Acid-catalyzed [2 + 2 + 2] cycloaddition of two cyanamides and one ynamide: Highly regioselective synthesis of 2,4,6-triaminopyrimidines

Article abstract of DOI:10.1039/d1ob00513h

Triflic acid (10 mol%) catalyzes the highly regioselective [2 + 2 + 2] cycloaddition between two cyanamides and one ynamide to grant the 2,4,6-triaminopyrimidine core. The developed synthetic method is effective for the preparation of a family of the diversely substituted heterocyclic products (30 examples; yields up to 94%). The synthesis can be easily scaled up and conducted in gram quantities. As demonstrated by the post-functionalizations involving the amino-substituents, the obtained heterocycles represent a useful platform for the construction of miscellaneous pyrimidine-based frameworks. The performed density functional theory calculations verified a particular role of H+, functioning as an electrophilic activator, in the regioselectivity of the cycloaddition.

Full text of DOI:10.1039/d1ob00513h

Organic &
Biomolecular Chemistry
View Article Online
View Journal
PAPER
Acid-catalyzed [2 + 2 + 2] cycloaddition of two
cyanamides and one ynamide: highly regioselective
synthesis of 2,4,6-triaminopyrimidines†
Cite this: DOI: 10.1039/d1ob00513h
a
Alexey Yu. Dubovtsev, *a Valeria V. Zvereva, a Nikolay V. Shcherbakov,
a,b
Dmitry V. Dar’in, a Alexander S. Novikov a and Vadim Yu. Kukushkin
*
Triflic acid (10 mol%) catalyzes the highly regioselective [2 + 2 + 2] cycloaddition between two cyana-
mides and one ynamide to grant the 2,4,6-triaminopyrimidine core. The developed synthetic method is
effective for the preparation of a family of the diversely substituted heterocyclic products (30 examples;
yields up to 94%). The synthesis can be easily scaled up and conducted in gram quantities. As demon-
strated by the post-functionalizations involving the amino-substituents, the obtained heterocycles
represent a useful platform for the construction of miscellaneous pyrimidine-based frameworks. The
performed density functional theory calculations verified a particular role of H+, functioning as an electro-
philic activator, in the regioselectivity of the cycloaddition.
Received 17th March 2021,
Accepted 26th April 2021
DOI: 10.1039/d1ob00513h
rsc.li/obc
core, which is an important heterocyclic platform in natural
product- and pharmaceutical chemistry.20–24 Thus, Louie and
Introduction
[2 + 2 + 2] Cycloadditions leading to amino-functionalized coworkers proposed a method for the [2 + 2 + 2] cycloaddition
N-heterocycles are among the most important applications of between cyanamides and tethered cyanoalkynes in the pres-
cyanamide1,2 synthons. These cycloadditions can be divided ence of the catalytic system comprised of FeI2 and i-PrPDAI.25
into three groups (Scheme 1) according to the number and The Maulide group reported the [2 + 2 + 2] cycloaddition
nature of the reactants. Group A comprises the reactions of a limited scope (one example has been provided) that
between one cyanamide and two nitriles; group B covers the includes two N,N-dimethylcyanamides and one thio-
cycloadditions between one cyanamide and two alkynes; and substituted alkyne; this integration requires a stoichiometric
group C involves the interplay between one cyanamide, one amount of TfOH.26
nitrile and one alkyne.
In continuation of our project on cyanamide chemistry,27–30
The overwhelming majority of studies on the [2 + 2 + 2] we recently reported on the reaction dichotomy of cyanamides
cycloaddition of cyanamides is focused on the synthesis of with respect to β-arylynamides: under gold(I)-catalyzed con-
2-aminopyridines (Type B) under metal-catalyzed conditions ditions type C [2 + 2 + 2] cycloaddition and side-[4 + 2]-cyclo-
(M = Fe,3,4 Ir,5 Co,6,7 Ni,8,9 Ru,10–12 Rh13). Type A reactions— addition (the latter involves ynamide β-aryl-moiety) occur sim-
mainly include the trimerization of cyanamides to give amino-
1,3,5-triazines—proceed under the action of Lewis acids (e.g.,
Y(OTf)3,14 [Al(NMe2)3]2 15) or other reactive species (LiHMDS,16
Tf2O,17 Na,18 PhLi19).
