.2 Hz, 2 H),
7.26 (d, J = 8.4 Hz, 2 H), 7.06 (d, J = 8.7 Hz, 2 H), 6.90 (d, J = 8.6 Hz, 2 H),
4.61 (s, 1 H), 3.80 (s, 3 H), 3.25 (dd, J = 12.9, 7.0 Hz, 2 H), 2.41 (s, 3 H),
1.40–1.33 (m, 2 H), 1.24–1.14 (m, 2 H), 0.83 (t, J = 7.3 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 159.18, 154.80, 141.91, 141.14,
129.18, 128.37, 127.44, 126.04, 115.33, 55.60, 41.24, 31.54, 21.53,
19.87, 13.75.
Yield: 79 mg (93%); yellow solid; mp 154–155 °C.
IR (neat): 1597, 1247, 1101, 830, 805 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.86–7.80 (m, 2 H), 7.28 (s, 2 H), 7.17–
7.11 (m, 4 H), 6.86 (d, J = 8.1 Hz, 4 H), 3.79 (d, J = 1.6 Hz, 6 H), 2.41 (s,
3 H).
13C NMR (101 MHz, CDCl3): δ = 158.21, 152.76, 142.06, 140.69,
129.18, 128.22, 126.47, 125.99, 114.66, 55.48, 21.46.
HRMS (ESI): m/z [M + H]+ calcd for C22H24N3O4S: 426.1488; found:
426.1494.
N-{(Benzylamino)[(4-methoxyphenyl)amino]methylene}toluene-
sulfonamide (4am)
The title compound was prepared according to the typical procedure.
Yield: 26 mg (32%); yellow sticky liquid.
N-[(tert-Butylamino)(phenylamino)methylene]toluenesulfon-
IR (neat): 1557, 1511, 1364, 1248, 1129, 1091, 811, 676 cm–1
.
amide (4aq)
The title compound was prepared according to the typical procedure.
1H NMR (400 MHz, CDCl3): δ = 8.84 (s, 1 H), 7.72 (d, J = 8.2 Hz, 2 H),
7.20 (d, J = 8.2 Hz, 5 H), 7.13–6.98 (m, 4 H), 6.86 (d, J = 8.5 Hz, 2 H),
5.08 (s, 1 H), 4.44 (d, J = 5.6 Hz, 2 H), 3.75 (s, 3 H), 2.40 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 159.10, 154.70, 141.91, 140.80,
137.70, 129.13, 128.60, 128.25, 127.46, 127.21, 127.37, 125.97,
115.29, 55.50, 45.10, 21.47.
Yield: 66 mg (>98%); white solid; mp 80–81 °C.
IR (neat): 1712, 1580, 1361, 1140, 1072, 750, 653 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.88 (s, 1 H), 7.84 (dd, J = 8.3, 1.8 Hz, 2
H), 7.44–7.37 (m, 2 H), 7.28 (ddd, J = 9.0, 7.3, 0.8 Hz, 3 H), 7.12 (d, J =
7.5 Hz, 2 H), 4.69 (s, 1 H), 2.40 (s, 3 H), 1.30 (d, J = 2.1 Hz, 9 H).
13C NMR (101 MHz, CDCl3): δ = 153.01, 141.91, 141.05, 135.83,
130.24, 129.22, 127.38, 125.99, 125.67, 52.66, 29.25, 21.55.
HRMS (ESI): m/z [M + H]+ calcd for C22H24N3O3S: 410.1538; found:
410.1559.
HRMS (ESI): m/z [M + H]+ calcd for C18H24N3O2S: 346.1589; found:
346.1614.
N-{[(4-Chlorophenyl)amino][(4-methoxyphenyl)amino]methy-
lene}toluenesulfonamide (4an)
The title compound was prepared according to the typical procedure.
N-[(tert-Butylamino)(1-naphthylamino)methylene]toluenesul-
Yield: 78 mg (91%); pale yellow solid; mp 157–158 °C.
fonamide (4ar)
IR (neat): 1608, 1541, 1509, 1248, 1138, 1095, 829, 687 cm–1
.
The title compound was prepared according to the typical procedure.
1H NMR (400 MHz, CDCl3): δ = 8.59 (s, 1 H), 7.82 (d, J = 7.5 Hz, 2 H),
7.37–7.11 (m, 8 H), 6.93 (d, J = 8.3 Hz, 2 H), 3.82 (s, 3 H), 2.41 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 159.15, 152.10, 142.35, 140.41,
134.78, 130.80, 129.28, 129.08, 127.79, 127.18, 126.01, 124.08,
115.27, 55.54, 21.47.
