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Direct synthesis of N2-unprotected five-membered

Cite this: Org. Chem. Front., 2022, 9,
cyclic guanidines by regioselective [3 + 2] annula-
1574 tion of aziridines and cyanamides†
Chuan-Chuan Wang, a,b Xin-Lu Wang,a Qing-Ling Zhang,a Juntao Liu,b
Zhi-Wei Ma,b Zhi-Jing Liub and Ya-Jing Chen *a

Received 27th December 2021,
Accepted 22nd January 2022
DOI: 10.1039/d1qo01926k
rsc.li/frontiers-organic
A novel and efficient [3 + 2] annulation of 2-substituted aziridines and N-tosyl cyanamides via a domino
regioselective ring-opening/5-exo-dig cyclization procedure has been developed, allowing the direct
preparation of N2-unprotected five-membered cyclic guanidines in good to excellent yields under mild
conditions without metals and strong bases. Moreover, the highly biologically interesting urea analogues
could also be conveniently obtained via hydrolysis of the produced guanidines.

Introduction [3 + 2] cycloaddition between carbodiimides and aziridines

Among the vast array of nitrogen-containing heterocycles, five-
membered cyclic guanidines are particularly remarkable
motifs since they are prevalent in various medicines and bio-
active molecules.1 Meanwhile, some five-membered cyclic gua-
nidines are also efficient catalysts and good metal ligands in
organic synthesis.2 As shown in Fig. 1, palau’amine A, isolated
from the marine sponge Stylotella agminata, exhibits wonder-
ful immunosuppressive and antitumor activities.3 Tri-guani-
dine alkaloid KB343 B, isolated from a Palauan zoantharian
Epizoanthus illoricatus, shows potent cytotoxicity in cultured
cancer cells.4 Clonidine C is an antihypertensive drug used
especially to treat essential hypertension.5 trans-1,2-
Diaminocyclohexane derived guanidine D is an efficient cata-
lyst used in the synthesis of the natural AChE inhibitor
(−)-huperzine A.6
Fascinated by their versatile properties, numerous studies
have been conducted for the development of powerful
methods for the construction of five-membered cyclic guani-
dines.7 Among them, intramolecular cyclization of chain-gua-
nidines or amino amidines (Scheme 1A, method 1),8 amin-
ation of Vilsmeier-like precursors or thioureas (method 2),9
(method 3),10 [3 + 2] cycloaddition of alkenes with diaziridini-
mines or chain-guanidines (method 4),11 and transition metal-
catalyzed amination/cyclization of unsaturated chain-guani-
dines (method 5)12 are common strategies to synthesize these
building blocks. However, these protocols always provide N2-
protected cyclic guanidines, and the removal of protecting
groups sometimes proved to be quite challenging. Therefore,
direct strategies for the construction of N2-unprotected five-
membered cyclic guanidines from conveniently available start-
ing materials are still in great demand.
According to the retrosynthetic analysis shown in
Scheme 1B, the target N2-unprotected five-membered cyclic
guanidines could be synthesized by [3 + 2] cyclization between
nitrogen-containing 1,3-dipoles A and cyanamide anions B.
Moreover, aziridines 1 are versatile 1,3-dipole or 1,3-zwitterion
precursors with high atom-economy, furnishing various nitro-
gen-containing heterocycles via [3 + m] cyclization promoted
by Lewis acids or transition metals.13 On the other hand, cya-
namide anions B could be readily in situ generated from
N-tosyl cyanamides 2 via desulfonylation.14 On the basis of our
continuous efforts to develop efficient methods for the prepa-
ration of valuable heterocycles,15 we wondered whether the

a
School of Pharmaceutical Sciences, Key Laboratory of Advanced Drug Preparation
Technologies, Ministry of Education of China; Co-Innovation Center of Henan
Province for New Drug R & D and Preclinical Safety, Zhengzhou University, 100
Science Avenue, Zhengzhou 450001, Henan, China. E-mail: chenyj@zzu.edu.cn
b
Faculty of Science, Livestock Product Quality Inspection Institute, Henan University
of Animal Husbandry and Economy, No. 146 Yingcai Street, Zhengzhou 450044,
Henan, China
† Electronic supplementary information (ESI) available. CCDC 2129607–2129609.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/d1qo01926k Fig. 1 Representative five-membered cyclic guanidine compounds.

