Synthesis of Naamidine A and Selective Access to N2-Acyl-2-aminoimidazole Analogues

Article abstract of DOI:10.1021/acs.joc.5b01703

A short and scalable synthesis of naamidine A, a marine alkaloid with a selective ability to inhibit epidermal growth factor receptor (EGFR)-dependent cellular proliferation, has been achieved. A key achievement in this synthesis was the development of a

Full text of DOI:10.1021/acs.joc.5b01703

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Article
A synthesis of naamidine A and selective
access to N2-acyl-2-aminoimidazole analogues.
Joseph B. Gibbons, Justin M. Salvant, Rachel M. Vaden, Ki-Hyeok Kwon, Bryan E. Welm, and Ryan E. Looper
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01703 • Publication Date (Web): 11 Sep 2015
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A synthesis of naamidine A and selective access to N2ꢀacylꢀ2ꢀaminoimidazole
analogues.
Joseph B. Gibbons a, Justin M. Salvant a, Rachel M. Vaden a, KiꢀHyeok Kwon a,
Bryan E. Welm b and Ryan E. Looper*a
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aDepartment of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, UT, 84112
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bImmunobiology and Cancer Program, Oklahoma Medical Research Foundation, 825 Northeast 13th Street, Oklahoma City, OK, 73104
Abstract: A short and scaleable synthesis of naamidine A, a marine alkaloid with a selective ability to inhibit
epidermal growth factor receptor (EGFR) dependent cellular proliferation, has been achieved. A key
achievement in this synthesis was the development of a regioselective hydroamination of a monoꢀprotected
propargylguanidine to deliver N3ꢀprotected cyclic eneꢀguanidines. This permits the extension of this methodology
to prepare N2ꢀacyl analogues in a fashion that obviates the troublesome acylation of the free 2ꢀaminoimidazoles
which typically yields mixtures of N2- and N2,N2ꢀdiacylated products.
Introduction: Marine sponges from the Leucetta family have produced a wealth of natural products comprising
highly functionalized 2ꢀaminoimidazoles (2ꢀAIs).1 This family of alkaloids effects a number of diverse biological
activities (Figure 1). Naamine D (1), for example, has been shown to be a moderate inhibitor of iNOS, an
isozyme scrutinized for its involvement in a number of diseases.2 Naamine D was also shown to be active against
the opportunistic pathogen in AIDS patients, C. neoformas (MIC = 6.25 µg/mL). N,N-Dimethylnaamine D (2),
was active against an antimicrobial panel consisting of E. coli, S. aureus., B. subtilis. and C. albicans.3 Kealiinine
B (3) was recently reported to show antiꢀproliferative activity (IC50 ~ 10 µM) against the breast cancer cell line
T47D while other kealiinine analogues have displayed modest activity against MCF7 proliferation.4,5 Isonaamine
C (4) was found to be cytotoxic to a variety of cell lines6 while leucettamine A was found to be a leukotriene B4
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(LTB4) antagonist.7 These examples clearly demonstrate that the 2ꢀaminoimidazole, bearing a variety of
substitution patterns, serves as an important heterocyclic scaffold for small molecule drug discovery.
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Our interest in this family stems from the selective cytotoxicity of naamidine A (6). Studies by Ireland and
coworkers determined 6 to be a selective inhibitor for EGFꢀmediated growth in epidermal growth factor receptor
(EGFR) transfected NIH3T3 cells (IC50 = 11.3 µM), yet displayed a 21ꢀfold decrease in potency against insulinꢀ
mediated growth (IC50 = 242 µM).8 This particular selectivity prompted in vivo studies, where nude mice
xenografts of EGFꢀoverexpressing A431 epidermal carcinoma displayed 87.4% tumor growth inhibition when
treated with 6 at 25 mg/kg. Although many compounds affect EGFR signaling, 6 is the first known example to
stimulate phosphotransferase activity of extracellular regulated kinases ERK1/2.9 This sustained increase in
MAPK activity has been shown to be a result of naamidine Aꢀinduced expression of p21, leading to inhibition of
cyclinꢀdependent kinase activity and activation of caspases 3, 8, and 9.10 Since EGFR signaling pathway is
overexpressed in many human tumors, the ability to selectively inhibit EGFRꢀmediated proliferation represents
an important strategy for new chemotherapeutics. Herein, we report the synthesis of 6, as well as related
analogues via regioselective construction of cyclic eneꢀguanidines.
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Figure 1. Representative Leucetta alkaloids.