Yield: 69 mg (87%); white solid; mp 142–143 °C.
IR (neat): 1712, 1548, 1356, 1221, 1142, 1082, 802, 714 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.08 (s, 1 H), 8.12–7.83 (m, 4 H), 7.71
(d, J = 8.1 Hz, 1 H), 7.68–7.29 (m, 7 H), 4.43 (s, 1 H), 2.44 (s, 3 H), 1.22
(s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 153.76, 142.05, 141.15, 134.73,
131.50, 129.78, 129.33, 128.85, 128.62, 127.45, 127.19, 126.31,
125.72, 124.99, 122.37, 52.67, 29.23, 21.63.
HRMS (ESI): m/z [M + H]+ calcd for C21H21ClN3O3S: 430.0987; found:
430.0986.
N-{[(4-Cyanophenyl)amino][(4-methoxyphenyl)amino]methy-
lene}toluenesulfonamide (4ao)
HRMS (ESI): m/z [M + H]+ calcd for C22H26N3O2S: 396.1746; found:
396.1745.
The title compound was prepared according to the typical procedure.
Yield: 69 mg (82%); white solid; mp 175–177 °C.
IR (neat): 1614, 1509, 1250, 1139, 1097, 838, 663 cm–1
N-(tert-Butyl)-N′-tosylmorpholine-4-carboximidamide (4as)
The title compound was prepared according to the typical procedure.
Yield: 66 mg (98%); white solid; mp 178–179 °C.
.
IR (neat): 1561, 1512, 1276, 1138, 1083, 885, 712 cm–1
.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 8.0 Hz, 2 H), 7.24 (d, J = 7.9
Hz, 2 H), 5.29 (s, 1 H), 3.78–3.73 (m, 4 H), 3.53–3.46 (m, 4 H), 2.39 (s, 3
H), 1.18 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 157.49, 141.48, 141.45, 128.90,
125.79, 66.15, 53.99, 49.19, 29.60, 21.29.
Dimethyl [(tert-Butylamino)(phenylamino)methylene]phospho-
ramidate (4bd)
The title compound was prepared according to the typical procedure.
Yield: 37 mg (63%); yellow sticky liquid.
IR (neat): 1624, 1542, 1364, 1205, 1038, 829, 784 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C16H26N3O3S: 340.1705; found:
340.1703.
1H NMR (400 MHz, CDCl3): δ = 7.41–7.34 (m, 2 H), 7.25–7.14 (m, 3 H),
4.77 (s, 1 H), 3.75 (d, J = 2.3 Hz, 3 H), 3.72 (d, J = 2.3 Hz, 3 H), 1.38 (d, J
= 2.2 Hz, 9 H).
13C NMR (101 MHz, CDCl3): δ = 154.38 (d, J = 7.5 Hz), 137.10, 129.74,
126.07, 124.95, 52.72 (d, J = 6.2 Hz), 51.71, 29.03.
N-[(tert-Butylamino)(cyanamido)methylene]toluenesulfonamide
(4at)10f
The title compound was prepared according to the typical procedure.
HRMS (ESI): m/z [M + H]+ calcd for C13H23N3O3P: 300.1477; found:
300.1481.
Yield: 54 mg (92%); white solid; mp 182–184 °C.
1H NMR (400 MHz, DMSO-d6): δ = 7.57 (d, J = 8.0 Hz, 2 H), 7.26 (d, J =
7.9 Hz, 2 H), 6.80 (s, 1 H), 3.75 (s, 1 H), 2.33 (s, 3 H), 1.18 (s, 9 H).
13C NMR (101 MHz, DMSO-d6): δ = 160.88, 142.71, 140.43, 128.84,
125.56, 50.54, 28.87, 20.92.
N-[(tert-Butylamino)(phenylamino)methylene]benzamide (4ca)14
The title compound was prepared according to the typical procedure.
Yield: 54 mg (92%); white solid; mp 96–97 °C.
1H NMR (400 MHz, DMSO-d6): δ = 8.08 (d, J = 7.2 Hz, 2 H), 7.53–7.36
(m, 5 H), 7.33 (d, J = 7.7 Hz, 2 H), 7.24–7.16 (m, 1 H), 1.49 (s, 9 H).