In contrast to the wealth of types A and B cycloadditions,
only two examples of type C reactions are known. Both
reported transformations accomplished the aminopyrimidine
aSaint Petersburg State University, Universitetskaya Nab. 7/9,
199034 Saint Petersburg, Russian Federation. E-mail: a.dubovtsev@spbu.ru,
v.kukushkin@spbu.ru
bSouth Ural State University, 76, Lenin Av., 454080 Chelyabinsk, Russian Federation
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1ob00513h
Scheme 1 Types of [2 + 2 + 2] cycloadditions involving cyanamides.
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
Scheme 2 Unselective gold-catalyzed (a, ref. 31) and highly regioselective acid-catalyzed (b, this work) cycloadditions of cyanamides and
ynamides.
ultaneously (Scheme 2a).31 By varying the Au-catalyzed reaction compounds, post-functionalizations involving the amino-sub-
conditions, the regioselectivity of the [2 + 2 + 2] cycloaddition stituents were carried out. Appropriate theoretical calculations
can be increased, however, the side-[4 + 2]-reaction leading to verified the role of H+, functioning as an electrophilic activa-
isoquinolines cannot be completely suppressed and the iso- tor, in the regioselectivity of the [2 + 2 + 2] cycloaddition.
lation/purification of the target pyrimidines therefore rep-
Screening of electrophilic activators
resent a separate task.
In our search for suitable catalysts providing the highly
regioselective [2 + 2 + 2] cycloaddition of cyanamides and yna-
mides, we turned to Brønsted acids. These acids can be
employed as an alternative to gold-based catalysts32–39 in view
of the isolobality of H+ and LAu+.40–44 We now report on the
facile triflic acid-catalyzed (10 mol%) integration of two cyana-
mides and one ynamide. In contrast to the previous nonspeci-
fic method leading simultaneously to pyrimidines and isoqui-
nolines (Scheme 2a) and utilizing the gold-based catalysts,31
the use of catalytic amounts of TfOH leads to the highly regio-
selective [2 + 2 + 2] cycloaddition (Scheme 2b) to give a variety
of useful 2,4,6-triaminopyrimidines. All our experimental and
theoretical results relevant to this novel synthetic method are
detailed in the following sections.
We began our studies by exploring the reactivity of ynamide 1a
toward N,N-dimethylcyanamide (2a) in the presence of various
electrophilic activators (Table 1). Previously, when gold(I) com-
plexes were used31 (entries 1 and 2), in addition to the desired
2,4,6-triaminopyrimidine 3a, derived from the [2 + 2 + 2] cyclo-
addition, we obtained 1,3-diaminoisoquinoline 4a that orig-
inates from the formal [4 + 2] cycloaddition. The model reac-
tion in the presence of TfOH (10 mol%), taken instead of the
gold species, gave pyrimidine 3a (65%) as the only heterocyclic
product (entry 3). In this case, the significant formation of 5,
as a result of the hydration of 1a, was observed but the side
isoquinoline was not detected in the reaction mixture.
Catalytic amounts of weaker Brønsted acids were ineffective
(entries 4–6), but superacidic bistriflimide (Tf2NH, entry 7)
showed the result comparable to that observed for TfOH. The
target pyrimidine was also obtained selectively when such
Lewis acids as BF3·Et2O or TMSOTf were applied as the cata-
lysts (entries 8 and 9); even traces of the [4 + 2] cycloaddition
product were not detected (entries 3–9).
Results and discussion
For this study, we addressed ynamides,45–49 i.e. alkynes featur-
ing an amide substituent at the CuC bond. The ynamide con-
jugated system is highly nucleophilic and capable of activation
by such isolobal electrophiles as Au+ or H+. The successful re-
placement of gold-based catalysts by H+ in some reactions has
been demonstrated,50,51 although such examples are more an
exception than the general rule. We also took into account that
Brønsted acids catalyze some other cycloadditions of either
cyanamides,26 or ynamides;40,41 however, acid-catalyzed cyana-
mide and ynamide integration has never been reported.
TfOH that showed the best result was chosen for further
study. The experiments were carried out in dry DCE with
freshly distilled TfOH under dry argon atmosphere to prevent
the ynamide hydration. The optimizations of the reaction
temperature/time and catalyst loading revealed that the best
yield of 3a was achieved at 80 °C for 24 h with only 3 equiv. of
2a and 10 mol% of TfOH (entry 14).
