Hetero-Tetradehydro-Diels-Alder Cycloaddition of Enynamides and Cyanamides: Gold-Catalyzed Generation of Diversely Substituted 2,6-Diaminopyridines

Article abstract of DOI:10.1021/acs.joc.1c00558

Gold(I)-catalyzed hetero-tetradehydro-Diels-Alder cycloaddition of enynamides and cyanamides comprises an efficient route to diversely substituted 2,6-diaminopyridines (28 examples; yields up to 99%). The reaction proceeds under very mild conditions (DCM, rt) with high functional group tolerance. The obtained 2,6-diaminopyridines represent a useful synthetic platform with an easily modulated substitution pattern for subsequent functionalizations of both the pyridine core and the N-substituents.

Full text of DOI:10.1021/acs.joc.1c00558

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Article
Hetero-Tetradehydro-Diels−Alder Cycloaddition of Enynamides and
Cyanamides: Gold-Catalyzed Generation of Diversely Substituted
2,6-Diaminopyridines
Nikolay V. Shcherbakov, Dmitry V. Dar’in, Vadim Yu. Kukushkin,* and Alexey Yu. Dubovtsev*
Cite This: J. Org. Chem. 2021, 86, 7218−7228
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ABSTRACT: Gold(I)-catalyzed hetero-tetradehydro-Diels−Alder cycloaddi-
tion of enynamides and cyanamides comprises an efficient route to diversely
substituted 2,6-diaminopyridines (28 examples; yields up to 99%). The reaction
proceeds under very mild conditions (DCM, rt) with high functional group
tolerance. The obtained 2,6-diaminopyridines represent a useful synthetic
platform with an easily modulated substitution pattern for subsequent
functionalizations of both the pyridine core and the N-substituents.
Scheme 2. Hetero-TDDA Reactions
INTRODUCTION
■
In the field of Diels−Alder (DA) reactions, [4 + 2]
cycloadditions of substrates featuring triple bonds are
commonly categorized as dehydro-DAs,1−3 while the cyclo-
addition of enynes and alkynes is subclassified as tetradehydro-
Diels−Alder (TDDA) reactions (Scheme 1).
Scheme 1. TDDA Reaction between Enynes and Alkynes
Practical application of TDDA reactions are severely limited,
because they usually require harsh conditions, and/or complex
prefunctionalized substrates (for the intramolecular variants).
However, because TDDA cycloadditions allow the creation of
benzene ring(s) in a single step, there is a demand for
development of new practically feasible routes to such [4 + 2]
integrations. While TDDA reactions in general are rare, hetero-
TDDA reactions that provide access to aromatic heterocycles
are almost unique. Only three examples of hetero-TDDA
cycloadditions have been reported (Scheme 2B). These
include the nucleophilic addition of 1-lithium-1-en-3-ynes to
p-tolunitrile4 and the TfOH-promoted interaction of enynylox-
azolidin-2-ones with nitriles5 giving in both cases fused
pyridines. These two methods have a limited scope and
involve the use of equivalent amounts of highly aggressive
reagents, namely BuLi4 or TfOH.5 In contrast, the single
known catalytic method allows the formation of 2-methox-
ypyridines from ynol ethers and nitriles under relatively mild
conditions using the gold-based catalytic system Et3PAuCl/
AgSbF6.6 Notably, in all these cases4−6 conventional nitriles
RCN (R = Alk, Ar) were used as coreactants.
Received: March 9, 2021
Published: May 7, 2021
Based on these results4−6 and considering the relevant
successful examples of Au-catalyzed carbo-TDDA cyclo-
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additions,7,8 we now attempted gold-catalyzed hetero-TDDA
reactions with such activated alkynes as enynamides. First, the
application of gold for various catalytic conversions of alkynes
is a cutting-edge research area9−17 and the focus of the
upcoming special issue of Chemical Reviews scheduled for Aug.
2021; the first articles18−27 have already been published.
Second, ynamides28−33 are widely used synthetic building
blocks that combine high reactivity and various substitution
patterns, but at the same time, the reactions of enyna-
mides34−38 are poorly explored. As the initial idea for this
study, we assumed that enynamides can also be involved in the
intermolecular hetero-TDDA cycloaddition with nitriles RCN
and that this integration should lead to 2-aminopyridines
(Scheme 2A). All our results relevant to this novel synthetic
route are disclosed in sections that follow.
a
Table 1. Optimization of the Synthesis of 5a
b
entry
Catalyst
Solvent
Yield,
%
1
2
3
4
5
6
7
8
Ph3PAuCl/AgNTf2
IPrAuCl/AgNTf2
JohnPhosAuCl/AgNTf2
IPrAuCl/AgOTf
IPrAuCl/AgSbF6
IPrAuNTf2
DCM
DCM
DCM
DCM
DCM
DCM
DCM
PhMe
THF
MeCN
DCE
DCM
DCM
84
89
88
71
81
87
−
AgNTf2
RESULTS AND DISCUSSION
IPrAuCl/AgNTf2
IPrAuCl/AgNTf2
IPrAuCl/AgNTf2
IPrAuCl/AgNTf2
IPrAuCl/AgNTf2
IPrAuCl/AgNTf2
80
63
83
90
85
92
■
9
To prove our hypothesis, we first attempted the gold-catalyzed
interaction between enynamide 1a and conventional nitriles
(MeCN, PhCN), but no hetero-TDDA reaction species were
detected (Scheme 3). A complex reaction mixture was
10
11
12
13
c
d
e
a
All reactions were carried out on a 0.1 mmol scale (0.2 M).
Scheme 3. Gold-Catalyzed Cycloadditions of Enynamide 1a
b
1
Estimated by H NMR spectroscopy using durene as an internal
c
d
e
standard. 60 °C, 3 h. 3 mol % of IPrAuCl/AgNTf2 was used. 1.5
equiv of Me2NCN was used.
reduced to 3 mol % without significant loss of the yield (entry
12). In summary, the best synthetic results to achieve 5a from
enynamide 1a were obtained with only 1.5 equiv of 4a and 5
mol % of IPrAuCl/AgNTf2 in DCM at rt for 24 h (entry 13).
With the optimal conditions at hand, the substrate scope and
limitations for the synthesis of 2,6-diaminopyridines 5 were
examined. We tested various enynamides 1 in their reactions
with dimethylcyanamide (Table 2). The cycloadditions
proceed smoothly with the reactants featuring various
electron-withdrawing N-sulfonyl substituents (5a−c). Pyridine
5d bearing a cyclic carbamate substituent was obtained in good
yield, and its structure was further confirmed by single-crystal
X-ray diffraction (CCDC 2062892). Ynamides featuring N-
phenyl and functional-substituted N-alkyl groups delivered the
corresponding pyridines in good to excellent yields (5e−i).
The reaction conditions were applicable to the hetero-TDDA
cycloadditions of ynamides with diverse R1-substituents. Thus,
diversified functionalities can be introduced into the fifth
position of pyrimidine ring, including aryl (5j−5m, 5p),
heteroaryl (5o), and alkyl (5q) fragments. The conjugated
dienynamide 1n was successfully converted to the correspond-
ing 5-alkenylpyridine 5n. The pyridine bearing a methyl
substituent in the 4-position (5r) was obtained in excellent
yield. The cycloaddition was carried out in a bidirectional
manner giving bispyridine benzene 5s.
The cyanamide scope of the studied hetero-TDDA reaction
is shown in Table 3. All tested disubstituted cyanamides gave
the corresponding pyridines in good and excellent yields. Our
protocol was applicable for introducing a variety of cyclic
amino-functionalities, such as, pyrrolidine, piperidine, morpho-
line, and tetrahydroisoquinoline fragments into the sixth
position of the pyridine core (6f−i). Complex reaction
mixtures were obtained when we used cyanamides containing
free NH-fragments (NH2CN, PhNHCN, n-BuNHCN). These
facts are probably related to the competing gold-catalyzed
hydroamination of starting ynamides.48 Nevertheless, pyridines
obtained in the case of acetonitrile. When benzonitrile was
used, the only identified product was pyrimidine 3 derived
from the known39,40 [2 + 2 + 2] cycloaddition of one ynamide
and two PhCN; the alkene fragment of 1a remained intact.
It is known41 (and it is also our experience40,42,43) that the
chemistry of cyanamides44,45 is often dramatically different
from the chemistry of conventional organonitriles; this
different reactivity is typically associated with the push−pull
nature of cyanamides. Hence, as the next step, we replaced
nitriles 2, unreactive in the attempted hetero-TDDA reaction,
with dimethylcyanamide 4a. In line with our expectations, in
the case of Me2NCN, the desired 2,6-diaminopyridine 5a was
obtained as the only product. Inspired by these results, we
optimized conditions of this novel hetero-TDDA reaction and
extended its scope.
To optimize the reaction conditions, some popular gold-
based catalysts were tested: these experiments included ligand
and counterion variations (Table 1, entries 1−6).46,47 The
system IPrAuCl/AgNTf2 demonstrated the best results (entry
2); AgNTf2 alone does not catalyze the reaction (entry 7).
Among the employed solvents (entries 2, 8−10), DCM gave
the highest yield. Interestingly, when neat acetonitrile was used
as a solvent, the [4 + 2] and [2 + 2 + 2] cycloaddition products
of 1a and MeCN were not detected, again confirming that
conventional nitriles are unreactive in the hetero-TDDA
cycloaddition. The reaction can also be performed at 60 °C
in DCE in just 3 h (entry 11). The catalyst loading can be
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a b
,
a b
,
Table 2. Reactivity Screening for Ynamides 1
Table 3. Reactivity Screening for Cyanamides 4
a
b
All reactions were carried out on a 0.2 mmol scale (0.2 M). Isolated
yield.
Having developed a new efficient method for the
construction of the 2,6-diaminopyridine core, we then focused
on studying its postmodifications (Scheme 4). Pyridine 5a was
Scheme 4. Post-functionalizations of Pyridines 5 and 6
a
b
All reactions were carried out on a 0.2 mmol scale (0.2 M). Isolated
c
yield. 15 mol % of IPrAuCl/AgNTf2 was used.
6b−d, bearing easily cleavable benzyl N-protective groups,
were obtained in excellent yields. Also, we scaled the synthesis
of 6c up to 1.0 mmol, and the isolated yield was 95%. The
preparation of 5a can be conducted on a gram scale (91%
isolated yield).
The 2-aminopyridine and 2,6-diaminopyridine motifs are
widely represented among natural compounds, such as α-
carbolines,49,50 and numerous synthetic drug candidates.51−54
Moreover, these heterocycles are used in organometallic
chemistry as ligands55 and in materials chemistry as macro-
molecular linkers.56 Although the synthetic routes to simply
substituted 2-aminopyridines are known (e.g., Chichibabin
reaction,57 Buchwald−Hartwig aminations of halopyri-
dines,58,59 and various multicomponent condensations),60−62
the preparation of target compounds with complex substitution
patterns is typically a challenging task.41,63
easily halogenated in the third position; the resulting bromo-
and iodo- pyridines (7 and 8) could serve as precursors for
cross-coupling strategies. The modification of the amino
substituent in the second position is demonstrated by the
denosylation of compound 6d. Finally, pyridine 6c gave the di-
and mono-debenzylation products (10 and 10′) under the
catalytic hydrogenolysis conditions.
A plausible mechanism64−67 for the gold-catalyzed hetero-
TDDA reaction is given in Scheme 5. The coordination of the
cationic gold to the enynamide triple bond gives π-complex A,
whereupon cyanamide 4 attacks A to give nitrilium ion B.