13C NMR (101 MHz, DMSO-d6): δ = 175.02, 157.26, 138.68, 137.38,
Diphenyl [(tert-Butylamino)(phenylamino)methylene]phosphora-
midate (4ba)10f
The title compound was prepared according to the typical procedure.
131.04, 129.40, 128.42, 127.98, 125.12, 123.70, 51.70, 29.11.
Yield: 76 mg (90%); pale yellow solid; mp 184–185 °C.
1H NMR (400 MHz, CDCl3): δ = 8.70 (s, 1 H), 7.39–7.24 (m, 10 H), 7.21
(d, J = 7.3 Hz, 1 H), 7.12 (dd, J = 7.1, 3.5 Hz, 2 H), 7.06 (d, J = 7.8 Hz, 2
H), 4.69 (s, 1 H), 1.12 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 154.72 (d, J = 8.0 Hz), 151.55 (d, J = 7.3
Hz), 136.59, 129.76, 129.16, 126.41, 125.12, 124.11, 120.62 (d, J = 4.7
Hz), 51.73, 28.70.
N-[(tert-Butylamino)(phenylamino)methylene]-4-methylbenz-
amide (4cb)
The title compound was prepared according to the typical procedure.
Yield: 53 mg (86%); white solid; mp 118–119 °C.
IR (neat): 1577, 1352, 1217, 900, 772, 698 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 12.18 (s, 1 H), 8.21–8.11 (m, 2 H),
7.44–7.36 (m, 2 H), 7.30–7.16 (m, 5 H), 4.89 (s, 1 H), 2.40 (s, 3 H), 1.50
(s, 9 H).
Diphenyl {[(2,6-Dimethylphenyl)amino](phenylamino)methy-
lene}phosphoramidate (4bb)
The title compound was prepared according to the typical procedure.
13C NMR (101 MHz, CDCl3): δ = 177.25, 157.92, 141.34, 136.63,
136.30, 130.06, 129.13, 128.68, 126.53, 125.14, 52.37, 29.67, 21.61.
HRMS (ESI): m/z [M + H]+ calcd for C19H24N3O: 310.1919; found:
310.1926.
Yield: 77 mg (82%); white solid; mp 138–140 °C.
IR (neat): 1622, 1585, 1488, 1197, 926, 773 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.72 (s, 1 H), 7.49–6.72 (m, 17 H), 5.95
(s, 1 H), 2.16 (s, 6 H).
4-Bromo-N-[(tert-butylamino)(phenylamino)methylene]benz-
amide (4cc)
13C NMR (101 MHz, CDCl3): δ = 154.45, 151.56, 151.46, 136.99 (d, J =
9.1 Hz), 132.76, 129.22, 128.58, 128.86, 124.60, 124.28, 122.07,
120.77 (d, J = 4.6 Hz), 17.90.
HRMS (ESI): m/z [M + H]+ calcd for C27H27N3O3P : 472.1790; found:
472.1801.
The title compound was prepared according to the typical procedure.
Yield: 67 mg (89%); white solid; mp 121–122 °C.
IR (neat): 1576, 1393, 1352, 1009, 897, 774 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 12.10 (s, 1 H), 8.12 (d, J = 8.3 Hz, 2 H),
7.55 (d, J = 8.4 Hz, 2 H), 7.46–7.36 (m, 2 H), 7.33–7.17 (m, 3 H), 4.93 (s,
1 H), 1.49 (s, 9 H).
Diphenyl [(tert-Butylamino)(butylamino)methylene]phosphora-
midate (4bc)
The title compound was prepared according to the typical procedure.
13C NMR (101 MHz, CDCl3): δ = 176.11, 158.09, 137.93, 136.30,
131.11, 130.71, 130.13, 126.80, 125.84, 125.25, 52.47, 29.67.
HRMS (ESI): m/z [M + H]+ calcd for C18H21BrN3O: 374.0868; found:
374.0870.
Yield: 72 mg (89%); white solid; mp 67–68 °C.
IR (neat): 1616, 1592, 1489, 1202, 1162, 918, 774 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.33–7.16 (m, 8 H), 7.08 (dd, J = 9.0, 4.1
Hz, 2 H), 2.98 (s, 2 H), 1.45–1.44 (m, 2 H), 1.35–1.28 (m, 2 H), 1.19 (s, 9
H), 0.88 (t, J = 7.2 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 156.49 (d, J = 9.5 Hz), 151.68 (d, J = 7.2
Hz), 129.03, 123.82, 120.51 (d, J = 4.8 Hz), 51.28, 41.27, 30.84, 29.14,
19.81, 13.55.