TfOH-catalyzed synthesis of 2,4,6-triaminopyrimidines and its
applications
The scenario of this work is the following: we performed
the screening of electrophilic activators for the [2 + 2 + 2] cyclo- With the optimal conditions at hand, the substrate scope and
addition of cyanamides and ynamides (with particular focus limitations for the synthesis of 2,4,6-triaminopyrimidines 3
on H+) and also uncovered the synthetic potential of this were examined. Initially we explored different cyanamides with
highly regioselective reaction. For some of the synthesized ynamide 1a, taken as the alkyne component (Table 2). The
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2021

View Article Online
Organic & Biomolecular Chemistry
Paper
Table 1 Optimization of the synthesis of 3aa
Yields,b %
Entry
Catalyst, mol%
t, °C
Time, h
Conversion,b %
3a
4a
5
1
2
3
4
5
6
7
8
Ph3PAuNTf2, 5
IPrAuNTf2, 5
TfOH, 10
60
60
60
60
60
60
60
60
60
rt
80
80
80
80
80
3
3
3
3
3
3
3
3
3
24
24
24
24
24
24
58
97
89
17
23
15
86
71
80
45
72
99
96
98
45
31
46
65
—
—
—
61
50
58
14
61
86
80
88
32
21
48
—
—
—
—
—
—
—
—
—
—
—
—
—
2
3
18
15
20
13
22
20
16
28
5
TFA, 10
TsOH, 10
MsOH, 10
Tf2NH, 10
BF3·Et2O, 10
TMSOTf, 10
TfOH, 10
TfOH, 5
TfOH, 10
TfOH, 20
TfOH, 10
9
10c
11c
12c
13c
14c,d
15e
6
10
6
TfOH, 10
13
1
a All reactions were carried out on a 0.1 mmol scale (0.2 M). b Estimated by H NMR spectroscopy using durene as an internal standard. c Under
dry argon atmosphere. d 3 equiv. of 2a was used. e 1 equiv. of 2a was used.
application of all N,N-dimethyl-, N,N-diethyl- and bulky N,N-
diphenyl-cyanamides led to good yields of corresponding pyri-
Table 2 Reactivity screening for cyanamides 2a,b
midines 3a–c. The reaction conditions were effective for intro-
ducing a diversity of cyclic amino-functionalities, such as pyr-
rolidine, piperidine, tetrahydroisoquinoline, and morpholine
fragments, into the both 2nd and 6th positions of the pyrimi-
dine core (3d–g). Notably, complex reaction mixtures were
obtained when we attempted the preparation of pyrimidines
from cyanamides containing the free NH-fragments (NH2CN,
PhNHCN, n-BuNHCN). This reactivity pattern is probably
related to the competing ynamide hydroamination.52
Nevertheless, pyrimidines 3h,i, bearing easily cleavable benzyl
N-protective groups, were obtained in excellent yields.
Next, we tested various ynamides 1 in their reactions with
N,N-dimethylcyanamide (Table 3). The cycloadditions proceed
smoothly with the reactants featuring various electron-with-
drawing N-sulfonyl substituents (6a–c). On the contrary, pyri-
midine 6d bearing a cyclic carbamate substituent was obtained
in a rather poor yield. Ynamides featuring N-alkyl and
N-phenyl groups delivered the corresponding pyrimidines in
good to excellent yields (6e–h). In contrast to our previous
method,31 the reaction conditions were applicable to the [2 + 2
+ 2] cycloaddition of ynamides with diverse R1-substituents
(6i–t). Thus various functionalities can be introduced into the
5th position of pyrimidine ring, including alkenyl (6o), high
electron-donor aryl (6j,m,n), and heteroaryl (6p,s) moieties. In
the case of activation by gold complexes,31 the [4 + 2] cyclo-
a All reactions were carried out on a 0.2 mmol scale (0.2 M). b Isolated
yield.
addition is the main reactive route for such electron-rich yna-
mides. Terminal ynamides 1q,r were successfully converted
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
Table 3 Reactivity screening for ynamides 1a,b
Given the value of 2,4,6-triaminopyrimidines for medicinal
chemistry, we were eager to demonstrate the further utility of
our synthetic approach (Scheme 3). The preparation of 7 can
be conducted on a gram scale, while post-functionalizations of
compounds 3i and 7 were illustrated by the detosylation and
debenzylations of the amino-substituents at the 2nd, 4th, and
6th positions of the pyrimidine rings.
Reaction mechanism and DFT calculations
Plausible mechanisms of both [2 + 2 + 2] and [4 + 2] ynamide-
cyanamide integrations are given in Scheme 4. Highly reactive
ketiminium intermediate A is generated by the action of an
electrophile (H+ or LAu+) on ynamide 1. Further attack of A by
cyanamide 2 leads to nitrilium ion B. In turn, two reaction
pathways for intermediate B could be assumed: (i) the inter-
action of B with another molecule of 2 leads to the closure
of the pyrimidine ring of 3; (ii) when R1 is an aryl (in particu-
lar, phenyl), an intramolecular Friedel–Crafts reaction could
lead to isoquinolines 4. The second pathway is realized exclu-
sively when the gold-based catalysts are used as activators
(E = LAu).