Results and Discussion: The structural novelty of 6 and other highly substituted 2ꢀAI scaffolds has generated
interest in several synthetic laboratories.11ꢀ16 We previously reported the synthesis of naamine A (8) via an
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additionꢀhydroaminationꢀisomerization sequence utilizing the propargylcyanamide 7 (Scheme 1).17 Analogous to
the syntheses of 6 by Ohta and Watson, we were able to add the NꢀMeꢀdehydrohydantoin selectively to N2 via
silylated Nꢀmethylparabanic acid (Scheme 1).11,12 However, the transamination reaction of the piperidinone to the
free 2ꢀaminoimidazole proved problematic on larger scales. We had also simultaneously discovered the tandem
addition – hydroamination sequence that was reported by Van der Eycken employing N,Nꢀdiboc guanidines.
Removal of the Boc groups with TFA in this sequence presented problems, as cleavage of electron rich groups at
N1 was quite facile under acidic conditions (e.g. those needed for the synthesis of isonaamine C). Furthermore,
while trying to access simplified naamidine A analogues, exemplified by the reaction of 9 with 2ꢀfluorobenzoyl
chloride, an unfavorable 1:2 mixture of monoꢀacylated and diacylated N2 products (10:11) was obtained. A recent
report by Jiang and coworkers identified the same problem, requiring forcing conditions or extra protecting group
manipulations to obtain the monoꢀacylꢀ2ꢀaminoimidazoles in low to moderate yields, reinforcing the need for a
high yielding and selective strategy to access monoꢀsubstituted 2ꢀaminoimidazoles.18
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Scheme 1. First generation synthesis of naamidine A and analogues.
These shortcomings necessitated a revised synthesis of 6 that would allow for a) reproducible and scaleable
procedures, b) the presence of acid labile groups, and c) differential protection of N2/N3 for selective
functionalization. Our attempts to address these issues are presented in the synthesis of naamidine A (Scheme 2).
Cu(I)ꢀmediated A3ꢀcoupling of the required amine, alkyne, and aldehyde gave 12 (Scheme 2).19 Deallylation with
Pd(0) gave the secondary propargylamine (13) in good yield.10 Instead of installing the diꢀBoc guanidine14, we
prepared the monoꢀacylguanidine 14 using the activated Cbzꢀcyanamide potassium salt guanylation conditions
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previously developed in our laboratory.2` It is important to note that four pathways are operable in the cyclization
of 14: N3ꢀ versus N2ꢀ cyclization and 5ꢀexoꢀdig versus 6ꢀendo dig cyclization. We knew that monoꢀacylguandines
prefer the tautomeric form in which the imino tautomer is directly conjugated with the acyl group and the other
nitrogen forms a hydrogen bond to the carbonyl (as depicted in 10). This would suggest that the unconjugated
nonꢀbonding lone pair on N3ꢀ would initiate cyclization. We also knew that the Ag(I)ꢀcatalyzed cyclization
proceeds preferentially in a 5ꢀexoꢀdig fashion, however, with an electron rich alkyne substituent selectivity can be
significantly diminished. For example, when unsubstituted at C5, pꢀMeOPh substituted propargylguanidines
cyclize with only modest 5ꢀexoꢀdig selectivity ~2:1.14 To our delight treatment of 14 with AgNO3 in CH2Cl2
provided a single isomer (15) in 87% isolated yield. The regioselectivity of this process was ultimately supported
by Xꢀray crystallography of the intermediate 18b (Figure 2 below). Importantly this leaves N2ꢀ open for
subsequent functionalization. The Cbz group is readily cleaved under standard hydrogenolysis conditions.
Fortunately, isomerization of the exocyclic alkene provides the 2ꢀaminoimidazole nucleus before it can be
reduced. The benzyl ether is also cleaved during this step to provided naamine A in quantitative yield. Again the
NꢀMeꢀhydantoin can be installed by Ohta’s method to provide naamidine A in good yield. This sequence has
proven to be robust and scalable, delivering gram quantities of naamidine A in 6 steps and 33% overall yield.
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Scheme 2. Synthesis of naamdine A (6).