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Table 1 Optimization of the reaction conditionsa

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Yieldc (%)

Entry Additive Solvent Time (h) 3aa 4aa

1 TBAF CH3CN 10 68 18
2 CsF CH3CN 10 48 14
3 KF CH3CN 10 45 16
4 AgF CH3CN 24 NP NP
5 K2CO3 CH3CN 48 15 5
6 Et3N CH3CN 48 12 4
7 CsF/18-crown-6 CH3CN 5 75 24
8 CsF/18-crown-6 THF 24 50 49
9 CsF/18-crown-6 Toluene 10 50 23
10 CsF/18-crown-6 DCM 5 73 24
11 CsF/18-crown-6 DCE 10 72 24
Scheme 1 Previous works and our design. 12 CsF/18-crown-6 Dioxane 48 42 28
13d CsF/18-crown-6 CH3CN 12 73 24
14e CsF/18-crown-6 CH3CN 5 61 22
[3 + 2] cyclization of aziridines 1 with N-tosyl cyanamides 2 a
Unless otherwise specified, all reactions were performed with
could open a direct entry for the construction of the privileged 0.20 mmol of 1a, 0.24 mmol of 2a, 0.40 mmol of additive and 100 mg
of 4 Å MS in 2.0 mL of solvent. The molar ratio of CsF : 18-crown-6 is
N2-unprotected five-membered cyclic guanidine skeleton.
1 : 1. b The structure of 4aa was confirmed by single crystal X-ray diffr-
Herein, we disclose our efforts on this research project. action analysis. c Isolated yield. d 0 °C. e The annulation between 1a
and PhNHCN.

Results and discussion

We began our study using N-tosyl aziridine 1a and N-tosyl-N-
phenyl cyanamide 2a as the model substrates to explore the
optimal reaction conditions. To our delight, when the reaction
was conducted in CH3CN using TBAF as the desulfonylation
reagent, the two regioisomeric cyclic guanidines 3aa and 4aa 16
could be simultaneously obtained in 68% and 18% isolated
yields, respectively. In order to improve the yield and regio-
selectivity, we first screened different additives (Table 1,
entries 2–7). While replacing TBAF with CsF or KF, the desired
cyclic guanidines 3aa and 4aa were generated in reduced yields
(Table 1, entries 2 and 3). When AgF was used as the desulfo-
nylation reagent, the reaction failed to give the cycloguanidine
products probably due to the poor solubility of AgF (Table 1,
entry 4). The use of nonfluorinated bases such as K2CO3 and
Et3N resulted in a sharp drop in the yield of the desired pro-
ducts (Table 1, entries 5 and 6). Moreover, the addition of
18-crown-6 significantly improved the total yield up to 99%
(75% for 3aa and 24% for 4aa) and reduced the reaction time
to 5 h (Table 1, entry 7). The solvent screening showed that
acetonitrile was the optimal choice in terms of regioselectivity
and reactivity (Table 1, entries 8–12). To further improve the
regioselectivity, we conducted the reaction at a lower tempera-
ture (0 °C). However, no improvement in the regioselectivity
was observed albeit with a prolonged reaction time (Table 1,
entry 13). We further studied the annulation between aziridine
1a and PhNHCN (Table 1, entry 14). The desired cyclic guani-
dines 3aa and 4aa were produced in 61% and 22% yields,
respectively, indicating that N-Ts cyanamide was the better
annulation partner. Moreover, we found that the reaction
yields for the cyclization between 1a and 2a in the absence of
4 Å MS were not constant, probably due to the adverse effect of
water in the system, and the addition of 4 Å MS could avoid
this disadvantage.