Next, cyclization of B followed by aromatization/protodeaura-
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method also include scalability and the possibility of further
modifications of the obtained heterocyclic products. In
conclusion, we showed the uniqueness of the chemical
behavior of enynamides in comparison with β-aryl-substituted
analogues. We hope that the use of enynamides will open up
new frontiers in gold catalysis.
Scheme 5. Plausible Mechanism for Generation of 5 and 6
EXPERIMENTAL SECTION
■
General Information. NMR spectra were recorded at ambient
temperature with a Bruker Avance III 400 instrument at 400.13 MHz
(1H NMR) and 100.61 MHz (13C NMR) in CDCl3. Chemical shifts
(δ) are given in ppm relative to resonances of the solvents (1H: δ =
7.26 for residual CHCl3 peak; 13C: δ = 77.2 for CDCl3). Mass spectra
were recorded on Bruker MicroTOF (ESI) and Bruker maXis HRMS-
ESI-QTOF instruments. Chromatographic separation was carried out
on Macherey−Nagel silica gel 60 M (0.04−0.063 mm). Analytical
TLC was performed on unmodified Merck ready-to-use plates (TLC
silica gel 60 F254); detection was achieved with a UV lamp. Melting
points were measured with a Stuart smp30 apparatus. Gold complexes
(IPrAuNTf2,69 Ph3PAuCl,70 JohnPhosAuCl71) were synthesized
accordingly to the published protocols. Known enynamides 1 were
prepared according to the literature procedures.34,72 The solvents
were purified using standard techniques and stored over activated 4 Å
molecular sieves before use. Other reagents were purchased from
commercial vendors and were used as received. For known
tion leads to pyridine 5, whereas the catalyst is regenerated.
Unlike conventional nitriles Alk(Ar)CN giving only the
pyrimidine species (Scheme 3),39 cyanamide sp-carbon of the
key intermediate B is sufficiently electrophilic for intra-
molecular attack by the alkene fragment. Thus, the employ-
ment of push−pull cyanamides is a crucial factor for this gold-
catalyzed hetero-TDDA cycloaddition. In contrast to our
method that utilizes exclusively cyanamides, Barluenga and
Aguilar succeeded in employing the conventional nitriles in the
gold-catalyzed TDDA reaction with enyne ethers (Scheme 2).6
We assume that this reaction occurred due to the push−pull
nature of the employed alkyne substrates, where the methoxy
substituents at the triple bonds are conjugated with the ester
fragments (see the postulated mechanism in ref 6). In another
work, these authors also noted this effect.68 Very likely, for the
conductance of the TDDA reaction, one of the substrates (viz.,
enyne or nitrile) should exhibit the push−pull character.
The above reaction scheme (Scheme 5) is relevant to the
gold-catalyzed formal [4 + 2] cycloaddition β-arylynamides
and cyanamides to furnish 1,3-diaminoisoquinolines, which we
reported earlier.40 In contrast to enynamides 1, which react
with cyanamides at room temperature to give 2,6-diaminopyr-
imidines, the cyclization of nitrilium ions generated from β-
arylynamides and cyanamides is not easy and it requires harsh
conditions (80 °C). This is probably related to the need for
dearomatization of the aryl substituent, whereas, for
enynamides 1, cyclization of the nitrile cation B is preferable.
For the same reason, in a large number of cases, the competing
[2 + 2 + 2] cycloaddition of one alkyne and two cyanamides
becomes prevalent for β-arylynamides. For enynamides 1 even
traces of the possible side products (derived from the [2 + 2 +
2] reaction) were not detected.
1
compounds 1c−e,g,o the H and 13C NMR spectra are consistent
with previously reported literature.
General Procedure for the Synthesis of Starting Enyna-
mides 1. A 50 mL round-bottom flask was charged with amide (1.0
mmol), 1,1-dibromo-1-alkene (1.2 mmol, 1.2 equiv), Cs2CO3 (1.30 g,
4.0 mmol, 4.0 equiv), and copper(I) iodide (24 mg, 0.125 mmol, 12.5
mol %). The flask was fitted with a rubber septum, evacuated under
high vacuum, and backfilled with argon. Dry and degassed DMF (5
mL) and N,N′-dimethylethylenediamine (22 mg, 0.25 mmol, 25 mol
%) were next added, and the blue or green suspension was heated at
70 °C in an oil bath for 24 h with stirring. After completion, all
volatile components were removed in vacuo and the residue was
purified by silica gel chromatography eluting with hexane/EtOAc to
afford enynamides 1.
(E)-N,4-Dimethyl-N-(4-phenylbut-3-en-1-yn-1-yl)benzene-
sulfonamide (1a).72 Yellow solid (224 mg, 72%); mp 83.5−84.5 °C
(hexane/EtOAc); Rf 0.30 (hexane/EtOAc 8:1); 1H NMR (400 MHz,
CDCl3) δ 7.83 (d, J = 8.3 Hz, 2H), 7.40−7.23 (m, 7H), 6.83 (d, J =
16.2 Hz, 1H), 6.22 (d, J = 16.2 Hz, 1H), 3.12 (s, 3H), 2.46 (s, 3H);
13C{H} NMR (100 MHz, CDCl3) δ 145.0, 139.8, 136.5, 133.4, 130.0,
128.8, 128.5, 127.9, 126.2, 107.6, 86.1, 68.9, 39.5, 21.8; HRMS (ESI):
m/z [M + H]+ calcd for C18H17NO2SNa+, 334.0872; found, 334.0873.
(E)-4-Fluoro-N-methyl-N-(4-phenylbut-3-en-1-yn-1-yl)benzene-
sulfonamide (1b). Yellow solid (218 mg, 69%); mp 60.0−61.5 °C
(hexane/EtOAc); Rf 0.30 (hexane/EtOAc 8:1); 1H NMR (400 MHz,
CDCl3) δ 8.00−7.93 (m, 2H), 7.39−7.23 (m, 7H), 6.85 (d, J = 16.2
Hz, 1H), 6.22 (d, J = 16.2 Hz, 1H), 3.14 (s, 3H); 13C{H} NMR (100
MHz, CDCl3) δ 165.9 (d, JF = 256.4 Hz), 140.2, 136.3, 132.4 (d, JF =
3.2 Hz), 130.6 (d, JF = 9.6 Hz), 128.8, 128.6, 126.2, 116.7 (d, JF =
22.7 Hz), 107.2, 85.6, 69.0, 39.4; HRMS (ESI): m/z [M + H]+ calcd
for C17H14FNO2SNa+, 338.0621; found, 338.0615.
(E)-N-Methyl-N-(4-phenylbut-3-en-1-yn-1-yl)methane-
sulfonamide (1c).72 Brown solid (165 mg, 70%); mp 78.0−80.0 °C
(hexane/EtOAc); Rf 0.40 (hexane/EtOAc 2:1); 1H NMR (400 MHz,
CDCl3) 7.36−7.23 (m, 5H), 6.86 (d, J = 16.2 Hz, 1H), 6.21 (d, J =
16.2 Hz, 1H), 3.24 (s, 3H), 3.08 (s, 3H); 13C{H} NMR (100 MHz,
CDCl3) δ 140.2, 136.4, 128.9, 128.6, 126.3, 107.3, 85.2, 69.3, 39.3,
36.9; HRMS (ESI): m/z [M + H]+ calcd for C12H13NO2SNa+,
258.0559; found, 258.0555.
CONCLUSIONS
■
In summary, we reported a new example of a rare hetero-
TDDA cycloaddition. Our method is based on the integration
of enynamides and cyanamides under the gold catalysis
conditions. In contrast to a few previously reported cases of
hetero-TDDA transformations involving conventional nitriles,
the application of push−pull cyanamides, as the reaction
partners of enynamides, leads to the formation of a pyridine
backbone under essentially mild conditions allowing high
functional group tolerance. The advantages of the proposed
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(E)-3-(4-Phenylbut-3-en-1-yn-1-yl)oxazolidin-2-one (1d).73
Brown solid (117 mg, 55%); mp 106.5−108.0 °C (hexane/EtOAc);
16.0 Hz, 1H), 3.17 (s, 3H), 2.47 (s, 3H); 13C{H} NMR (100 MHz,
CDCl3) δ 145.0, 136.8, 134.0, 133.9, 133.6, 131.0, 130.1, 128.9, 128.8,
128.0, 126.5, 126.1, 125.7, 123.7, 123.4, 110.3, 86.1, 69.3, 39.5, 21.9;
HRMS (ESI): m/z [M + H]+ calcd for C22H19NO2SNa+, 384.1029;
found, 384.1025.
1
Rf 0.40 (hexane/EtOAc 1:1); H NMR (400 MHz, CDCl3) δ 7.38−
7.27 (m, 5H), 6.93 (d, J = 16.2 Hz, 1H), 6.25 (d, J = 16.2 Hz, 1H),
4.49−4.45 (m, 2H), 3.99−3.95 (m, 2H); 13C{H} NMR (100 MHz,
CDCl3) δ 156.6, 140.3, 136.3, 128.8, 128.6, 126.2, 107.0, 81.2, 71.0,
63.2, 47.1; HRMS (ESI): m/z [M + H]+ calcd for C13H11NO2Na+,
236.0682; found, 236.0680.
(E)-N,4-Dimethyl-N-(pent-3-en-1-yn-1-yl)benzenesulfonamide
(1q). Colorless solid (204 mg, 82%); mp 78.5−80.0 °C (hexane/
1
EtOAc); Rf 0.50 (hexane/EtOAc 4:1); H NMR (400 MHz, CDCl3)
δ 7.77 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 6.09−6.00 (m,
1H), 5.54−5.49 (m, 1H), 3.04 (s, 3H), 2.44 (s, 3H), 1.76 (dd, J = 6.8,
1.8 Hz, 3H); 13C{H} NMR (100 MHz, CDCl3) δ 144.8, 139.1, 133.4,
129.8, 127.9, 109.9, 82.1, 67.7, 39.4, 21.7, 18.6; HRMS (ESI): m/z
[M + Na]+ calcd for C13H15NNaO2S+, 272.0716; found, 272.0720.
(E)-N,4-Dimethyl-N-(3-methyl-4-phenylbut-3-en-1-yn-1-yl)-
benzenesulfonamide (1r). Yellowish solid (215 mg, 66%); mp 57.5−
(E)-N-Benzyl-4-methyl-N-(4-phenylbut-3-en-1-yn-1-yl)benzene-
sulfonamide (1e).74 Yellowish solid (263 mg, 68%); mp 84.5−86 °C
(hexane/EtOAc); Rf 0.30 (hexane/EtOAc 8:1); 1H NMR (400 MHz,
CDCl3) δ 7.78 (d, J = 8.3 Hz, 2H), 7.33−7.24 (m, 12H), 6.71 (d, J =
16.2 Hz, 1H), 6.15 (d, J = 16.2 Hz, 1H), 4.56 (s, 2H), 2.45 (s, 3H);
13C{H} NMR (100 MHz, CDCl3) δ 144.8, 139.6, 136.6, 135.0, 134.7,
129.9, 128.9, 128.8, 128.7, 128.48, 128.47, 127.9, 126.2, 107.7, 84.9,
71.2, 55.9, 21.8; HRMS (ESI): m/z [M + H]+ calcd for
C24H21NO2SNa+, 410.1185; found, 410.1180
(E)-N-Allyl-4-methyl-N-(4-phenylbut-3-en-1-yn-1-yl)benzene-
sulfonamide (1f). Brown oil (135 mg, 40%); Rf 0.30 (hexane/EtOAc
8:1); 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.2 Hz, 2H), 7.41−
7.22 (m, 7H), 6.83 (d, J = 16.2 Hz, 1H), 6.24 (d, J = 16.2 Hz, 1H),
5.78 (ddt, J = 16.6, 10.1, 6.3 Hz, 1H), 5.33−5.22 (m, 2H), 4.03 (d, J =
6.3 Hz, 2H), 2.46 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ 144.8,
139.6, 136.4, 134.7, 130.9, 129.9, 128.7, 128.4, 127.7, 126.0, 120.1,
107.5, 84.4, 70.6, 54.4, 21.6; HRMS (ESI): m/z [M + H]+ calcd for
C20H19NO2SNa+, 360.1029; found, 360.1022.