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With the ability to control the regioselectivity of the monoꢀacylpropargylguanidine cyclization, we returned our
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attention to generating N2ꢀsubstituted analogues (Scheme 3). We envisioned 15 as an ideal intermediate for
selective N2-acylation as N3ꢀ is protected and the iminoꢀtautomer is forced C2=N2 and should yield only monoꢀ
acylation products. Indeed, both electron rich and electron poor aryl chlorides gave the N2ꢀmonoacylguanidines
16aꢀd in excellent yields (Table 1). Alkanoylchlorides are also reactive to give 16eꢀf. Most notably,
hydrogenation conditions that cleaved the Cbz group, isomerized the eneꢀguanidine and cleaved the phenolic
benzylether in the preparation of 8 resulted in no reaction in the conversion of 16a→17a. More forcing conditions
(elevated H2 pressures) could initiate reductive cleavage of the Cbz group and isomerization but the benzyl ether
was surprisingly difficult to cleave. Ultimately, a nonꢀsupported Pd(II) catalyst was successful, providing the fully
deprotected targets 17aꢀf in excellent overall yields.
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Scheme 3. Generation of N2ꢀacyl naamidine A analogues.
To complement our focused library, the same methodology was involved in the construction of C5ꢀphenyl, C4ꢀ
benzyl analogues (Scheme 4). The same synthetic sequence accessing 15 was also employed to prepare
substrates 18a and 18b.19 Acylation of these intermediates gave N2ꢀsubstituted precursors 19aꢀh in excellent
yields. Hydrogenation over palladium on carbon, with 60 psi H2, was sufficient to effect the deprotection with
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isomerization and deliver the 2ꢀaminoimidazole analogues 20aꢀh. Confirmation of N2ꢀselective acylation was
confirmed by Xꢀray crystallography of 20h.
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Again, 18b was characterized by Xꢀray crystallography confirming that the initial hydroamination proceeds to
give the N3ꢀprotected intermediates (Figure 2). The fact that the acylation / deprotection with isomerization
sequence yields the monoꢀN2ꢀsubstituted 2ꢀaminoimidazoles was ultimately confirmed by Xꢀray crystallography
of product 20h. This structure shows that even in the now aromatized aminoimidazole nucleus the exocyclic N2ꢀ
iminotautomer is preferred with Hꢀ bonding between N3 and the N2ꢀacyl group with a C2ꢀN3 imino bond length
of 1.33 Å.
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Scheme 4. Generation of N2ꢀacyl 2ꢀaminoimidazoles.
Studies to evaluate the cytotoxicity of 17aꢀe and 20aꢀi revealed that 20h was effective against metastatic tumor
cells derived from a chemoresistant breast cancer patient (PE1007070 cells) with an EC50 = 8.8 µM.22 Moreover,
20h did not significantly affect the viability of immortalized, nontumorogenic mammary tissue (hTERTꢀHMEC
cells), suggesting a cancerꢀspecific mechanism of action. The effect of 20h on cell viability was also measured in
a breast cancer cell line (MCFꢀ7) and an untransformed mammary epithelial cell line (MCFꢀ10A) (Figure 3). As
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with the patientꢀderived cells, 20h was found to significantly reduce the viability of MCFꢀ7 cells (EC50 = 1.4 µM)
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while having no significant effect on the untransformed mammary cell line.
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Figure 2. Xꢀray structures of 18b / 20h.
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Despite the reported selectivity of naamidine A (6) to inhibit proliferation in EGFR transfected NIH3T3 cells,
no selectivity was observed in the antiꢀproliferative activity of MCFꢀ7 versus MCFꢀ10A cells (EC50 = 5.9 and 8.1
µM respectively). Taken together, these results suggest that the natural product inspired N2ꢀacylꢀ2ꢀ
aminoimidazoles can exploit cancer selective mechanisms to cause cell death. Studies to further understand this
mechanism and evaluate its therapeutic potential are underway.
Figure 3. Antiproliferative effects of naamidine A and 20h.
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Conclusion: In summary, we have shown that monoꢀacylguanidines preferentially adopt the Nꢀacylꢀimino
tautomer and that this can be reliable used to predict reactivity. Thus the hydroamination of monoꢀ
acylpropargylguanidines can be effected regioselectively to generate N3ꢀacylꢀ2ꢀaminoimidazoles and
subsequently free 2ꢀaminoimidazoles after deprotection with isomerization of the Cbz protected variants. This
strategy further exploits the confined N2ꢀimino tautomer to allow selective N2ꢀacylation and deliver these
analogues without contamination from the diacylated derivatives. The effectiveness of this approach was
demonstrated by completing a gramꢀscale synthesis of both naamine A and naamidine A. The discovery of 20h as
a more selective antiꢀproliferative agent than naamidine A highlights the necessity to efficiently prepare monoꢀ
N2ꢀacylꢀ2ꢀaminoimidazoles to further study this selectivity.
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Experimental section
General Considerations.
