Exploring hydroamination-cycloaddition-fragmentation sequences to access polycyclicguanidines and vinyl-2-aminoimidazoles

Article abstract of DOI:10.1016/j.tet.2017.08.052

The intramolecular hydroamination of a guanidine on an eneyne unit affords a guanidine-substituted diene capable of reacting with dienophiles. These substrates undergo [4+2]-cycloaddition reactions to generate a series of complex cyclic- and spirocyclic-guanidines. Select substrates can further undergo a ring opening-elimination cascade that ultimately reveals a vinyl-2-aminoimidazole. As such this cascade reaction may find application in the synthesis of oroidin-type natural products and their analogues.

Full text of DOI:10.1016/j.tet.2017.08.052

Tetrahedron 73 (2017) 6067e6079
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Exploring hydroamination-cycloaddition-fragmentation sequences to
access polycyclicguanidines and vinyl-2-aminoimidazoles
Ki-Hyeok Kwon, Anne V. Edwards, Miao Yang, Ryan E. Looper*
Department of Chemistry, University of Utah 315 S 1400 E, Salt Lake City, UT, 8103, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The intramolecular hydroamination of a guanidine on an eneyne unit affords a guanidine-substituted
diene capable of reacting with dienophiles. These substrates undergo [4þ2]-cycloaddition reactions to
generate a series of complex cyclic- and spirocyclic-guanidines. Select substrates can further undergo a
ring opening-elimination cascade that ultimately reveals a vinyl-2-aminoimidazole. As such this cascade
reaction may find application in the synthesis of oroidin-type natural products and their analogues.
© 2017 Elsevier Ltd. All rights reserved.
Received 16 July 2017
Received in revised form
28 August 2017
Accepted 29 August 2017
Available online 1 September 2017
Keywords:
Cycloaddition
Heterocycle
Alkaloids
2-Aminoimidazoles
Hydroamination
1. Introduction
interested in extending the utility of this propargylguanidine
hydroamination sequence to rapidly construct complex polycyclic
Marine sponges have been a prolific source of pyrrole-2-
aminoimidazole alkaloids (PAIs).1,2 Members of this family have
been prized for their biological activities, especially as anti-tumors
agents, anti-microbial or anti-biofilm agents.3 Besides their po-
tential utility as therapeutics leads, the community has been
fascinated with the genesis of the more structurally complex
members of this family from the simple building blocks e.g. oroidin
and hymenedin (Fig. 1). Initial hypotheses suggested that these
dimeric products were forged by electrocyclic reactions ([2þ2] or
[4þ2] cycloadditions) of the vinyl-2-aminoimidazole fragment or
from stepwise addition/isomerization sequences of the rapidly
interconverting iminium ion tautomers of the 2-aminoimidazole
core.4
guanidine scaffolds via the intermediacy of a guanidine-substituted
diene, akin to the oroidin biosynthetic manifold. We envisioned
that extension of the alkyne to an enyne would generate substrates
at the same oxidation state as the vinyl-2-aminoimidazoles, albeit
transposed (Scheme 1B). While the reactivity of many heteroatom
substituted dienes have been studied, this represents an unknown
class of guanidine-substituted dienes.
Herein we explore the reactivity of these dienes to generate
polycyclic guanidinium ion containing compounds and compounds
that are structurally aligned with the PAIs. These complex struc-
tures arise from simple linear precursors via
a cascade
hydroamination-[4þ2]-cycloaddition sequence.
However, Molinksi and Romo have recently shown that these
cyclized and/or dimerized homologues arise from an enzymatic
process. More specifically through the generation of a radical
cation, via SET to an oxido-reductase.
2. Results and discussion
2.1. 6-Endo-selective hydroamination/[4þ2] cycloaddition
We have previously demonstrated that propargylguanidines can
be regiodivergently cyclized to the 5-exo product with Ag(I) or to
the 6-endo product with Rh(II) catalysis (Scheme 1A).5 We became
We began by examining the hydraomination-[4þ2]-
cycloaddition cascade reaction with guanidine 1a (Scheme 2).
Exposure of 1a to Rh(II) cleanly gave the 6-endo product 2a in 70%
yield. This guanidine-substituted diene cleanly reacted with 4-
phenyl-1,2,4-triazole-3,5-dione at room temperature to give 3a in
94% yield. Exploratory reactions showed that the diene 2a does not
spontaneously react with electron poor dieneophiles (e.g. acrylates,
* Corresponding author.
E-mail address: r.looper@utah.edu (R.E. Looper).
http://dx.doi.org/10.1016/j.tet.2017.08.052
0040-4020/© 2017 Elsevier Ltd. All rights reserved.

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K.-H. Kwon et al. / Tetrahedron 73 (2017) 6067e6079
Fig. 1. Biogenesis of complex pyrrole-2-aminoimidazole alkaloids from simple
precursors.
Scheme 3. Scope of the 6-endo-selective hydroamination/[4þ2]-cycloaddition
Scheme 1. Applications of ene-ynes in the guanidine hydroamination sequence.
sequence.
quinones or fumarates) suggesting that the di-acylated guanidine
renders the diene relatively electron poor. The hydroamination-
cycloaddition cascade can be carried out in a one-pot sequence to
afford 3a in 74% isolated yield. Deprotection of the guanidine with
trifluoroacetic acid followed by salt exchange gave 4a as a crystal-
line hydrochloride, the structure of which was confirmed by X-ray
crystallography.
This reaction development permitted the synthesis of a focused
library of these polycyclic guanidines (Scheme 3). Substitutions on
the guanidine nitrogen (N1) are universally tolerated. As demon-
strated, both cyclic and acyclic ene-ynes participate to give tetra- or
tri-cyclic guanidines respectively (e.g. 4b-4g). Other triazolinediones
can be employed (4g). Substituents on the dihydroaminopyrimidine
effectively control the approach of the dienophile to give the adducts
4h-i as single diastereomers.
2.2. 5-Exo-selective hydroamination/[4þ2] cycloaddition
We then investigated the [4þ2]-cycloaddition reaction on the 5-
exo-dig derived dienes (Scheme 4). Interestingly hydroamination of
1c under Ag(I) conditions gave 7a in poor yield as the minor
regiosiomer All other substrates in this series cyclize with >10:1
selectivity favoring the expected 5-exo-dig product. Reaction of 7a
with 4-phenyl-1,2,4-triazole-3,5-dione proceeded cleanly to give
Scheme 2. 6-endo-selective hydroamination/[4þ2]-cycloaddition sequence to access
polyclicguanidines.
Scheme 4. 5-exo-selective hydroamination/[4þ2]-cycloaddition sequence.

K.-H. Kwon et al. / Tetrahedron 73 (2017) 6067e6079
6069
the protected spirocyclic guanidine 8a. Deprotection of 8a with TFA
for 30 min followed by salt exchange gave 9a in good yield, the
structure of which was ultimately confirmed by X-ray crystallog-
raphy. On working with this compound we ultimately observed
that it decomposed when stored in solution, to give a compound
that appeared to be an isomer of 9a as suggested by an identical
mass (ultimately proven to be compound 10a in Scheme 6).
Insight into this decomposition was gained when studying the
same reaction on substrate 1h (Scheme 5). Cyclization of 1h in the
presence of Ag(I) gave 7b in good yield as a single regioisomer.
Substitution at the alpha-position of the propargylguanidine favors
the kinetically preferred 5-exo-dig product. Cycloaddition of the
resultant diene gives 8b as a single diastereomer. Deprotection of 8b
with TFA does not lead to the deprotected spirocycle but instead the
allylic aminal fragments to reveal the vinyl-2-aminoimidazole 10b.
The structure of 10b was confirmed by X-ray crystallography
and the spectral data were consistent with those of the isomer
obtained from the decomposition of 9a. Presumably the more
substituted 2-aminoimidazole ring in 8b fragments faster via sta-
bilization of the intermediate N-acyliminium ion.
It was subsequently found that deprotection of the cycloadducts
with 1:1 TFA:CH2Cl2 for >2 h universally provides the ring-opened
vinyl-2-aminoimidazoles 10a-i in good yield (Scheme 6).6
Having noted that the di-Boc-guanidine substituted dienes react
with very reactive dienophiles, we also examined their participa-
tion in the acylnitroso Diels-Alder reaction (Scheme 7). Using Read
de Alaniz's conditions, we were able to generate the acylnitroso
intermediate in-situ by oxidation of the N-hydroxycarbamate 11.7
This smoothly underwent cycloaddition with the dienes 2a,f,g to
give the adducts 12a-c in moderate to good yield. These cycload-
ditions afford a single regio-isomer, confirmed in 12a by HMBC
correlation of the C12 methine proton to the carbonyl of the ben-
zylcarbamate. This is consistent with the more electron rich end of
the diene reacting with the nitrogen of the acylnitroso system as
previously demonstrated.7b These intermediates can be depro-
tected without reduction of the internal alkene to give 13a-c.
We also examined a hydroamination-Michael addition-[4þ2]-
cycloaddition sequence (Scheme 8). Reaction of the guanidine 14
with Ag(I) delivers the bicyclic guanidine substituted diene 15 in
good yield. Reaction with 4-phenyl-1,2,4-triazole-3,5-dione gave
the spirocycle 16. This example further serves to illustrate that
guanidine substituted dienes that are only mono-acylated are
competent dienes as well.
Scheme 6. Scope of the [4þ2]-Cycloaddition-fragmentation sequence to access vinyl-
2-aminoimidazoles.
Boc-guanidines generally undergo selective Rh(II)-mediated 6-endo-
dig or Ag(I)-mediated 5-exo-dig hydroamination. The hydroamination
products behave as electron poor dienes but can participate in [4þ2]-
cycloadditions with activated dienophiles. Cycloaddition of the 5-
exo-dig products with a triazolinediones generates a spirocyclic
allylic aminal which is prone to elimination to reveal a vinyl-2-
aminoimidazole. As such, this sequence may find use in the prepa-
ration of PAI natural products or analogues. Given the successful re-
action of mono-acylsubstituted dienes, we are currently examining
the ability of these more electron-rich systems to engage a wider
variety of dieneophiles to access other complex and interesting
structures.
3. Conclusion
In conclusion, we have demonstrated that ene-yne containing di-
Scheme
sequence.
5. 5-exo-selective
hydroamination/[4þ2]-cycloaddition-fragmentation
Scheme 7. [4þ2]-Cycloaddition sequence with an acylnitroso-dienophile.

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K.-H. Kwon et al. / Tetrahedron 73 (2017) 6067e6079
propargylguanidine as a pale yellow solid (0.549 g, 71% yield).
Rf ¼ 0.45 (20% ethyl acetate/n-hexanes). 1H NMR (500 MHz, CDCl3)
d
10.07 (s. 1H), 6.09 (s, 1H), 4.39 (s, 2H), 3.09 (s, 3H), 2.09 (m, 4H),
1.61 (m, 2H), 1.57 (m, 2H), 1.49 (s, 18H) ppm; 13C{1H} NMR
(100 MHz, CDCl3) 163.3, 153.6, 150.2, 137.4, 120.5, 87.5, 82.7, 79.3,
d
77.6, 36.4, 32.2, 28.9, 28.4, 28.3, 26.5, 22.5, 21.8 ppm; LRMS (ESI)
Calculated for C21H34N3O4 m/z (MþH): 392.3, Obsd 392.4.
4.2.1.2. 1-(3-(cyclohex-1-en-1-yl)prop-2-yn-1-yl)-1-(cyclo-
propylmethyl)-di-Boc-guanidine (1b). Prepared according to the
general procedure 1, to give the propargylguanidine as white solid
in 67% yield (0.573 g). Rf ¼ 0.68 (40% ethyl acetate/n-hexanes). 1H
NMR (500 MHz, CDCl3) d 9.82 (s, 1H), 6.06 (s, 1H), 4.51 (s, 2H), 3.46
(s, 2H), 2.00 (m, 4H), 1.61 (m, 2H),1.57 (m, 2H),1.49 (s, 18H), 1.07 (m,
1H), 0.56 (m, 2H), 0.31 (m, 2H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
Scheme 8. Hydroamination-Michael addition -[4þ2]-cycloaddition sequence.
d
162.3, 154.6, 150.5, 135.1, 120.1, 86.8, 81.7, 80.6, 79.2, 52.1, 38.2,
29.0, 28.1, 28.0, 25.5, 22.1, 21.4, 8.9, 3.7 ppm; LRMS (ESI) Calculated
for C24H38N3O4 m/z (MþH): 432.3, Obsd. 432.4.
4. Experimental section
4.1. General experimental considerations
4.2.1.3. 1-Benzyl-1-(3-(cyclohex-1-en-1-yl)prop-2-yn-1-yl)-di-Boc-
guanidine (1c). Prepared according to the general procedure 1, to
give the propargylguanidine as white solid in 71% yield (0.657 g).
Rf ¼ 0.55 (40% ethyl acetate/n-hexanes). 1H NMR (500 MHz, CDCl3)
Unless otherwise noted all starting materials were either known
compounds or were obtained from commercial sources and used
without purification. All reactions requiring anhydrous conditions
were performed under a positive pressure of nitrogen using flame-
dried glassware. Rhodium (II) octanoate, Silver nitrate, and Silver
acetate were purchased from Sigma-Aldrich. Dichloromethane
(CH2Cl2), acetonitrile (CH3CN), toluene (C6H5CH3), tetrahydrofuran
(THF) and diethyl ether (Et2O) were degassed with argon and
passed through a solvent purification system (J.C. Meyer of Glass
Contour) containing either alumina or molecular sieves. Flash
chromatography was performed by CombiFlash Rf (TELEDYNE ISCO)
or on Merk silica gel Kieselgel 60 (230e400 mesh) from EM science
with the indicated solvent.
d
9.91 (s, 1H), 7.33e7.26 (m, 5H), 6.07 (s, 1H), 4.83 (s, 2H), 4.21 (s,
2H), 2.08 (m, 4H), 1.62 (m, 2H), 1.57 (m, 2H), 1.50 (s, 18H) ppm; 13
C
{1H} NMR (100 MHz, CDCl3)
d
155.4, 153.8, 150.7, 136.1, 135.6, 128.7,
128.5, 127.8, 120.3, 87.5, 82.3, 80.3, 79.8, 51.4, 38.7, 29.2, 28.3, 25.7,
22.4, 21.6 ppm; LRMS (ESI) Calculated for C27H38N3O4 m/z (MþH):
468.3, Obsd. 468.4.
4.2.1.4. 1-(3-(cyclohex-1-en-1-yl)prop-2-yn-1-yl)-1-(2,4-
dimethoxybenzyl)-di-Boc-guanidine (1d). Prepared according to the
general procedure 1, to give the propargylguanidine as white solid
in 83% yield (0.703 g). Rf ¼ 0.71 (40% ethyl acetate/n-hexanes). 1H
1H NMR spectra were recorded on Varian Unity-300, Inova-400,
or VXR-500 MHz spectrometers as indicated. The chemical shifts (d)
NMR (500 MHz, CDCl3) d 9.97 (s,1H), 7.33e7.27 (m, 5H), 5.27 (s,1H),
of proton resonances are reported relative to CDCl3, DMSO-d5, or
CD3OD using the following format: chemical shift [multiplicity
(s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet,
app ¼ apparent), coupling constant(s) (J in Hz), integral].1,2 13C NMR
spectra were recorded at 75, 100, or 125 MHz. The chemical shifts of
carbon resonances are reported relative to the deuterated solvent
peak.
Infrared spectra were recorded on a Nicolet 380-FT IR spec-
trometer fitted with a SmartOrbit sample system. All absorptions
are reported in cm-1 relative to polystyrene (1601 cm-1).
Mass spectra were obtained at the University of Utah CIF on a
Micromass Quattro II (ESI/APCI) for LRMS or an LCT XE premier
(ESI/APCI-TOF) for HRMS.
5.22 (s, 1H), 4.83 (s, 2H), 4.24 (s, 2H), 1.86 (s, 3H), 1.51 (s, 9H), 1.49 (s,
9H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
d
162.4, 155.3, 150.6,
135.8, 128.6, 128.2, 127.7, 126.2, 122.4, 86.6, 82.4, 82.1, 79.6, 51.3,
38.4, 28.4, 28.3, 23.3 ppm; LRMS (ESI) Calculated for C24H34N3O4 m/
z (MþH): 428.3, Obsd. 428.3.
4.2.1.5. 1-(3-(cyclohex-1-en-1-yl)prop-2-yn-1-yl)-1-(2,4-
dimethoxybenzyl)-di-Boc-guanidine (1e). Prepared according to the
general procedure 1, to give the propargylguanidine as white solid
in 68% yield (0.700 g). Rf ¼ 0.56 (40% ethyl acetate/n-hexanes). 1H
NMR (500 MHz, CDCl3)
d 9.44 (s, 1H), 7.22 (m, 1H), 6.46 (m, 2H),
6.07 (s, 1H), 4.59 (br, 2H), 4.25 (s, 2H), 3.83 (s, 3H), 3.78 (s, 3H), 2.08
(m, 4H), 1.62 (m, 2H), 1.57 (m, 2H), 1.51 (s, 9H), 1.50 (s, 9H) ppm; 13
{1H} NMR (100 MHz, CDCl3)
161.3, 160.8, 158.1, 152.5, 150.2, 134.6,
C
d
4.2. Synthetic procedures and characterization data
131.4, 120.0, 115.4, 103.9, 98.2, 86.3, 81.1, 80.6, 78.4, 77.5, 59.8, 55.0,
54.9, 46.2, 28.8, 27.9, 27.8, 25.2, 21.9, 21.2 ppm; LRMS (ESI) Calcu-
lated for C29H42N3O6 m/z (MþH): 528.3, Obsd. 528.3.
4.2.1. General procedure 1 for the guanylation of propargyl amines
S-2a-i to form 1a-i
To a stirring solution of S-methyl-N,N0-diBocpseudothiourea (1.1
equiv), HgO (1.1 equiv), and triethylamine (3.0 equiv) in CH2Cl2 was
added the appropriate propargyl amine (1.0 equiv). The reaction
was stirred at room temperature until complete as judged by TLC.
The reaction mixture was filtered through a short plug of Celite,
concentrated, and purified by column chromatography to yield the
propargylguanidine.
4.2.1.6. 1-(benzo[d][1,3]dioxol-5-ylmethyl)-1-(4-methylpent-4-en-2-
yn-1-yl)-di-Boc-guanidine (1f). Prepared according to the general
procedure 1, to give the propargylguanidine as white solid in 81%
yield (0.756 g). Rf ¼ 0.48 (20% ethyl acetate/n-hexanes). 1H NMR
(500 MHz, CDCl3) d 10.0 (s, 1H), 6.83e6.74 (m, 3H), 5.93 (s, 2H), 5.28
(s, 1H), 5.23 (s, 1H), 4.72 (s, 2H), 4.23 (s, 2H), 1.87 (s, 9H), 1.50 (s, 9H)
ppm; 13C{1H} NMR (100 MHz, CDCl3)
d
162.3, 155.1, 150.5, 147.9,
147.2, 129.3, 126.1, 122.3, 121.8, 108.1, 101.0, 86.5, 82.2, 82.0, 79.5,
51.0, 38.1, 28.1, 28.0, 23.2 ppm; LRMS (ESI) Calculated for
4.2.1.1. 1-(3-(cyclohex-1-en-1-yl)prop-2-yn-1-yl)-1-methyl-di-Boc-
guanidine (1a). The general procedure 1 was used to yield the
C25H34N3O6 m/z (MþH): 472.2, Obsd. 472.4.