1
59.5 °C (hexane/EtOAc); Rf 0.30 (hexane/EtOAc 8:1); H NMR
(400 MHz, CDCl3) δ 7.85 (d, J = 8.3 Hz, 2H), 7.41−7.32 (m, 4H),
7.28−7.22 (m, 3H), 6.73 (s, 1H), 3.13 (s, 3H), 2.47 (s, 3H), 2.47 (d,
J = 1.4 Hz, 3H); 13C{H} NMR (100 MHz, CDCl3) δ 144.9, 137.0,
134.6, 133.5, 130.0, 129.0, 128.4, 128.0, 127.2, 119.3, 83.4, 73.1, 39.5,
21.8, 19.5; HRMS (ESI): m/z [M + H]+ calcd for C19H19NO2SNa+,
348.1029; found, 348.1024.
Synthesis of Enynamide 1i. A 50 mL round-bottom flask was
charged with N-phenylmethanesulfonamide (171 mg, 1.0 mmol),
(E)-N-Cyclopropyl-4-methyl-N-(4-phenylbut-3-en-1-yn-1-yl)-
benzenesulfonamide (1g).75 Brown oil (250 mg, 74%); Rf 0.30
(hexane/EtOAc 8:1); 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.3
Hz, 2H), 7.40−7.24 (m, 7H), 6.84 (d, J = 16.2 Hz, 1H), 6.25 (d, J =
16.2 Hz, 1H), 2.81 (tt, J = 7.0, 3.6 Hz, 1H), 2.46 (s, 3H), 0.92−0.85
(m, 2H), 0.83−0.75 (m, 2H); 13C{H} NMR (100 MHz, CDCl3) δ
144.9, 139.6, 136.5, 134.0, 129.9, 128.8, 128.4, 128.1, 126.1, 107.6,
84.1, 70.3, 33.0, 21.8, 6.6; HRMS (ESI): m/z [M + H]+ calcd for
C20H19NO2SNa+, 360.1029; found, 360.1022.
K2CO3 (415 mg, 3.0 mmol, 3.0 equiv), 1,10-phenanthroline
monohydrate (59.5 mg, 0.3 mmol, 30 mol %), and CuSO4·5H2O
(49.9 mg, 0.2 mmol, 20 mol %). The flask was fitted with a rubber
septum, evacuated under high vacuum, and backfilled with argon. Dry
and degassed toluene (10 mL) and (E)-(4-bromobut-1-en-3-yn-1-
yl)benzene (228 mg, 1.1 mmol, 1.1 equiv) were next added, and the
suspension was heated at 80 °C in an oil bath for 12 h with stirring.
After completion, all volatile components were removed in vacuo and
the residue was purified by silica gel chromatography eluting with
hexane/EtOAc to afford enynamides 1i.
(E)-N-Phenyl-N-(4-phenylbut-3-en-1-yn-1-yl)methane-
sulfonamide (1i).34 Brown solid (40.0 mg, 13%); mp 89.0−91.0 °C
(hexane/EtOAc); Rf 0.35 (hexane/EtOAc 4:1); 1H NMR (400 MHz,
CDCl3) δ 7.56 (d, J = 8.1 Hz, 2H), 7.45 (t, J = 7.6 Hz, 2H), 7.39−
7.27 (m, 6H), 6.94 (d, J = 16.2 Hz, 1H), 6.30 (d, J = 16.2 Hz, 1H),
3.15 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ 140.8, 138.9, 136.4,
129.7, 128.9, 128.7, 128.6, 126.3, 125.8, 107.2, 84.1, 70.7, 37.1;
HRMS (ESI): m/z [M + H]+ calcd for C17H15NO2SNa+, 320.0716;
found, 320.0709.
General Procedure for the Gold(I)-Catalyzed Synthesis of
Pyridines 5 and 6. IPrAuCl (6.2 mg, 10.0 μmol, 5 mol %) and
AgNTf2 (3.9 mg, 10.0 μmol, 5 mol %) in one portion were added to
the solution of enynamide (1, 0.2 mmol) and cyanamide 4 (0.3 mmol,
1.5 equiv) in DCM (1.0 mL). The resulting mixture was stirred at
room temperature for 24 h. After completion, all volatile components
were removed in vacuo, and the residue was purified by silica gel
chromatography eluting with hexane/EtOAc to afford pyridines 5 and
6.
(E)-N-(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-4-methyl-N-(4-phenyl-
but-3-en-1-yn-1-yl)benzenesulfonamide (1h). Brown oil (267 mg,
1
60%); Rf 0.35 (hexane/EtOAc 4:1); H NMR (400 MHz, CDCl3) δ
7.73 (d, J = 8.3 Hz, 2H), 7.37−7.23 (m, 7H), 6.82 (d, J = 16.2 Hz,
1H), 6.71−6.59 (m, 3H), 6.25 (d, J = 16.2 Hz, 1H), 5.89 (s, 2H),
3.59−3.53 (m, 2H), 2.90−2.84 (m, 2H), 2.43 (s, 3H); 13C{H} NMR
(100 MHz, CDCl3) δ 147.8, 146.5, 144.8, 139.8, 136.6, 134.9, 131.3,
129.9, 128.9, 128.5, 127.7, 126.2, 122.1, 109.5, 108.5, 107.7, 101.1,
84.3, 71.2, 53.2, 34.4, 21.8; HRMS (ESI): m/z [M + H]+ calcd for
C26H23NO4SNa+, 468.1240; found, 468.1238.
N,4-Dimethyl-N-((3E,5E)-6-phenylhexa-3,5-dien-1-yn-1-yl)-
benzenesulfonamide (1n). Yellow solid (280 mg, 83%); mp 117.0−
1
118.5 °C (hexane/EtOAc); Rf 0.40 (hexane/EtOAc 4:1); H NMR
(400 MHz, CDCl3) δ 7.81 (d, J = 8.3 Hz, 2H), 7.41−7.37 (m, 4H),
7.32 (t, J = 7.6 Hz, 2H), 7.25−7.22 (m, 1H), 8.80 (dd, J = 15.6, 10.8
Hz, 1H), 6.67−6.56 (m, 2H), 5.78 (d, J = 15.2 Hz, 1H), 3.11 (s, 3H),
2.47 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ 144.9, 140.4, 137.0,
134.1, 133.5, 130.0, 128.8, 128.2, 128.0, 127.9, 126.7, 110.8, 87.2,
69.2, 39.5, 21.8; HRMS (ESI): m/z [M + Na]+ calcd for
C20H19NNaO2S+, 360.1034; found, 360.1029.
(E)-N,4-Dimethyl-N-(4-(thiophen-2-yl)but-3-en-1-yn-1-yl)-
benzenesulfonamide (1o).72 Yellow oil (167 mg, 53%); Rf 0.50
(hexane/EtOAc 4:1); 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.4
Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.17 (dd, J = 4.8, 1.5 Hz, 1H),
6.99−6.95 (m, 2H), 6.93 (d, J = 15.9 Hz, 1H), 6.03 (d, J = 15.9 Hz,
1H), 3.10 (s, 3H), 2.46 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ
144.9, 141.5, 133.4, 132.9, 130.00, 127.9, 127.8, 126.7, 125.2, 106.8,
86.4, 68.5, 39.40 21.8; HRMS (ESI): m/z [M + Na]+ calcd for
N-(6-(Dimethylamino)-5-phenylpyridin-2-yl)-N,4-dimethyl-
benzenesulfonamide (5a). Colorless solid (69.4 mg, 91%); mp
1
113.0−115.0 °C (hexane/EtOAc); Rf 0.30 (hexane/EtOAc 8:1); H
NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.3 Hz, 2H), 7.44−7.36 (m,
5H), 7.30−7.27 (m, 1H), 7.24 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 7.9
Hz, 1H), 3.32 (s, 3H), 2.53 (s, 6H), 2.40 (s, 3H); 13C{H} NMR (100
MHz, CDCl3) δ 157.6, 150.3, 143.6, 141.7, 140.1, 135.4, 129.5, 128.8,
128.2, 127.7, 127.1, 122.0, 110.3, 41.3, 35.6, 21.7; HRMS (ESI): m/z
[M + H]+ calcd for C21H23N3O2SNa+, 404.1403; found, 404.1403.
N-(6-(Dimethylamino)-5-phenylpyridin-2-yl)-4-fluoro-N-methyl-
benzenesulfonamide (5b). Colorless solid (73.2 mg, 95%); mp
+
C16H15NNaO2S2 , 340.0436; found, 340.0441.
(E)-N,4-Dimethyl-N-(4-(naphthalen-1-yl)but-3-en-1-yn-1-yl)-
benzenesulfonamide (1p). Brown oil (300 mg, 83%); Rf 0.35
(hexane/EtOAc 4:1); 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.0
Hz, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.84 (d, J = 1.8 Hz, 1H), 7.80 (d, J
= 8.2 Hz, 1H), 7.63 (d, J = 6.6 Hz, 1H), 7.60 (s, 1H), 7.57−7.48 (m,
2H), 7.45 (t, J = 7.7 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 6.30 (d, J =
1
103.0−105.0 °C (hexane/EtOAc); Rf 0.50 (hexane/EtOAc 4:1); H
NMR (400 MHz, CDCl3) δ 7.72 (dd, J = 8.9, 5.1 Hz, 2H), 7.45−7.35
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(m, 5H), 7.29 (t, J = 7.0 Hz, 1H), 7.12 (t, J = 8.6 Hz, 2H), 7.06 (d, J
= 7.9 Hz, 1H), 3.31 (s, 3H), 2.52 (s, 6H); 13C{H} NMR (100 MHz,
CDCl3) δ 165.3 (d, JF = 254.4 Hz), 158.2, 150.0, 141.7, 140.4, 134.3
(d, JF = 3.3 Hz), 130.5 (d, JF = 9.3 Hz), 128.8, 128.1, 127.1, 122.2,
116.0 (d, JF = 22.5 Hz), 110.4, 41.1, 35.8; HRMS (ESI): m/z [M +
Na]+ calcd for C20H20FN3O2SNa+, 408.1152; found, 408.1162.
N-(6-(Dimethylamino)-5-phenylpyridin-2-yl)-N-methylmethane-
sulfonamide (5c). Colorless solid (56.2 mg, 92%); mp 124.5−126.5
128.2, 127.0, 121.4, 108.2, 41.5. 41.3; HRMS (ESI): m/z [M + Na]+
calcd for C20H21N3O2SNa+, 390.1247; found, 390.1244.
N-(6-(Dimethylamino)-5-(o-tolyl)pyridin-2-yl)-N,4-dimethyl-
benzenesulfonamide (5j). Colorless oil (75.1 mg, 95%); Rf 0.35
(hexane/EtOAc 8:1); 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.3
Hz, 2H), 7.28 (d, J = 7.8 Hz, 1H), 7.24−7.18 (m, 6H), 7.03 (d, J =
7.8 Hz, 1H), 3.32 (s, 3H), 2.49 (s, 6H), 2.40 (s, 3H), 2.09 (s, 3H);
13C{H} NMR (100 MHz, CDCl3) δ 157.5, 150.3, 143.5, 141.9, 140.3,
136.2, 135.3, 130.2, 129.8, 129.3, 127.8, 127.3, 126.1, 121.1, 109.0,
40.3, 35.7, 21.7, 19.8; HRMS (ESI): m/z [M + H]+ calcd for
C22H25N3O2SNa+, 418.1560; found, 418.1557.