Intrigued by this mechanistic dichotomy illustrated on
Scheme 2, we were interested in obtaining theoretical data
shedding the light on the crucial role of Brønsted acids in the
highly regioselective [2 + 2 + 2] cycloaddition of ynamides and
cyanamides. We carried out DFT calculations (B3LYP/MWB60
(Au) and 6-31G*(other atoms) level of theory) for the intra-
molecular cyclization of the adduct of PhCuCN(Me)Ms and di-
methylcyanamide, when either a gold entity (Ph3PAu, IPrAu,
a All reactions were carried out on a 0.2 mmol scale (0.2 M). b Isolated
yield. c 20 mol% of TfOH was used.
into corresponding 5-unsubstituted pyrimidines 6q,r. The
cycloaddition was carried out in a bidirectional manner giving
bispyrimidine 6t.
Scheme 3 Gram-scale synthesis of 7 and post-functionalizations of 3i
and 7.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2021

View Article Online
Organic & Biomolecular Chemistry
Paper
Scheme 4 A plausible mechanism for generation of 3 and 4.
Scheme 5 The DFT calculations results.
Me3PAu), or H+ are used as the electrophilic activators for H+ (by 3.4 kcal mol−1). In the case of the strong electron-
(Scheme 5). donating and bulky IPr ligand, the energy barrier to the cycli-
We compared the energy of both possible geometrically iso- zation is further reduced (by 4.0 kcal mol−1). The calculated
meric nitrilium intermediate E and F. In the case of acid (X = energies for hypothetical product, reagent, and transition state
H), isomer F (for which undesirable intramolecular cyclization when X = Me3PAu only slightly differ from the value for X =
is not possible) turned out to be more energetically favorable Ph3PAu.
compared to the corresponding gold species. Next we com-
The right half of Scheme 5 shows the transition states for
pared the energies of transition states for cyclization of E to G. cyclization E to G, when X = H, Me3PAu, Ph3PAu, and IPrAu. In
The calculations indicate that the transition state for the acti- the case of activation by a proton, the distance between the
vation by Ph3PAu+ is more energetically beneficial than that phenyl ortho-carbon and the cyanamide carbon is much
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
higher (2.360 Å) than in the cases of activation by gold; the in contrast to the gold-catalyzed approach, provides good
latter distances change insignificantly for various LAu yields of the products derived from β-aryl ynamides containing
(2.103–2.114 Å).
electron-donor substituents. Thus, the employment of triflic
Finally, we calculated the activation barrier for the addition acid in the cycloaddition represents an attractive alternative to
of dimethylcyanamide to adduct E, which leads to the [2 + 2 + the gold catalyzed route. We believe that our results would be
2] product. When X = H, this barrier was 8.1 kcal mol−1, which of particular importance for the search of an appropriate cata-
is significantly lower than that for the cyclization of E to G lytic system for cycloadditions involving both cyanamides and
(18.6 kcal mol−1). When X = IPrAu, the activation energy for ynamides.
the addition of dimethylcyanamide to E increases to 18.9 kcal
mol−1
.
These calculations are fully consistent with our experi-
mental data demonstrating the growing trend of isoquinoline
formation in a row of the electrophilic activators TfOH ≪
Ph3PAuNTf2 < IPrAuNTf2 (Table 1). When the cycloaddition is
catalyzed by triflic acid (X = H), only the energetically ben-
eficial [2 + 2 + 2] pathway is observed even for ynamides
bearing electron-rich aryl fragments at the β-position. On the
contrary, an increase of the donor properties of the substitu-
ents X (H < Ph3PAu < IPrAu) favors the intramolecular Friedel–
Crafts reaction of nitrilium ions E because the presence of a
more donating substituent increases the electron density at
the ortho-positions of the phenyl ring thus making it more sen-
sitive to the electrophilic attacks. Very likely, the steric factors
also affect the selectivity of cycloadditions: the presence of the
bulky gold-containing substituents X brings the phenyl ring
and the cyanamide carbon in adduct E closer together, favor-
ing the formation of the isoquinoline.