N-[(tert-Butylamino)(phenylamino)methylene]-4-methoxybenz-
amide (4cd)
The title compound was prepared according to the typical procedure.
Yield: 62 mg (96%); pale yellow solid; mp 98–99 °C.
IR (neat): 1568, 1352, 1250, 1220, 1140, 768 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C21H31N3O3P: 404.2103; found:
1H NMR (400 MHz, CDCl3): δ = 12.13 (s, 1 H), 8.28–8.19 (m, 2 H),
7.44–7.33 (m, 2 H), 7.27–7.17 (m, 3 H), 6.97–6.88 (m, 2 H), 4.91 (s, 1
H), 3.83 (s, 3 H), 1.49 (s, 9 H).
404.2101.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

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G. Qiao et al.
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Synthesis
13C NMR (101 MHz, CDCl3): δ = 176.80, 162.09, 157.72, 136.64,
131.64, 130.89, 130.01, 126.44, 125.07, 113.10, 55.31, 52.27, 29.63.
HRMS (ESI): m/z [M + H]+ calcd for C19H24N3O2: 326.1869; found:
326.1869.
13C NMR (101 MHz, CDCl3): δ = 175.99, 157.90, 151.09, 149.35,
137.20, 136.81, 136.03, 129.85, 129.42, 129.26, 128.57, 127.37,
126.51, 124.94, 120.96, 52.25, 29.44.
HRMS (ESI): m/z [M + H]+ calcd for C21H23N4O: 347.1872; found:
347.1886.
N-[(tert-Butylamino)(phenylamino)methylene]-4-cyanobenz-
amide (4ce)
N-[(Cyclohexylamino)(phenylamino)methylene]benzamide (4ci)
The title compound was prepared according to the typical procedure.
Yield: 49 mg (76%); white solid; mp 112–113 °C.
The title compound was prepared according to the typical procedure.
Yield: 58 mg (91%); white solid; mp 146–148 °C.
IR (neat): 1713, 1577, 1357, 1221, 782, 705 cm–1
.
IR (neat) 1589, 1361, 1221, 753, 712 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 12.04 (s, 1 H), 8.36–8.29 (m, 2 H),
7.75–7.66 (m, 2 H), 7.50–7.40 (m, 2 H), 7.34–7.21 (m, 3 H), 4.99 (s, 1
H), 1.50 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 174.88, 158.33, 143.00, 135.95,
131.82, 130.19, 129.42, 127.05, 125.32, 118.94, 114.06, 52.61, 29.64.
1H NMR (400 MHz, CDCl3): δ = 12.10 (s, 1 H), 8.26 (d, J = 6.9 Hz, 2 H),
7.51–7.34 (m, 5 H), 7.34–7.17 (m, 3 H), 4.84 (s, 1 H), 4.16 (s, 1 H), 2.05
(d, J = 10.6 Hz, 2 H), 1.67 (dd, J = 33.1, 13.0 Hz, 3 H), 1.43 (dd, J = 23.8,
11.9 Hz, 2 H), 1.27–1.08 (m, 3 H).
13C NMR (101 MHz, CDCl3): δ = 177.56, 157.85, 138.80, 136.35,
131.15, 130.10, 129.12, 127.92, 126.71, 125.25, 50.24, 33.19, 25.62,
24.86.
HRMS (ESI): m/z [M + H]+ calcd for C19H21N4O: 321.1715; found:
321.1717.
HRMS (ESI): m/z [M + H]+ calcd for C20H24N3O: 322.1919; found:
322.1923.
N-[(tert-Butylamino)(phenylamino)methylene]-2-naphthamide
(4cf)
N-[(Cyclohexylamino)(phenylamino)methylene]-3-methylbenz-
amide (4cj)
The title compound was prepared according to the typical procedure.
Yield: 59 mg (86%); white solid; mp 86–88 °C.
The title compound was prepared according to the typical procedure.
IR (neat): 1578, 1367, 1339, 1223, 791, 758 cm–1
.
Yield: 62 mg (93%); green sticky liquid.