N-(6-(Dimethylamino)-5-(p-tolyl)pyridin-2-yl)-N,4-dimethyl-
benzenesulfonamide (5k). Colorless oil (60.9 mg, 77%); Rf 0.40
(hexane/EtOAc 8:1); 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.2
Hz, 2H), 7.40 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.23 (d, J
= 8.1 Hz, 2H), 7.19 (d, J = 7.9 Hz, 2H), 7.07 (d, J = 7.9 Hz, 1H), 3.31
(s, 3H), 2.52 (s, 6H), 2.40 (s, 3H), 2.38 (s, 3H); 13C{H} NMR (100
MHz, CDCl3) δ 158.2, 150.0, 143.5, 141.5, 137.5, 136.7, 135.4,
129.43, 129.42, 128.0, 127.8, 121.9, 110.1, 41.1, 35.6, 21.7, 21.4;
HRMS (ESI): m/z [M + H]+ calcd for C22H25N3O2SNa+, 418.1560;
found, 418.1557.
N-(6-(Dimethylamino)-5-(4-methoxyphenyl)pyridin-2-yl)-N,4-
dimethylbenzenesulfonamide (5l). Colorless oil (70.0 mg, 85%); Rf
0.50 (hexane/EtOAc 4:1); 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J
= 8.3 Hz, 2H), 7.39 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 8.7 Hz, 2H), 7.23
(d, J = 8.1 Hz, 2H), 7.09 (d, J = 7.9 Hz, 1H), 6.93 (d, J = 8.7 Hz, 2H),
3.84 (s, 3H), 3.30 (s, 3H), 2.53 (s, 6H), 2.40 (s, 3H); 13C{H} NMR
(100 MHz, CDCl3) δ 158.7, 158.0, 149.9, 143.5, 141.4, 135.3, 132.5,
129.4, 129.2, 127.8, 122.0, 114.2, 110.5, 55.4, 41.2, 35.6, 21.7; HRMS
(ESI): m/z [M + H]+ calcd for C22H26N3O3S+, 412.1689; found,
412.1668.
1
°C (hexane/EtOAc); Rf 0.35 (hexane/EtOAc 4:1); H NMR (400
MHz, CDCl3) δ 7.45−7.37 (m, 5H), 7.29 (tt, J = 6.4, 1.9 Hz, 1H),
6.81 (d, J = 7.9 Hz, 1H), 3.40 (s, 3H), 3.16 (s, 3H), 2.72 (s, 6H);
13C{H} NMR (100 MHz, CDCl3) δ 158.2, 150.8, 142.1, 140.3, 128.8,
128.1, 127.0, 121.8, 107.9, 41.3, 38.2, 35.8; HRMS (ESI): m/z [M +
Na]+ calcd for C15H19N3O2SNa+, 328.1090; found, 328.1102
3-(6-(Dimethylamino)-5-phenylpyridin-2-yl)oxazolidin-2-one
(5d). Colorless solid (47.6 mg, 84%); mp 144.0−145.5 °C (hexane/
EtOAc); Rf 0.45 (hexane/EtOAc 2:1); 1H NMR (400 MHz, CDCl3)
δ 7.64 (d, J = 8.1 Hz, 1H), 7.49−7.42 (m, 3H), 7.38 (t, J = 7.6 Hz,
2H), 7.29−7.25 (m, 1H), 4.47 (t, J = 8.2 Hz, 2H), 4.33 (t, J = 8.3 Hz,
2H), 2.71 (s, 6H); 13C{H} NMR (100 MHz, CDCl3) δ 157.7, 157.2,
147.8, 142.1, 140.5, 128.7, 128.2, 126.8, 119.9, 103.2, 62.2, 44.2, 41.3;
HRMS (ESI): m/z [M + Na]+ calcd for C16H17N3O2Na+, 306.1213;
found, 306.1222.
N-Benzyl-N-(6-(dimethylamino)-5-phenylpyridin-2-yl)-4-methyl-
benzenesulfonamide (5e). Yellow oil (84.2 mg, 92%); Rf 0.30
(hexane/EtOAc 8:1); 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.2
Hz, 2H), 7.41−7.32 (m, 7H), 7.31−7.23 (m, 5H), 7.20 (t, J = 7.2 Hz,
1H), 7.00 (d, J = 7.9 Hz, 1H), 5.08 (s, 2H), 2.50 (s, 6H), 2.42 (s,
3H); 13C{H} NMR (100 MHz, CDCl3) δ 158.1, 148.6, 143.5, 141.6,
140.2, 137.6, 136.6, 129.5, 128.7, 128.4, 128.2, 128.1, 127.8, 127.3,
127.0, 122.5, 112.3, 51.4, 41.2, 21.7; HRMS (ESI): m/z [M + H]+
calcd for C27H27N3O2SNa+, 480.1716; found, 480.1711.
N-Allyl-N-(6-(dimethylamino)-5-phenylpyridin-2-yl)-4-methyl-
benzenesulfonamide (5f). Yellowish oil (61.9 mg, 76%); Rf 0.35
(hexane/EtOAc 8:1); 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.3
Hz, 2H), 7.45−7.35 (m, 5H), 7.30−7.27 (m, 1H), 7.24 (d, J = 8.1 Hz,
2H), 7.02 (d, J = 7.9 Hz, 1H), 5.92 (ddt, J = 16.0, 10.3, 5.8 Hz, 1H),
5.25 (dd, J = 17.2, 1.5 Hz, 1H), 5.11 (dd, J = 10.2, 1.4 Hz, 1H), 4.49
(dt, J = 5.7, 1.2 Hz, 2H), 2.52 (s, 6H), 2.41 (s, 3H); 13C{H} NMR
(100 MHz, CDCl3) δ 158.3, 148.9, 143.4, 141.6, 140.5, 136.7, 134.0,
129.4, 128.7, 128.1, 127.8, 127.0, 122.2, 117.9, 111.3, 50.7, 41.2, 21.7;
HRMS (ESI): m/z [M + Na]+ calcd for C23H25N3O2SNa+, 430.1560;
found, 430.1566.
N-Cyclopropyl-N-(6-(dimethylamino)-5-phenylpyridin-2-yl)-4-
methylbenzenesulfonamide (5g). Yellowish oil (79.1 mg, 97%); Rf
0.30 (hexane/EtOAc 8:1); 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J
= 8.3 Hz, 2H), 7.48−7.36 (m, 5H), 7.31−7.28 (d, 1H), 7.26 (d, J =
8.1 Hz, 2H), 6.85 (d, J = 7.7 Hz, 1H), 2.77 (tt, J = 6.9, 3.6 Hz, 1H),
2.50 (s, 6H), 2.43 (s, 3H), 0.90−0.85 (m, 2H), 0.79−0.74 (m, 2H);
13C{H} NMR (100 MHz, CDCl3) δ 158.6, 151.3, 143.4, 141.4, 140.5,
N-(5-(4-Bromophenyl)-6-(dimethylamino)pyridin-2-yl)-N,4-
dimethylbenzenesulfonamide (5m). Colorless oil (85.6 mg, 93%);
1
Rf 0.30 (hexane/ethyl acetate 8:1); H NMR (400 MHz, CDCl3) δ
7.59 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 7.9 Hz,
1H), 7.31 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.09 (d, J =
7.9 Hz, 1H), 3.32 (s, 3H), 2.54 (s, 6H), 2.40 (s, 3H); 13C{H} NMR
(100 MHz, CDCl3) δ 158.1, 150.5, 143.6, 141.4, 139.4, 135.5, 131.9,
129.7, 129.5, 127.7, 120.8, 120.3, 109.9, 41.2, 35.6, 21.7; HRMS
(ESI): m/z [M + H]+ calcd for C21H22BrN3O2SNa+, 482.0508; found,
482.0507.
(E)-N-(6-(Dimethylamino)-5-styrylpyridin-2-yl)-N,4-dimethyl-
benzenesulfonamide (5n). Colorless oil (67.6 mg, 83%); Rf 0.25
(hexane/EtOAc 8:1); 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.1
Hz, 1H), 7.56−7.50 (m, 4H), 7.36 (t, J = 7.6 Hz, 2H), 7.28−7.24 (m,
1H), 7.22 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.1 Hz, 1H), 7.10 (d, J =
16.4 Hz, 1H), 6.95 (d, J = 16.3 Hz, 1H), 3.29 (s, 3H), 2.74 (s, 6H),
2.40 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ 159.5, 150.4, 143.6,
137.7, 137.1, 135.1, 129.4, 128.9, 128.5, 127.8, 127.7, 126.5, 125.6,
120.0, 111.9, 42.2, 35.6, 21.7; HRMS (ESI): m/z [M + Na]+ calcd for
C23H25N3NaO2S+, 430.1560; found, 430.1565.
135.8, 129.2, 128.7, 128.6, 128.1, 127.0, 123.2, 113.4, 41.1, 30.5, 21.7,
8.4; HRMS (ESI): m/z [M + Na]+ calcd for C23H25N3O2SNa+,
430.1560; found, 430.1551.
N-(6-(Dimethylamino)-5-(thiophen-2-yl)pyridin-2-yl)-N,4-
dimethylbenzenesulfonamide (5o). Colorless solid (55.0 mg, 71%);
mp 88.5−89.5 °C (hexane/EtOAc); Rf 0.35 (hexane/EtOAc 8:1); 1H
NMR (400 MHz, CDCl3) δ 7.59−7.56 (m, 3H), 7.29 (dd, J = 5.1, 1.2
Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.18 (dd, J = 3.5, 1.2 Hz, 1H), 7.13
(dd, J = 3.5, 1.2 Hz, 1H), 7.04 (dd, J = 5.2, 3.6 Hz, 1H), 3.31 (s, 3H),
2.59 (s, 6H), 2.40 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ 158.6,
150.5, 143.6, 141.3, 141.0, 135.3, 129.5, 127.7, 127.1, 125.5, 125.4,
116.3, 110.6, 41.4, 35.5, 21.7; HRMS (ESI): m/z [M + Na]+ calcd for
N-(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-N-(6-(dimethylamino)-5-
phenylpyridin-2-yl)-4-methylbenzenesulfonamide (5h). Colorless
1
oil (92.8 mg, 90%); Rf 0.45 (hexane/EtOAc 4:1); H NMR (400
MHz, CDCl3) δ 7.58 (d, J = 8.3 Hz, 2H), 7.47−7.36 (m, 5H), 7.29 (t,
J = 7.2 Hz, 1H), 7.21 (d, J = 8.1 Hz, 2H), 7.02 (d, J = 7.8 Hz, 1H),
6.72−6.62 (m, 3H), 5.90 (s, 2H), 4.03−3.97 (m, 2H), 2.88−2.82 (m,
2H), 2.55 (s, 6H), 2.39 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ
158.4, 148.8, 147.7, 146.2, 143.4, 141.6, 140.4, 136.5, 132.9, 129.4,
128.8, 128.1 127.7, 127.0, 122.4, 122.0, 112.2, 109.5, 108.4, 101.0,
49.7, 41.3, 35.6, 21.7; HRMS (ESI): m/z [M + Na]+ calcd for
C29H29N3O4SNa+, 538.1771; found, 538.1777.