With the optimal reaction conditions in hand, the substrate
scope of this annulation was then investigated with a diverse
set of aziridines 1 and cyanamides 2 (Scheme 2). Firstly, 2-ary-
laziridines 1 with diverse substituents were tested
(Scheme 2A). Overall, easily accessible 2-arylaziridines 1b–1l
bearing electron-withdrawing or electron-donating substitu-
ents at the ortho-, meta- or para-position all were well tolerated,
affording the corresponding cyclic guanidines 3ba–3la in good
to excellent yields (56–90%). The regioselectivities for electron-
donating substituent substituted 2-arylaziridines 1 were
superior to those of electron-withdrawing group-involved sub-
strates. For example, the regioselectivities for ortho-chloro-sub-
stituted aziridine 1b and ortho-methyl-substituted aziridine 1c
were 3 : 1 and 9 : 1, respectively. Besides, more sterically hin-
dered aziridines produced higher regioselectivities compared
to substrates with little hindrance. For instance, the regio-
selectivity for ortho-methyl-substituted aziridine 1c was much
higher than those for meta- or para-methyl-substituted aziri-
dines 1f and 1j. Ring-condensed 2-naphthyl-substituted aziri-
dine 1m was also an applicable substrate, affording the
desired cyclic guanidine 3ma with 82% yield and 5 : 1 regio-
selectivity. Moreover, N-( phenylsulfonyl)-2-phenyl-aziridine 1n
also reacted smoothly with N-phenyl cyanamide 2a, providing

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Scheme 2 Scope for the reaction involving 2-arylaziridines. Unless
otherwise specified, all reactions were performed with 0.20 mmol of 1,
0.24 mmol of 2, 0.40 mmol of CsF, 0.40 mmol of 18-crown-6 and
100 mg of 4 Å MS in 2.0 mL of CH3CN at room temperature. The listed
yields are the isolated yields for 3. The regioselectivity was detected by
crude 1H-NMR. a The structure of 3ai was confirmed by single crystal
X-ray diffraction analysis.
3na with 66% yield and 3 : 1 regioselectivity. Then, diversely
substituted cyanamides 2 were evaluated under the standard
reaction conditions (Scheme 2B). The desired products 3ab–
3ao 17 were obtained with good yields (59–78%) and regio-
selectivities (2 : 1 to 5 : 1). The reaction seemed to be insensi-
tive to the electronic features of the substituents on cyana-
mides 2. Nevertheless, the regioselectivities for sterically con-
gested substrates were superior to those of cyanamides with
less steric effects. For instance, the regioselectivities for ortho-
substituted cyanamides 2 are better than those for meta- or
para-substituted cyanamides.
Considering that the regioselectivity for the ring-opening of
aziridines 1 was strongly dependent on the nature of the sub-
stituent at the C-2 position, we continued to study the reaction
of 2-alkylaziridines 1o–1s and N-tosyl-N-phenyl cyanamide 2a
(Scheme 3). To our delight, the ring-opening was selective for
the sterically less hindered C-3 position, affording cyclic guani-
dines 4oa–4sa as single products in good to excellent yields,
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Scheme 3 Scope for the reaction involving 2-alkylaziridines. Unless
otherwise specified, all reactions were performed with 0.20 mmol of 1,
0.24 mmol of 2, 0.40 mmol of CsF, 0.40 mmol of 18-crown-6 and
100 mg of 4 Å MS in 2.0 mL of CH3CN at room temperature. The listed
yields are the isolated yields for 4. a The yield for the gram-scale reac-
tion. b The structure of 4oh was confirmed by single crystal X-ray
diffraction analysis.
and the regioisomer 3 was not observed. It is worth mention-
ing that 2-benzylaziridine 1o could afford the desired cyclic
guanidine 4oa in 99% yield. To further illustrate the prepara-
tive utility of this cascade annulation reaction, a gram-scale
reaction (2.5 mmol of 1o) was carried out, furnishing 4oa in a
comparable yield (95%). Then, various substituted cyanamides
2 were tested with 2-benzylaziridine 1o. Both electron-donating
and electron-withdrawing substituted cyanamides 2 were well
tolerated, exclusively affording the desired cyclic guanidines
4 18 in good to excellent yields (75–99%).
On the other hand, cyclic urea scaffolds are frequent in
many biologically active molecules,19 and we further studied
the transformations of cyclic guanidines 3 and 4 to the corres-
ponding cyclic urea analogues. The desired ureas 5 and 6
could be obtained in excellent yields (86–99%) via hydrolysis
under the action of sodium nitrite and sodium acetate in 50%
acetic acid (Scheme 4). Finally, deprotection of the urea
product was also accomplished by treatment of 6oa with mag-
nesium chips in methanol,20 affording deprotected urea 7 in
95% yield (Scheme 5).