Author contributions
A.Yu.D. conceptualized the research project. A.Yu.D., V.V.Z.,
and N.V.S. conducted the experiments and prepared the ESI.†
A.S.N. performed the DFT calculations. A.Yu.D., D.V.D., and V.
Y.K. designed the experiments and wrote the paper. All
authors have given approval to the final version of the
manuscript.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
A. Yu. D. thanks the Russian Science Foundation for support
of these studies (grant 20-73-10022). 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. We are much obliged to Center for
Magnetic Resonance and Center for Chemical Analysis and
Material Research (both belonging to Saint Petersburg State
University) for physicochemical measurements.
Conclusions
The previously studied [2 + 2 + 2] cycloadditions between cyana-
mides and alkynes were mainly focused on the construction of
amino-substituted pyridines and triazines. Herein we developed
a facile, atom-economic, and high-yielding route toward the
pharmaceutically significant 2,4,6-triaminopyrimidines. Our
method is based on the highly regioselective TfOH-catalyzed
(10 mol%) integration of two cyanamides and one ynamide,
which operates under mild conditions, utilize easily available
substrates, and can be performed on a gram scale. The versati-
lity of the obtained pyrimidine platform was demonstrated by
useful post-functionalizations of the amino-substituents at the
2nd, 4th, and 6th positions of the pyrimidine rings.
Notes and references
1 M. Prabhath, L. Williams, S. Bhat and P. Sharma, Recent
Advances in Cyanamide Chemistry: Synthesis and
Applications, Molecules, 2017, 22, 615.
2 M.-H. Larraufie, G. Maestri, M. Malacria, C. Ollivier,
L. Fensterbank and E. Lacôte, The Cyanamide Moiety,
Synthesis and Reactivity, Synthesis, 2012, 44, 1279–1292.
3 N. A. Spahn, M. H. Nguyen, J. Renner, T. K. Lane and
J. Louie, Regioselective Iron-Catalyzed [2+2+2] Cycloaddition
Reaction Forming 4,6-Disubstituted 2-Aminopyridines from
Terminal Alkynes and Cyanamides, J. Org. Chem., 2017, 82,
234–242.
4 C. Wang, D. Wang, F. Xu, B. Pan and B. Wan, Iron-
Catalyzed Cycloaddition Reaction of Diynes and
Cyanamides at Room Temperature, J. Org. Chem., 2013, 78,
3065–3072.
In contrast to our previous method31 for the cyanamide–
ynamide integration, which utilizes Au-based catalysts and
leads to the mixtures of isoquinolines and pyrimidines,
Brønsted acids (in particular TfOH) highly regioselectively pro-
motes the [2 + 2 + 2] cycloaddition to give the pyrimidine core.
The DFT calculation data are in line with our experimental
observations and both approaches reveal that the side-[4 + 2]-
cycloaddition to give isoquinolines is totally suppressed by the
switch from the gold-based activators to H+. The probable
cause of the observed selectivity is the combined action of elec-
tronic and steric factors. The yields of triaminopyrimidines
obtained by the method reported here are comparable to those
for the gold catalytic reaction. At the same time this method,
5 R. Takeuchi, S. Fujisawa, Y. Yoshida, J. Sagano,
T. Hashimoto and A. Matsunami, Synthesis of
Multisubstituted Azatriphenylenes by Iridium-Catalyzed
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2021

View Article Online
Organic & Biomolecular Chemistry
Paper
[2+2+2] Cycloaddition of Biaryl-Linked Diynes with Nitriles, 19 H. J. Anderson, N.-C. Wang and E. T. P. Jwili, Reaction of
J. Org. Chem., 2018, 83, 1852–1860.
Phenyllithium with Some N,N-Disubstitiited Cyanamides,
6 L. V. R. Boñaga, H.-C. Zhang, A. F. Moretto, H. Ye,
Can. J. Chem., 1971, 49, 2315–2320.
D. A. Gauthier, J. Li, G. C. Leo and B. E. Maryanoff, 20 C. Mo, Z. Zhang, C. P. Guise, X. Li, J. Luo, Z. Tu, Y. Xu,
Synthesis of Macrocycles via Cobalt-Mediated [2+2+2]
Cycloadditions, J. Am. Chem. Soc., 2005, 127, 3473–3485.
7 L. V. R. Boñaga, H.-C. Zhang and B. E. Maryanoff, Cobalt-
mediated cyclotrimerisation of bis-alkynes and cyana-
mides, Chem. Commun., 2004, 2394–2395.