1H NMR (400 MHz, CDCl3): δ = 12.26 (s, 1 H), 8.81 (s, 1 H), 8.36 (dd, J =
8.6, 1.4 Hz, 1 H), 7.98 (d, J = 7.4 Hz, 1 H), 7.91–7.81 (m, 2 H), 7.55–7.45
(m, 2 H), 7.43–7.40 (m, 2 H), 7.25 (dd, J = 12.9, 4.3 Hz, 3 H), 4.95 (s, 1
H), 1.55 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 177.05, 157.90, 136.40, 136.26,
134.84, 132.78, 129.97, 129.65, 129.32, 127.53, 127.30, 127.00,
126.50, 125.83, 125.81, 125.06, 52.33, 29.59.
IR (neat) 1570, 1498, 1449, 1360, 756, 695 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 12.11 (s, 1 H), 8.06 (s, 2 H), 7.42 (t, J =
7.5 Hz, 2 H), 7.35–7.15 (m, 5 H), 4.82 (s, 1 H), 4.15 (s, 1 H), 2.41 (s, 3
H), 2.06 (d, J = 9.9 Hz, 2 H), 1.83–1.56 (m, 3 H), 1.44 (dd, J = 24.1, 12.1
Hz, 2 H), 1.32–1.09 (m, 3 H).
13C NMR (101 MHz, CDCl3): δ = 177.62, 157.67, 138.63, 137.28,
136.27, 131.78, 129.92, 129.64, 127.70, 126.53, 126.18, 125.06, 50.14,
33.06, 25.52, 24.73, 21.43.
HRMS (ESI): m/z [M + H]+ calcd for C22H24N3O: 346.1919; found:
346.1930.
HRMS (ESI): m/z [M + H]+ calcd for C21H26N3O: 336.2076; found:
336.2052.
N-[(tert-Butylamino)(phenylamino)methylene]furan-2-carbox-
amide (4cg)
N-[(Cyclohexylamino)(phenylamino)methylene]-4-methylbenz-
amide (4ck)
The title compound was prepared according to the typical procedure.
Yield: 53 mg (93%); white solid; mp 78–79 °C.
The title compound was prepared according to the typical procedure.
IR (neat): 1578, 1474, 1396, 1355, 1220, 867, 754 cm–1
.
Yield: 60 mg (90%); white solid; mp 110–113 °C.
1H NMR (400 MHz, CDCl3): δ = 11.66 (s, 1 H), 7.54 (s, 1 H), 7.46–7.36
(m, 2 H), 7.28–7.22 (m, 3 H), 7.12 (d, J = 3.3 Hz, 1 H), 6.48–6.46 (m, 1
H), 4.89 (s, 1 H), 1.47 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 168.69, 157.73, 152.98, 144.82,
136.31, 130.06, 126.70, 125.22, 114.52, 111.40, 52.52, 29.57.
IR (neat) 1564, 1359, 1140, 755, 700 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 12.12 (s, 1 H), 8.15 (d, J = 6.4 Hz, 2 H),
7.41 (t, J = 7.1 Hz, 2 H), 7.23 (dd, J = 14.9, 4.8 Hz, 4 H), 4.81 (s, 1 H),
4.30–3.96 (m, 1 H), 2.40 (s, 2 H), 2.12–2.00 (m, 2 H), 1.67 (dd, J = 32.8,
12.8 Hz, 2 H), 1.43 (dd, J = 23.3, 11.5 Hz, 2 H), 1.32–1.09 (m, 3 H).
13C NMR (101 MHz, CDCl3): δ = 177.48, 157.60, 141.26, 137.66,
136.02, 129.89, 129.02, 128.53, 126.46, 125.05, 50.05, 33.04, 25.50,
24.71, 21.48.
HRMS (ESI): m/z [M + H]+ calcd for C16H20N3O2: 286.1556; found:
286.1566.
N-[(tert-Butylamino)(phenylamino)methylene]quinoline-6-car-
boxamide (4ch)
HRMS (ESI): m/z [M + H]+ calcd for C21H26N3O: 336.2076; found:
336.2066.
The title compound was prepared according to the typical procedure.
Yield: 66 mg (96%); white solid; mp 112–114 °C.
4-Chloro-N-[(cyclohexylamino)(phenylamino)methylene]benz-
amide (4cl)
IR (neat): 1578, 1460, 1366, 1214, 797, 757 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 12.09 (s, 1 H), 8.87–8.77 (m, 1 H), 8.64
(s, 1 H), 8.49 (d, J = 8.8 Hz, 1 H), 8.14 (d, J = 7.6 Hz, 1 H), 8.03 (d, J = 8.8
Hz, 1 H), 7.33–7.24 (m, 3 H), 7.20–7.09 (m, 3 H), 4.90 (s, 1 H), 1.43 (s, 9
H).