To gain insight into the cyclization mechanism and verify
the ring-opening pathway of aziridines, the annulation of cya-
namide 2a with enantiopure aziridines (S)-1a (99% ee) and (S)-
1o (99% ee) was studied (Scheme 6A). The desired cyclic guani-
dine products were obtained with no loss of enantiopurity
(99% ee). These results suggest that the ring-opening of aziri-
dines 1 is stereospecific (SN2 or loose SN2 pathway), occurring
after the attack by cyanamide anions B, in situ formed from
N-tosyl cyanamides 2 by desulfonylation via intermediate A
(Scheme 6B). The nucleophilic attack of cyanamide anions B
on the more sterically hindered side of the aziridine ring gen-
erates intermediate D, which affords the expected cyclic guani-
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Scheme 4 Transformation of cyclic guanidines to ureas. Unless other-
wise noted, all reactions were performed with 0.2 mmol of cyclic guani-
dines 3 or 4, 5.0 mmol of NaNO2 and 4.0 mmol of AcONa in 4.0 mL of
50% AcOH at 50 °C. The listed yields are the isolated yields.
Scheme 5 Deprotection of 6oa. The reaction was performed with
0.2 mmol of 6oa and 3.0 mmol of Mg in 4.0 mL of MeOH at 70 °C. The
listed yield is the isolated yield.
Scheme 6 Controlled reactions using optically pure substrates and a
proposed mechanism. a The ee values were determined via the corres-
ponding ureas.
dine product 3 after the 5-exo-dig cyclization/protonation pro-
cedure (Scheme 6B, path a). In another possibility (Scheme 6B,
path b), the ring-opening reaction of aziridine 1 occurs at the
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less sterically hindered side to form intermediate F, which
undergoes intramolecular cyclization and protonation to
furnish the cyclic guanidine product 4. Overall, the regio-
selectivity of this annulation reaction is strongly dependent on
the nature of the R2 group on aziridines 1. If R2 is an aryl
group, path a is favored, whereas if R2 is an alkyl group, path b
is favored.
Conclusions
In conclusion, we developed a direct strategy for the regio-
selective synthesis of N2-unprotected five-membered cyclic
guanidines from various 2-substituted aziridines and N-tosyl
cyanamides under mild conditions via a cascade SN2 ring-
opening/5-exo-dig cyclization pathway. The regioselectivity is
greatly affected by the nature of the substituents on aziridines.
The ring-opening attack mainly occurs on the 2-substituted
carbon atom for aryl-substituted aziridines, while the attack on
the 3-unsubstituted carbon exclusively occurs for alkyl-substi-
tuted aziridines. Moreover, the corresponding five-membered
cyclic ureas could be conveniently obtained in excellent yields
via hydrolysis of cyclic guanidines. Further investigations on
the biological activities of the produced five-membered cyclic
guanidines and ureas are underway in our laboratory.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We acknowledge Prof. Chen-Guo Feng and Prof. Xiao-Di Yang
(Shanghai University of Traditional Chinese Medicine) for
their help in the characterization of compounds. We acknowl-
edge the financial support from the Natural Science
Foundation of Henan Province (grant no. 212300410152), the
Key Scientific and Technological Project of Henan Province
(grant no. 212102110439), Henan University of Animal
Husbandry and Economy (grant no. 2019HNUAHEDF011 and
XKYCXJJ2020006) and the Key Scientific Research Project for
Colleges and Universities of Henan Province (grant no.
22B150005).
Notes and references
1 (a) Y. Okuyama, R. Okamoto, S. Mukai, K. Kinoshita,
T. Sato and N. Chida, Synthesis of Saxitoxin and Its
Derivatives, Org. Lett., 2020, 22, 8697–8701;
(b) K. Murakami, T. Toma, T. Fukuyama and S. Yokoshima,
Total Synthesis of Tetrodotoxin, Angew. Chem., Int. Ed.,
2020, 59, 6253–6257.