8 P. Kumar, S. Prescher and J. Louie, A Serendipitous
Discovery: Nickel Catalyst for the Cycloaddition of Diynes
with Unactivated Nitriles, Angew. Chem., Int. Ed., 2011, 50,
10694–10698.
9 R. M. Stolley, M. T. Maczka and J. Louie, Nickel-Catalyzed
[2+2+2] Cycloaddition of Diynes and Cyanamides,
Eur. J. Org. Chem., 2011, 3815–3824.
10 F. Ye, M. Haddad, V. Michelet and V. Ratovelomanana-
Vidal, Solvent-free ruthenium trichloride-mediated [2+2+2]
cycloaddition of α{,}ω-diynes and cyanamides: a convenient
A. V. Patterson, J. B. Smaill, X. Ren, X. Lu and K. Ding,
2-Aminopyrimidine Derivatives as New Selective Fibroblast
Growth Factor Receptor 4 (FGFR4) Inhibitors, ACS Med.
Chem. Lett., 2017, 8, 543–548.
21 M. S. Tichenor, R. L. Thurmond, J. D. Venable and
B. M. Savall, Functional Profiling of 2-Aminopyrimidine
Histamine H4 Receptor Modulators, J. Med. Chem., 2015,
58, 7119–7127.
22 S. Lee, D. Lim, E. Lee, N. Lee, H. Lee, J. Cechetto,
M. Liuzzi, L. H. Freitas-Junior, J. S. Song, M. A. Bae,
S. Oh, L. Ayong and S. B. Park, Discovery of Carbohybrid-
Based 2-Aminopyrimidine Analogues As a New Class of
Rapid-Acting Antimalarial Agents Using Image-Based
Cytological Profiling Assay, J. Med. Chem., 2014, 57, 7425–
7434.
access to 2-aminopyridines, Org. Chem. Front., 2017, 4, 23 Y. T. Han, G.-I. Choi, D. Son, N.-J. Kim, H. Yun, S. Lee,
1063–1068.
D. J. Chang, H.-S. Hong, H. Kim, H.-J. Ha, Y.-H. Kim,
H.-J. Park, J. Lee and Y.-G. Suh, Ligand-Based Design,
11 H. Chowdhury and A. Goswami, A Quick Access to 1-(2-
Pyridyl)indoles via Solvent-Free Ruthenium(II)-Catalyzed
Chemo- and Regioselective [2+2+2] Cycloaddition of
α,ω-Diynes and N-Cyanoindoles, Adv. Synth. Catal., 2017,
359, 314–322.
Synthesis,
and
Biological
Evaluation
of
2-Aminopyrimidines,
a
Novel Series of Receptor for
Advanced Glycation End Products (RAGE) Inhibitors,
J. Med. Chem., 2012, 55, 9120–9135.
12 F. Ye, C. Tran, L. Jullien, T. Le Saux, M. Haddad, 24 M. W. Martin, J. Newcomb, J. J. Nunes, D. C. McGowan,
V. Michelet and V. Ratovelomanana-Vidal, Synthesis of
Fluorescent Azafluorenones and Derivatives via
Ruthenium-Catalyzed [2+2+2] Cycloaddition, Org. Lett.,
2018, 20, 4950–4953.
D. M. Armistead, C. Boucher, J. L. Buchanan, W. Buckner,
L. Chai, D. Elbaum, L. F. Epstein, T. Faust, S. Flynn,
P. Gallant, A. Gore, Y. Gu, F. Hsieh, X. Huang, J. H. Lee,
D. Metz, S. Middleton, D. Mohn, K. Morgenstern,
M. J. Morrison, P. M. Novak, A. Oliveira-dos-Santos,
D. Powers, P. Rose, S. Schneider, S. Sell, Y. Tudor,
S. M. Turci, A. A. Welcher, R. D. White, D. Zack, H. Zhao,
L. Zhu, X. Zhu, C. Ghiron, P. Amouzegh, M. Ermann,
J. Jenkins, D. Johnston, S. Napier and E. Power, Novel
2-Aminopyrimidine Carbamates as Potent and Orally Active
Inhibitors of Lck: Synthesis, SAR, and in Vivo
Antiinflammatory Activity, J. Med. Chem., 2006, 49, 4981–
4991.
a
13 K. M. Medas, R. W. Lesch, F. B. Edioma, S. P. Wrenn,
V. Ndahayo and S. P. Mulcahy, Metal-Catalyzed
Cyclotrimerization Reactions of Cyanamides: Synthesis of
2-Aryl-α-carbolines, Org. Lett., 2020, 22, 3135–3139.