All reactions requiring anhydrous conditions were performed under a positive pressure of nitrogen using
flameꢀdried glassware. Acetonitrile (MeCN), dichloromethane (CH2Cl2), and toluene (PhMe) were degassed with
nitrogen and passed through activated alumina. Methanol (MeOH) and triethylamine (Et3N) were distilled from
CaH2 immediately prior to use. Reactions were monitored to completion by TLC and visualized by a dual
short/long wave UV lamp and stained with an aqueous solution of potassium permanganate and/or organic
solution of phosphomolybdic acid. Flash chromatography was performed on silica gel Siliaflash P60 (40ꢀ63 ꢁm).
Infrared spectra were recorded as thin films and absorptions are reported in cmꢀ1 relative to polystyrene (1601 cmꢀ
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1). HRMS mass spectra were determined by ESI/APCIꢀTOF. H NMR and spectra were recorded at 500 MHz
and 300 MHz spectrometers as indicated. The chemical shifts (δ) of proton resonances were reported relative to
the deuterated solvent peak (7.26 ppm for CDCl3, 3.31 for CD3OD, and 2.50 ppm for DMSOꢀd6) using the
following format: chemical shift [multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet),
coupling constant(s) (J in Hz), integral. 13C NMR spectra were recorded at 125 MHz and 75 MHz. The chemical
shifts (δ) of carbon resonances were reported relative to the deuterated solvent peak (77.2 ppm for CDCl3 and
39.5 for DMSOꢀd6).
Procedures for the Synthesis of Naamidine A. N-Allyl-1-(4-(benzyloxy)phenyl)-4-(4-methoxyphenyl)-
N-methylbut-3-yn-2-amine (12). To a 500 mL pressure flask equipped with a stir bar was added 4ꢀ
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methoxyphenylacetylene (5.35 mL, 40.5 mmol), Nꢀallylmethylamine (3.46 mL, 36.4 mmol), p-OBnꢀ
phenylacetaldehyde (9.2 g, 40.5 mmol), CuBr (0.52 g, 3.6 mmol), acetonitrile (140 mL) and 1 g of ovenꢀdried 4Å
molecular sieves. The flask was heated at 80 ºC for 24 hours, and then allowed to cool to room temperature. The
mixture was filtered through Celite and rinsed with EtOAc (500 mL). The organic layer was washed with
aqueous solutions of saturated NaHCO3 (500 mL) and brine (500 mL). The organic layer was dried over Na2SO4.
After filtration, the organic layer was concentrated and purified via flash chromatography using 4:1
hexanes/EtOAc to give 8 as a dark red oil (10.8 g, 65%). Rf = 0.35 (4:1 hexanes/EtOAc); 1H NMR (CDCl3, 300
MHz): δ 7.37ꢀ7.27 (m, 4H), 7.24 (d, J = 8.8 Hz, 2H), 7.24 (overlapped, 1H), 7.15 (d, J = 8.3 Hz, 2H), 6.84 (d, J =
8.8 Hz, 2H), 6.73 (d, J = 8.8 Hz, 2H), 5.78 (ddt, J = 6.4, 10.7, 17.1 Hz, 1H), 5.14 (dd, J = 1.5, 17.1 Hz, 1H), 5.05
(dd, J = 2.0, 10.3 Hz, 1H), 4.95 (s, 2H), 3.72 (dd, J = 6.4, 8.8 Hz, 1H), 3.70 (s, 3H), 3.15 (dd, J = 5.9, 13.7 Hz,
1H), 3.03 (dd, J = 7.3, 13.5 Hz, 1H), 2.27 (s, 3H) ppm. 13C NMR (CDCl3, 75 MHz): δ 159.2, 157.4, 137.2, 136.0,
133.0 131.2, 130.4, 128.5, 127.8, 127.4, 117.6, 115.5, 114.5, 113.8, 88.5, 85.0, 69.9, 58.4, 58.2, 55.2, 39.5, 37.7
ppm. IR (thin film) 2954, 1606, 1508, 1454, 1420, 1381, 1289, 1243, 1173, 1106, 1026, 921, 831, 807, 791, 732,
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696 cmꢀ1 HRMS (ESI+) Calculated for C28H30NO2 m/z (M+H) 412.2277, Obsd. 412.2278.
.