N-(6-(Dimethylamino)-5-phenylpyridin-2-yl)-N-phenylmethane-
sulfonamide (5i). Yellow solid (59.5 mg, 81%); mp 168.0−170.0 °C
(hexane/EtOAc); Rf 0.35 (hexane/EtOAc 4:1); 1H NMR (400 MHz,
CDCl3) δ 7.50−7.35 (m, 9H), 7.32−7.27 (m, 2H), 6.19 (d, J = 7.9
Hz, 1H), 3.55 (s, 3H), 2.77 (s, 6H); 13C{H} NMR (100 MHz,
CDCl3) δ 158.2, 152.3, 142.2, 140.5, 139.9, 129.7, 129.7, 128.8, 128.6,
+
C19H21N3NaO2S2 , 410.0967; found, 410.0974.
N-(6-(Dimethylamino)-5-(naphthalen-1-yl)pyridin-2-yl)-N,4-
dimethylbenzenesulfonamide (5p). Yellowish solid (82.0 mg, 95%);
mp 146.0−148.0 °C (hexane/EtOAc); Rf 0.40 (hexane/EtOAc 8:1);
1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.1 Hz, 1H), 7.83 (d, J =
8.2 Hz, 1H), 7.64 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.52−
7.48 (m, 2H), 7.45−7.38 (m, 3H), 7.28 (d, J = 8.1 Hz, 2H), 7.08 (d, J
= 7.9 Hz, 1H), 3.39 (s, 3H), 2.43 (s, 3H), 2.41 (s, 6H); 13C{H} NMR
(100 MHz, CDCl3) δ 158.0, 150.7, 143.5, 142.9, 138.4, 135.5, 133.8,
131.6, 129.4, 128.5, 127.79, 127.76, 127.0, 126.2, 126.1, 126.0, 125.7,
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119.0, 108.4, 40.3, 35.7, 21.7; HRMS (ESI): m/z [M + H]+ calcd for
C25H25N3O2SNa+, 454.1560; found, 454.1563.
N-(6-(Diphenylamino)-5-phenylpyridin-2-yl)-N-methylmethane-
sulfonamide (6e). Yellowish oil (62.7 mg, 73%); Rf 0.35 (hexane/
EtOAc 4:1); 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.0 Hz, 1H),
7.16 (d, J = 6.4 Hz, 2H), 7.12−7.05 (m, 8H), 6.92−6.83 (m, 6H),
3.26 (s, 3H), 2.80 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ 155.4,
152.6, 146.7, 142.7, 137.9, 128.9, 128.8, 128.5, 128.2, 127.1, 124.4,
123.3, 112.9, 39.2, 35.8; HRMS (ESI): m/z [M + H]+ calcd for
C25H23N3O2SNa+: 452.1403; found, 452.1405.
N-(6-(Dimethylamino)-5-methylpyridin-2-yl)-N,4-dimethyl-
benzenesulfonamide (5q). Colorless oil (52.4 mg, 92%); Rf 0.45
(hexane/EtOAc 4:1); 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 8.4
Hz, 2H), 7.34 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.06 (d, J
= 7.8 Hz, 1H), 3.22 (s, 3H), 2.63 (s, 6H), 2.39 (s, 3H), 2.24 (s, 3H);
13C{H} NMR (100 MHz, CDCl3) δ 160.6, 149.3, 143.3, 141.1, 135.0,
N,4-Dimethyl-N-(5-phenyl-6-(pyrrolidin-1-yl)pyridin-2-yl)-
benzenesulfonamide (6f). Brownish oil (61.9 mg, 76%); Rf 0.40
(hexane/EtOAc 8:1); 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.3
Hz, 2H), 7.38−7.27 (m, 6H), 7.24 (d, J = 8.1 Hz, 2H), 6.97 (d, J =
7.9 Hz, 1H), 3.33 (s, 3H), 2.97−2.92 (m, 4H), 2.40 (s, 3H), 1.70−
1.64 (m, 4H); 13C{H} NMR (100 MHz, CDCl3) δ 154.9, 150.4,
143.4, 141.6, 140.5, 135.7, 129.4, 129.2, 128.1, 127.8, 126.7, 119.8,
107.6, 50.1, 35.6, 25.7, 21.7; HRMS (ESI): m/z [M + Na]+ calcd for
C23H25N3O2SNa+, 430.1560; found, 430.1572.
N,4-Dimethyl-N-(5-phenyl-6-(piperidin-1-yl)pyridin-2-yl)-
benzenesulfonamide (6g). Colorless oil (70.0 mg, 83%); Rf 0.45
(hexane/EtOAc 8:1); 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.3
Hz, 2H), 7.54 (d, J = 7.1 Hz, 2H), 7.44 (d, J = 7.9 Hz, 1H), 7.39 (t, J
= 7.6 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.16
(d, J = 7.9 Hz, 1H), 3.29 (s, 3H), 2.89−2.84 (m, 4H), 2.40 (s, 3H),
1.45−1.39 (m, 2H), 1.38−1.31 (m, 4H); 13C{H} NMR (100 MHz,
CDCl3) δ 158.6, 150.4, 143.5, 141.3, 140.1, 135.2, 129.4, 128.8,
127.83, 127.79, 127.2, 123.4, 111.5, 50.0, 35.7, 25.5, 24.7, 21.7;
HRMS (ESI): m/z [M + Na]+ calcd for C24H27N3O2SNa+, 444.1716;
found, 444.1717.
N,4-Dimethyl-N-(6-morpholino-5-phenylpyridin-2-yl)benzene-
sulfonamide (6h). Orange oil (66.9 mg, 79%); Rf 0.50 (hexane/
EtOAc 2:1); 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.2 Hz, 2H),
7.54 (d, J = 7.3 Hz, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.40 (t, J = 7.6 Hz,
2H), 7.30 (t, J = 7.5 Hz, 1H), 7.27−7.24 (m, 2H), 7.22 (d, J = 8.1 Hz,
1H), 3.52−3.48 (m, 4H), 3.30 (s, 3H), 2.90−2.86 (m, 4H), 2.41 (s,
3H); 13C{H} NMR (100 MHz, CDCl3) δ 157.6, 150.6, 143.7, 141.5,
139.4, 135.2, 129.5, 128.9, 127.9, 127.7, 127.5, 123.4, 112.3, 66.6,
49.1, 35.6, 21.7; HRMS (ESI): m/z [M + Na]+ calcd for
C23H25N3O3SNa+, 446.1509; found, 446.1505.
N-(6-(3,4-Dihydroisoquinolin-2(1H)-yl)-5-phenylpyridin-2-yl)-N-
methylmethanesulfonamide (6i). Yellowish oil (76.3 mg, 97%); Rf
0.35 (hexane/EtOAc 4:1); 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J
= 7.2 Hz, 2H), 7.48 (d, J = 7.9 Hz, 1H), 7.42 (t, J = 7.5 Hz, 2H), 7.33
(t, J = 7.3 Hz, 1H), 7.15−7.11 (m, 2H), 7.07−7.02 (m, 2H), 6.94 (d,
J = 7.9 Hz, 1H), 4.40 (s, 2H), 3.41 (s, 3H), 3.32 (t, J = 5.8 Hz, 2H),
3.03 (s, 3H), 2.66 (t, J = 5.7 Hz, 2H); 13C{H} NMR (100 MHz,
CDCl3) δ 157.9, 151.0, 142.1, 139.9, 135.2, 134.8, 129.0, 128.9, 128.0,
127.4, 126.7, 126.3, 126.0, 123.3, 109.8, 50.7, 47.5, 37.7, 35.8, 28.4;
HRMS (ESI): m/z [M + H]+ calcd for C22H23N3O2SNa+, 416.1403;
found, 416.1404.
129.3, 127.8, 120.5, 112.9, 41.5, 35.8, 21.6, 18.7; HRMS (ESI): m/z
[M + Na]+ calcd for C16H21N3NaO2S+, 342.1247; found, 342.1253.
N-(6-(Dimethylamino)-4-methyl-5-phenylpyridin-2-yl)-N,4-
dimethylbenzenesulfonamide (5r). Colorless solid (77.5 mg, 98%);
mp 125.0−126.0 °C (hexane/EtOAc); Rf 0.30 (hexane/EtOAc 8:1);
1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.3 Hz, 2H), 7.39 (t, J =
7.5 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.20
(d, J = 6.9 Hz, 2H), 6.96 (s, 1H), 3.27 (s, 3H), 2.41 (s, 3H), 2.40 (s,
6H), 2.05 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ 159.0, 149.9,
148.7, 143.4, 138.9, 135.5, 130.3, 129.3, 128.6, 127.9, 126.9, 122.7,
112.7, 41.3, 35.7, 21.7, 21.1; HRMS (ESI): m/z [M + H]+ calcd for
C22H26N3O2S+, 396.1740; found, 396.1728.
N,N′-(1,4-Phenylenebis(6-(dimethylamino)pyridine-5,2-diyl))bis-
(N,4-dimethylbenzenesulfonamide) (5s). Was additionally recrystal-
lized from hexane/EtOAc and obtained as a yellow solid with an 85%
purity (NMR assay; with an admixture of IPr76), 104.0 mg, 70%; mp
1
208.0−210.0 °C (hexane/EtOAc); Rf 0.50 (hexane/EtOAc 2:1); H
NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.2 Hz, 4H), 7.47−7.45 (m,
6H), 7.30−7.24 (m, 6H), 7.11 (d, J = 7.9 Hz, 2H), 3.33 (s, 6H), 2.56
(s, 12H), 2.41 (s, 6H); 13C{H} NMR (100 MHz, CDCl3) δ 159.5,
150.4, 143.6, 137.7, 137.1, 135.1, 129.4, 128.9, 128.5, 127.8, 127.7,
126.5, 125.6, 120.0, 111.9, 42.2, 35.6, 21.7; HRMS (ESI): m/z [M +
+
Na]+ calcd for C36H40N6NaO4S2 , 707.2445; found, 707.2451.
N-(6-(Diethylamino)-5-phenylpyridin-2-yl)-N-methylmethane-
sulfonamide (6a). Colorless oil (66.0 mg, 99%); Rf 0.30 (hexane/
1
EtOAc 8:1); H NMR (400 MHz, CDCl3) δ 7.46−7.36 (m, 5H),
7.32−7.27 (m, 1H), 6.86 (d, J = 7.9 Hz, 1H), 3.39 (s, 3H), 3.13 (q, J
= 7.0 Hz, 4H), 3.09 (s, 3H), 0.96 (t, J = 7.0 Hz, 6H); 13C{H} NMR
(100 MHz, CDCl3) δ 157.6, 150.8, 142.1, 140.5, 128.8, 128.2, 127.2,
123.7, 109.1, 44.4, 37.6, 35.9, 12.9; HRMS (ESI): m/z [M + H]+
calcd for C17H23N3O2SNa+, 356.1403; found, 356.1402.
N-(6-(Benzyl(methyl)amino)-5-phenylpyridin-2-yl)-N,4-dimethyl-
benzenesulfonamide (6b). Yellow oil (80.5 mg, 88%); Rf 0.30
(hexane/EtOAc 8:1); 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.2
Hz, 2H), 7.46 (d, J = 7.9 Hz, 1H), 7.43 (d, J = 7.1 Hz, 2H), 7.37 (t, J
= 7.6 Hz, 2H), 7.30−7.26 (m, 1H), 7.24−7.15 (m, 6H), 7.04−6.99
(m, 2H), 4.19 (s, 2H), 3.22 (s, 3H), 2.43 (s, 3H), 2.38 (s, 3H);
13C{H} NMR (100 MHz, CDCl3) δ 157.4, 150.4, 143.5, 142.1, 140.2,
138.9, 135.3, 129.5, 128.8, 128.34, 128.33, 128.0, 127.7, 127.1, 126.9,
122.0, 110.7, 56.1, 39.3, 35.6, 21.7; HRMS (ESI): m/z [M + Na]+
calcd for C27H27N3O2SNa+, 480.1716; found, 480.1725.