14 A. Díaz-Ortiz, A. de la Hoz, A. Moreno, A. Sánchez-Migallón
and G. Valiente, Synthesis of 1{,}3{,}5-triazines in solvent-
free conditions catalysed by silica-supported lewis acids,
Green Chem., 2002, 4, 339–343.
15 P. Dornan, C. N. Rowley, J. Priem, S. T. Barry, T. J. Burchell,
T. K. Woo and D. S. Richeson, Atom efficient cyclotrimeri- 25 T. K. Lane, M. H. Nguyen, B. R. D’Souza, N. A. Spahn and
zation of dimethylcyanamide catalyzed by aluminium
amide: a combined experimental and theoretical investi-
gation, Chem. Commun., 2008, 3645–3647.
J. Louie, The iron-catalyzed construction of 2-aminopyrimi-
dines from alkynenitriles and cyanamides, Chem.
Commun., 2013, 49, 7735–7737.
16 X. Chen, S.-D. Bai, L. Wang and D.-S. Liu, Reactions of 26 L.-G. Xie, S. Niyomchon, A. J. Mota, L. González and
Bis(silyl-substituted) Methyllithium with α-Hydrogen-free
Nitriles into 1,3,5-Triazines, Heterocycles, 2005, 65, 1425–1430.
17 A. Herrera, A. Riaño, R. Moreno, B. Caso, Z. D. Pardo,
N. Maulide, Metal-free intermolecular formal cycloaddi-
tions enable an orthogonal access to nitrogen heterocycles,
Nat. Commun., 2016, 7, 10914.
I. Fernández, E. Sáez, D. Molero, A. Sánchez-Vázquez and 27 A. Y. Dubovtsev, D. V. Dar’in and V. Y. Kukushkin, Three-
R. Martínez-Alvarez, One-Pot Synthesis of 1,3,5-Triazine
Derivatives via Controlled Cross-Cyclotrimerization of
Nitriles: A Mechanism Approach, J. Org. Chem., 2014, 79,
7012–7024.
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.
28 V. A. Rassadin, V. P. Boyarskiy and V. Y. Kukushkin, Facile
Gold-Catalyzed Heterocyclization of Terminal Alkynes and
Cyanamides Leading to Substituted 2-Amino-1,3-Oxazoles,
Org. Lett., 2015, 17, 3502–3505.
18 M. Cariou and J. Simonet, Comparison of chemical and
electrochemical reduction of cyanamides: an example of
cathodic decyanation, Can. J. Chem., 1991, 69, 861–864.
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
29 V. A. Rassadin, D. P. Zimin, G. Z. Raskil’dina, A. Y. Ivanov, 41 L.-G. Xie, S. Shaaban, X. Chen and N. Maulide, Metal-Free
V. P. Boyarskiy, S. S. Zlotskii and V. Y. Kukushkin, Solvent-
and halide-free synthesis of pyridine-2-yl substituted ureas
through facile C-H functionalization of pyridine: N -oxides,
Green Chem., 2016, 18, 6630–6636.
Synthesis of Highly Substituted Pyridines by Formal
[2+2+2] Cycloaddition under Mild Conditions, Angew.
Chem., Int. Ed., 2016, 55, 12864–12867.
42 D. V. Patil, S. W. Kim, Q. H. Nguyen, H. Kim, S. Wang,
T. Hoang and S. Shin, Brønsted Acid Catalyzed Oxygenative
Bimolecular Friedel–Crafts-type Coupling of Ynamides,
Angew. Chem., Int. Ed., 2017, 56, 3670–3674.
30 D. P. Zimin, D. V. Dar’in, V. Yu. Kukushkin and
A. Yu. Dubovtsev, Oxygen Atom Transfer as Key To Reverse
Regioselectivity in the Gold(I)-Catalyzed Generation of
Aminooxazoles from Ynamides, J. Org. Chem., 2021, 86, 43 L. L. Baldassari, A. de la Torre, J. Li, D. S. Lüdtke and
1748–1757.
N. Maulide, Ynamide Preactivation Allows a Regio- and
Stereoselective Synthesis of α,β-Disubstituted Enamides,
Angew. Chem., Int. Ed., 2017, 56, 15723–15727.
31 A. Y. Dubovtsev, N. V. Shcherbakov, D. V. Dar’in and
V. Y. Kukushkin, The Dichotomy of Gold-catalyzed
Interplay between Cyanamides and Ynamides: Controllable 44 V. Tona, S. A. Ruider, M. Berger, S. Shaaban,
Switch from [2+2+2] to [4+2] Cycloaddition, Adv. Synth.