2 (a) S. Dong, X. Feng and X. Liu, Chiral guanidines and
their derivatives in asymmetric synthesis, Chem. Soc. Rev.,
Org. Chem. Front., 2022, 9, 1574–1579 | 1577

Research Article
2018, 47, 8525–8540; (b) C. W. Kee and M. W. Wong,
Bicyclic Guanidine-Catalyzed Asymmetric Cycloaddition
Reaction of Anthrones—Bifunctional Binding Modes and
Origin of Stereoselectivity, J. Org. Chem., 2020, 85, 15139–
15153; (c) S. Das, Q. Hu, A. Kondoh and M. Terada,
Enantioselective Protonation: Hydrophosphinylation of 1,1-
Published on 24 January 2022. Downloaded by Indian Institute of Technology Kanpur on 3/31/2024 1:20:37 PM.
Vinyl Azaheterocycle N-Oxides Catalyzed by Chiral Bis(gua-
nidino)iminophosphorane Organosuperbase, Angew.
Chem., Int. Ed., 2021, 60, 1417–1422; (d) X.-Y. Cui, Y. Ge,
S. M. Tan, H. Jiang, D. Tan, Y. Lu, R. Lee and C.-H. Tan,
(Guanidine)copper Complex-Catalyzed Enantioselective
Dynamic Kinetic Allylic Alkynylation under Biphasic
Condition, J. Am. Chem. Soc., 2018, 140, 8448–8455.
3 R. B. Kinnel, H.-P. Gehrken and P. J. Scheuer, Palau’amine:
a cytotoxic and immunosuppressive hexacyclic bisguani-
dine antibiotic from the sponge Stylotella agminate, J. Am.
Chem. Soc., 1993, 115, 3376–3377.
4 K. Matsumura, T. Taniguchi, J. D. Reimer, S. Noguchi,
M. J. Fujita and R. Sakai, KB343, a Cyclic Tris-guanidine
Alkaloid from Palauan Zoantharian Epizoanthus illorica-
tus, Org. Lett., 2018, 20, 3039–3043.
5 (a) A. Pio-Abreu and L. F. Drager, Resistant Hypertension:
Time to Consider the Best Fifth Anti-Hypertensive
Treatment, Curr. Hypertens. Rep., 2018, 20, 67;
(b) P. Bousquet, A. Hudson, J. A. Garcia-Sevilla and J.-X. Li,
Imidazoline Receptor System: The Past, the Present, and
the Future, Pharmacol. Rev., 2020, 72, 50–79.
6 Q.-B. Pan and D.-W. Ma, Chiral Guanidine Catalyzed
Annulation to the Core Structure of (-)-Huperzine A,
Chin. J. Chem., 2003, 21, 793–796.
7 (a) S. R. Paladugu, C. K. James and R. E. Looper, A Direct
C11 Alkylation Strategy on the Saxitoxin Core: A Synthesis
of (+)-11-Saxitoxinethanoic Acid, Org. Lett., 2019, 21, 7999–
8002; (b) L. Wang, Y. Chi, W. Zhang and Z. Xi, Transition-
Metal-Catalyzed Guanylation Reaction of Amines with
Carbodiimides Constructing Guanidines, Chin. J. Org.
Chem., 2018, 38, 1341–1349; (c) J. Li, Z. Li, Y. Zhang, W. Xu
and S. Xu, Progress on the Synthesis and Applications of
Cyanamides, Chin. J. Org. Chem., 2017, 37, 1903–1915;
(d) S. B. L. Silva, F. Oberhänsli, M.-A. Tribalat, G. Genta-
Jouve, J.-L. Teyssié, M.-Y. Dechraoui-Bottein, J.-F. Gallard,
L. Evanno, E. Poupon and O. P. Thomas, Insights into the
Biosynthesis of Cyclic Guanidine Alkaloids from
Crambeidae Marine Sponges, Angew. Chem., Int. Ed., 2019,
58, 520–525.
8 (a) D. H. O’Donovan and I. Rozas, New methods for the
preparation of aryl 2-iminoimidazolidines, Tetrahedron
Lett., 2012, 53, 4532–4535; (b) T. Imaoka, M. Iwata and
K. Nagasawa, Synthesis of a Quaternary N, N′-Aminal-
Containing A-E Ring System of Palau′amine via an
Enamide-Type Overman Rearrangement Reaction,
Eur. J. Org. Chem., 2018, 2572–2578.