Synthesis of 6c (1 mmol Scale). IPrAuCl (31.0 mg, 50.0 μmol, 5
mol %) and AgNTf2 (19.5 mg, 50.0 μmol, 5 mol %) in one portion
were added to the solution of ynamide 1a (311 mg, 1.0 mmol) and
N,N-dibenzylcyanamide (333 mg, 1.5 mmol, 1.5 equiv) in DCM (5.0
mL). The resulting mixture was stirred at room temperature for 24 h.
After completion, DCM was removed in vacuo and the residue was
purified by silica gel chromatography eluting with hexane/EtOAc to
afford pyridine 6c (507 mg, 95%).
Synthesis of 5a (Gram Scale). IPrAuCl (155 mg, 0.25 mmol, 5
mol %) and AgNTf2 (97.5 mg, 0.25 mmol, 5 mol %) in one portion
were added to the solution of 1a (1.56 g, 5.0 mmol) and N,N-
dimethylcyanamide (526 mg, 7.5 mmol, 1.5 equiv) in DCM (5.0 mL).
The resulting mixture was stirred at room temperature for 24 h. After
completion, DCM was removed in vacuo and the residue was purified
by silica gel chromatography eluting with hexane/EtOAc to afford
pyridine 5a (1.74 g, 91%).
N-(6-(Dibenzylamino)-5-phenylpyridin-2-yl)-N, 4-
dimethylbenzenesulfonamide (6c). Colorless oil (105.7 mg, 99%);
1
Rf 0.30 (hexane/EtOAc 8:1); H NMR (400 MHz, CDCl3) δ 7.54−
7.47 (m, 5H), 7.40 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 7.1 Hz, 1H), 7.24−
7.19 (m, 7H), 7.14 (d, J = 8.1 Hz, 2H), 6.95 (dd, J = 6.9 Hz, J = 2.3
Hz, 4H), 4.05 (s, 4H), 3.09 (s, 3H), 2.37 (s, 3H); 13C{H} NMR (100
MHz, CDCl3) δ 157.2, 150.6, 143.5, 142.1, 140.0, 139.0, 135.1, 129.5,
129.0, 128.3 (×2), 128.1, 127.8, 127.4, 126.9, 123.5, 112.0, 53.5, 35.6,
21.7; HRMS (ESI): m/z [M + Na]+ calcd for C33H31N3O2SNa+,
556.2029; found, 556.2019.
N-(6-(Dibenzylamino)-5-phenylpyridin-2-yl)-N-methyl-4-
nitrobenzenesulfonamide (6d). Orange solid (103.9 mg, 92%); mp
61.5−63.0 °C (hexane/EtOAc); Rf 0.50 (hexane/EtOAc 4:1); 1H
NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.9 Hz, 2H), 7.70 (d, J = 8.8
Hz, 1H), 7.55−7.51 (m, 3H), 7.43 (t, J = 7.6 Hz, 2H), 7.33 (t, J = 7.4
Hz, 2H), 7.25−7.19 (m, 6H), 7.16 (d, J = 7.9 Hz, 1H), 6.93 (dd, J =
6.5 Hz, J = 2.8 Hz, 4H), 4.00 (s, 4H), 3.09 (s, 3H); 13C{H} NMR
(100 MHz, CDCl3) δ 157.3, 150.1, 149.9, 143.8, 142.5, 139.7, 138.6,
129.2, 129.0, 128.5, 128.2, 128.0, 127.8, 127.2, 124.7, 124.0, 112.5,
53.6, 36.0; HRMS (ESI): m/z [M + Na]+ calcd for C32H28N4O4SNa+,
587.1723; found, 587.1740.
Bromination of 5a. The solution of bromine (17.6 mg, 0.11
mmol, 1.1 equiv) in CHCl3 (1.0 mL) was added dropwise to the
solution of 5a (38.5 mg, 0.1 mmol) in CHCl3 (1.0 mL) with stirring
at room temperature. When the color of bromine ceased to disappear,
the reaction was quenched by the addition of 10% aqueous solution of
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Na2S2O3 (5 mL) and was extracted with DCM (3 × 10 mL). The
combined organic extracts were dried over anhydrous Na2SO4. After
filtration, the solvent was removed in vacuo and the residue was
purified by silica gel chromatography, eluting with hexane/EtOAc (8/
1) to afford bromopyridine 7.
N-(3-Bromo-6-(dimethylamino)-5-phenylpyridin-2-yl)-N,4-
dimethylbenzenesulfonamide (7). Colorless solid (45.6 mg, 99%);
mp 164.5−166.5 °C (hexane/EtOAc); Rf 0.30 (hexane/EtOAc 8:1);
1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.3 Hz, 2H), 7.66 (s, 1H),
EtOAc 4:1); 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.3 Hz, 2H),
7.46−7.35 (m, 5H), 7.32 (d, J = 7.8 Hz, 1H), 7.24−7.12 (m, 7H),
6.96 (d, J = 7.8 Hz, 1H), 4.97 (t, J = 5.8 Hz, 1H), 4.35 (d, J = 5.8 Hz,
2H), 3.20 (s, 3H), 2.37 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ
154.1, 151.5, 143.3, 140.3, 139.1, 137.6, 135.6, 129.4, 129.4, 129.0,
128.5, 127.9, 127.7, 127.2, 126.9, 119.0, 108.3, 45.3, 35.7, 21.7;
HRMS (ESI): m/z [M + Na]+ calcd for C26H25N3NaO2S+, 466.1560;
found, 466.1563.
7.43−7.39 (m, 4H), 7.36−7.28 (m, 3H), 3.10 (s, 3H), 2.49 (s, 6H),
2.44 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ 157.7, 148.3, 145.3,
143.5, 138.9, 135.7, 129.3, 128.90, 128.88, 128.0, 127.7, 126.4, 109.0,
41.0, 37.0, 21.7; HRMS (ESI): m/z [M + Na]+ calcd for
C21H22BrN3O2SNa+, 484.0488; found, 484.0496.
Iodination of 5a. Iodine (25.4 mg, 0.11 mmol, 1.1 equiv) was
added to the solution of 5a (38.5 mg, 0.1 mmol) and Ag2SO4 (31.2
mg, 0.1 mmol, 1.0 equiv) in EtOH (1.0 mL) with stirring at room
temperature. The resulting mixture was stirred for 1 h. When the
reaction was quenched by the addition of 10% aqueous solution of
Na2S2O3 (5 mL) and was extracted with DCM (3 × 10 mL). The
combined organic extracts were dried over anhydrous Na2SO4. After
filtration, the solvent was removed in vacuo and the residue was
purified by silica gel chromatography, eluting with hexane/EtOAc (8/
1) to afford iodopyridine 8.
N-(6-(Dimethylamino)-3-iodo-5-phenylpyridin-2-yl)-N,4-
dimethylbenzenesulfonamide (8). Colorless solid (48.7 mg, 96%);
mp 178.5−180.5 °C (hexane/EtOAc); Rf 0.30 (hexane/EtOAc 8:1);
1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.81 (d, J = 8.3 Hz, 2H),
7.41−7.37 (m, 4H), 7.35−7.28 (m, 3H), 3.08 (s, 3H), 2.47 (s, 6H),
2.44 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ 158.5, 151.7, 151.1,
143.4, 138.9, 135.6, 129.2, 129.0, 128.9, 128.0, 127.7, 126.5, 81.7,
40.9, 37.2, 21.7; HRMS (ESI): m/z [M + Na]+ calcd for
C21H22IN3O2SNa+, 530.0370; found, 530.0367.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00558.
■
sı
Experimental procedures, copies of H and 13C{1H}
NMR spectra and XRD data (PDF)
FAIR data, including the primary NMR FID files, for
compounds 1a−1i; 1n−1r; 5a−5s; 6a−6i; 7−10; and
10′ (ZIP)
1
Accession Codes
CCDC 2062892 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Vadim Yu. Kukushkin − Saint Petersburg State University,
199034 Saint Petersburg, Russian Federation; South Ural
State University, 454080 Chelyabinsk, Russian Federation;
orcid.org/0000-0002-2253-085X; Email: v.kukushkin@
spbu.ru
Alexey Yu. Dubovtsev − Saint Petersburg State University,
199034 Saint Petersburg, Russian Federation; orcid.org/
0000-0001-6576-814X; Email: a.dubovtsev@spbu.ru
Denosylation of 5a. PhSH (13.2 mg, 0.12 mmol, 1.2 equiv) and
K2CO3 (20.7 mg, 0.15 mmol, 1.5 equiv) were added to the solution of
6d (56.4 mg, 0.1 mmol) in MeCN (1.0 mL). The resulting mixture
was stirred at 60 °C in an oil bath for 12 h. After completion, all
volatile components were removed in vacuo and the residue was
purified by silica gel chromatography eluting with hexane/EtOAc (8/
1) to afford pyridine 9.
N2,N2-Dibenzyl-N6-methyl-3-phenylpyridine-2,6-diamine (9).
Yellow solid (19.7 mg, 52%); mp 97.0−98.5 °C (hexane/EtOAc);
Rf 0.40 (hexane/EtOAc 8:1); 1H NMR (400 MHz, CDCl3) δ 7.48 (d,
J = 7.3 Hz, 2H), 7.37−7.29 (m, 3H), 7.25−7.16 (m, 7H), 7.10 (d, J =
6.8 Hz, 4H), 6.01 (d, J = 8.1 Hz, 1H), 4.33 (br. s, 1H, NH), 4.21 (s,
4H), 2.89 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ 157.9, 157.5,
142.2, 141.6, 139.7, 128.7, 128.6, 128.5, 128.2, 126.7, 126.1, 115.5,
Authors
Nikolay V. Shcherbakov − Saint Petersburg State University,
199034 Saint Petersburg, Russian Federation
Dmitry V. Dar’in − Saint Petersburg State University, 199034
Saint Petersburg, Russian Federation
+
97.6, 53.4, 29.4; HRMS (ESI): m/z [M + H]+ calcd for C26H26N3 ,
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00558
380.2121; found, 380.2130.
Debenzylation of 6c. A 50 mL round-bottom flask containing 6c
(53.4 mg, 0.1 mmol) and 10% palladium on carbon (10.6 mg, 0.01
mmol, 10 mol %) was fitted with a rubber septum, evacuated under
high vacuum and backfilled with hydrogen. Degassed MeOH (5 mL)
was next added. The flask was equipped with a hydrogen balloon, and
the black suspension was heated at 50 °C in an oil bath for 24 h with
stirring. After completion, all volatile components were removed in
vacuo and the residue was purified by silica gel chromatography
eluting with hexane/EtOAc (4/1) to afford di- and monodebenzy-
lated pyridines 10 and 10′ respectively.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.Yu.D. thanks the Russian Science Foundation for support of
these studies (Grant 20-73-10022). We are much obliged to
the Center for Magnetic Resonance, Center for Chemical
Analysis and Material Research, Center for X-ray Diffraction
Studies (all belonging to Saint Petersburg State University) for
physicochemical measurements. V.Yu.K. thanks South Ural
State University (Act 211 Government of the Russian
Federation, Contract 02.A03.21.0011) for putting facilities at
the author’s disposal.
N-(6-Amino-5-phenylpyridin-2-yl)-N,4-dimethylbenzene-
sulfonamide (10). Colorless solid (23.7 mg, 67%); mp 85.0−86.3 °C
(hexane/EtOAc); Rf 0.25 (hexane/EtOAc 4:1); 1H NMR (400 MHz,
CDCl3) δ 7.62 (d, J = 8.3 Hz, 2H), 7.47−7.41 (m, 4H), 7.37 (d, J =
8.0 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 7.05 (d, J = 8.0 Hz, 1H), 4.42
(s, 2H), 3.27 (s, 3H), 2.41 (s, 3H); 13C{H} NMR (100 MHz,
CDCl3) δ 154.5, 151.6, 143.6, 139.6, 137.8, 135.4, 129.5, 129.2, 128.8,
127.8, 127.8, 118.6, 109.8, 35.6, 21.7.; HRMS (ESI): m/z [M + H]+
calcd for C19H20N3O2S+, 354.1271; found, 354.1278.
