10.1002/chem.201905219
Chemistry - A European Journal
FULL PAPER
ring closure to afford ring-fused N-acylguanidines. Both reaction
pathways showed broad structural substrate tolerance,
generating 32 novel twisted-cyclic guanidines in up to 96% yield
and 23 ring-fused N-acylguanidines in up to 90% yield. The
transformation benefits from demonstrated scalability and the use
of accessible and diversely substituted starting materials which
are commercially obtained or derived from anthranilic acid in two
high-yielding steps. Twisted-cyclic guanidines have found utility
in our antiviral program, offering exceptional plasma stability
compared to our related benzamidine scaffold. The method was
also deployed in the expedient synthesis of a known antitumor
agent containing the ring-fused N-acylguanidine scaffold. Hence,
the desired ring-fused guanidine 40 was synthesized in only four
steps and in 55% yield which is three steps shorter and with an 8-
fold increase in yield compared to the published report.[7b] The
divergent yet tractable nature of this transformation to generate
two distinct classes of bioactive guanidines with high efficiency is
expected to facilitate the development of new guanidine-
containing frameworks.
(UW-Madison) for assistance with the crystal structure
determination. This work made use of instrumentation at the
UW−Madison Medicinal Chemistry Center and the Analytical
Instrumentation Center, both within the UW-Madison School of
Pharmacy.
Conflicts of interest
There are no conflicts to declare.
Keywords: guanidine • twisted guanidine• quinazolinone •
rearrangement • ring-fused guanidine
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Experimental Section
For a detailed description of the synthesis of starting materials
and final products, see the Supporting Information.
2-((1,3-dimethylimidazolidin-2-ylidene)amino)-N-phenylbenzamide
(34a) To a microwave vial was added 2-chloroquinazolin-4(3H)-one (31a,
51 mg, 0.2 mmol), N,N′-dimethylethylenediamine (32a, 0.03 mL, 0.26
mmol), NEt3 (0.085 mL, 0.6 mmol) and CH3CN (2 mL). After heating the
mixture under microwave irradiation at 150 °C for 2 h, the cooled mixture
was diluted with CH2Cl2 (20 mL) and washed with saturated NaHCO3
solution (15 mL). The aqueous layer was then washed with CH2Cl2 (20
mL). The combined organic layer was dried with MgSO4, filtered and
purified by flash column. Eluent: 40% - 60% ethyl acetate/hexane; yield:
57 mg, 92%; white solid, m.p. 165-167 °C. 1H NMR (400 MHz, CDCl3) δ
12.33 (s, 1H), 8.27 (dd, J = 8.0, 1.8 Hz, 1H), 7.78 – 7.67 (m, 2H), 7.33 (t,
J = 7.9 Hz, 2H), 7.30 – 7.23 (m, 1H), 7.06 (t, J = 7.6 Hz, 1H), 7.01 – 6.92
(m, 1H), 6.83 (dd, J = 8.2, 2.1 Hz, 1H), 3.41 (s, 4H), 2.75 (s, 6H). 13C NMR
(101 MHz, CDCl3) δ 165.4, 157.4, 148.3, 139.6, 131.5, 131.1, 129.0, 124.1,
123.3, 122.9, 120.5, 120.1, 48.5, 35.3. HRMS (ESI) m/z for C18H21N4O+
(M+H)+, 309.1710 (Calc.), found 309.1713.
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(38a)
Following the procedure for 34a, used 31a (51 mg, 0.2 mmol), N-
methylethylenediamine (32k, 0.023 mL, 0.26 mmol), NEt3 (0.085 mL, 0.6
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35 mg, 86%; white solid, m.p. 177-178 °C. 1H NMR (400 MHz, CDCl3) δ
8.11 (dd, J = 7.9, 1.6 Hz, 1H), 7.56 (ddd, J = 8.5, 7.0, 1.6 Hz, 1H), 7.39
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161.3, 153.1, 151.0, 134.4, 126.6, 124.9, 122.7, 117.8, 47.1, 40.5, 31.9.
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202.0977.
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Acknowledgements
JEG acknowledges funding from the National Institutes of Health
(1R01AI118814). The authors wish to thank Amelia Wheaton
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