9 (a) S. Haaf, E. Kaifer, H. Wadepohl and H.-J. Himmel, Use
of Crown Ether Functions as Secondary Coordination
Spheres for the Manipulation of Ligand–Metal
Intramolecular Electron Transfer in Copper–Guanidine
1578 | Org. Chem. Front., 2022, 9, 1574–1579
View Article Online
Organic Chemistry Frontiers
Complexes, Chem. – Eur. J., 2021, 27, 959–970;
(b) M. McMullan, B. Kelly, H. B. Mihigo, A. P. Keogh,
F. Rodriguez, I. Brocos-Mosquera, A. García-Bea,
P. Miranda-Azpiazu, L. F. Callado and I. Rozas, Di-aryl gua-
nidinium derivatives: Towards improved α2-Adrenergic
affinity and antagonist activity, Eur. J. Med. Chem., 2021,
209, 112947; (c) G. Yan, B. L. Zekarias, X. Li, V. A. Jaffett,
I. A. Guzei and J. E. Golden, Divergent 2-Chloroquinazolin-
4(3H)-one Rearrangement: Twisted-Cyclic Guanidine
Formation or Ring-Fused N-Acylguanidines via a Domino
Process, Chem. – Eur. J., 2020, 26, 2486–2492.
10 (a) D. C. D. Butler, G. A. Inman and H. Alper, Room
Temperature Ring-Opening Cyclization Reactions of
2-Vinylaziridines with Isocyanates, Carbodiimides, and
Isothiocyanates Catalyzed by [Pd(OAc)2]/PPh3, J. Org.
Chem., 2000, 65, 5887–5890; (b) T. Vlaar, R. C. Cioc,
P. Mampuys, B. U. W. Maes, R. V. Orru and E. Ruijter,
Sustainable Synthesis of Diverse Privileged Heterocycles by
Palladium-Catalyzed Aerobic Oxidative Isocyanide
Insertion, Angew. Chem., Int. Ed., 2012, 51, 13058–13061.
11 (a) B. Zhao, H. Du and Y. Shi, Cu(I)-Catalyzed
Cycloguanidination of Olefins, Org. Lett., 2008, 10, 1087–
1090; (b) N. M. Hewlett and J. J. Tepe, Total Synthesis of
the Natural Product (±)-Dibromophakellin and Analogues,
Org. Lett., 2011, 13, 4550–4553; (c) V. R. R. Kovvuri, H. Xue
and D. Romo, Generation and Reactivity of 2-Amido-1,3-
diaminoallyl Cations: Cyclic Guanidine Annulations via
Net (3+2) and (4+3) Cycloadditions, Org. Lett., 2020, 22,
1407–1413.
12 (a) Z. J. Garlets, M. Silvi and J. P. Wolfe, Synthesis of Cyclic
Guanidines via Silver-Catalyzed Intramolecular Alkene
Hydroamination Reactions of N-Allylguanidines, Org. Lett.,
2016, 18, 2331–2334; (b) M. J. Gainer, N. R. Bennett,
Y. Takahashi and R. E. Looper, Regioselective Rhodium(II)-
Catalyzed Hydroaminations of Propargylguanidines, Angew.