The title compound was prepared according to the typical procedure.
Yield: 58 mg (82%); white solid; mp 121–123 °C.
IR (neat) 1564, 1397, 1359, 776, 694 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

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G. Qiao et al.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 12.03 (s, 1 H), 8.09 (d, J = 81.3 Hz, 2 H),
7.73–6.90 (m, 6 H), 4.85 (s, 1 H), 4.12 (s, 1 H), 2.08 (t, J = 23.6 Hz, 2 H),
1.81–1.55 (m, 3 H), 1.43 (d, J = 7.6 Hz, 2 H), 1.19 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 176.33, 157.77, 137.20, 137.12,
135.99, 130.43, 130.05, 128.00, 126.78, 125.23, 50.17, 33.05, 25.46,
24.72.
1H NMR (400 MHz, CDCl3): δ = 12.04 (s, 1 H), 8.24 (d, J = 6.3 Hz, 2 H),
7.58–7.32 (m, 7 H), 7.26–7.09 (m, 4 H), 6.09 (s, 1 H), 2.36 (s, 6 H).
13C NMR (101 MHz, CDCl3): δ = 178.48, 157.49, 138.18, 137.21,
136.56, 132.54, 131.34, 129.24, 129.12, 128.63, 127.91, 124.63,
122.83, 18.29.
HRMS (ESI): m/z [M + H]+ calcd for C22H22N3O: 344.1763; found:
344.1757.
HRMS (ESI): m/z [M + H]+ calcd for C20H23ClN3O: 356.1530; found:
356.1512.
N-[Bis(tert-butylamino)methylene]benzamide (4cq)15
The title compound was prepared according to the typical procedure.
Yield: 45 mg (82%); colorless sticky liquid.
1H NMR (400 MHz, DMSO-d6): δ = 10.68 (s, 1 H), 8.27–8.14 (m, 2 H),
7.47–7.32 (m, 3 H), 4.45 (s, 1 H), 1.49 (s, 18 H).
4-Bromo-N-[(cyclohexylamino)(phenylamino)methylene]benz-
amide (4cm)
The title compound was prepared according to the typical procedure.
Yield: 71 mg (89%); white solid; mp 115–116 °C.
IR (neat) 1563, 1395, 1359, 774, 696 cm–1
.
13C NMR (101 MHz, DMSO-d6): δ = 176.23, 158.87, 139.41, 130.65,
1H NMR (400 MHz, CDCl3): δ = 12.02 (s, 1 H), 8.10 (d, J = 7.6 Hz, 2 H),
7.54 (d, J = 7.2 Hz, 1 H), 7.43 (t, J = 7.2 Hz, 1 H), 7.27 (dd, J = 11.4, 4.5
Hz, 2 H), 4.84 (s, 1 H), 4.12 (s, 1 H), 2.03 (d, J = 10.2 Hz, 2 H), 1.67 (dd, J
= 30.4, 12.5 Hz, 3 H), 1.42 (dd, J = 23.6, 11.7 Hz, 2 H), 1.21 (d, J = 33.6
Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 176.40, 157.74, 137.65, 132.89,
130.97, 130.66, 130.03, 126.79, 125.79, 125.21, 50.16, 33.03, 25.45,
24.70.
128.84, 127.80, 51.70, 30.00.
N-[(tert-Butylamino)(2-pyridylamino)methylene]benzamide
(4cr)7b
The title compound was prepared according to the typical procedure.
Yield: 39 mg (65%); white solid; mp 89–92 °C.
1H NMR (400 MHz, CDCl3): δ = 13.45 (s, 1 H), 10.52 (s, 1 H), 8.31–8.24
(m, 2 H), 8.20 (d, J = 5.0 Hz, 1 H), 7.65–7.59 (m, 1 H), 7.49–7.40 (m, 3
H), 6.95–6.90 (m, 1 H), 6.87 (d, J = 8.3 Hz, 1 H), 1.63 (s, 9 H).
HRMS (ESI): m/z [M + H]+ calcd for C20H23BrN3O: 400.1024; found:
400.1014.
13C NMR (101 MHz, CDCl3): δ = 176.73, 156.91, 153.27, 145.95,
138.95, 138.54, 131.20, 129.14, 127.99, 117.79, 113.87, 52.37, 29.55.