Catal., 2020, 362, 2672–2682.
32 A. S. K. Hashmi, Dual Gold Catalysis, Acc. Chem. Res., 2014,
47, 864–876.
M. Padmanaban, L.-G. Xie, L. González and N. Maulide,
Divergent ynamide reactivity in the presence of azides – an
experimental and computational study, Chem. Sci., 2016, 7,
6032–6040.
33 A. S. K. Hashmi, Gold-Catalyzed Organic Reactions Gold- 45 Y.-C. Hu, Y. Zhao, B. Wan and Q.-A. Chen, Reactivity of yna-
Catalyzed Organic Reactions, Chem. Rev., 2007, 107, 3180–
3211.
mides in catalytic intermolecular annulations, Chem. Soc.
Rev., 2021, 2582–2625.
34 A. S. K. Hashmi and G. J. Hutchings, Gold Catalysis, Angew. 46 G. Evano, B. Michelet and C. Zhang, The anionic chemistry
Chem., Int. Ed., 2006, 45, 7896–7936. of ynamides: A review, C. R. Chim., 2017, 20, 648–664.
35 H. S. Yeom and S. Shin, Catalytic access to α-oxo gold car- 47 G. Evano, A. Coste and K. Jouvin, Ynamides: Versatile Tools
benes by N-O bond oxidants, Acc. Chem. Res., 2014, 47,
in Organic Synthesis, Angew. Chem., Int. Ed., 2010, 49,
966–977.
2840–2859.
36 S. Shin, The effect of acceptor-substituted alkynes in gold- 48 X.-N. Wang, H.-S. Yeom, L.-C. Fang, S. He, Z.-X. Ma,
catalyzed intermolecular reactions, Pure Appl. Chem., 2014,
86, 373–379.
37 A. Y. Dubovtsev, N. V. Shcherbakov, D. V. Dar’in and
B. L. Kedrowski and R. P. Hsung, Ynamides in Ring
Forming Transformations, Acc. Chem. Res., 2014, 47, 560–
578.
V. Y. Kukushkin, Nature of the Nucleophilic Oxygenation 49 K. A. DeKorver, H. Li, A. G. Lohse, R. Hayashi, Z. Lu,
Reagent Is Key to Acid-Free Gold-Catalyzed Conversion of
Terminal and Internal Alkynes to 1,2-Dicarbonyls, J. Org.
Chem., 2020, 85, 745–757.
Y. Zhang and R. P. Hsung, Ynamides: A Modern Functional
Group for the New Millennium, Chem. Rev., 2010, 110,
5064–5106.
38 A. Y. Dubovtsev, D. V. Dar’in and V. Y. Kukushkin, Gold(I)- 50 Y. Zhao, C. Wang, Y. Hu and B. Wan, Brønsted acid-cata-
Catalyzed Oxidation of Acyl Acetylenes to Vicinal
Tricarbonyls, Org. Lett., 2019, 21, 4116–4119.
39 A. Y. Dubovtsev, D. V. Dar’in, M. Krasavin and
lyzed formal [5+2+1] cycloaddition of ynamides and isoxa-
zoles with water: access to oxygen-bridged tetrahydro-1{,}4-
oxazepines, Chem. Commun., 2018, 54, 3963–3966.
V. Yu. Kukushkin, Gold-Catalyzed Oxidation of Internal 51 L. Zhou, L. Yang, S. Dai, Y. Gao, R. Fang, A. M. Kirillov and
Alkynes into Benzils and its Application for One-Pot
Synthesis of Five-, Six-, and Seven-Membered
Azaheterocycles, Eur. J. Org. Chem., 2019, 1856–1864.
L. Yang, Insight into the reaction mechanism and chemo-
selectivity in the cycloaddition of ynamides and isoxazoles
with H2O, Catal. Sci. Technol., 2020, 10, 240–251.
40 Y. Wang, L.-J. Song, X. Zhang and J. Sun, Metal-Free 52 S. Kramer, K. Dooleweerdt, A. T. Lindhardt, M. Rottländer
[2+2+2] Cycloaddition of Ynamides and Nitriles: Mild and
Regioselective Synthesis of Fully Substituted Pyridines,
Angew. Chem., Int. Ed., 2016, 55, 9704–9708.
and T. Skrydstrup, Highly Regioselective Au(I)-Catalyzed
Hydroamination of Ynamides and Propiolic Acid
Derivatives with Anilines, Org. Lett., 2009, 11, 4208–4211.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2021