Chem., Int. Ed., 2011, 50, 684–687; (c) K.-H. Kwon,
C. M. Serrano, M. Koch, L. R. Barrows and R. E. Looper,
Synthesis of Bicyclic Guanidines via Cascade
Hydroamination/Michael Additions of Mono-N-acryloylpro-
pargylguanidines, Org. Lett., 2014, 16, 6048–6051;
(d) B. P. Zavesky, N. R. Babij, J. A. Fritz and J. P. Wolfe,
Synthesis of Cyclic Guanidines via Pd-Catalyzed Alkene
Carboamination, Org. Lett., 2013, 15, 5420–5423;
(e) L. J. Peterson, J. Luo and J. P. Wolfe, Synthesis of Cyclic
Guanidines Bearing N-Arylsulfonyl and N-Cyano Protecting
Groups via Pd-Catalyzed Alkene Carboamination Reactions,
Org. Lett., 2017, 19, 2817–2820; (f) B. P. Zavesky, N. R. Babij
and J. P. Wolfe, Synthesis of Substituted
2-Aminoimidazoles via Pd-Catalyzed Alkyne
Carboamination Reactions. Application to the Synthesis of
Preclathridine Natural Products, Org. Lett., 2014, 16, 4952–
4955; (g) L. J. Peterson, J. K. Kirsch and J. P. Wolfe, Pd-
Catalyzed Alkene Diamination Reactions of Nitrogen
Electrophiles: Synthesis of Cyclic Guanidines and Ureas
Bearing Dialkylaminomethyl Groups, Org. Lett., 2018, 20,
3513–3517; (h) S. Ohuchi, H. Koyama and H. Shigehisa,
This journal is © the Partner Organisations 2022

Organic Chemistry Frontiers
Catalytic Synthesis of Cyclic Guanidines via Hydrogen
Atom Transfer and Radical-Polar Crossover, ACS Catal.,
2021, 11, 900–906; (i) M. Daniel, F. Blanchard, S. Nocquet-
Thibault, K. Cariou and R. H. Dodd, Halocyclization of
Unsaturated Guanidines Mediated by Koser’s Reagent and
Lithium Halides, J. Org. Chem., 2015, 80, 10624–10633.
Published on 24 January 2022. Downloaded by Indian Institute of Technology Kanpur on 3/31/2024 1:20:37 PM.
13 (a) A. Bhattacharyya, C. K. Shahi, S. Pradhan and
M. K. Ghorai, Stereospecific Synthesis of 1,4,5,6-
Tetrahydropyrimidines via Domino Ring-Opening
Cyclization of Activated Aziridines with α-Acidic
Isocyanides, Org. Lett., 2018, 20, 2925–2928; (b) R. Yi, X. Li
and B. Wan, Ring-opening and cyclization of aziridines
with aryl azides: metal-free synthesis of 6-(triflyloxy)quino-
lines, Org. Chem. Front., 2018, 5, 3488–3493; (c) H. Li,
S. Huang, Y. Wang and C. Huo, Oxidative Dehydrogenative
[2+3]-Cyclization of Glycine Esters with Aziridines Leading
to Imidazolidines, Org. Lett., 2018, 20, 92–95; (d) L. Tu,
Z. Li, T. Feng, S. Yu, R. Huang, J. Li, W. Wang, Y. Zheng
and J. Liu, Access to Imidazolidines via 1,3-Dipolar
Cycloadditions of 1,3,5-Triazinanes with Aziridines, J. Org.
Chem., 2019, 84, 11161–11169; (e) T. Kaicharla, A. Jacob,
R. G. Gonnade and A. T. Biju, AgOTf-catalyzed dehydrative
[3+2] annulation of aziridines with 2-naphthols, Chem.
Commun., 2017, 53, 8219–8222; (f ) I. A. Wani, M. Sayyad
and M. K. Ghorai, Chem. Commun., 2017, 53, 4386–4389;
(g) M. Vijay, V. Satheesh, S. V. Kumar and
T. Punniyamurthy, Regiospecific Bi-Catalysed Domino
C-N/C-S Bonds Formation: Synthesis of 1,4-Thiazines/1,4-
Thiomorpholines, Adv. Synth. Catal., 2018, 360, 3030–3037.
14 (a) S. V. Bhat, D. Robinson, J. E. Moses and P. Sharma,
Synthesis of Oxadiazol-5-imines via the Cyclizative Capture
of in Situ Generated Cyanamide Ions and Nitrile Oxides,
Org. Lett., 2016, 18, 1100–1103; (b) P. Sharma, S. V. Bhat,
M. R. R. Prabhath, A. Molino, E. Nauha, D. J. D. Wilson
and J. E. Moses, Synthesis of 1,2,4-Triazol-3-imines via
Selective Stepwise Cycloaddition of Nitrile Imines with
Organo-cyanamides, Org. Lett., 2018, 20, 4263–4266;
(c) C.-C. Wang, Y.-L. Qu, X.-H. Liu, Z.-W. Ma, B. Yang,
Z.-J. Liu, X.-P. Chen and Y.-J. Chen, Synthesis of Five-
Membered Cyclic Guanidines via Cascade [3+2]