K.-H. Kwon et al. / Tetrahedron 73 (2017) 6067e6079
6071
4.2.1.7. 1-(2,4-dimethoxybenzyl)-1-(4-methylpent-4-en-2-yn-1-yl)-
di-Boc-guanidine (1g). Prepared according to the general procedure
1, to give the propargylguanidine as white solid in 50% yield
(0.483 g). Rf ¼ 0.63 (40% ethyl acetate/n-hexanes). 1H NMR
J ¼ 5.1 Hz, 1H), 3.78 (d, J ¼ 4.9 Hz, 1H), 3.33 (d, J ¼ 6.8 Hz, 1H), 2.17
(m, 4H), 1.70 (m, 2H), 1.60 (m, 2H), 1.54 (s, 9H), 1.41 (s, 9H), 1.06 (m,
1H), 0.50 (m, 2H), 0.20 (m, 2H) ppm; 13C{1H} NMR (100 MHz,
CDCl3)
d 160.5, 150.4, 149.5, 143.2, 132.2, 126.3, 110.3, 82.0, 78.4,
(500 MHz, CDCl3)
d
9.42 (s, 1H), 7.20 (m, 1H), 6.45 (m, 2H), 5.27 (s,
53.4, 44.4, 28.2, 27.9, 25.6, 25.5, 22.6, 22.1, 9.0, 3.4 ppm; LRMS (ESI)
1H), 5.21 (s, 1H), 4.59 (s, 2H), 4.26 (s, 2H), 3.84 (s, 3H), 3.79 (s, 3H),
Calculated for C24H38N3O4 m/z (MþH): 432.3, Obsd. 432.4.
1.87 (s, 3H), 1.51 (s, 18H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
d
161.4, 160.9, 158.2, 150.4, 131.5, 126.2, 121.8, 115.4, 104.1, 98.4, 85.8,
4.2.2.3. tert-butyl
(E)-3-benzyl-2-((tert-butoxycarbonyl)imino)-6-
82.7, 81.3, 78.7, 55.1, 46.5, 36.4, 28.0, 27.9, 23.2 ppm; LRMS (ESI)
Calculated for C26H38N3O6 m/z (MþH): 488.3, Obsd. 488.5.
(cyclohex-1-en-1-yl)-3,4-dihydropyrimidine-1(2H)-carboxylate (2c).
Prepared according to the general procedure 2, to give 6-endo-dig
cyclized guanidine as a white solid in 76% yield (6-endo-dig:5-exo-
dig ¼ >20:1), (0.327 g). Rf ¼ 0.25 (20% ethyl acetate/n-hexanes). 1H
4.2.1.8. 1-(cyclopropylmethyl)-1-(5-methyl-1-phenylhex-5-en-3-yn-
2-yl)-di-Boc-guanidine (1h). Prepared according to the general
procedure 1, to give the propargylguanidine as white solid in 22%
yield (0.210 g). Rf ¼ 0.50 (20% ethyl acetate/n-hexanes). 1H NMR
NMR (500 MHz, CDCl3)
d 7.31e7.21 (m, 5H), 6.41 (s, 1H), 5.51 (t,
J ¼ 5.1 Hz, 1H), 4.70 (s, 2H), 3.55 (d, J ¼ 4.1 Hz, 2H), 2.19 (m, 2H), 2.15
(m, 2H), 1.69 (m, 2H), 1.61 (m, 2H), 1.55 (s, 9H), 1.43 (s, 9H) ppm; 13
{1H} NMR (100 MHz, CDCl3)
160.5, 151.0, 149.6, 143.3, 136.2, 132.2,
C
(500 MHz, CDCl3)
d
8.97 (s, 1H), 7.35e7.21 (m, 5H), 5.20 (s, 1H), 5.18
d
(s, 1H), 3.52 (m, 1H), 3.34 (dd, J ¼ 14.7, 6.9 Hz, 1H), 3.27 (dd, J ¼ 12.7,
4.9 Hz, 1H), 2.98 (dd, J ¼ 12.7, 9.8 Hz, 1H), 1.80 (s, 3H), 1.51 (s, 9H),
1.49 (s, 9H), 1.24 (m, 1H), 0.59 (m, 2H), 0.35 (m, 1H) ppm; 13C{1H}
128.6, 127.9, 127.5, 126.5, 110.5, 82.3, 78.7, 52.1, 43.6, 28.2, 28.0, 25.6,
25.5, 22.6, 22.1 ppm; LRMS (ESI) Calculated for C27H38N3O4 m/z
(MþH): 468.3, Obsd. 468.4.
NMR (100 MHz, CDCl3)
d 161.9, 153.2, 150.8, 137.3, 129.9, 128.3,
126.9, 126.2, 122.1, 88.0, 85.7, 81.9, 79.3, 53.5, 51.5, 41.4, 28.3, 28.2,
23.3, 10.8, 5.7, 4.3 ppm; LRMS (ESI) Calculated for C28H40N3O4 m/z
(MþH): 482.3, Obsd. 482.5.
4.2.2.4. tert-butyl
(E)-3-benzyl-2-((tert-butoxycarbonyl)imino)-
6-(prop-1-en-2-yl)-3,4-dihydropyrimidine-1(2H)-carboxylate (2d).
Prepared according to the general procedure 2, to give 6-endo-dig
cyclized guanidine as a white solid in 79% yield (6-endo-dig:5-exo-
dig ¼ >20:1), (0.338 g). Rf ¼ 0.57 (40% ethyl acetate/n-hexanes). 1H
4.2.1.9. 1-Benzyl-1-(4-(cyclohex-1-en-1-yl)-1-phenylbut-3-yn-2-yl)-
di-Boc-guanidine (1i). Prepared according to the general procedure
1, to give the propargylguanidine as pale yellow solid in 78% yield
(0.861 g). Rf ¼ 0.51 (40% ethyl acetate/n-hexanes). 1H NMR
NMR (500 MHz, CDCl3)
d 7.30e7.21 (m, 5H), 5.72 (s, 1H), 5.65 (t,
J ¼ 4.3 Hz, 1H), 5.07 (s, 1H), 4.71 (s, 2H), 3.58 (d, J ¼ 3.4 Hz, 2H), 1.93
(s, 3H),1.55 (s, 9H),1.43 (s, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
(500 MHz, CDCl3)
d
8.85 (s, 1H), 7.36e7.18 (m, 10H), 5.94 (s, 1H),
d 160.4, 150.9, 149.4, 142.9, 138.3, 136.1, 128.6, 127.8, 127.5, 115.1,
4.97 (br, 1H), 4.62 (d, J ¼ 16.7 Hz, 1H), 3.15 (dd, J ¼ 12.7, 4.4 Hz, 1H),
2.76 (dd, J ¼ 12.2, 9.8 Hz, 1H), 2.02 (m, 2H), 1.95 (m, 2H), 1.53 (m,
4H), 1.48 (s, 9H), 1.47 (s, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
112.9, 82.9, 78.7, 52.1, 43.6, 28.2, 27.8, 20.0 ppm; LRMS (ESI)
Calculated for C24H34N3O4 m/z (MþH): 428.3, Obsd. 428.3.
d
159.5, 154.3, 150.3, 138.4, 137.2, 128.6, 127.3, 127.1, 126.5, 126.3,
4.2.2.5. tert-butyl (E)-2-((tert-butoxycarbonyl)imino)-3-(2,4-
dimethoxybenzyl)-6-(prop-1-en-2-yl)-3,4-dihydropyrimidine-1(2H)-
carboxylate (2e). Prepared according to the general procedure 2, to
give 6-endo-dig cyclized guanidine as a pale yellow solid in 70%
yield (6-endo-dig:5-exo-dig ¼ >20:1), (0.341 g). Rf ¼ 0.41 (40% ethyl
125.8, 122.3, 88.7, 84.8, 82.6, 78.9, 49.8, 46.3, 28.5, 28.3, 27.4, 24.7,
22.8, 21.7 ppm; LRMS (ESI) Calculated for C34H44N3O4 m/z (MþH):
558.3, Obsd. 558.5.
4.2.2. General procedure 2 for the 6-endo cyclization of the
propargyl guanidines 1a-g
acetate/n-hexanes). 1H NMR (500 MHz, CDCl3)
d 7.13 (m, 1H), 6.41
(m, 2H), 5.71 (s, 1H), 5.71 (s, 1H), 5.62 (t, J ¼ 5.5 Hz, 1H), 5.05 (s, 1H),
4.64 (s, 2H), 3.77 (s, 3H), 3.75 (s, 3H), 3.60 (d, J ¼ 5.0 Hz, 2H), 1.91 (s,
3H), 1.54 (s, 9H), 1.43 (s, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
To a stirring solution of the appropriate propargylguanidine
(1.0 mmol) in CH2Cl2 (0.07 M) was added rhodium(II) octanoate
dimer (10 mol%) and 4-nitrobenzoic acid (0.2 equiv). The reaction
was stirred at room temperature until the reaction was complete by
TLC. After completion, the reaction mixture was concentrated by
rotary evaporation, and purified by column chromatography to
yield 6-endo-dig cyclized guanidine.
d
160.5, 160.4, 158.6, 150.9, 149.5, 142.9, 138.4, 130.6, 116.6, 114.9,
113.3, 104.3, 98.3, 82.6, 78.4, 55.3, 55.2, 46.7, 43.4, 28.3, 27.9,
20.0 ppm; LRMS (ESI) Calculated for C26H38N3O6 m/z (MþH): 488.3,
Obsd. 488.3.
4.2.2.6. tert-butyl
(E)-3-(benzo[d][1,3]dioxol-5-ylmethyl)-2-((tert-
4.2.2.1. tert-butyl (E)-2-((tert-butoxycarbonyl)imino)-6-(cyclohex-1-
butoxycarbonyl)imino)-6-(prop-1-en-2-yl)-3,4-dihydropyrimidine-
1(2H)-carboxylate (2f). Prepared according to the general proced-
ure 2, to give 6-endo-dig cyclized guanidine as a pale yellow solid in
76% yield (6-endo-dig:5-exo-dig ¼ 10:1), (0.358 g). Rf ¼ 0.50 (40%
en-1-yl)-3-methyl-3,4-dihydropyrimidine-1(2H)-carboxylate
(2a).
The general procedure 2 was used to yield 6-endo-dig cyclized
guanidine as a white solid (6-endo-dig:5-exo-dig ¼ >20:1), (0.274 g,
total 70% yield). Rf ¼ 0. 28 (60% ethyl acetate/n-hexanes). 1H NMR
ethyl acetate/n-hexanes). 1H NMR (500 MHz, CDCl3)
d 6.74e6.70
(500 MHz, CDCl3)
d
6.35 (s. 1H), 5.61 (t, J ¼ 5.2 Hz, 1H), 3.70 (d,
(m, 3H), 5.92 (s, 2H), 5.71 (s, 1H), 5.67 (t, J ¼ 5.0 Hz, 1H), 5.06 (s, 1H),
J ¼ 4.3 Hz, 2H), 3.05 (s, 3H), 2.16 (m, 4H), 1.69 (m, 2H), 1.60 (m, 2H),
4.60 (s, 2H), 3.58 (d, J ¼ 3.9 Hz, 2H), 1.93 (s, 3H), 1.55 (s, 9H), 1.43 (s,
1.54 (s, 9H), 1.41 (s, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
9H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
d 160.3,150.8,149.3,147.9,
d
160.4, 150.5, 149.6, 143.2, 132.4, 126.5, 110.0, 82.3, 78.7, 47.3, 37.7,
28.3, 28.1, 25.7, 25.6, 22.7, 22.3 ppm; LRMS (ESI) Calculated for
21H34N3O4 m/z (MþH): 392.3, Obsd. 392.3.
147.1, 142.8, 138.3, 129.8, 121.4, 115.0, 112.9, 108.4, 108.2, 101.0, 82.8,
78.6, 51.8, 28.2, 27.8, 19.9 ppm; LRMS (ESI) Calculated for
C
C25H34N3O6 m/z (MþH): 472.2, Obsd. 472.3.
4.2.2.2. tert-butyl (E)-2-((tert-butoxycarbonyl)imino)-6-(cyclohex-1-
en-1-yl)-3-(cyclopropylmethyl)-3,4-dihydropyrimidine-1(2H)-
carboxylate (2b). Prepared according to the general procedure 2, to
give 6-endo-dig cyclized guanidine as a white solid in 31% yield (6-
endo-dig:5-exo-dig ¼ >20:1), (0.134 g). Rf ¼ 0.74 (40% ethyl acetate/
4.2.2.7. tert-butyl (E)-3,4-dibenzyl-2-((tert-butoxycarbonyl)imino)-
6-(cyclohex-1-en-1-yl)-3,4-dihydropyrimidine-1(2H)-carboxylate
(2g). Prepared according to the general procedure 2, to give 6-
endo-dig cyclized guanidine as a white solid in 96% yield (6-endo-
dig:5-exo-dig ¼ >20:1), (0.535 g). Rf ¼ 0.56 (40% ethyl acetate/n-
n-hexanes). 1H NMR (500 MHz, CDCl3)
d
6.37 (s, 1H), 5.64 (t,
hexanes). 1H NMR (500 MHz, CDCl3)
d 7.31e7.07 (m, 10H), 6.44 (s,