N-[(Cyclohexylamino)(phenylamino)methylene]-4-methoxybenz-
amide (4cn)
N-[(tert-Butylamino)(phenylamino)methylene]-2-phenylacet-
amide (4cs)
The title compound was prepared according to the typical procedure.
Yield: 67 mg (95%); white solid; mp 87–88 °C.
IR (neat) 1565, 1359, 1249, 784, 694 cm–1
The title compound was prepared according to the typical procedure.
Yield: 37 mg (61%); colorless sticky liquid.
.
1H NMR (400 MHz, CDCl3): δ = 12.11 (s, 1 H), 8.21 (d, J = 7.6 Hz, 2 H),
7.41 (t, J = 7.3 Hz, 2 H), 7.26 (d, J = 1.7 Hz, 2 H), 6.91 (d, J = 7.7 Hz, 2 H),
4.79 (s, 1 H), 4.13 (s, 1 H), 3.84 (s, 2 H), 2.05 (d, J = 10.7 Hz, 2 H), 1.67
(dd, J = 33.4, 12.7 Hz, 3 H), 1.43 (dd, J = 23.9, 11.9 Hz, 2 H), 1.27–1.09
(m, 3 H).
13C NMR (101 MHz, CDCl3): δ = 177.12, 162.04, 157.47, 156.68,
131.42, 130.85, 129.86, 126.31, 125.02, 112.98, 55.24, 50.03, 33.06,
25.50, 24.73.
Compound 4cs exists in three different tautomeric forms according to
the results of the 1H NMR spectra recorded at different temperatures
(Scheme 7, Figure 2). At 25 °C, the chemical shift of the H in tertiary
butyl was δ = 1.31 and 1.36; that of H in methylene was δ = 3.49 and
3.54. At 50 °C, the chemical shift of H in tertiary butyl and methylene
slightly centralized with δ = 1.32, 1.38 and δ = 3.51, 3.55. At 80 °C, H
in methylene centralized to a single peak at δ = 3.54. In addition,
UPLC-MS (ESI) results showed that only m/z [M + H]+ = 310 was ex-
tracted, according to chromatography spectra.
HRMS (ESI): m/z [M + H]+ calcd for C21H26N3O2: 352.2025; found:
352.2015.
t-Bu
t-Bu
t-Bu
O
HN
O
N
O
HN
N-[(Benzylamino)(phenylamino)methylene]benzamide (4co)7f
The title compound was prepared according to the typical procedure.
Yield: 46 mg (70%); colorless sticky liquid.
1H NMR (400 MHz, DMSO-d6): δ = 11.97 (s, 1 H), 8.93 (s, 1 H), 8.05 (s,
2 H), 7.58–7.32 (m, 11 H), 7.25 (d, J = 17.8 Hz, 2 H), 4.68 (d, J = 5.2 Hz,
2 H).
Ph
Ph
Ph
Ph
Ph
Ph
N
N
N
N
N
N
H
H
H
H
Scheme 7
IR (neat): 1650, 1600, 1555, 1499, 1236, 698, 668 cm–1
.
13C NMR (101 MHz, DMSO-d6): δ = 175.62, 158.29, 138.59, 130.98,
HRMS (ESI): m/z [M + H]+ calcd for C19H24N3O: 310.1919; found:
128.61, 128.47, 128.43, 128.27, 127.86, 127.31, 127.05, 124.40, 44.48.
310.1935.
N-[(tert-Butylimino)methylene]benzamide (5a)10b
The title compound was prepared according to the typical procedure.
Yield: 145 mg (72%); pale yellow liquid.
N-{[(2,6-Dimethylphenyl)amino](phenylamino)methylene}benz-
amide (4cp)
The title compound was prepared according to the typical procedure.
Yield: 38 mg (56%); white solid; mp 137–140 °C.
1H NMR (400 MHz, CDCl3): δ = 8.17–8.05 (m, 2 H), 7.58–7.51 (m, 1 H),
7.45–7.39 (m, 2 H), 1.51 (s, 9 H).
IR (neat): 1605, 1567, 1446, 1353, 753, 690 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

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G. Qiao et al.
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Synthesis
Yield: 136 mg (54%); yellow liquid.
1H NMR (400 MHz, CDCl3): δ = 8.68 (s, 1 H), 8.13 (d, J = 8.6 Hz, 1 H),
7.94 (d, J = 8.0 Hz, 1 H), 7.84 (d, J = 8.6 Hz, 2 H), 7.57–7.47 (m, 2 H),
1.51 (s, 9 H) (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 174.58, 135.60, 132.42, 131.33,
131.14, 129.42, 128.11, 127.92, 127.60, 126.38, 125.30, 58.95, 31.27.