REFERENCES
■
(1) Wessig, P.; Mu
Chem. Rev. 2008, 108 (6), 2051−2063.
̈
ller, G. The Dehydro-Diels−Alder Reaction.
N-(6-(Benzylamino)-5-phenylpyridin-2-yl)-N,4-dimethylbenzene-
sulfonamide (10′). Colorless oil (9.8 mg, 22%); Rf 0.50 (hexane/
7225
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(2) Li, W.; Zhou, L.; Zhang, J. Recent Progress in Dehydro-
(Genative) Diels−Alder Reaction. Chem. - Eur. J. 2016, 22 (5), 1558−
1571.
(3) Wessig, P.; Matthes, A.; Pick, C. The Photo-Dehydro-Diels−
Alder (PDDA) Reaction. Org. Biomol. Chem. 2011, 9 (22), 7599−
7605.
(4) Dubbaka, S. R.; Kienle, M.; Mayr, H.; Knochel, P. Copper(I)-
Mediated Oxidative Cross-Coupling between Functionalized Alkynyl
Lithium and Aryl Magnesium Reagents. Angew. Chem., Int. Ed. 2007,
46 (47), 9093−9096.
(22) Ye, L.-W.; Zhu, X.-Q.; Sahani, R. L.; Xu, Y.; Qian, P.-C.; Liu,
R.-S. Nitrene Transfer and Carbene Transfer in Gold Catalysis. Chem.
Rev. 2020. DOI: 10.1021/acs.chemrev.0c00348.
(23) Campeau, D.; Rayo, D. F. L.; Mansour, A.; Muratov, K.;
Gagosz, F. Gold-Catalyzed Reactions of Specially Activated Alkynes,
Allenes, and Alkenes. Chem. Rev. 2020. DOI: 10.1021/acs.chem-
rev.0c00788.
(24) Li, D.; Zang, W.; Bird, M. J.; Hyland, C. J. T.; Shi, M. Gold-
Catalyzed Conversion of Highly Strained Compounds. Chem. Rev.
2020. DOI: 10.1021/acs.chemrev.0c00624.
(25) Hendrich, C. M.; Sekine, K.; Koshikawa, T.; Tanaka, K.;
Hashmi, A. S. K. Homogeneous and Heterogeneous Gold Catalysis
for Materials Science. Chem. Rev. 2020. DOI: 10.1021/acs.chem-
rev.0c00824.
(26) Lu, Z.; Li, T.; Mudshinge, S. R.; Xu, B.; Hammond, G. B.
Optimization of Catalysts and Conditions in Gold(I) Catalysis
Counterion and Additive Effects. Chem. Rev. 2021. DOI: 10.1021/
acs.chemrev.0c00713.
(27) Witzel, S.; Hashmi, A. S. K.; Xie, J. Light in Gold Catalysis.
Chem. Rev. 2021. DOI: 10.1021/acs.chemrev.0c00841.
(28) Hu, Y.-C.; Zhao, Y.; Wan, B.; Chen, Q.-A. Reactivity of
Ynamides in Catalytic Intermolecular Annulations. Chem. Soc. Rev.
2021, 50, 2582.
(29) Evano, G.; Michelet, B.; Zhang, C. The Anionic Chemistry of
Ynamides: A Review. C. R. Chim. 2017, 20 (6), 648−664.
(30) Evano, G.; Coste, A.; Jouvin, K. Ynamides: Versatile Tools in
Organic Synthesis. Angew. Chem., Int. Ed. 2010, 49 (16), 2840−2859.
(31) Wang, X.-N.; Yeom, H.-S.; Fang, L.-C.; He, S.; Ma, Z.-X.;
Kedrowski, B. L.; Hsung, R. P. Ynamides in Ring Forming
Transformations. Acc. Chem. Res. 2014, 47 (2), 560−578.
(32) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.;
Zhang, Y.; Hsung, R. P. Ynamides: A Modern Functional Group for
the New Millennium. Chem. Rev. 2010, 110 (9), 5064−5106.
(33) Tian, X.; Song, L.; Hashmi, A. S. K. α-Imino Gold Carbene
Intermediates from Readily Accessible Sulfilimines: Intermolecular
Access to Structural Diversity. Chem. - Eur. J. 2020, 26 (15), 3197−
3204.
(34) Shu, C.; Wang, Y.-H.; Shen, C.-H.; Ruan, P.-P.; Lu, X.; Ye, L.-
W. Gold-Catalyzed Intermolecular Ynamide Amination-Initiated Aza-
Nazarov Cyclization: Access to Functionalized 2-Aminopyrroles. Org.
Lett. 2016, 18 (13), 3254−3257.
(35) Singh, R. R.; Liu, R.-S. Gold-Catalyzed Imination/Mannich
Reaction Cascades of 3-En-1-Ynamides with Anilines and Aldehydes
to Enable 1,5-Nitrogen Functionalizations. Adv. Synth. Catal. 2016,
358 (9), 1421−1427.
(36) Dateer, R. B.; Pati, K.; Liu, R.-S. Gold-Catalyzed Synthesis of
Substituted 2-Aminofurans via Formal [4 + 1]-Cycloadditions on 3-
En-1-Ynamides. Chem. Commun. 2012, 48 (57), 7200−7202.
(37) Nguyen, Q. H.; Nguyen, N. H.; Kim, H.; Shin, S. Synthesis of γ-
Substituted Carbonyl Compounds from DMSO-Mediated Oxidation
of Enynamides: Mechanistic Insights and Carbon- and Hetero-
Functionalizations. Chem. Sci. 2019, 10 (38), 8799−8805.
(38) Nguyen, N. H.; Nguyen, Q. H.; Biswas, S.; Patil, D. V.; Shin, S.
β-Oxidation of Ynamides into N,O-Acetals by MCPBA: Application
in Enantioselective Intermolecular Transacetalization. Org. Lett. 2019,
21 (22), 9009−9013.
(5) Xie, L.-G.; Niyomchon, S.; Mota, A. J.; González, L.; Maulide, N.
Metal-Free Intermolecular Formal Cycloadditions Enable an
Orthogonal Access to Nitrogen Heterocycles. Nat. Commun. 2016,
7 (1), 10914.
́
(6) Barluenga, J.; Fernández-Rodríguez, M. A.; García-García, P.;
Aguilar, E. Gold-Catalyzed Intermolecular Hetero-Dehydro-Diels−
Alder Cycloaddition of Captodative Dienynes with Nitriles: A New
Reaction and Regioselective Direct Access to Pyridines. J. Am. Chem.
Soc. 2008, 130 (9), 2764−2765.
(7) Zhao, Q.; León Rayo, D. F.; Campeau, D.; Daenen, M.; Gagosz,
F. Gold-Catalyzed Formal Dehydro-Diels−Alder Reactions of Ene-
Ynamide Derivatives Bearing Terminal Alkyne Chains: Scope and
Mechanistic Studies. Angew. Chem., Int. Ed. 2018, 57 (41), 13603−
13607.
(8) Zamani, F.; Babaahmadi, R.; Yates, B. F.; Gardiner, M. G.;
Ariafard, A.; Pyne, S. G.; Hyland, C. J. T. Dual Gold-Catalyzed
Cycloaromatization of Unconjugated (E)-Enediynes. Angew. Chem.,
Int. Ed. 2019, 58 (7), 2114−2119.
(9) Hashmi, A. S. K. Dual Gold Catalysis. Acc. Chem. Res. 2014, 47
(3), 864−876.
(10) Hashmi, A. S. K. Gold-Catalyzed Organic Reactions Gold-
Catalyzed Organic Reactions. Chem. Rev. 2007, 107, 3180−3211.
(11) Hashmi, A. S. K.; Hutchings, G. J. Gold Catalysis. Angew.
Chem., Int. Ed. 2006, 45 (47), 7896−7936.
(12) Yeom, H. S.; Shin, S. Catalytic Access to α-Oxo Gold Carbenes
by N-O Bond Oxidants. Acc. Chem. Res. 2014, 47 (3), 966−977.
(13) Shin, S. The Effect of Acceptor-Substituted Alkynes in Gold-
Catalyzed Intermolecular Reactions. Pure Appl. Chem. 201486 (3),
373−379..
(14) Kim, H.; Choi, S. Y.; Shin, S. Asymmetric Synthesis of
Dihydropyranones via Gold(I)-Catalyzed Intermolecular [4 + 2]
Annulation of Propiolates and Alkenes. Angew. Chem., Int. Ed. 2018,
57 (40), 13130−13134.
(15) Dubovtsev, A. Y.; Shcherbakov, N. V.; Dar’in, D. V.;
Kukushkin, V. Y. Nature of the Nucleophilic Oxygenation Reagent
Is Key to Acid-Free Gold-Catalyzed Conversion of Terminal and
Internal Alkynes to 1,2-Dicarbonyls. J. Org. Chem. 2020, 85 (2), 745−
757.
(16) Dubovtsev, A. Y.; Dar’in, D. V.; Kukushkin, V. Y. Gold(I)-
Catalyzed Oxidation of Acyl Acetylenes to Vicinal Tricarbonyls. Org.
Lett. 2019, 21 (11), 4116−4119.
(17) Dubovtsev, A. Y.; Dar’in, D. V.; Krasavin, M.; Kukushkin, V. Y.
Gold-Catalyzed Oxidation of Internal Alkynes into Benzils and Its
Application for One-Pot Synthesis of Five-, Six-, and Seven-
Membered Azaheterocycles. Eur. J. Org. Chem. 2019, 2019, 1856−
1864.
(39) Karad, S. N.; Liu, R.-S. Regiocontrolled Gold-Catalyzed [2 +
2+2] Cycloadditions of Ynamides with Two Discrete Nitriles to
Construct 4-Aminopyrimidine Cores. Angew. Chem., Int. Ed. 2014, 53
(34), 9072−9076.
(18) Mato, M.; Franchino, A.; García-Morales, C.; Echavarren, A. M.
Gold-Catalyzed Synthesis of Small Rings. Chem. Rev. 2020.
DOI: 10.1021/acs.chemrev.0c00697.
(19) Wang, T.; Hashmi, A. S. K. 1,2-Migrations onto Gold Carbene
Centers. Chem. Rev. 2020. DOI: 10.1021/acs.chemrev.0c00811.
(20) Reyes, R. L.; Iwai, T.; Sawamura, M. Construction of Medium-
Sized Rings by Gold Catalysis. Chem. Rev. 2020. DOI: 10.1021/
acs.chemrev.0c00793.
(21) Rocchigiani, L.; Bochmann, M. Recent Advances in Gold(III)
Chemistry: Structure, Bonding, Reactivity, and Role in Homogeneous
Catalysis. Chem. Rev. 2020. DOI: 10.1021/acs.chemrev.0c00552.
(40) Dubovtsev, A. Y.; Shcherbakov, N. V.; Dar’in, D. V.;
Kukushkin, V. Y. The Dichotomy of Gold-Catalyzed Interplay
between Cyanamides and Ynamides: Controllable Switch from [2 +
2+2] to [4 + 2] Cycloaddition. Adv. Synth. Catal. 2020, 362 (13),
2672−2682.
(41) Lane, T. K.; D’Souza, B. R.; Louie, J. Iron-Catalyzed Formation
of 2-Aminopyridines from Diynes and Cyanamides. J. Org. Chem.
2012, 77 (17), 7555−7563.