6072
K.-H. Kwon et al. / Tetrahedron 73 (2017) 6067e6079
1H), 5.32 (d, J ¼ 6.9 Hz, 1H), 5.15 (d, J ¼ 15.2 Hz, 1H), 4.12 (d,
J ¼ 15.2 Hz, 1H), 3.68 (m, 1H), 2.67 (m, 2H), 2.20 (m, 3H), 2.01 (m,
1H), 1.69 (m, 2H), 1.61 (m, 2H), 1.58 (s, 9H),1.50 (s, 9H) ppm; 13C{1H}
d
7.49e7.34 (m, 5H), 4.60 (m, 1H), 4.43 (m, 1H), 4.35 (dd, J ¼ 14.3,
1.5 Hz, 1H), 3.77 (dd, J ¼ 14.3, 7.2 Hz, 1H), 3.46 (m, 1H), 3.42 (dd,
J ¼ 14.3, 7.8 Hz, 1H), 3.19 (dd, J ¼ 14.3, 6.0 Hz, 1H), 2.45 (m, 1H), 1.89
(m, 2H), 1.72 (m, 1H), 1.54 (m, 1H), 1.49 (s, 9H), 1.45 (m, 1H), 1.42 (s,
9H), 1.33 (m, 1H), 1.05 (m, 1H), 0.52 (m, 1H), 0.45 (m, 1H), 0.21 (m,
NMR (100 MHz, CDCl3)
d 160.6, 150.8, 149.9, 142.1, 137.2, 136.3,
132.4, 129.4, 128.7, 128.5, 128.3, 127.7, 126.8, 126.7, 113.7, 82.3, 78.8,
56.3, 51.3, 39.5, 28.3, 28.1, 25.6, 25.5, 22.6, 22.2 ppm; LRMS (ESI)
Calculated for C34H44N3O4 m/z (MþH): 558.3, Obsd 558.2.
2H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
d 159.6, 155.1, 151.6, 149.7,
149.3, 134.7, 130.9, 129.2, 128.4, 125.4, 119.4, 82.9, 79.0, 57.4, 54.8,
52.8, 47.1, 31.1, 28.6, 28.3, 28.1,27.0, 24.3, 9.2, 3.9, 3.2 ppm; LRMS
(ESI) Calculated for C32H43N6O6 m/z (MþH): 607.3, Obsd. 607.3.
4.2.2.8. tert-butyl
(E)-4-benzyl-2-((tert-butoxycarbonyl)imino)-3-
(cyclopropylmethyl)-6-(prop-1-en-2-yl)-3,4-dihydropyrimidine-
1(2H)-carboxylate (2h). Prepared according to the general pro-
cedure 2, to give 6-endo-dig cyclized guanidine as a white solid in
54% yield (6-endo-dig:5-exo-dig ¼ 3:2), (0.260 g). Rf ¼ 0.26 (20%
4.2.3.3. tert-butyl
(4aR,9aS,E)-3-benzyl-2-((tert-butoxycarbonyl)
imino)-6,8-dioxo-7-phenyl-3,4,4a,7,8,9a,10,11,12,13-decahydro-6H-
pyrimido[5,4-c][1,2,4]triazolo[1,2-a]cinnoline-1(2H)-carboxylate
(3c). Prepared according to the general procedure 3, to give the
polycyclic guanidine as white solid in 95% yield (0.183 g). Rf ¼ 0.43
(40% ethyl acetate/n-hexanes). 1H NMR (500 MHz, CDCl3)
ethyl acetate/n-hexanes). 1H NMR (500 MHz, CDCl3)
d 7.32e7.15 (m,
5H), 5.70 (s, 1H), 5.58 (d, J ¼ 6.9 Hz, 1H), 5.07 (t, J ¼ 1.5 Hz, 1H), 4.01
(m, 1H), 3.47 (dd, J ¼ 14.3, 7.1 Hz, 1H), 3.19 (dd, J ¼ 14.3, 6.5 Hz, 1H),
3.00 (dd, J ¼ 12.6, 5.4 Hz, 1H), 2.71 (dd, J ¼ 12.6, 10.5 Hz, 1H), 1.89 (s,
3H), 1.56 (s, 9H), 1.49 (s, 9H), 1.05 (m, 1H), 0.55 (m, 2H), 0.23 (m, 2H)
d
7.45e7.23 (m, 10H), 5.30 (d, J ¼ 15.2 Hz, 1H), 4.55 (m, 1H), 4.40 (m,
1H), 4.06 (dd, J ¼ 14.3, 1.6 Hz, 1H), 4.01 (d, J ¼ 15.2 Hz, 1H), 3.75 (dd,
J ¼ 14.3, 7.3 Hz, 1H), 3.53 (m, 1H), 2.41 (m, 1H), 1.97 (m, 1H), 1.90 (m,
1H), 1.77 (m, 1H), 1.58 (m, 1H), 1.54 (s, 9H), 1.47 (s, 9H), 1.37 (m, 1H),
ppm; 13C{1H} NMR (100 MHz, CDCl3)
d 160.8, 150.5, 149.9, 141.8,
138.7, 137.4, 129.5, 128.7, 127.0, 116.8, 115.3, 82.9, 78.9, 57.5, 53.5,
40.1, 28.4, 28.2, 20.1, 9.6, 4.2, 3.8 ppm; LRMS (ESI) Calculated for
1.29 (m, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
d 159.4, 154.3,
C
28H40N3O4 m/z (MþH): 482.3, Obsd. 482.4.
151.7, 149.6, 149.2, 136.5,135.0, 130.8,129.1, 128.5,128.2,128.1, 127.7,
125.2, 119.2, 83.0, 79.1, 56.4, 54.7, 51.6, 47.0, 30.9, 28.5, 28.3, 28.1,
27.0, 24.3 ppm; LRMS (ESI) Calculated for C35H43N6O6 m/z (MþH):
643.3, Obsd. 643.3.
4.2.2.9. tert-butyl (E)-3,4-dibenzyl-2-((tert-butoxycarbonyl)imino)-
6-(prop-1-en-2-yl)-3,4-dihydropyrimidine-1(2H)-carboxylate (2i).
Prepared according to the general procedure 2, to give 6-endo-dig
cyclized guanidine as a white solid in 70% yield (6-endo-dig:5-exo-
dig ¼ >20:1), (0.362 g). Rf ¼ 0.60 (40% ethyl acetate/n-hexanes). 1H
4.2.3.4. tert-butyl (R,E)-2-benzyl-3-((tert-butoxycarbonyl)imino)-5-
methyl-8,10-dioxo-9-phenyl-2,3,6,9,10,11a-hexahydro-8H-pyrimido
NMR (500 MHz, CDCl3)
d
7.33e7.05 (m, 10H), 5.77 (s, 1H), 5.50 (d,
[5,4-c][1,2,4]triazolo[1,2-a]pyridazine-4(1H)-carboxylate
(3d).
J ¼ 7.0 Hz, 1H), 5.18 (d, J ¼ 15.1 Hz, 1H), 5.12 (s, 1H), 4.09 (d,
Prepared according to general procedure 3, to the give polycyclic
J ¼ 15.1 Hz, 1H), 3.74 (m, 1H), 2.71 (m, 2H), 1.91 (s, 3H), 1.60 (s, 9H),
guanidine as white solid in 73% yield (0.132 g). Rf ¼ 0.39 (40% ethyl
1.53 (s, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
d
160.6, 150.9,
acetate/n-hexanes). 1H NMR (500 MHz, CDCl3)
d 7.48e7.25 (m,
149.8, 141.9, 138.6, 137.1, 136.3, 129.4, 128.6, 128.3, 127.8, 127.0, 116.7,
115.3, 83.0, 79.0, 56.4, 51.8, 39.5, 28.3, 28.1, 20.0 ppm; LRMS (ESI)
Calculated for C31H40N3O4 m/z (MþH): 518.3, Obsd. 518.2.
10H), 4.86 (d, J ¼ 15.2 Hz, 1H), 4.60 (m, 1H), 4.46 (d, J ¼ 15.2 Hz, 1H),
4.27 (d, J ¼ 16.3 Hz, 1H), 3.99 (d, J ¼ 16.3 Hz, 1H), 3.74 (m, 2H), 2.10
(s, 3H),1.55 (s, 9H),1.49 (s, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
d
160.0, 153.3, 151.3, 149.2, 136.1, 130.8, 129.4, 128.9, 128.6, 128.5,
4.2.3. General procedure 3 for the cycloaddition of the guanidine
dienes 2a-i
127.9, 127.5, 125.5, 122.3, 114.6, 83.6, 79.5, 54.6, 52.4, 47.3, 46.1, 28.4,
28.3, 15.7 ppm; LRMS (ESI) Calculated for C32H39N6O6 m/z (MþH):
603.3, Obsd. 603.4.
To a stirring solution of the desired 6-endo-dig cyclic guanidine
(diene, 1 equiv) in CH2Cl2 (0.07 M) was added the appropriate tri-
azoledione (dienophile, 1.2 equiv). The reaction was stirred at room
temperature until judged complete by TLC. After completion, the
reaction mixture was concentrated by rotary evaporation, and pu-
rified by column chromatography to yield polycyclic guanidine.
4.2.3.5. tert-butyl (R,E)-3-((tert-butoxycarbonyl)imino)-2-(2,4-
dimethoxybenzyl)-5-methyl-8,10-dioxo-9-phenyl-2,3,6,9,10,11a-hex-
ahydro-8H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]pyridazine-4(1H)-
carboxylate (3e). Prepared according to the general procedure 3, to
give the polycyclic guanidine as pale yellow solid in 50% yield
(0.099 g). Rf ¼ 0.47 (40% ethyl acetate/n-hexanes). 1H NMR
4.2.3.1. tert-butyl (4aR,9aS,E)-2-((tert-butoxycarbonyl)imino)-3-
methyl-6,8-dioxo-7-phenyl-3,4,4a,7,8,9a,10,11,12,13-decahydro-6H-
pyrimido[5,4-c][1,2,4]triazolo[1,2-a]cinnoline-1(2H)-carboxylate
(3a). Prepared using the general procedure 3 to yield the polycyclic
guanidine as a pale yellow solid, (0.160 g, 94% yield). Rf ¼ 0.46 (40%
(500 MHz, CDCl3)
d 7.45e7.33 (m, 5H), 7.15 (m, 1H), 6.38 (m, 2H),
4.94 (d, J ¼ 14.7 Hz, 1H), 4.55 (m, 1H), 4.22 (d, J ¼ 16.5 Hz, 1H), 4.20
(d, J ¼ 14.7 Hz, 1H), 3.72 (s, 3H), 3.71 (s, 3H), 3.69 (m, 1H), 2.05 (s,
3H), 1.53 (s, 9H), 1.46 (s, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
ethyl acetate/n-hexanes). 1H NMR (500 MHz, CDCl3)
d
7.51e7.36 (m.
d 160.7, 159.8, 158.9, 153.0, 151.1, 151.0, 149.1, 131.2, 130.8, 129.2,
5H), 4.57 (m, 1H), 4.44 (m, 1H), 3.99 (dd, J ¼ 14.0, 3.0 Hz, 1H), 3.84
(dd, J ¼ 14.0, 7.5 Hz, 1H), 3.39 (m, 1H), 3.02 (s, 3H), 2.49 (m, 1H), 1.92
(m, 2H), 1.78 (m, 1H), 1.57 (m, 2H), 1.53 (s, 9H), 1.45 (s, 9H), 1.38 (m,
128.4, 127.0, 125.3, 122.2, 116.4, 104.2, 98.3, 83.0, 78.9, 55.3, 55.2,
54.9, 46.6, 46.5, 45.9, 28.3, 28.1, 15.5 ppm; LRMS (ESI) Calculated for
C34H43N6O8 m/z (MþH): 663.3, Obsd. 663.4.
1H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
d 159.3, 154.5, 151.1, 149.5,
149.0, 134.3, 130.7, 129.1, 128.2, 125.3, 118.7, 82.9, 78.9, 55.2, 54.8,
50.1, 37.3, 30.8, 28.5, 28.2, 28.0, 26.6, 24.1 ppm; LRMS (ESI) Calcu-
lated for C29H39N6O6 m/z (MþH): 567.3, Obsd. 567.4.
4.2.3.6. tert-butyl (R,E)-2-(benzo[d][1,3]dioxol-5-ylmethyl)-3-((tert-
butoxycarbonyl)imino)-5-methyl-8,10-dioxo-9-phenyl-2,3,6,9,10,11a-
hexahydro-8H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]pyridazine-
4(1H)-carboxylate (3f). Prepared according to the general proced-
ure 3, to give the polycyclic guanidine as pale yellow solid in 60%
yield (0.116 g). Rf ¼ 0.35 (40% ethyl acetate/n-hexanes). 1H NMR
4.2.3.2. tert-butyl
(4aR,9aS,E)-2-((tert-butoxycarbonyl)imino)-3-
(cyclopropylmethyl)-6,8-dioxo-7-phenyl-3,4,4a,7,8,9a,10,11,12,13-
decahydro-6H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]cinnoline-1(2H)-
carboxylate (3b). Prepared according to the general procedure 3, to
give the polycyclic guanidine as white solid in 35% yield (0.064 g).
Rf ¼ 0.45 (40% ethyl acetate/n-hexanes). 1H NMR (500 MHz, CDCl3)
(500 MHz, CDCl3)
d 7.48e7.36 (m, 5H), 6.76 (s, 1H), 6.72 (m, 2H),
5.90 (m, 2H), 4.76 (d, J ¼ 15.1 Hz, 1H), 4.60 (m, 1H), 4.60 (m, 1H),
4.34 (d, J ¼ 15.1 Hz, 1H), 4.28 (d, J ¼ 16.1 Hz, 1H), 4.02 (d, J ¼ 16.1 Hz,
1H), 3.77 (dd, J ¼ 13.7, 4.0 Hz,1H), 3.69 (dd, J ¼ 13.7, 7.4 Hz,1H), 2.09