N-[(tert-Butylimino)methylene]thiophene-2-carboxamide (5g)10f
The title compound was prepared according to the typical procedure.
Yield: 123 mg (59%); pale yellow liquid.
1H NMR (400 MHz, CDCl3): δ = 7.83–7.76 (m, 1 H), 7.57–7.52 (m, 1 H),
7.12–7.04 (m, 1 H), 1.50 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 168.67, 139.32, 133.14, 132.98,
128.03, 59.04, 31.18.
Figure 2
Funding Information
13C NMR (101 MHz, CDCl3): δ = 174.63, 133.89, 129.72, 128.21, 58.97,
31.33.
This project is supported by the National Natural Science Foundation
of China (No. 21672256), the National S&T Pillar Program of China
(2015BAK45B01), and Chinese Universities Scientific Fund
N-[(tert-Butylimino)methylene]-4-methylbenzamide (5b)10f
The title compound was prepared according to the typical procedure.
Yield: 149 mg (69%); colorless liquid.
(2017QC152).
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1H NMR (400 MHz, CDCl3): δ = 7.99 (dd, J = 8.2, 1.8 Hz, 2 H), 7.22 (d, J
= 6.9 Hz, 2 H), 2.39 (s, 3 H), 1.50 (s, 9 H).
Supporting Information
13C NMR (101 MHz, CDCl3): δ = 174.44, 143.78, 131.20, 129.79,
Supporting information for this article is available online at
128.93, 58.87, 31.31, 21.60.
https://doi.org/10.1055/s-0036-1588576.
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N-[(tert-Butylimino)methylene]-4-chlorobenzamide (5c)10f
The title compound was prepared according to the typical procedure.
Yield: 132 mg (56%); colorless liquid.
1H NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 8.4 Hz, 2 H), 7.38 (d, J = 8.4
Hz, 2 H), 1.51 (s, 9 H).
References
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13C NMR (101 MHz, CDCl3): δ = 173.70, 139.38, 132.42, 131.09,
128.49, 59.07, 31.28.
N-[(tert-Butylimino)methylene]-4-(trifluoromethyl)benzamide
(5d)10f
The title compound was prepared according to the typical procedure.
Yield: 143 mg (53%); colorless liquid.
1H NMR (400 MHz, CDCl3): δ = 8.21 (d, J = 8.2 Hz, 2 H), 7.68 (d, J = 8.2
Hz, 2 H), 1.53 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 173.60, 137.11, 134.19 (q, J = 32.5 Hz),
129.98, 128.27, 125.20 (q, J = 3.7 Hz), 123.72 (q, J = 272.6 Hz), 59.19,
31.23.
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26.
N-[(tert-Butylimino)methylene]-4-methoxybenzamide (5e)10f
The title compound was prepared according to the typical procedure.
Yield: 141 mg (61%); yellow liquid.
1H NMR (400 MHz, CDCl3): δ = 8.11–7.90 (m, 2 H), 6.93–6.86 (m, 2 H),
3.85 (s, 3 H), 1.49 (s, 9 H).
(6) Rudrawar, S.; Dyason, J. C.; Rameix-Welti, M.-A.; Rose, F. J.;
Kerry, P. S.; Russell, R. J. M.; van der Werf, S.; Thomson, R. J.;
Naffakh, N.; von Itzstein, M. Nat. Commun. 2010, 1, 113.
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S.; Costa, M. S. B.; Napolitano, H. B.; Lariucci, C.; Vencato, I. Tet-
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M. C. M.; Ramos, G. C. D. O.; Alt, H. G. Phosphorus, Sulfur Silicon
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rahedron Lett. 2006, 47, 6955. (e) Tan, D.; Mottillo, C.; Katsenis,
13C NMR (101 MHz, CDCl3): δ = 173.79, 163.61, 131.89, 126.49,
113.41, 58.84, 55.35, 31.33.
N-[(tert-Butylimino)methylene]-2-naphthamide (5f)10f
The title compound was prepared according to the typical procedure.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

K
G. Qiao et al.
Paper
Synthesis
A. D.; Štrukil, V.; Friščič, T. Angew. Chem. Int. Ed. 2014, 53, 9321.
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