Cycloaddition of α-Haloamides with Organo-cyanamides,
J. Org. Chem., 2021, 86, 3546–3554.
15 (a) C.-C. Wang, Z.-W. Ma, Y.-L. Qu, Z.-J. Liu, X.-P. Chen,
J. Zhou and Y.-J. Chen, Synthesis of Sulfamate-Fused
This journal is © the Partner Organisations 2022
View Article Online
Research Article
2-Aminopyrroles via an Isocyanide-Based Three
Component [1+2+2] Annulation, Chem. – Asian J., 2020, 15,
560–563; (b) X.-H. Liu, C.-C. Wang, X.-L. Wang, Z.-W. Ma,
L. Meng, D. Ding, J.-T. Liu and Y.-J. Chen, Synthesis of
Spirobarbiturate Piperidin-2-one Derivatives via Cascade
Aza-Michael/Michael Cyclization Reaction, Chin. J. Org.
Chem., 2021, 41, 4450–4458; (c) C.-C. Wang, X.-L. Liu,
X.-L. Wang, H.-P. Cui, Z.-W. Ma, D. Ding, J.-T. Liu and
Y.-J. Chen, Synthesis of Functionalized 4,1-
Benzothiazepines via a [4+3] Annulation between Aza-o-
Quinone Methides and Pyridinium 1,4-
ZwitterionicThiolates, Adv. Synth. Catal., 2022, 364, 296–
301; (d) B. Wei, J. Zhou, J.-J. Xu, J. Cui, F.-F. Ping, J.-J. Ling
and Y.-J. Chen, Discovery of coumarin-derived imino sulfo-
nates as a novel class of potential cardioprotective agents,
Eur. J. Med. Chem., 2019, 184, 111779; (e) J. Zhou,
H. Zhang, X.-L. Chen, Y.-L. Qu, Q. Zhu, C.-G. Feng and
Y.-J. Chen, Regio- and Diastereoselective Access to
4-Imidazolidinones via an Aza-Mannich Initiated
Cyclization of Sulfamate-Derived Cyclic Imines with α-Halo
Hydroxamates, J. Org. Chem., 2019, 84, 9179–9187;
(f) C.-C. Wang, J. Zhou, Z.-W. Ma, X.-P. Chen and
Y.-J. Chen, Synthesis of spirobarbiturate-pyrrolidinones via
a domino aza-Michael/SN2 cyclization of barbiturate-
derived alkenes with N-alkoxy α-haloamides, Org. Biomol.
Chem., 2019, 17, 9200–9208.
16 CCDC 2129607 (4aa),† see the ESI for details.
17 CCDC 2129608 (3ai),† see the ESI for details.
18 CCDC 2129609 (4oh),† see the ESI for details.
19 (a) J. Liu, P. P. Shao, D. Guiadeen, A. Krikorian, W. Sun,
Q. Deng, A.-M. Cumiskey, R. A. Duffy, B. A. Murphy,
K. Mitra, D. G. Johns, J. L. Duffy and P. Vachal, Cholesteryl
ester transfer protein (CETP) inhibitors based on cyclic
urea, bicyclic urea and bicyclic sulfamide cores, Bioorg.
Med. Chem. Lett., 2021, 32, 127668; (b) G. V. De Lucca and
P. Y. S. Lam, De novo design, discovery and development of
cyclic urea HIV protease inhibitors, Drugs Future, 1998, 23,
987–994; (c) D. E. Ehmann, H. Jahić, P. L. Ross, R. F. Gu,
J. Hu, G. Kern, G. K. Walkup and S. L. Fisher, Avibactam is
a covalent, reversible, non–β-lactam β-lactamase inhibitor,
Proc. Natl. Acad. Sci. U. S. A., 2012, 109, 11663–11668.
20 Z. Tao, B. B. Gilbert and S. E. Denmark, Catalytic,
Enantioselective syn-Diamination of Alkenes, J. Am. Chem.
Soc., 2019, 141, 19161–19170.
Org. Chem. Front., 2022, 9, 1574–1579 | 1579