K.-H. Kwon et al. / Tetrahedron 73 (2017) 6067e6079
6073
(s, 3H),1.55 (s, 9H),1.48 (s, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
159.9, 153.3, 151.3, 151.2, 149.2, 148.1, 147.4, 130.8, 129.8, 129.4,
128.6, 127.5, 125.4, 122.2, 122.1, 108.9, 108.4, 101.2, 83.5, 79.4, 54.6,
52.2, 46.9, 46.1, 28.4, 28.2, 15.7 ppm; LRMS (ESI) Calculated for
{1H} NMR (100 MHz, CDCl3)
d
159.8, 153.4, 151.9, 151.0, 149.6, 137.0,
d
136.4, 130.7, 129.9, 129.4, 129.0, 128.6, 128.5, 128.4, 127.8, 127.5,
127.3, 125.5, 123.0, 83.3, 79.6, 62.3, 58.6, 52.6, 45.9, 43.2, 28.4, 28.3,
15.3 ppm; LRMS (ESI) Calculated for C39H45N6O6 m/z (MþH): 693.3,
Obsd. 693.4.
C
33H39N6O8 m/z (MþH): 647.3, Obsd. 647.3.
4.2.3.7. tert-butyl (R,E)-2-(benzo[d][1,3]dioxol-5-ylmethyl)-3-((tert-
butoxycarbonyl)imino)-5-methyl-8,10-dioxo-9-phenyl-2,3,6,9,10,11a-
hexahydro-8H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]pyridazine-
4(1H)-carboxylate (3g). Prepared according to the general proced-
ure 3, to give the polycyclic guanidine as pale yellow solid in 61%
yield (0.110 g). Rf ¼ 0.29 (40% ethyl acetate/n-hexanes). 1H NMR
4.2.4. General procedure 4 for the deprotection and salt exchange of
guanidines 3a-j
A 50 mL round-bottom flask was charged with the appropriate
polycyclic guanidine (0.2 mmol). The CH2Cl2/TFA mixture (1:1,
4.0 mL) was added. The reaction mixture was stirred at room
temperature for 2 h. The crude mixture was taken up in MeOH and
2 M HCl in ethyl ether was added. The mixture was again concen-
trated and the resulting solid triturated with ethyl ether. The solid
was then collected to give the title compound.
(500 MHz, CDCl3)
d 6.74e6.71 (m, 3H), 5.92 (s, 2H), 4.74 (d,
J ¼ 15.1 Hz, 1H), 4.48 (m, 1H), 4.34 (d, J ¼ 15.1 Hz, 1H), 4.18 (dd,
J ¼ 16.1, 2.0 Hz, 1H), 3.92 (dd, J ¼ 16.1, 2.0 Hz, 1H), 3.68 (qd, J ¼ 7.3,
5.4 Hz, 2H), 2.05 (d, J ¼ 1.5 Hz, 3H), 1.54 (s, 9H), 1.47 (s, 9H), 1.23 (t,
J ¼ 7.3 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
d
159.8, 154.5,
4.2.4.1. (4aR,9aS)-2-imino-3-methyl-7-phenyl-1,2,3,4,4a,9a,10,11,12,13-
decahydro-6H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]cinnoline-6,8(7H)-
dione (4a). Prepared according to the general procedure 4 to afford
the HCl salt as a white powder (69 mg, 85%). 1H NMR (500 MHz,
152.3, 151.2, 149.2, 148.0, 147.3, 129.7, 127.5, 122.3, 122.0, 108.8,
108.3, 101.1, 83.3, 79.3, 54.4, 52.1, 46.9, 45.8, 34.5, 28.3, 28.2, 15.6,
13.4 ppm; LRMS (ESI) Calculated for C29H39N6O8 m/z (MþH): 599.3,
Obsd. 599.4.
DMSO-d6) d 10.84 (s, 1H), 8.20 (s, 2H), 7.50e7.42 (m. 5H), 4.67 (s, 1H),
4.39 (d, J ¼ 8.8 Hz, 1H), 4.29 (d, J ¼ 7.3 Hz, 1H), 3.63 (t, J ¼ 8.6 Hz, 1H),
4.2.3.8. tert-butyl (4aR,9aS,E)-3,4-dibenzyl-2-((tert-butoxycarbonyl)
imino)-6,8-dioxo-7-phenyl-3,4,4a,7,8,9a,10,11,12,13-decahydro-6H-
pyrimido[5,4-c][1,2,4]triazolo[1,2-a]cinnoline-1(2H)-carboxylate
(3h). Prepared according to the general procedure 3, to give the
polycyclic guanidine as white solid in 67% yield (0.147 g). Rf ¼ 0.67
(40% ethyl acetate/n-hexanes). 1H NMR (500 MHz, CDCl3)
3.07 (s, 4H), 2.17 (m, 1H), 1.81 (m, 1H), 1.78 (m, 2H), 1.54 (m, 1H), 1.34
(m,1H),1.20 (m,1H) ppm; 13C{1H} NMR (100 MHz, DMSO-d6)
d 153.9,
151.5,149.1, 130.8,128.8,128.1, 126.0, 117.6, 114.2, 53.2, 49.1, 49.0, 37.3,
30.2, 26.8, 26.3, 23.5 ppm; HRMS (ESI) Calculated for C19H23N6O2 m/z
(MþH): 367.1882, Obsd. 367.1890.
d
7.47e7.19 (m, 13H), 7.03 (m, 2H), 5.12 (d, J ¼ 15.0 Hz, 1H), 4.66 (dd,
4.2.4.2. (4aR,9aS)-3-(cyclopropylmethyl)-2-imino-7-phenyl-
1,2,3,4,4a,9a,10,11,12,13-decahydro-6H-pyrimido[5,4-c][1,2,4]triazolo
[1,2-a]cinnoline-6,8(7H)-dione (4b). Prepared according to the gen-
eral procedure 4, to give the polycyclic guanidine as white solid in
J ¼ 11.0, 2.3 Hz, 1H), 4.38 (s, 1H), 4.36 (m, 1H), 3.61 (m, 1H), 3.27 (dd,
J ¼ 13.2, 2.8 Hz, 1H), 2.90 (dd, J ¼ 12.3, 12.3 Hz, 1H), 2.84 (d,
J ¼ 15.0 Hz, 1H), 2.33 (m, 1H),1.89 (m, 1H), 1.83 (m, 1H), 1.73 (m, 1H),
1.56 (s, 9H), 1.51 (s, 9H), 1.49 (m, 1H), 1.27 (m, 1H), 1.16 (m, 1H) ppm;
66% yield (59 mg). 1H NMR (500 MHz, DMSO-d6)
d 10.41 (s, 1H), 7.98
13C{1H} NMR (100 MHz, CDCl3)
d
159.3, 154.7, 151.9, 149.6, 149.3,
(s, 2H), 7.53e7.41 (m, 5H), 4.64 (m,1H), 4.51 (dd, J ¼ 12.4, 5.7 Hz,1H),
4.42 (dd, J ¼ 8.4, 2.0 Hz, 1H), 3.63 (t, J ¼ 12.4 Hz, 1H), 3.39 (m, 2H),
2.94 (m,1H), 2.17 (m,1H), 1.91 (m,1H),1.80 (m, 2H),1.55 (m,1H), 1.37
137.1, 136.7, 134.8, 130.7, 129.7, 129.1, 128.9, 128.5, 128.2, 128.1, 127.5,
127.1, 125.3, 119.5, 82.9, 79.0, 63.0, 59.3, 54.4, 52.1, 43.3, 30.6, 28.3,
28.2, 28.1, 26.8, 24.2 ppm; LRMS (ESI) Calculated for C42H49N6O6 m/
z (MþH): 733.4, Obsd. 733.4.
(m,1H),1.24 (m,1H),1.04 (m,1H), 0.54 (m,1H), 0.31 (m,1H) ppm; 13
C
{1H} NMR (100 MHz, DMSO-d6)
d 156.1, 152.6, 151.3, 132.3, 130.2,
129.7, 127.5, 119.4, 117.0, 55.8, 55.5, 51.6, 49.7, 31.9, 28.3, 28.1, 25.3,
9.8, 4.2, 4.1 ppm; HRMS (ESI) Calculated for C22H28N6O2 m/z (MþH):
408.2274, Obsd. 408.2285.
4.2.3.9. tert-butyl (11aR,E)-1-benzyl-3-((tert-butoxycarbonyl)imino)-
2-(cyclopropylmethyl)-5-methyl-8,10-dioxo-9-phenyl-2,3,6,9,10,11a-
hexahydro-8H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]pyridazine-4(1H)-
carboxylate (3i). Prepared according to general procedure 3, to give
the polycyclic guanidine as white solid in 83% yield (0.164 g).
Rf ¼ 0.10 (20% ethyl acetate/n-hexanes). 1H NMR (500 MHz, CDCl3)
4.2.4.3. (4aR,9aS)-3-benzyl-2-imino-7-phenyl-1,2,3,4,4a,9a,10,11,12,13-
decahydro-6H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]cinnoline-6,8(7H)-
dione (4c). Prepared according to the general procedure 4, to give the
polycyclic guanidine as white solid in 90% yield (79 mg). 1H NMR
d
7.56e7.24 (m, 10H), 5.06 (dd, J ¼ 10.4, 4.9 Hz, 1H), 4.55 (s, 1H), 4.40
(d, J ¼ 16.6 Hz,1H), 3.98 (d, J ¼ 16.6 Hz,1H), 3.68 (dd, J ¼ 14.2, 6.3 Hz,
1H), 3.20 (dd, J ¼ 13.2, 4.9 Hz, 1H), 2.99 (dd, J ¼ 13.2, 10.3 Hz, 1H),
2.13 (s, 3H), 2.09 (dd, J ¼ 14.2, 7.3 Hz, 1H), 1.60 (s, 9H), 1.56 (s, 9H),
0.78 (m, 1H), 0.50 (m, 1H), 0.36 (m, 1H), 0.05 (m, 2H) ppm; 13C{1H}
(500 MHz, DMSO-d6) d 11.00 (s, 1H), 8.53 (s, 2H), 7.49e7.34 (m, 10H),
4.82 (d, J ¼ 16.2 Hz, 1H), 4.66 (d, J ¼ 16.2 Hz, 1H), 4.63 (s, 1H), 4.40 (d,
J ¼ 10.4 Hz, 1H), 4.30 (dd, J ¼ 12.2, 5.2 Hz,1H), 3.56 (t, J ¼ 11.9 Hz, 1H),
3.12 (m, 1H), 2.15 (m, 1H), 1.89 (m, 1H), 1.78 (m, 2H), 1.54 (m, 1H), 1.34
NMR (100 MHz, CDCl3)
d
160.1, 154.7, 151.9, 151.0, 149.6, 136.9,130.8,
(m,1H),1.24 (m,1H) ppm; 13C{1H} NMR (100 MHz, DMSO-d6)
d 154.0,
130.4, 129.5, 129.0, 128.7, 127.2, 125.7, 123.0, 83.2, 79.5, 63.1, 58.3,
53.2, 46.0, 43.7, 28.4, 28.3, 15.3, 9.5, 5.0, 2.1 ppm; LRMS (ESI)
Calculated for C36H45N6O6 m/z (MþH): 657.3, Obsd. 657.3.
151.5, 149.2, 134.5, 130.9, 128.9, 128.8, 128.2, 128.0, 127.4, 126.1, 117.7,
114.7, 53.3, 52.0, 49.2, 46.8, 30.2, 26.9, 26.4, 23.6 ppm; HRMS (ESI)
Calculated for C25H27N6O2 m/z (MþH): 443.2195, Obsd. 443.2205.
4.2.3.10. tert-butyl
(11aR,E)-1,2-dibenzyl-3-((tert-butoxycarbonyl)
4.2.4.4. (R)-2-benzyl-3-imino-5-methyl-9-phenyl-1,2,3,4,6,11a-hex-
ahydro-8H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]pyridazine-8,10(9H)-
dione (4d). Prepared according to the general procedure 4, to give
the polycyclic guanidine as white solid in 63% yield (55 mg). 1H
imino)-5-methyl-8,10-dioxo-9-phenyl-2,3,6,9,10,11a-hexahydro-8H-
pyrimido[5,4-c][1,2,4]triazolo[1,2-a]pyridazine-4(1H)-carboxylate
(3j). Prepared according to general procedure 3, to give the poly-
cyclic guanidine as white solid in 65% yield (0.135 g). Rf ¼ 0.53 (40%
NMR (500 MHz, DMSO-d6)
d 10.83 (s, 1H), 8.38 (s, 2H), 7.49e7.32
ethyl acetate/n-hexanes). 1H NMR (500 MHz, CDCl3)
d
7.48e7.20 (m,
(m, 10H), 4.70 (d, J ¼ 15.9 Hz, 1H), 4.63 (m, 1H), 4.54 (d, J ¼ 15.9 Hz,
13H), 6.89 (m, 2H), 5.06 (d, J ¼ 14.7 Hz, 1H), 4.42 (s, 1H), 4.41 (dd,
J ¼ 10.7, 3.9 Hz,1H), 4.27 (d, J ¼ 16.6 Hz,1H), 3.83 (d, J ¼ 16.6 Hz,1H),
3.23 (dd, J ¼ 13.7, 3.9 Hz, 1H), 3.00 (d, J ¼ 14.7 Hz, 1H), 2.89 (dd,
1H), 4.22 (m, 2H), 3.94 (d, J ¼ 15.3 Hz, 1H), 3.44 (t, J ¼ 11.5 Hz, 1H),
1.88 (s, 3H) ppm; 13C{1H} NMR (100 MHz, DMSO-d6)
d 152.9, 151.2,
150.6, 134.2, 130.7, 128.6, 127.9, 127.8, 127.1, 125.8, 119.9, 106.9, 51.8,
48.6, 46.4, 44.8,13.8 ppm; HRMS (ESI) Calculated for C22H24N6O2 m/
J ¼ 13.7, 10.7 Hz, 1H), 2.13 (s, 3H), 1.58 (s, 9H), 1.52 (s, 9H) ppm; 13
C