7226
https://doi.org/10.1021/acs.joc.1c00558
J. Org. Chem. 2021, 86, 7218−7228

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(42) Zimin, D. P.; Dar’in, D. V.; Kukushkin, V. Yu.; Dubovtsev, A.
Yu. Oxygen Atom Transfer as Key To Reverse Regioselectivity in the
Gold(I)-Catalyzed Generation of Aminooxazoles from Ynamides. J.
Org. Chem. 2021, 86 (2), 1748−1757.
(43) Dubovtsev, A. Y.; Dar’in, D. V.; Kukushkin, V. Y. Three-
Component [2 + 2+1] Gold(I)-Catalyzed Oxidative Generation of
Fully Substituted 1,3-Oxazoles Involving Internal Alkynes. Adv. Synth.
Catal. 2019, 361, 2926−2935.
(44) Prabhath, M.; Williams, L.; Bhat, S.; Sharma, P. Recent
Advances in Cyanamide Chemistry: Synthesis and Applications.
Molecules 2017, 22 (4), 615.
Press: 1988; Vol. 44, pp 1−79. DOI: 10.1016/S0065-2725(08)60261-
5.
(58) Maiti, D.; Buchwald, S. L. Orthogonal Cu- and Pd-Based
Catalyst Systems for the O- and N-Arylation of Aminophenols. J. Am.
Chem. Soc. 2009, 131 (47), 17423−17429.
(59) Shen, Q.; Hartwig, J. F. [(CyPF-TBu)PdCl2]: An Air-Stable,
One-Component, Highly Efficient Catalyst for Amination of
Heteroaryl and Aryl Halides. Org. Lett. 2008, 10 (18), 4109−4112.
(60) Teague, S. J. Synthesis of Heavily Substituted 2-Amino-
pyridines by Displacement of a 6-Methylsulfinyl Group. J. Org. Chem.
2008, 73 (24), 9765−9766.
(61) Du, X.-X.; Zi, Q.-X.; Wu, Y.-M.; Jin, Y.; Lin, J.; Yan, S.-J. An
Environmentally Benign Multi-Component Reaction: Regioselective
Synthesis of Fluorinated 2-Aminopyridines Using Diverse Properties
of the Nitro Group. Green Chem. 2019, 21 (6), 1505−1516.
(62) Weng, Y.; Kuai, C.; Lv, W.; Cheng, G. Synthesis of 2-
Aminopyridines via a Base-Promoted Cascade Reaction of N-
Propargylic β-Enaminones with Formamides. J. Org. Chem. 2018,
83 (9), 5002−5008.
(63) Londregan, A. T.; Jennings, S.; Wei, L. General and Mild
Preparation of 2-Aminopyridines. Org. Lett. 2010, 12 (22), 5254−
5257.
(64) Hashmi, A. S. K. Homogeneous Gold Catalysis Beyond
Assumptions and Proposals  Characterized Intermediates. Angew.
Chem., Int. Ed. 2010, 49, 5232−5241.
(65) Lauterbach, T.; Asiri, A. M.; Hashmi, A. S. K. Organometallic
Intermediates of Gold Catalysis. In Advances in Organometallic
Chemistry; Academic Press Inc.: 2014; Vol. 62, pp 261−297.
DOI: 10.1016/B978-0-12-800976-5.00005-9.
(66) Wang, Y.; Song, L.-J.; Zhang, X.; Sun, J. Metal-Free [2 + 2+2]
Cycloaddition of Ynamides and Nitriles: Mild and Regioselective
Synthesis of Fully Substituted Pyridines. Angew. Chem., Int. Ed. 2016,
55 (33), 9704−9708.
(67) Xie, L.-G.; Shaaban, S.; Chen, X.; Maulide, N. Metal-Free
Synthesis of Highly Substituted Pyridines by Formal [2 + 2+2]
Cycloaddition under Mild Conditions. Angew. Chem., Int. Ed. 2016,
55 (41), 12864−12867.
(68) Fernández-García, J. M.; Fernández-Rodríguez, M.; Aguilar, E.
Catalytic Intermolecular Hetero-Dehydro-Diels−Alder Cycloaddi-
tions: Regio- and Diasteroselective Synthesis of 5,6-Dihydropyridin-
2-Ones. Org. Lett. 2011, 13 (19), 5172−5175.
(69) Ricard, L.; Gagosz, F. Synthesis and Reactivity of Air-Stable N-
Heterocyclic Carbene Gold(I) Bis(Trifluoromethanesulfonyl)Imidate
Complexes. Organometallics 2007, 26 (19), 4704−4707.
(70) Rassadin, V. A.; Boyarskiy, V. P.; Kukushkin, V. Y. Facile Gold-
Catalyzed Heterocyclization of Terminal Alkynes and Cyanamides
Leading to Substituted 2-Amino-1,3-Oxazoles. Org. Lett. 2015, 17
(14), 3502−3505.
(71) Minkler, S.; Isley, N.; Lippincott, D.; Krause, N.; Lipshutz, B.
Leveraging the Micellar Effect: Gold-Catalyzed Dehydrative Cycliza-
tions in Water at Room Temperature. Org. Lett. 2014, 16 (3), 724−
726.
(72) Gawade, S.; Huple, D.; Liu, R.-S. Zn(II)- or Ag(I)-Catalyzed
1,4-Metathesis Reactions between 3-En-1-Ynamides and Nitro-
soarenes. J. Am. Chem. Soc. 2014, 136 (8), 2978−2981.
(73) Davies, P. W.; Cremonesi, A.; Dumitrescu, L. Intermolecular
and Selective Synthesis of 2,4,5-Trisubstituted Oxazoles by a Gold-
Catalyzed Formal [3 + 2] Cycloaddition. Angew. Chem., Int. Ed. 2011,
50 (38), 8931−8935.
(74) Coste, A.; Karthikeyan, G.; Couty, F.; Evano, G. Copper-
Mediated Coupling of 1,1-Dibromo-1-Alkenes with Nitrogen
Nucleophiles: A General Method for the Synthesis of Ynamides.
Angew. Chem. 2009, 121 (24), 4445−4449.
(45) Larraufie, M.-H.; Maestri, G.; Malacria, M.; Ollivier, C.;
̂
Fensterbank, L.; Lacote, E. The Cyanamide Moiety, Synthesis and
Reactivity. Synthesis 2012, 44 (09), 1279−1292.
(46) Schießl, J.; Schulmeister, J.; Doppiu, A.; Wörner, E.; Rudolph,
M.; Karch, R.; Hashmi, A. S. K. An Industrial Perspective on Counter
Anions in Gold Catalysis: Underestimated with Respect to “Ligand
Effects. Adv. Synth. Catal. 2018, 360 (13), 2493−2502.
(47) Schießl, J.; Schulmeister, J.; Doppiu, A.; Wörner, E.; Rudolph,
M.; Karch, R.; Hashmi, A. S. K. An Industrial Perspective on Counter
Anions in Gold Catalysis: On Alternative Counter Anions. Adv. Synth.
Catal. 2018, 360 (20), 3949−3959.
(48) Kramer, S.; Dooleweerdt, K.; Lindhardt, A. T.; Rottländer, M.;
Skrydstrup, T. Highly Regioselective Au(I)-Catalyzed Hydroamina-
tion of Ynamides and Propiolic Acid Derivatives with Anilines. Org.
Lett. 2009, 11 (18), 4208−4211.
(49) Nakao, Y.; Yeung, B. K. S.; Yoshida, W. Y.; Scheuer, P. J.; Kelly-
Borges, M. Kapakahine B, a Cyclic Hexapeptide with an.Alpha.-
Carboline Ring System from the Marine Sponge Cribrochalina
Olemda. J. Am. Chem. Soc. 1995, 117 (31), 8271−8272.
(50) Kim, J.-S.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H.
Structure of Mescengricin, a Novel Neuronal Cell Protecting
Substance Produced by Streptomyces Griseoflavus. Tetrahedron Lett.
1997, 38 (19), 3431−3434.
(51) Veale, C. G. L.; Laming, D.; Swart, T.; Chibale, K.; Hoppe, H.
C. Exploring the Antiplasmodial 2-Aminopyridines as Potential
Antitrypanosomal Agents. ChemMedChem 2019, 14 (24), 2034−
2041.
(52) Kang, S.; Li, H.; Tang, W.; Martásek, P.; Roman, L. J.; Poulos,
T. L.; Silverman, R. B. 2-Aminopyridines with a Truncated Side Chain
To Improve Human Neuronal Nitric Oxide Synthase Inhibitory
Potency and Selectivity. J. Med. Chem. 2015, 58 (14), 5548−5560.
(53) González Cabrera, D.; Douelle, F.; Younis, Y.; Feng, T.-S.; Le
Manach, C.; Nchinda, A.; Street, L. J.; Scheurer, C.; Kamber, J.;
White, K. L.; Montagnat, O. D.; Ryan, E.; Katneni, K.; Mohammed
Zabiulla, K.; Joseph, J. T.; Bashyam, S.; Waterson, D.; Witty, M. J.;
Charman, S. A.; Wittlin, S.; Chibale, K. Structure−Activity Relation-
ship Studies of Orally Active Antimalarial 3,5-Substituted 2-Amino-
pyridines. J. Med. Chem. 2012, 55 (24), 11022−11030.
(54) Connolly, S.; Aberg, A.; Arvai, A.; Beaton, H. G.; Cheshire, D.
R.; Cook, A. R.; Cooper, S.; Cox, D.; Hamley, P.; Mallinder, P.;
Millichip, I.; Nicholls, D. J.; Rosenfeld, R. J.; St-Gallay, S. A.; Tainer,
J.; Tinker, A. C.; Wallace, A. V. 2-Aminopyridines as Highly Selective
Inducible Nitric Oxide Synthase Inhibitors. Differential Binding
Modes Dependent on Nitrogen Substitution. J. Med. Chem. 2004, 47
(12), 3320−3323.
(55) Flock, J.; Suljanovic, A.; Torvisco, A.; Schoefberger, W.; Gerke,
B.; Pöttgen, R.; Fischer, R. C.; Flock, M. The Role of 2,6-
Diaminopyridine Ligands in the Isolation of an Unprecedented,
Low-Valent Tin Complex. Chem. - Eur. J. 2013, 19 (46), 15504−
15517.
(56) Shi, Z.; Li, Y.; Gong, H.; Liu, M.; Xiao, S.; Liu, H.; Li, H.; Xiao,
S.; Zhu, D. Self-Assembly and Characterization of Supramolecular
[60]Fullerene-Containing 2,6-Diacylamidopyridine with Uracil De-
rivative by Hydrogen-Bonding Interaction. Org. Lett. 2002, 4 (7),
1179−1182.
(75) Jadhav, A. M.; Gawade, S. A.; Vasu, D.; Dateer, R. B.; Liu, R. S.
ZnII- and AuI-Catalyzed Regioselective Hydrative Oxidations of 3-
En-1-Ynes with Selectfluor: Realization of 1,4-Dioxo and 1,4-
Oxohydroxy Functionalizations. Chem. - Eur. J. 2014, 20 (7),
1813−1817.
(57) Mcgill, C. K.; Rappa, A. Advances in the Chichibabin Reaction.
In Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic
7227
https://doi.org/10.1021/acs.joc.1c00558
J. Org. Chem. 2021, 86, 7218−7228

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(76) Bantreil, X.; Nolan, S. P. Synthesis of N-Heterocyclic Carbene
Ligands and Derived Ruthenium Olefin Metathesis Catalysts. Nat.
Protoc. 2011, 6 (1), 69−77.
7228
https://doi.org/10.1021/acs.joc.1c00558
J. Org. Chem. 2021, 86, 7218−7228