6074
K.-H. Kwon et al. / Tetrahedron 73 (2017) 6067e6079
z (MþH): 404.1961, Obsd. 404.1971.
3.55 (dd, J ¼ 14.6, 6.2 Hz, 1H), 3.39 (d, J ¼ 14.6, 3.8 Hz, 1H), 3.32 (d,
J ¼ 14.6, 3.8 Hz, 1H), 2.87 (dd, J ¼ 14.6, 7.5 Hz, 1H), 1.82 (s, 3H), 1.03
4.2.4.5. (R)-2-(2,4-dimethoxybenzyl)-3-imino-5-methyl-9-phenyl-
1,2,3,4,6,11a-hexahydro-8H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]pyr-
idazine-8,10(9H)-dione (4e). Prepared according to the general
procedure 4, to give the polycyclic guanidine as white solid in 70%
(m, 1H), 0.64 (m, 1H), 0.56 (m, 1H), 0.31 (m, 1H), 0.21 (m, 1H) ppm;
13C{1H} NMR (100 MHz, CD3OD)
d 157.8, 155.9, 153.6, 137.1, 132.7,
131.6, 130.3, 130.1, 129.8, 128.7, 127.5, 121.2, 118.9, 61.2, 60.0, 54.2,
47.0, 40.2, 14.4, 10.1, 5.2, 3.3 ppm; HRMS (ESI) Calculated for
yield (70 mg). 1H NMR (500 MHz, DMSO-d6)
d
10.87 (s, 1H), 8.34 (s,
C26H30N6O2 m/z (MþH): 458.2430, Obsd. 458.2436.
2H), 7.48e7.42 (m, 5H), 7.24 (m, 1H), 6.60 (s, 1H), 6.51 (m, 1H), 4.60
(d, J ¼ 15.2 Hz, 1H), 4.54 (m, 1H), 4.47 (d, J ¼ 15.2 Hz, 1H), 4.32 (d,
J ¼ 7.8 Hz,1H), 4.20 (d, J ¼ 14.7 Hz,1H), 3.92 (d, J ¼ 14.7 Hz,1H), 3.79
(s, 3H), 3.74 (s, 3H), 3.36 (m, 1H), 1.88 (s, 3H) ppm; 13C{1H} NMR
4.2.4.10. (11aR)-1,2-dibenzyl-3-imino-5-methyl-9-phenyl-
1,2,3,4,6,11a-hexahydro-8H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]pyr-
idazine-8,10(9H)-dione (4j). Prepared according to general procedure
4, to give the polycyclic guanidine as white solid in 87% yield (92 mg).
(100 MHz, DMSO-d6)
d 160.7, 159.8, 158.9, 153.0, 151.1, 151.0, 149.1,
131.2, 130.8, 129.2, 128.4, 127.0, 125.3, 122.2, 116.4, 104.2, 98.3, 83.0,
78.9, 55.3, 55.2, 54.9, 46.6, 46.5, 45.9, 28.3, 28.1, 15.5 ppm; HRMS
(ESI) Calculated for C24H27N6O4 m/z (MþH): 463.2094, Obsd.
463.2099.
1H NMR (500 MHz, DMSO-d6)
d 10.20 (s, 1H), 8.39 (s, 2H), 7.53e7.13
(m, 15H), 5.03 (d, J ¼ 16.5 Hz, 1H), 4.91 (s,1H), 4.44 (q, J ¼ 4.3 Hz, 1H),
4.37 (d, J ¼ 16.5 Hz, 1H), 4.23 (d, J ¼ 15.3 Hz, 1H), 4.04 (d, J ¼ 15.3 Hz,
1H), 3.44 (dd, J ¼ 14.3, 4.0 Hz, 1H), 3.28 (dd, J ¼ 14.3, 4.6 Hz, 1H), 1.79
(s, 3H) ppm; 13C{1H} NMR (100 MHz, DMSO-d6)
d 155.7, 153.1, 151.9,
4.2.4.6. (R)-2-(benzo[d][1,3]dioxol-5-ylmethyl)-3-imino-5-methyl-9-
phenyl-1,2,3,4,6,11a-hexahydro-8H-pyrimido[5,4-c][1,2,4]triazolo
[1,2-a]pyridazine-8,10(9H)-dione (4f). Prepared according to the
general procedure 4, to give the polycyclic guanidine as white solid
135.3, 135.2, 131.1, 130.5, 128.9, 128.5, 128.2, 127.9, 127.2, 126.8, 126.3,
119.2, 116.1, 59.1, 57.0, 50.1, 45.8, 37.4, 14.3 ppm; HRMS (ESI) Calcu-
lated for C29H29N6O2 m/z (MþH): 493.2352, Obsd. 493.2355.
in 88% yield (85 mg). 1H NMR (500 MHz, DMSO-d6)
d
10.93 (s, 1H),
4.2.5. General procedure 5 for the cyclization of propargylguanidines
using silver (I)
8.51 (s, 2H), 7.48e7.40 (m, 5H), 6.94e6.82 (m, 3H), 6.01 (s, 1H), 6.72
(m, 2H), 5.90 (m, 2H), 4.76 (d, J ¼ 15.1 Hz, 1H), 4.60 (m, 1H), 4.60 (m,
1H), 4.34 (d, J ¼ 15.1 Hz, 1H), 4.28 (d, J ¼ 16.1 Hz, 1H), 4.02 (d,
J ¼ 16.1 Hz, 1H), 3.77 (dd, J ¼ 13.7, 4.0 Hz, 1H), 3.69 (dd, J ¼ 13.7,
7.4 Hz, 1H), 2.09 (s, 3H), 1.55 (s, 9H), 1.48 (s, 9H) ppm; 13C{1H} NMR
To a stirring solution of the preferred propargylguanidine
(1.0 mmol) in CH2Cl2 (0.07 M) was added silver acetate (10 mol%)
and acetic acid (3.0 equiv). After completion, the reaction mixture
was concentrated by rotary evaporation, and purified by column
chromatography to give 5-exo-dig cyclized guanidine.
(100 MHz, DMSO-d6)
d 153.2, 151.1, 150.9, 147.7, 147.1, 131.0, 128.9,
128.2, 128.0, 126.1, 121.3, 120.1, 108.5, 108.1, 107.0, 101.2, 51.7, 48.8,
46.2, 45.0, 13.9 ppm; HRMS (ESI) Calculated for C23H23N6O4 m/z
(MþH): 447.1781, Obsd. 447.1782.
4.2.5.1. tert-butyl (2E,5Z)-3-benzyl-2-((tert-butoxycarbonyl)imino)-
5-(cyclohex-1-en-1-ylmethylene)imidazolidine-1-carboxylate (7a).
The general procedure 5 was used to give 5-exo-dig cyclized gua-
nidine as a white solid in 85% yield (5-exo-dig:6-endo-dig ¼ 2:3),
(0.398 g). Rf ¼ 0.50 (40% ethyl acetate/n-hexanes). 1H NMR
4.2.4.7. (R)-2-(benzo[d][1,3]dioxol-5-ylmethyl)-9-ethyl-3-imino-5-
methyl-1,2,3,4,6,11a-hexahydro-8H-pyrimido[5,4-c][1,2,4]triazolo
[1,2-a]pyridazine-8,10(9H)-dione (4g). Prepared according to the
general procedure 4, to give the polycyclic guanidine as white solid
(500 MHz, CDCl3) d 7.34e7.26 (m, 5H), 5.75 (s, 1H), 5.49 (s, 1H), 4.58
(s, 2H), 3.70 (s, 2H), 2.22 (m, 2H), 2.13 (m, 2H), 1.63 (m, 4H), 1.54 (s,
in 81% yield (70 mg). 1H NMR (500 MHz, DMSO-d6)
d
10.88 (s, 1H),
9H), 1.47 (s, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
d
159.2, 151.9,
8.46 (s, 2H), 6.93e6.82 (m, 3H), 6.02 (s, 2H), 4.68 (d, J ¼ 16.1 Hz,1H),
4.55 (d, J ¼ 16.1 Hz, 1H), 4.51 (m, 1H), 4.20 (dd, J ¼ 11.7, 4.9 Hz, 1H),
4.12 (d, J ¼ 15.7 Hz, 1H), 3.81 (d, J ¼ 15.7 Hz, 1H), 3.39 (m, 3H), 1.85
(s, 3H), 1.10 (t, J ¼ 7.1 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, DMSO-
149.3, 135.6, 134.1, 129.3, 128.8, 128.4, 127.9, 126.0, 120.3, 83.5, 79.2,
49.7, 48.4, 28.3, 28.1, 27.0, 25.8, 22.7, 22.2 ppm; LRMS (ESI) Calcu-
lated for C27H38N3O4 m/z (MþH): 468.3, Obsd. 468.3.
d6)
d
154.3, 151.9, 151.2, 147.7, 147.1, 128.0, 121.3, 120.3, 108.4, 108.1,
4.2.5.2. tert-butyl
(2E,5Z)-3,4-dibenzyl-2-((tert-butoxycarbonyl)
107.1, 101.2, 51.7, 48.6, 46.3, 44.8, 33.7, 13.9, 12.9 ppm; HRMS (ESI)
Calculated for C19H23N6O4 m/z (MþH): 399.1781, Obsd. 399.1783.
imino)-5-(cyclohex-1-en-1-ylmethylene)imidazolidine-1-carboxylate
(7b). Prepared according to the general procedure 5, to give the 5-
exo-dig cyclized guanidine as a white solid in 85% yield (5-exo-
dig:6-endo-dig ¼ >20:1), (0.474 g). Rf ¼ 0.50 (40% ethyl acetate/n-
4 . 2 . 4 . 8 . ( 4 a R , 9 a S ) - 3 , 4 - d i b e n z y l - 2 - i m i n o - 7 - p h e n y l -
1,2,3,4,4a,9a,10,11,12,13-decahydro-6H-pyrimido[5,4-c][1,2,4]triazolo
[1,2-a]cinnoline-6,8(7H)-dione (4h). Prepared according to the
general procedure 4, to give the polycyclic guanidine as white solid
hexanes). 1H NMR (500 MHz, CDCl3)
d 7.35e7.01 (m, 10H), 5.52 (s,
1H), 5.07 (d, J ¼ 15.1 Hz, 1H), 4.72 (s, 1H), 4.13 (d, J ¼ 15.1 Hz, 1H),
3.63 (dd, J ¼ 9.4, 4.2 Hz, 1H), 2.86 (dd, J ¼ 13.0, 9.4 Hz, 1H), 2.41 (dd,
J ¼ 13.0, 9.4 Hz,1H), 2.20 (m,1H), 2.07 (m, 3H),1.72 (m, 2H),1.64 (m,
1H), 1.55 (s, 9H), 1.52 (s, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
in 80% yield (91 mg). 1H NMR (500 MHz, DMSO-d6)
d 10.20 (s, 1H),
8.54 (s, 2H), 7.51e7.14 (m, 15H), 5.00 (d, J ¼ 16.6 Hz, 1H), 4.97 (s, 1H),
4.48 (s, 2H), 4.09 (d, J ¼ 16.6 Hz, 1H), 3.44 (d, J ¼ 12.7 Hz, 1H), 3.23
(d, J ¼ 12.7 Hz, 1H), 2.94 (m, 1H), 2.27 (m, 1H), 1.83 (m, 2H), 1.78 (m,
1H), 1.55 (m, 1H), 1.32 (m, 1H), 1.02 (m, 1H) ppm; 13C{1H} NMR
d
159.6, 152.1, 149.8, 136.2, 136.1, 134.1, 130.0, 129.7, 129.0, 128.5,
128.4, 128.1, 127.1, 122.3, 83.4, 79.4, 61.7, 46.9, 38.8, 28.4, 28.3, 26.9,
25.9, 22.9, 22.4 ppm; LRMS (ESI) Calculated for C34H44N3O4 m/z
(MþH): 558.3, Obsd. 558.3.
(100 MHz, DMSO-d6)
d 165.7, 154.5, 149.7, 135.8, 135.4, 131.0, 130.3,
128.8, 128.6, 128.5, 128.2, 127.9, 127.1, 126.6, 126.2, 123.8, 117.1, 60.0,
59.5, 53.3, 50.7, 39.0, 31.0, 27.2, 26.7, 23.4 ppm; HRMS (ESI) Calcu-
lated for C32H33N6O2 m/z (MþH): 533.2665, Obsd. 533.2671.
4.2.5.3. tert-butyl (2E,5Z)-3-benzyl-2-((tert-butoxycarbonyl)imino)-5-
(2-methylallylidene)imidazolidine-1-carboxylate (7c). Prepared ac-
cording to the general procedure 5, to give the 5-exo-dig cyclized
guanidine as a white solid in 54% yield (5-exo-dig:6-endo-dig ¼ 10:1),
4.2.4.9. (11aR)-1-benzyl-2-(cyclopropylmethyl)-3-imino-5-methyl-
9-phenyl-1,2,3,4,6,11a-hexahydro-8H-pyrimido[5,4-c][1,2,4]triazolo
[1,2-a]pyridazine-8,10(9H)-dione (4i). Prepared according to the
general procedure 4, to give the polycyclic guanidine as white solid
(0.231 g). Rf
(500 MHz, CDCl3)
(s, 2H), 3.72 (d, J ¼ 1.0 Hz, 2H), 1.94 (s, 3H), 1.54 (s, 9H), 1.46 (s, 9H)
ppm; 13C{1H} NMR (100 MHz, CDCl3)
159.5, 152.1, 149.2, 140.3,
135.5, 128.9, 128.6, 128.5, 128.0, 119.1, 117.5, 84.2, 79.4, 49.6, 48.5,
¼
0.49 (40% ethyl acetate/n-hexanes). 1H NMR
d
7.35e7.27 (m, 5H), 5.60 (s, 1H), 5.00 (s, 2H), 4.60
in 72% yield (71 mg). 1H NMR (500 MHz, CD3OD)
d
7.57e7.29 (m,
d
10H), 4.97 (s, 2H), 4.30 (d, J ¼ 15.9 Hz, 1H), 4.06 (d, J ¼ 15.9 Hz, 1H),

K.-H. Kwon et al. / Tetrahedron 73 (2017) 6067e6079
6075
28.4, 28.1, 21.2 ppm; LRMS (ESI) Calculated for C24H34N3O4 m/z
(MþH): 428.3, Obsd. 428.3.
(m, 1H), 0.26 (m, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
d
159.7,
151.6, 149.4, 140.0, 135.9, 130.7, 129.2, 128.4, 127.1, 121.0, 117.4, 83.6,
79.1. 62.1, 47.7, 38.8, 28.2, 28.1, 20.8, 9.4, 4.8, 3.3 ppm; LRMS (ESI)
Calculated for C28H40N3O4 m/z (MþH): 482.3, Obsd. 482.3.
4.2.5.4. tert-butyl
(2E,5Z)-3,4-dibenzyl-2-((tert-butoxycarbonyl)
(7d).
imino)-5-(2-methylallylidene)imidazolidine-1-carboxylate
Prepared according to the general procedure 5, to give the 5-exo-dig
cyclized guanidine as a white solid in 90% yield (5-exo-dig:6-endo-
dig ¼ >20:1), (0.466 g). Rf ¼ 0.47 (40% ethyl acetate/n-hexanes). 1H
4.2.6. General procedure 6 to form the cycloaddition of guanidine
dienes 7a-h
To a stirring solution of the desired 5-exo-dig cyclic guanidine
(diene, 1 equiv) in CH2Cl2 (0.07 M) was added the appropriate tri-
azoledione (dienophile, 1.2 equiv). The reaction was stirred at room
temperature until judged complete by TLC. After completion, the
reaction mixture was concentrated by rotary evaporation, and pu-
rified by column chromatography to yield polycyclic guanidine.
NMR (500 MHz, CDCl3)
d
7.36e7.00 (m, 10H), 5.07 (d, J ¼ 15.1 Hz,
1H), 4.92 (s, 1H), 4.83 (s, 1H), 4.78 (s, 1H), 4.16 (d, J ¼ 15.1 Hz, 1H),
3.66 (dd, J ¼ 9.7, 4.6 Hz, 1H), 2.86 (dd, J ¼ 13.1, 4.6 Hz, 1H), 2.46 (dd,
J ¼ 13.1, 9.7 Hz, 1H), 1.56 (s, 3H), 1.56 (s, 9H), 1.51 (s, 9H) ppm; 13C
{1H} NMR (100 MHz, CDCl3)
d 159.7, 152.0, 149.4, 140.0, 135.9, 135.8,
130.6, 129.9, 129.0, 128.5, 128.4, 128.1, 127.1, 83.8, 79.4, 61.5, 46.9,
38.8, 28.3, 28.2, 20.9 ppm; LRMS (ESI) Calculated for C31H40N3O4 m/
z (MþH): 518.3, Obsd. 518.4.
4.2.6.1. tert-butyl
(4R,10a0R,E)-1-benzyl-2-((tert-butoxycarbonyl)
imino)-10,30-dioxo-20-phenyl-20,30,80,90,100,10a0-hexahydro-10H,70H-
spiro[imidazolidine-4,50-[1,2,4]triazolo[1,2-a]cinnoline]-3-
carboxylate (8a). Prepared according to the general procedure 6, to
give the spiro-cyclic guanidine as white solid in 61% yield (0.118 g).
Rf ¼ 0.32 (40% ethyl acetate/n-hexanes). 1H NMR (500 MHz, CDCl3)
4.2.5.5. tert-butyl
(2E,5Z)-3-(benzo[d][1,3]dioxol-5-ylmethyl)-2-
((tert-butoxycarbonyl)imino)-5-(2-methylallylidene)imidazolidine-1-
carboxylate (7e). Prepared according to general procedure 5, to give
the 5-exo-dig cyclized guanidine as a white solid in 80% yield (5-
exo-dig:6-endo-dig ¼ 10:1), (0.377 g). Rf ¼ 0.45 (40% ethyl acetate/
d
7.61e7.27 (m, 10H), 5.35 (s, 1H), 5.22 (d, J ¼ 14.9 Hz, 1H), 4.40 (dd,
J ¼ 11.4, 3.5 Hz,1H), 4.20 (d, J ¼ 14.9 Hz,1H), 3.88 (d, J ¼ 11.2 Hz,1H),
3.50 (d, J ¼ 11.2 Hz, 1H), 2.46 (m, 1H), 2.40 (m, 1H), 2.14 (m, 1H), 1.96
(m, 1H), 1.90 (m, 1H), 1.60 (m, 1H), 1.49 (s, 9H), 1.42 (s, 9H), 1.37 (m,
n-hexanes). 1H NMR (500 MHz, CDCl3)
d 6.79e6.74 (m, 3H), 5.94 (s,
2H), 5.61 (s, 1H), 5.01 (s, 2H), 4.49 (s, 2H), 3.74 (s, 2H), 1.94 (s, 3H),
1.54 (s, 9H), 1.46 (s, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
1H), 1.30 (m, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
d 159.1,
d
159.3, 151.8, 149.0, 148.0, 147.4, 140.0, 129.0, 128.3, 121.9, 118.9,
153.2, 151.6, 149.6, 148.7, 142.5, 135.6, 131.1, 129.2, 128.8, 128.7,
128.4, 127.8, 126.2, 115.8, 83.4, 78.5, 73.8, 56.8, 54.4, 49.9, 34.2, 31.1,
28.5, 28.2, 24.3 ppm; LRMS (ESI) Calculated for C35H43N6O6 m/z
(MþH): 643.3, Obsd. 643.3.
117.3, 108.9, 108.3, 101.1, 84.0, 79.2, 49.3, 48.1, 28.2, 28.0, 21.0 ppm;
LRMS (ESI) Calculated for C25H34N3O6 m/z (MþH): 472.2, Obsd.
472.3.
4.2.5.6. tert-butyl (2E,5Z)-2-((tert-butoxycarbonyl)imino)-3-(2,4-
dimethoxybenzyl)-5-(2-methylallylidene)imidazolidine-1-
carboxylate (7f). Prepared according to general procedure 5, to give
the 5-exo-dig cyclized guanidine as a white solid in 60% yield (5-
exo-dig:6-endo-dig ¼ 9:1), (0.377 g). Rf ¼ 0.39 (40% ethyl acetate/n-
4.2.6.2. tert-butyl
(4R,5R,10a0R,E)-1,5-dibenzyl-2-((tert-butox-
ycarbonyl)imino)-10,30-dioxo-20-phenyl-20,30,80,90,100,10a0-hexahydro-
10H,70H-spiro[imidazolidine-4,50-[1,2,4]triazolo[1,2-a]cinnoline]-3-
carboxylate (8b). Prepared according to the general procedure 6, to
give the spiro-cyclic guanidine as white solid in 94% yield (0.207 g).
Rf ¼ 0.54 (40% ethyl acetate/n-hexanes). 1H NMR (500 MHz, CDCl3)
hexanes). 1H NMR (500 MHz, CDCl3)
d 7.20 (m, 1H), 6.44 (m, 2H),
5.59 (s, 1H), 4.99 (s, 1H), 4.98 (s, 1H), 4.54 (s, 2H), 3.79 (s, 3H), 3.78
d 7.59e7.35 (m, 5H), 7.23e7.14 (m, 8H), 6.95 (m, 2H), 5.49 (s, 1H),
(s, 3H), 3.75 (s, 2H), 1.93 (s, 3H), 1.54 (s, 9H), 1.46 (s, 9H) ppm; 13C
4.95 (dd, J ¼ 9.2, 5.2 Hz, 1H), 4.76 (d, J ¼ 15.6 Hz, 1H), 4.68 (d,
J ¼ 15.6 Hz, 1H), 4.22 (dd, J ¼ 11.6, 3.6 Hz, 1H), 2.96 (dd, J ¼ 15.6,
5.2 Hz, 1H), 2.75 (dd, J ¼ 15.6, 9.2 Hz, 1H), 2.30 (m, 1H), 2.20 (m, 1H),
2.00 (m, 1H), 1.69 (m, 1H), 1.61 (m, 1H), 1.49 (s, 9H), 1.40 (s, 9H), 1.28
(m, 1H), 0.79 (m, 1H), 0.68 (m, 1H) ppm; 13C{1H} NMR (100 MHz,
{1H} NMR (100 MHz, CDCl3)
d 160.7, 159.2, 158.6, 151.7, 148.9, 140.0,
131.4, 128.8, 118.3, 116.8, 115.6, 104.3, 98.2, 83.5, 78.7, 55.1, 49.4,
42.4, 28.1, 28.0, 20.8 ppm; LRMS (ESI) Calculated for C26H38N3O6 m/
z (MþH): 488.3, Obsd. 488.4.
CDCl3)
d 159.0, 152.9, 151.0, 149.8, 148.2, 141.4, 136.2, 135.8, 131.0,
4.2.5.7. tert-butyl (2E,5Z)-2-((tert-butoxycarbonyl)imino)-5-(cyclo-
hex-1-en-1-ylmethylene)-3-methylimidazolidine-1-carboxylate (7g).
Prepared according to the general procedure 5, to give the 5-exo-dig
cyclized guanidine as a white solid, (5-exo-dig:6-endo-dig ¼ 1:1),
(0.211 g, total 54% yield). Rf ¼ 0.21 (60% ethyl acetate/n-hexanes). 1H
129.1, 128.7, 128.4, 128.3, 128.2, 127.4, 126.8, 126.0, 112.2, 83.6, 78.5,
77.3, 63.7, 54.1, 48.8, 35.7, 34.2, 30.5, 28.5, 28.1, 26.8, 23.9 ppm;
LRMS (ESI) Calculated for C42H49N6O6 m/z (MþH): 733.4, Obsd.
733.4.
NMR (500 MHz, CDCl3)
d
5.76 (s. 1H), 5.58 (s, 1H), 3.90 (s, 2H), 2.97
4.2.6.3. tert-butyl (R,E)-1-benzyl-2-((tert-butoxycarbonyl)imino)-70-
methyl-10,30-dioxo-20-phenyl-20,30-dihydro-10H,80H-spiro[imidazolidine-
4,50-[1,2,4]triazolo[1,2-a]pyridazine]-3-carboxylate (8c). Prepared ac-
cording to the general procedure 6, to give the spiro-cyclic guanidine
as white solid in 56% yield (0.101 g). Rf ¼ 0.16 (40% ethyl acetate/n-
(s, 3H), 2.20 (m, 2H), 2.14 (m, 2H), 1.63 (m, 4H), 1.51 (s, 9H), 1.46 (s,
9H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
d
158.9,151.8,149.2,134.0,
129.1, 125.9, 119.9, 83.3, 78.9, 52.5,31.6, 28.1, 27.9, 26.8, 25.7, 22.6,
22.1 ppm; LRMS (ESI) Calculated for C21H34N3O4 m/z (MþH): 392.3,
Obsd. 392.4.
hexanes). 1H NMR (500 MHz, CDCl3)
d 7.58e7.26 (m,10H), 5.45 (s,1H),
5.14 (d, J ¼ 14.9 Hz, 1H), 4.24 (d, J ¼ 16.8 Hz, 1H), 4.22 (d, J ¼ 14.9 Hz,
1H), 3.99 (d, J ¼ 16.8 Hz, 1H), 3.80 (d, J ¼ 11.3 Hz, 1H), 3.47 (d,
J ¼ 11.3 Hz, 1H), 1.90 (s, 3H), 1.49 (s, 9H), 1.42 (s, 9H) ppm; 13C{1H}
4.2.5.8. tert-butyl (2E,5Z)-4-benzyl-2-((tert-butoxycarbonyl)imino)-
3-(cyclopropylmethyl)-5-(2-methylallylidene)imidazolidine-1-
carboxylate (7h). Prepared according to the general procedure 5, to
give the 5-exo-dig cyclized guanidine as a white solid in 79% yield
(5-exo-dig:6-endo-dig ¼ >20:1), (0.381 g). Rf ¼ 0.16 (20% ethyl ac-
NMR (100 MHz, CDCl3)
d 159.0, 152.7, 151.1, 150.0, 149.4, 135.4, 133.5,
130.9, 129.2, 128.7, 128.6, 128.4, 127.8, 126.0, 120.6, 83.3, 78.5, 73.7,
56.0, 49.6, 45.0, 28.4, 28.1, 19.9 ppm; LRMS (ESI) Calculated for
etate/n-hexanes). 1H NMR (500 MHz, CDCl3)
d
7.29 (m, 3H), 7.15 (m,
C32H39N6O6 m/z (MþH): 603.3, Obsd. 603.4.
2H), 4.92 (s, 1H), 4.87 (s, 1H), 4.80 (s, 1H), 4.06 (dd, J ¼ 9.8, 3.8 Hz,
1H), 3.70 (dd, J ¼ 14.6, 6.6 Hz,1H), 3.11 (dd, J ¼ 13.0, 3.8 Hz,1H), 3.00
(dd, J ¼ 14.6, 7.5 Hz, 1H), 2.48 (dd, J ¼ 13.0, 9.9 Hz, 1H), 1.88 (s, 3H),
1.54 (s, 9H),1.51 (s, 9H), 1.03 (m, 1H), 0.64 (m, 1H), 0.56 (m, 1H), 0.30
4.2.6.4. tert-butyl
(4R,5R,E)-1,5-dibenzyl-2-((tert-butoxycarbonyl)
imino)-70-methyl-10,30-dioxo-20-phenyl-20,30-dihydro-10H,80H-spiro
[imidazolidine-4,50-[1,2,4]triazolo[1,2-a]pyridazine]-3-carboxylate

6076
K.-H. Kwon et al. / Tetrahedron 73 (2017) 6067e6079
(8d). Prepared according to the general procedure 6, to give the
spiro-cyclic guanidine as pale yellow solid in 75% yield (0.156 g).
Rf ¼ 0.23 (40% ethyl acetate/n-hexanes). 1H NMR (500 MHz, CDCl3)
give the spiro-cyclic guanidine as pale yellow solid in 76% yield
(0.127 g). Rf ¼ 0.13 (40% ethyl acetate/n-hexanes). 1H NMR
(500 MHz, CDCl3)
d
7.59e7.33 (m, 5H), 5.43 (s,1H), 4.42 (dd, J ¼ 11.3,
d
7.48e7.12 (m, 13H), 5.61 (s, 1H), 5.04 (d, J ¼ 15.6 Hz, 1H), 4.88 (dd,
3.4 Hz, 1H), 4.00 (d, J ¼ 11.0 Hz, 1H), 3.82 (d, J ¼ 11.0 Hz, 1H), 3.00 (s,
3H), 2.53 (m, 1H), 2.42 (m, 1H), 2.16 (m, 1H), 2.00 (m, 1H), 1.94 (m,
1H), 1.61 (m, 1H), 1.49 (m, 1H), 1.46 (s, 9H), 1.41 (s, 9H), 1.36 (m, 1H)
J ¼ 11.2, 4.9 Hz,1H), 4.49 (d, J ¼ 15.6 Hz,1H), 3.88 (d, J ¼ 16.6 Hz,1H),
3.14 (dd, J ¼ 14.7, 4.4 Hz, 1H), 2.80 (d, J ¼ 16.6 Hz, 1H), 2.54 (dd,
J ¼ 14.7, 11.2 Hz, 1H), 1.77 (s, 3H), 1.50 (s, 9H), 1.36 (s, 9H) ppm; 13
C
ppm; 13C{1H} NMR (100 MHz, CDCl3)
d 158.8, 153.1, 151.5, 149.3,
{1H} NMR (100 MHz, CDCl3)
d
159.0, 151.9, 149.7, 149.5, 149.1, 135.4,
148.5, 142.6, 130.9, 129.0, 128.2, 126.0, 115.5, 83.0, 78.0, 73.6, 58.7,
54.2, 34.2, 32.2, 30.9, 28.3, 28.1, 28.0, 24.2 ppm; LRMS (ESI) Calcu-
lated for C29H39N6O6 m/z (MþH): 567.3, Obsd. 567.4.
135.3, 134.1, 130.8, 129.2, 128.8, 128.7, 128.4, 128.3, 128.2, 127.7,
126.8, 125.6, 117.3, 83.6, 78.9, 77.2, 62.0, 47.5, 43.9, 34.7, 28.5, 28.0,
20.1 ppm; LRMS (ESI) Calculated for C39H45N6O6 m/z (MþH): 693.3,
Obsd. 693.4.
4.2.6.9. tert-butyl (4R,5R,E)-5-benzyl-2-((tert-butoxycarbonyl)imino)-
1-(cyclopropylmethyl)-70-methyl-10,30-dioxo-20-phenyl-20,30-dihydro-
10H,80H-spiro[imidazolidine-4,5'-[1,2,4]triazolo[1,2-a]pyridazine]-3-
carboxylate (8i). Prepared according to general procedure 6, to give
the spiro-cyclic guanidine as white solid in 88% yield (0.173 g).
Rf ¼ 0.30 (40% ethyl acetate/n-hexanes). 1H NMR (500 MHz, CDCl3)
4.2.6.5. tert-butyl (R,E)-1-(benzo[d][1,3]dioxol-5-ylmethyl)-2-((tert-
butoxycarbonyl)imino)-70-methyl-10,30-dioxo-20-phenyl-20,30-dihy-
dro-10H,80H-spiro[imidazolidine-4,50-[1,2,4]triazolo[1,2-a]pyr-
idazine]-3-carboxylate (8e). Prepared according to the general
procedure 6, to give the spiro-cyclic guanidine as pale yellow solid
in 87% yield (0.169 g). Rf ¼ 0.17 (40% ethyl acetate/n-hexanes). 1H
d
7.51e7.13 (m, 10H), 5.57 (s, 1H), 5.24 (dd, J ¼ 11.3, 4.3 Hz, 1H), 4.04
(dd, J ¼ 14.6, 5.4 Hz, 1H), 3.92 (d, J ¼ 16.6 Hz, 1H), 3.37 (dd, J ¼ 14.6,
4.2 Hz, 1H), 2.88 (d, J ¼ 16.6 Hz, 1H), 2.79 (dd, J ¼ 14.6, 8.2 Hz, 1H),
2.67 (dd, J ¼ 14.6, 11.3 Hz, 1H), 1.77 (s, 3H), 1.48 (s, 9H), 1.35 (s, 9H),
1.13 (m, 1H), 0.63 (m, 1H), 0.51 (m, 1H), 0.22 (m, 2H) ppm; 13C{1H}
NMR (500 MHz, CDCl3)
d 7.58e7.34 (m, 5H), 6.83 (s, 1H), 6.74 (m,
2H), 5.92 (s, 2H), 5.46 (s, 1H), 5.01 (d, J ¼ 14.6 Hz, 1H), 4.24 (d,
J ¼ 17.1 Hz,1H), 4.13 (d, J ¼ 14.6 Hz,1H), 3.90 (d, J ¼ 17.1 Hz,1H), 3.78
(d, J ¼ 11.4 Hz, 1H), 3.48 (d, J ¼ 11.4 Hz, 1H), 1.90 (s, 3H), 1.49 (s, 9H),
NMR (100 MHz, CDCl3) d 159.0, 151.8, 150.0, 149.8,149.3,135.9,134.2,
1.42 (s, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
d
158.9, 152.5,
131.0, 129.3, 129.0, 128.6, 128.4, 127.0, 125.8, 117.7, 83.4, 78.6, 77.2,
61.8, 48.0, 44.0, 34.8, 28.5, 28.1, 20.2, 8.5, 5.2, 2.5 ppm; LRMS (ESI)
Calculated for C36H45N6O6 m/z (MþH): 657.3, Obsd. 657.4.
151.0, 150.0, 149.3, 148.0, 147.3, 133.6, 130.9, 129.1, 129.0, 128.4,
125.9, 122.0, 120.5, 109.0, 108.2, 101.1, 83.2, 78.5, 73.6, 55.9, 49.3,
45.0, 28.4, 28.0, 20.0 ppm; LRMS (ESI) Calculated for C33H39N6O8 m/
z (MþH): 647.3, Obsd. 647.4.
4.2.7. (4R,10a0R)-1-benzyl-2-imino-20-phenyl-80,90,100,10a0-
tetrahydro-10H,70H-spiro[imidazolidine-4,5'-[1,2,4]triazolo[1,2-a]
cinnoline]-10,30(20H)-dione (9a)
4.2.6.6. tert-butyl (R,E)-1-(benzo[d][1,3]dioxol-5-ylmethyl)-2-((tert-
butoxycarbonyl)imino)-20-ethyl-70-methyl-10,30-dioxo-20,30-dihydro-
10H,80H-spiro[imidazolidine-4,50-[1,2,4]triazolo[1,2-a]pyridazine]-3-
carboxylate (8f). Prepared according to the general procedure 6, to
give the spiro-cyclic guanidine as pale yellow solid in 91% yield
(0.163 g). Rf ¼ 0.17 (40% ethyl acetate/n-hexanes). 1H NMR
A 50 mL round-bottom flask was charged with the appropriate
polycyclic guanidine (0.2 mmol). The CH2Cl2/TFA mixture (1:1,
4.0 mL) was added. The reaction mixture was stirred at room
temperature for 2 h. The crude mixture was taken up in MeOH and
2 M HCl in ethyl ether was added. The mixture was again concen-
trated and the resulting solid triturated with ethyl ether. The solid
was then collected to give the title compound as white solid in 50%
(500 MHz, CDCl3) d 6.84 (s,1H), 6.76 (m, 2H), 5.94 (s, 2H), 5.41 (s, H),
4.98 (d, J ¼ 14.7 Hz, 1H), 4.17 (d, J ¼ 14.7 Hz, 1H), 4.14 (d, J ¼ 17.1 Hz,
1H), 3.81 (d, J ¼ 17.1 Hz, 1H), 3.72 (d, J ¼ 11.2 Hz, 1H), 3.63 (qd,
J ¼ 7.3, 2.1 Hz, 2H), 3.42 (d, J ¼ 11.2 Hz, 1H), 1.88 (s, 3H), 1.48 (s, 9H),
1.39 (s, 9H), 1.28 (t, J ¼ 7.3 Hz, 3H) ppm; 13C{1H} NMR (100 MHz,
yield (48 mg). 1H NMR (500 MHz, DMSO-d6)
d 9.81 (s, 1H), 8.56 (s,
2H), 7.52e7.32 (m, 10H), 5.56 (s, 1H), 4.79 (d, J ¼ 12.4 Hz, 1H), 4.56
(d, J ¼ 12.4 Hz, 1H), 4.42 (m, 1H), 4.15 (s, 1H), 3.79 (s, 1H), 2.37 (m,
1H), 2.18 (m, 2H), 1.83 (m, 1H), 1.75 (m, 1H), 1.55 (m, 1H), 1.37 (m,
CDCl3)
d 159.0, 152.2, 152.0, 151.4, 149.5, 148.1, 147.3, 133.4, 129.2,
122.1, 120.9, 109.1, 108.3, 101.2, 83.1, 78.6, 73.4, 55.8, 49.3, 45.0, 34.5,
28.5, 28.1, 20.0,13.5 ppm; LRMS (ESI) Calculated for C29H39N6O8 m/z
(MþH): 599.3, Obsd. 599.3.
1H), 1.21 (m, 1H) ppm; 13C{1H} NMR (100 MHz, DMSO-d6)
d 156.7,
152.0, 149.1, 140.8, 134.1, 130.4, 128.9, 128.4, 128.3, 127.8, 127.6,
126.0, 116.5, 72.6, 57.0, 53.7, 47.8, 32.7, 29.8, 27.3, 23.2 ppm; HRMS
(ESI) Calculated for C25H27N6O2 m/z (MþH): 443.2195, Obsd.
443.2197.
4.2.6.7. tert-butyl (R,E)-2-((tert-butoxycarbonyl)imino)-1-(2,4-
dimethoxybenzyl)-70-methyl-10,30-dioxo-20-phenyl-20,30-dihydro-
10H,80H-spiro[imidazolidine-4,50-[1,2,4]triazolo[1,2-a]pyridazine]-3-
carboxylate (8g). Prepared according to the general procedure 6, to
give the spiro-cyclic guanidine as pale yellow solid in 97% yield
(0.193 g). Rf ¼ 0.13 (40% ethyl acetate/n-hexanes). 1H NMR
4.2.8. General procedure 7 for the deprotection and fragmentation
of 8a-i
A 50 mL round-bottom flask was charged with the appropriate
polycyclic guanidine (0.2 mmol). The CH2Cl2/TFA mixture (1:1,
4.0 mL) was added. The reaction mixture was stirred at room
temperature for 2 h. The crude mixture was taken up in MeOH and
2 M HCl in ethyl ether was added. The mixture was again concen-
trated and the resulting solid triturated with ethyl ether. The solid
was then collected to give the title compound.
(500 MHz, CDCl3)
d 7.57e7.25 (m, 6H), 6.41 (m, 2H), 5.44 (s, 1H),
4.85 (d, J ¼ 14.5 Hz,1H), 4.39 (d, J ¼ 14.5 Hz, 1H), 4.21 (d, J ¼ 16.9 Hz,
1H), 3.89 (d, J ¼ 16.9 Hz, 1H), 3.87 (d, J ¼ 11.3 Hz, 1H), 3.75 (s, 6H),
3.47 (d, J ¼ 11.3 Hz, 1H), 1.88 (s, 3H), 1.48 (s, 9H), 1.40 (s, 9H) ppm;
13C{1H} NMR (100 MHz, CDCl3)
d 160.6, 158.9, 158.7, 152.3, 150.7,
149.9, 149.4, 132.9, 131.5, 131.0, 129.0, 128.2, 125.8, 120.7, 115.6,
104.3, 98.2, 82.9, 78.1, 73.6, 55.7, 55.3, 55.2, 44.8, 43.2, 28.4, 27.9,
19.8 ppm; LRMS (ESI) Calculated for C34H43N6O8 m/z (MþH): 663.3,
Obsd. 663.4.
4.2.8.1. (R,Z)-1-(2-((2-amino-1-benzyl-1H-imidazol-4-yl)methylene)
cyclohexyl)-4-phenyl-1,2,4-triazolidine-3,5-dione (10a). Prepared ac-
cording to the general procedure 7, to give the polycyclic guanidine
as white solid in 50% yield (48 mg). 1H NMR (500 MHz, DMSO-d6)
4.2.6.8. tert-butyl (4R,10a0R,E)-2-((tert-butoxycarbonyl)imino)-1-
methyl-10,30-dioxo-20-phenyl-20,30,80,90,100,10a0-hexahydro-10H,70H-
spiro[imidazolidine-4,50-[1,2,4]triazolo[1,2-a]cinnoline]-3-
carboxylate (8h). Prepared according to the general procedure 6, to
d 12.61 (s, 1H), 10.51 (s, 1H), 7.96 (s, 2H), 7.51e7.30 (m, 10H), 7.08 (s,
1H), 6.09 (s,1H), 5.15 (d, J ¼ 14.6 Hz, 1H), 5.10 (d, J ¼ 14.6 Hz,1H), 4.80
(s, 1H), 2.61 (m, 1H), 2.30 (m, 1H), 2.23 (m, 1H), 1.79 (m, 2H), 1.54 (m,
2H), 1.36 (m, 1H) ppm; 13C{1H} NMR (100 MHz, DMSO-d6)
d 153.1,

K.-H. Kwon et al. / Tetrahedron 73 (2017) 6067e6079
6077
152.8, 145.6, 140.1, 134.8, 131.3, 128.5, 127.8, 127.6, 127.3, 125.9, 121.7,
113.9, 113.1, 55.0, 47.4, 32.7, 29.2, 26.3, 20.2 ppm; HRMS (ESI)
Calculated for C25H28N6O2 m/z (MþH): 443.2195, Obsd. 443.2197.
4.2.8.7. (Z)-1-(3-(2-amino-1-(2,4-dimethoxybenzyl)-1H-imidazol-
4-yl)-2-methylallyl)-4-phenyl-1,2,4-triazolidine-3,5-dione (10g).
Prepared according to the general procedure 7, to give the poly-
cyclic guanidine as pale yellow solid in 80% yield (80 mg). 1H NMR
(500 MHz, DMSO-d6)
7.48e7.23 (m, 6H), 6.96 (s, 1H), 6.56e6.50 (m, 2H), 6.14 (s, 1H),
d 12.63 (s, 1H), 11.07 (s, 1H), 7.88 (s, 2H),
4.2.8.2. (R,Z)-1-(2-((2-amino-1,5-dibenzyl-1H-imidazol-4-yl)methy-
lene)cyclohexyl)-4-phenyl-1,2,4-triazolidine-3,5-dione
(10b).
4.97 (s, 2H), 4.33 (s, 2H), 3.79 (s, 3H), 3.73 (s, 3H), 1.82 (s, 3H) ppm;
Prepared according to the general procedure 7, to give the poly-
13C{1H} NMR (100 MHz, DMSO-d6)
d 160.9, 158.0, 152.7, 152.2,
cyclic guanidine as white solid in 85% yield (97 mg). 1H NMR
145.8, 135.7, 131.6, 130.2, 128.8, 127.8, 126.1, 126.0, 121.5, 114.9,
114.8, 114.5, 104.6, 98.5, 55.5, 55.3, 47.2, 43.5, 21.2 ppm; HRMS
(ESI) Calculated for C24H27N6O4 m/z (MþH): 463.2094, Obsd.
463.2094.
(500 MHz, DMSO-d6)
d 12.59 (s, 1H), 10.53 (s, 1H), 7.99 (s, 2H),
7.46e6.99 (m, 15H), 6.17 (s, 1H), 5.06 (d, J ¼ 17.5 Hz, 1H), 4.99 (d,
J ¼ 17.5 Hz, 1H), 4.89 (s, 1H), 3.82 (d, J ¼ 17.5 Hz, 1H), 3.78 (d,
J ¼ 17.5 Hz, 1H), 2.54 (m, 1H), 2.42 (m, 1H), 2.28 (m, 1H), 1.82 (m,
2H), 1.64 (m, 1H), 1.54 (s, 9H), 1.36 (m, 1H) ppm; 13C{1H} NMR
4.2.8.8. (R,Z)-1-(2-((2-amino-1-methyl-1H-imidazol-4-yl)methylene)
cyclohexyl)-4-phenyl-1,2,4-triazolidine-3,5-dione (10h). Prepared ac-
cording to the general procedure 7, to give the polycyclic guanidine
as white solid in 83% yield (67 mg). 1H NMR (500 MHz, DMSO-d6)
(100 MHz, DMSO-d6)
d 153.5, 153.2, 147.2, 142.5, 136.7, 134.7, 131.8,
128.7, 128.6, 128.5, 127.9, 127.8, 127.6, 126.6, 126.4, 126.1, 123.4,
119.3, 118.9, 55.4, 45.3, 33.0, 30.1, 27.8, 27.3, 20.5 ppm; HRMS (ESI)
Calculated for C32H34N6O2 m/z (MþH): 533.2665, Obsd. 533.2669.
d
12.57 (s, 1H), 10.59 (s, 1H), 7.77 (s, 2H), 7.46e7.37 (m, 5H), 7.02 (s,
1H), 6.09 (s, 1H), 4.81 (s, 1H), 3.43 (s, 3H), 2.63 (m, 1H), 2.37 (m, 1H),
2.23 (m, 1H), 1.82 (m, 2H), 1.53 (m, 2H), 1.37 (m, 1H) ppm; 13C{1H}
4.2.8.3. (Z)-1-(3-(2-amino-1-benzyl-1H-imidazol-4-yl)-2-
methylallyl)-4-phenyl-1,2,4-triazolidine-3,5-dione (10c). Prepared ac-
cording to the general procedure 7, to give the polycyclic guanidine
as white solid in 80% yield (70 mg). 1H NMR (500 MHz, DMSO-d6)
NMR (100 MHz, DMSO-d6)
d 153.1, 152.8, 145.8, 139.9, 131.4, 128.5,
127.6, 126.0, 121.1, 115.0, 113.0, 55.2, 32.8, 32.1, 29.4, 26.6, 20.3 ppm;
HRMS (ESI) Calculated for C19H23N6O2 m/z (MþH): 367.1882, Obsd.
367.1880.
d
12.63 (s, 1H), 11.02 (s, 1H), 7.99 (s, 2H), 7.50e7.31 (m, 10H), 7.25 (s,
1H), 6.16, (s, 1H), 5.17 (s, 2H), 4.35 (s, 2H), 1.84 (s, 3H) ppm; 13C{1H}
NMR (100 MHz, DMSO-d6) 152.6, 152.1, 145.8, 136.0, 135.2, 131.6,
d
4.2.8.9. (Z)-1-(3-(2-amino-5-benzyl-1-(cyclopropylmethyl)-1H-imi-
dazol-4-yl)-2-methylallyl)-4-phenyl-1,2,4-triazolidine-3,5-dione
(10i). Prepared according to the general procedure 7, to give the
polycyclic guanidine as white solid in 80% yield (79 mg). 1H NMR
128.8, 128.7, 128.0, 127.8, 127.5, 126.0, 122.0, 114.6, 114.5, 47.6, 47.2,
21.1 ppm; HRMS (ESI) Calculated for C22H23N6O2 m/z (MþH):
403.1882, Obsd. 403.1888.
(500 MHz, DMSO-d6)
d 12.53 (s, 1H), 10.96 (s, 1H), 7.76 (s, 2H),
7.50e7.19 (m, 10H), 6.28 (s, 1H), 4.49 (s, 2H), 4.00 (s, 2H), 3.66 (d,
J ¼ 4.2 Hz, 2H), 1.82 (s, 3H), 0.89 (m, 1H), 0.35 (m, 2H), 0.27 (m, 2H)
4.2.8.4. (Z)-1-(3-(2-amino-1,5-dibenzyl-1H-imidazol-4-yl)-2-
methylallyl)-4-phenyl-1,2,4-triazolidine-3,5-dione (10d). Prepared ac-
cording to the general procedure 7, to give the polycyclic guanidine as
white solid in 68% yield (72 mg). 1H NMR (500 MHz, DMSO-d6)
ppm; 13C{1H} NMR (100 MHz, DMSO-d6)
d 152.8, 152.2, 146.7, 137.0,
136.1, 131.7, 128.8, 128.7, 128.0, 127.8, 126.7, 126.1, 123.4, 119.0, 114.8,
47.3, 46.0, 27.8, 21.2, 10.0, 3.3 ppm; HRMS (ESI) Calculated for
d
12.73 (s, 1H), 11.05 (s, 1H), 7.96 (s, 2H), 7.52e7.02 (m, 15H), 6.30 (s,
1H), 5.05 (s, 2H), 4.12 (s, 2H), 3.82 (s, 2H), 1.83 (s, 3H) ppm; 13C{1H}
NMR (100 MHz, DMSO-d6) 152.8, 152.3, 147.2, 136.7, 136.6, 134.8,
C26H30N6O2 m/z (MþH): 458.2430, Obsd. 458.2430.
d
4.2.9. General procedure 8 for the hetero cycloaddition of cyclic
guanidines
131.8, 128.9, 128.7, 128.6, 128.0, 127.9, 127.7, 126.7, 126.2, 126.1, 123.6,
119.4, 114.9, 47.2, 45.3, 28.0, 21.3 ppm; HRMS (ESI) Calculated for
To a stirring solution of the preferred cyclic guanidine (diene, 1
equiv) and benzyl hydroxycarbamate 11 (dienophile, 1.2 equiv) in
THF (0.07 M) was added CuCl (20 mol%) and pyridine (5 mol%). The
reaction was stirred at room temperature open to the air until
completed by TLC. Upon completion, the reaction was quenched
with EDTA (0.5 M, pH 7.0), diluted with ethyl acetate and stirred for
30 min. The reaction was extracted with ethyl acetate three times
and the combined organic layers were then dried over Na2SO4,
filtered, and condensed by rotary evaporation. Purification was
accomplished by flash chromatography to give the polycyclic
guanidine.
C
29H29N6O2 m/z (MþH): 493.2352, Obsd. 493.2363.
4.2.8.5. (Z)-1-(3-(2-amino-1-(benzo[d][1,3]dioxol-5-ylmethyl)-1H-
imidazol-4-yl)-2-methylallyl)-4-phenyl-1,2,4-triazolidine-3,5-dione
(10e). Prepared according to the general procedure 7, to give the
polycyclic guanidine as pale yellow solid in 81% yield (78 mg). 1H
NMR (500 MHz, DMSO-d6) d 12.40 (s, 1H), 10.91 (s, 1H), 7.85 (s, 2H),
7.30e7.18 (m, 5H), 7.09 (s, 1H), 6.87 (s, 1H), 6.76e6.69 (m, 2H), 5.95
(s, 1H), 5.80 (s, 2H), 4.87 (s, 2H), 4.16 (s, 2H), 1.63 (s, 3H) ppm; 13C
{1H} NMR (100 MHz, DMSO-d6)
d 152.7, 152.3, 147.2, 145.7, 136.0,
131.7, 128.9, 128.8, 127.9, 126.1, 122.0, 121.8, 114.8, 114.4, 108.6, 108.4,
101.2, 47.5, 47.3, 21.2 ppm; HRMS (ESI) Calculated for C23H23N6O4
m/z (MþH): 447.1781, Obsd. 447.1785.
4.2.9.1. 6-Benzyl 1-(tert-butyl) (4aR,6aS,E)-2-((tert-butoxycarbonyl)
imino)-3-methyl-3,4,4a,6a,7,8,9,10-octahydro-1H-benzo[c]pyrimido
[4,5-e][1,2]oxazine-1,6(2H)-dicarboxylate (12a). The general pro-
cedure 8 was used to give the polycyclic guanidine as pale yellow
solid. (0.160 g, 72% yield). Rf ¼ 0.52 (40% ethyl acetate/n-hexanes).
4.2.8.6. (Z)-1-(3-(2-amino-1-(benzo[d][1,3]dioxol-5-ylmethyl)-1H-
imidazol-4-yl)-2-methylallyl)-4-ethyl-1,2,4-triazolidine-3,5-dione
(10f). Prepared according to the general procedure 7, to give the
polycyclic guanidine as white solid in 86% yield (75 mg). 1H NMR
1H NMR (500 MHz, CDCl3)
d
7.37e7.31 (m. 5H), 5.25 (d, J ¼ 12.7 Hz,
1H), 5.20 (d, J ¼ 12.7 Hz,1H), 4.80 (br, 1H), 3.59 (dd, J ¼ 14.07, 7.3 Hz,
1H), 3.25 (d, J ¼ 13.7 Hz, 1H), 3.16 (d, J ¼ 14.2 Hz, 1H), 2.98 (s, 3H),
2.10 (m, 1H), 1.85 (m, 2H), 1.68 (m, 2H), 1.51 (s, 9H), 1.45 (m, 1H), 1.41
(s, 9H), 1.32 (m, 1H), 1.27 (m, 1H) ppm; 13C{1H} NMR (100 MHz,
(500 MHz, DMSO-d6) d 12.58 (s, 1H), 10.63 (s, 1H), 8.01 (s, 2H), 7.24
(s, 1H), 7.05e6.88 (m, 3H), 6.09 (s, 1H), 6.00 (s, 2H), 5.05 (s, 2H), 4.24
(s, 2H), 3.42 (q, J ¼ 7.3 Hz, 2H), 1.72 (s, 3H), 1.10 (t, J ¼ 6.8 Hz, 3H)
ppm; 13C{1H} NMR (100 MHz, DMSO-d6)
d
154.0, 153.6, 147.5, 147.2,
CDCl3) d 159.4, 154.2, 151.7, 149.2, 136.0, 134.0, 128.7, 128.6, 128.4,
145.7, 136.2, 128.8, 122.0, 121.8, 114.5, 114.3, 108.6, 108.4, 101.2, 47.5,
47.1, 33.5, 21.1, 13.1 ppm; HRMS (ESI) Calculated for C19H23N6O4 m/z
(MþH): 399.1781, Obsd. 399.1786.
128.2, 82.6, 78.6, 76.6, 67.7, 56.4, 49.9, 37.5, 32.2, 28.3, 28.1, 28.0,
26.3, 24.8 ppm; LRMS (ESI) Calculated for C29H41N4O7 m/z (MþH):
567.3, Obsd. 567.4.

6078
K.-H. Kwon et al. / Tetrahedron 73 (2017) 6067e6079
4.2.9.2. 6-Benzyl 1-(tert-butyl) (4aR,6aS,E)-2-((tert-butoxycarbonyl)
imino)-3-(2,4-dimethoxybenzyl)-3,4,4a,6a,7,8,9,10-octahydro-1H-
48.0, 45.0, 30.2, 26.2, 25.9, 23.8 ppm; HRMS (ESI) Calculated for
19H27N4O3 m/z (MþH): 359.2083, Obsd. 359.2092.
C
benzo[c]pyrimido[4,5-e][1,2]oxazine-1,6(2H)-dicarboxylate
(12b).
Prepared according to the general procedure 8, to give the poly-
4.2.10.3. (R)-7-(benzo[d][1,3]dioxol-5-ylmethyl)-4-methyl-3,7,8,8a-
tetrahydro-2H-pyrimido[4,5-e][1,2]oxazin-6(5H)-imine (13c).
cyclic guanidine as pale yellow solid in 51% yield (0.141 g). Rf ¼ 0.33
(40% ethyl acetate/n-hexanes). 1H NMR (500 MHz, CDCl3)
d
7.31 (m,
Prepared according to general procedure 9 (0.3 mmol scale), to give
5H), 7.13 (m, 1H), 6.39 (m, 2H), 5.17 (d, J ¼ 14.2 Hz, 1H), 5.14 (d,
J ¼ 14.2 Hz, 1H), 5.05 (d, J ¼ 14.7 Hz, 1H), 4.76 (br, 1H), 4.07 (d,
J ¼ 14.7 Hz, 1H), 3.76 (s, 3H), 3.73 (s, 3H), 3.47 (dd, J ¼ 14.7, 7.3 Hz,
1H), 3.32 (m,1H), 3.22 (d, J ¼ 14.7 Hz,1H), 2.03 (m,1H),1.83 (m, 2H),
1.68 (m, 1H), 1.49 (s, 9H), 1.46 (m, 1H), 1.39 (s, 9H), 1.37 (m, 1H), 1.25
polycyclic guanidine as yellow solid in 95% yield (96 mg). 1H NMR
(500 MHz, DMSO-d6) d 11.02 (s, 1H), 8.40 (s, 2H), 6.94e6.82 (m, 3H),
6.01 (s, 2H), 4.97 (m, 1H), 4.59 (d, J ¼ 16.1 Hz, 1H), 4.53 (d,
J ¼ 16.1 Hz, 1H), 3.77 (d, J ¼ 15.7 Hz, 1H), 3.62 (m, 1H), 3.59 (d,
J ¼ 15.7 Hz, 1H), 3.13 (t, J ¼ 10.3 Hz, 1H), 1.77 (s, 3H) ppm; 13C{1H}
(m, 1H); 13C{1H} NMR (100 MHz, CDCl3)
d
160.6, 159.6, 159.0, 158.7,
NMR (100 MHz, DMSO-d6) d 151.3, 147.6, 147.1, 127.9, 121.9, 121.5,
154.4, 152.3, 149.5, 135.8, 130.5, 128.7, 128.6, 128.5, 128.4, 128.3,
128.2, 117.0, 104.4, 98.5, 82.8, 79.0, 77.2, 67.6, 55.5, 55.4, 47.2, 46.2,
32.4, 28.5, 28.4, 28.3, 28.1, 26.6, 24.9 ppm; LRMS (ESI) Calculated for
108.4, 108.3, 104.4, 101.2, 66.6, 51.9, 46.4, 45.4, 13.4 ppm; HRMS
(ESI) Calculated for C15H19N4O3 m/z (MþH): 303.11457, Obsd.
303.1458.
C
37H49N4O9 m/z (MþH): 693.3, Obsd. 693.5.
4.2.11. N-((E)-amino((cyclopropylmethyl)(4-methylpent-4-en-2-
yn-1-yl)amino)methylene)cinnamamide (14)
4.2.9.3. 2-Benzyl 5-(tert-butyl) (R,E)-7-(benzo[d][1,3]dioxol-5-
ylmethyl)-6-((tert-butoxycarbonyl)imino)-4-methyl-6,7,8,8a-tetra-
hydro-2H-pyrimido[4,5-e][1,2]oxazine-2,5(3H)-dicarboxylate (12c).
Prepared according to the general procedure 8, to give the poly-
cyclic guanidine as white solid in 61% yield (0.155 g). Rf ¼ 0.38 (40%
N-cyanocinnamamide (0.172 g, 1.0 mmol) was stirred in CH2Cl2
(10 mL). Chlorotrimethylsilane (0.152 mL, 1.2 mmol) and NEt3
(0.209 mL, 1.5 mmol) were then added and the mixture stirred for
15 min. Secondary amine S-2k (0.149 g, 1.0 mmol) was then added.
Upon completion (as judged by TLC on a basified reaction aliquot),
the reaction mixture was washed 3 times with NaHCO3 and then
washed with a sat. brine solution. The combined organic layers
were dried over Na2SO4, filtered and concentrated by rotary evap-
oration. Purification was accomplished by flash chromatography to
yield the propagylguaniline as a pale yellow oil (0.209 g, 65% yield).
Rf ¼ 0.44 (60% ethyl acetate/n-hexanes). 1H NMR (500 MHz, CDCl3)
ethyl acetate/n-hexanes). 1H NMR (500 MHz, CDCl3)
d 7.33 (m, 5H),
6.74e6.67 (m, 3H), 5.90 (s, 2H), 5.22 (d, J ¼ 12.2 Hz, 1H), 5.15 (d,
J ¼ 12.2 Hz, 1H), 4.81 (br, 1H), 4.68 (d, J ¼ 15.2 Hz, 1H), 4.36 (d,
J ¼ 15.7 Hz, 1H), 4.33 (d, J ¼ 15.2 Hz, 1H), 3.92 (d, J ¼ 15.7 Hz, 1H),
3.38 (dd, J ¼ 14.7, 7.3 Hz, 1H), 3.10 (d, J ¼ 14.7 Hz, 1H), 1.95 (s, 3H),
1.52 (s, 9H), 1.43 (s, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
d
159.9, 155.0, 151.8, 149.3, 148.0, 147.3, 135.8, 129.7, 128.7, 128.6,
128.3, 127.6, 123.9, 121.9, 108.9, 108.3, 101.1, 82.9, 79.3, 75.8, 68.1,
52.0, 48.3, 46.5, 28.3, 28.1, 14.8 ppm; LRMS (ESI) Calculated for
d
7.66 (d, J ¼ 16.2 Hz, 1H), 7.55 (m, 2H), 7.36e7.29 (m. 3H), 6.67 (d,
J ¼ 16.2 Hz, 1H), 5.29 (s, 1H), 5.24 (s, 1H), 4.50 (s, 2H), 3.46 (s, 2H),
C
33H41N4O9 m/z (MþH): 637.3, Obsd. 637.4.
1.86 (s, 3H), 1.08 (m, 1H), 0.59 (m, 2H), 0.34 (m, 2H) ppm; 13C{1H}
NMR (100 MHz, CDCl3)
d 177.8, 160.6, 139.9, 136.0, 129.2, 129.0,
4.2.10. General procedure 9 for the deprotection and salt exchange
of 12a-c
128.7, 127.9, 126.1, 122.7, 86.1, 82.7, 51.4, 37.2, 23.4, 9.6, 4.0 ppm;
LRMS (ESI) Calculated for C20H24N3O m/z (MþH): 322.2, Obsd.
322.2.
A 50 mL round-bottom flask was charged with the appropriate
polycyclic guanidine (0.2 mmol). The CH2Cl2/TFA mixture (1:1,
4.0 mL) was added. The reaction mixture was stirred at room
temperature for 2 h, then the solvent removed under reduced
pressure. The crude mixture was taken up in MeOH and 2 M HCl in
ethyl ether was added. The mixture was again concentrated and the
resulting solid triturated with ethyl ether. The solid was then
collected to give the title compound.
4.2.12. (R,Z)-1-(cyclopropylmethyl)-3-(2-methylallylidene)-7-
phenyl-2,3,6,7-tetrahydroimidazo[1,2-a]pyrimidin-5(1H)-one (15)
To a stirring solution of propargylguanidine 14 (0.5 mmol) in
acetonitrile (5.0 mL) was added silver nitrate (0.05 mmol, 10 mol%).
After completion, the reaction mixture was concentrated by rotary
evaporation, and purified by column chromatography to yield the
bicyclic guanidine as pale yellow solid in 83% yield (0.133 g).
Rf ¼ 0.43 (60% ethyl acetate/n-hexanes). 1H NMR (500 MHz, CDCl3)
4.2.10.1. (4aR,6aS)-3-methyl-4,4a,6,6a,7,8,9,10-octahydro-1H-benzo
[c]pyrimido[4,5-e][1,2]oxazin-2(3H)-imine (13a). Prepared accord-
ing to general procedure 9 (0.3 mmol scale), to give polycyclic
guanidine as yellow solid in 95% yield (74 mg). 1H NMR (500 MHz,
d
7.39e7.22 (m, 5H), 5.67 (s, 1H), 4.99 (s, 1H), 4.75 (s, 1H), 4.74 (dd,
J ¼ 10.8, 4.4 Hz, 1H), 4.13 (d, J ¼ 11.9 Hz, 1H), 4.05 (d, J ¼ 11.9 Hz, 1H),
3.33 (dd, J ¼ 14.0, 6.5 Hz,1H), 3.22 (dd, J ¼ 14.0, 6.5 Hz,1H), 2.84 (dd,
J ¼ 17.7, 4.4 Hz, 1H), 2.47 (dd, J ¼ 17.7, 10.8 Hz, 1H), 1.83 (s, 3H), 1.01
(m, 1H), 0.59 (m, 2H), 0.26 (m, 2H) ppm; 13C{1H} NMR (100 MHz,
CDCl3) d 166.3, 151.6, 143.5, 141.1, 128.6, 127.2, 126.5, 126.4, 116.1,
114.9, 56.4, 50.9, 49.1, 40.6, 22.0, 8.8, 3.7, 3.5 ppm; LRMS (ESI)
DMSO-d6) d 10.88 (s, 1H), 8.08 (s, 2H), 5.07 (s, 1H), 3.78 (s, 1H), 3.69
(s, 1H), 3.30 (d, J ¼ 12.2 Hz, 1H), 3.01 (s, 3H), 2.92 (d, J ¼ 12.2 Hz,1H),
2.10 (m, 1H), 1.78 (m, 3H), 1.71 (m, 1H), 1.51 (m, 2H), 1.15 (m, 1H)
ppm; 13C{1H} NMR (100 MHz, DMSO-d6)
d
151.7, 119.5, 111.1, 66.3,
54.7, 47.4, 37.2, 30.2, 26.1, 25.9, 23.7 ppm; HRMS (ESI) Calculated for
11H19N4O m/z (MþH): 223.1559, Obsd. 223.1561.
Calculated for C20H24N3O m/z (MþH): 322.2, Obsd. 322.2.
C
4.2.13. (3R,7R)-1-(cyclopropylmethyl)-70-methyl-20,7-diphenyl-
1,2,20,6,7-pentahydro-10H,5H,80H-spiro[imidazo[1,2-a]pyrimidine-
3,5'-[1,2,4]triazolo[1,2-a]pyridazine]-10,30,5-trione (16)
4.2.10.2. (4aR,6aS)-3-(2,4-dimethoxybenzyl)-4,4a,6,6a,7,8,9,10-
octahydro-1H-benzo[c]pyrimido[4,5-e][1,2]oxazin-2(3H)-imine
(13b). Prepared according to the general procedure 9 (0.3 mmol
scale), to give polycyclic guanidine as pale yellow solid in 89% yield
To a stirring solution of the desired 5-exo-dig cyclic guanidine
(diene, 1 equiv) in CH2Cl2 (0.07 M) was added the appropriate tri-
azoledione (dienophile, 1.2 equiv). After completion, the reaction
mixture was concentrated by rotary evaporation, and purified by
column chromatography to give the polycyclic guanidine as white
solid in 40% yield (0.060 g). Rf ¼ 0.33 (40% ethyl acetate/n-hexanes).
(105 mg). 1H NMR (500 MHz, DMSO-d6)
d 11.02 (s, 1H), 8.28 (s, 2H),
7.21 (m, 1H), 6.61e6.52 (m, 2H), 4.98 (m, 1H), 4.55 (d, J ¼ 15.7 Hz,
1H), 4.47 (d, J ¼ 15.7 Hz, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 3.55 (m, 1H),
3.15 (t, J ¼ 10.7 Hz, 1H), 2.95 (m, 1H), 2.10 (m, 1H), 1.77 (m, 3H), 1.50
(m, 2H), 1.17 (m, 1H); 13C{1H} NMR (100 MHz, DMSO-d6)
d
160.8,
1H NMR (500 MHz, CDCl3)
1H), 4.78 (dd, J ¼ 11.7, 4.9 Hz, 1H), 4.37 (d, J ¼ 16.6 Hz, 1H), 4.17 (d,
d
7.51e7.22 (m, 10H), 5.54 (d, J ¼ 1.5 Hz,
158.3, 151.5, 130.4, 119.7, 113.7, 104.7, 98.6, 66.4, 55.6, 55.3, 54.7,

K.-H. Kwon et al. / Tetrahedron 73 (2017) 6067e6079
6079
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of hydroxamic acids leads to a mild and versatile acylnitroso Ene reaction. J Am
Chem Soc. 2011;133(27):10430e10433;
J ¼ 9.8 Hz, 1H), 4.07 (d, J ¼ 16.6 Hz, 1H), 3.73 (d, J ¼ 9.8 Hz, 1H), 3.43
(dd, J ¼ 14.9, 6.9 Hz, 1H), 3.16 (dd, J ¼ 14.9, 6.9 Hz, 1H), 2.73 (dd,
J ¼ 16.6, 4.9 Hz, 1H), 2.40 (dd, J ¼ 16.6, 11.7 Hz, 1H), 1.94 (s, 3H), 1.01
(m, 1H), 0.55 (m, 2H), 0.23 (m, 2H) ppm; 13C{1H} NMR (100 MHz,
CDCl3)
d 167.9, 151.1, 150.2, 149.4, 144.2, 132.5, 131.1, 129.4, 128.7,
128.5, 127.2, 126.5, 125.7, 119.7, 72.0, 57.0, 56.5, 49.8, 45.4, 40.2, 20.1,
8.8, 3.7, 3.6 ppm; HRMS (ESI) Calculated for C28H29N6O3 m/z
(MþH): 497.2301, Obsd. 497.2309.
Acknowledgment
We are very grateful to Prof. J. Rainier and M. Sigman for helpful
discussions. REL thanks the NIH, General Medical Sciences (2R01
GM090082-A1, P41 GM08915) Amgen and Eli Lilly for financial
support. We thank Dr. Atta Aarif (U. of U. Chemistry) for help with
X-ray crystallography analysis.
Appendix A. Supplementary data
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oxidation of N-Substituted hydroxylamines: efficient and practical access to
nitroso compounds. Org Lett. 2012;14(14):3620e3623;
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2017.08.052.
(c) Chaiyaveij D, Cleary L, Batsanov AS, Marder TB, Shea KJ, Whiting A. Cop-
per(II)-Catalyzed room temperature aerobic oxidation of hydroxamic acids and
hydrazides to acyl-nitroso and azo intermediates, and their DielseAlder trap-
ping. Org Lett. 2011;13(13):3442e3443.
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