1-(4-(Benzyloxy)phenyl)-4-(4-methoxyphenyl)-N-methylbut-3-yn-2-amine (13). To a 500 mL round
bottom flask equipped with a stir bar was added 12 (10.7 g, 26.0 mmol), thiosalicylic acid (8.0 g, 52 mmol),
Pd(PPh3)4 (0.6 g, 0.5 mmol), and CH2Cl2 (260 mL). The reaction was allowed to stir at room temperature under
N2 overnight. The reaction mixture was concentrated and reꢀdissolved in EtOAc (200 mL). The organic layer
was washed with saturated NaHCO3 (200 mL) and brine (200 mL). The organic layer was dried over Na2SO4.
After filtration, the organic layer was concentrated and purified via flash chromatography using 100% EtOAc
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(with 0.5% Et3N) to give 13 as an orange oil (6.6 g, 91%). Rf = 0.35 (100% EtOAc); H NMR (CDCl3, 500
MHz): δ 7.45 (d, J = 7.3, 2H), 7.40 (t, J = 6.8 Hz, 2H), 7.34 (d, J = 8.8 Hz, 3H), 7.27 (d, J = 8.3 Hz, 2H), 6.95 (d,
J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 5.06 (s, 2H), 3.80 (s, 3H), 3.72 (t, J = 6.4 Hz, 1H), 2.98 (dd, J = 2.4, 9.4
Hz, 2H), 2.55 (s, 3H) ppm. 13C NMR (CDCl3, 125 MHz): δ 159.4, 157.7, 137.2, 133.0, 130.8, 128.7, 128.0,
127.6, 115.5, 114.7, 88.7, 84.6, 70.1, 55.3, 53.9, 41.3, 34.2 ppm. IR (thin film) 2933, 1606, 1508, 1454, 1441,
1380, 1289, 1244, 1173, 1107, 1027, 831, 737, 697, 668 cmꢀ1. HRMS (ESI+) Calculated for C25H26NO2 m/z
(M+H) 372.1964, Obsd. 372.1966.
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N-Cbz-1-(1-(4-(benzyloxy)phenyl)-4-(4-methoxyphenyl ) but-3-yn-2-yl)-1-methylguanidine (14). To a
250 mL round bottom flask equipped with a stir bar was added TMSCl (1.65 mL, 13.0 mmol),
benzyloxycarbonylcyanamide potassium salt (2.58 g, 12.0 mmol) and 50 mL acetonitrile. The reaction mixture
was allowed to stir for 10 min under N2. A solution of 13 (4.8 g, 13 mmol) in acetonitrile (15 mL) was added to
the suspension, and the reaction was allowed to stir for 1 h. The reaction mixture was concentrated to
approximately oneꢀquarter of the original volume, and then diluted with EtOAc (100 mL). The organic layer was
washed with aqueous solutions of saturated Na2CO3 (100 mL) and brine (100 mL). The organic layer was dried
over Na2SO4. After filtration, the organic layer was concentrated and purified via flash chromatography using 1:1
hexanes/EtOAc to give 14 as a yellow foam (5.9 g, 90%). Rf = 0.42 (1:1 hexanes/EtOAc); 1H NMR (CDCl3, 500
MHz): δ 7.44 (d, J = 7.3 Hz, 4H), 7.42ꢀ7.27 (m, 8H), 7.20 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.3 Hz, 2H), 6.83 (d, J
= 8.8 Hz, 2H), 6.02 (bs, 2H), 5.16 (d, J = 2.4 Hz, 2H), 5.03 (s, 2H), 3.80 (s, 3H), 3.04 (dd, J = 7.3, 13.2 Hz, 1H),
2.95 (dd, J = 6.4, 13.2 Hz, 1H), 2.90 (s, 3H) ppm. 13C NMR (CDCl3, 125 MHz): δ 173.1, 164.0, 160.7, 159.8,
157.9, 137.8, 137.1, 133.2, 130.7, 129.1, 128.7, 128.4, 128.0, 127.9, 127.7, 114.8, 114.0, 86.1, 84.9, 70.1, 66.8,
55.4, 50.2, 39.7 ppm. IR (thin film) 2934, 1642, 1589, 1536, 1508, 1440, 1378, 1280, 1244, 1172, 1152, 1107,
1026, 909, 831, 799, 732, 696 cmꢀ1. HRMS (ESI+) Calculated for C34H34N3O4 m/z (M+H) 548.2549, Obsd.
548.2556.
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Benzyl
(Z)-4-(4-(benzyloxy)benzyl)-2-imino-5-(4-methoxybenzylidene)-3-methylimidazolidine-1-
carboxylate (15). To a 25 mL round bottom flask equipped with a stir bar was added 14 (0.51 g, 0.91 mmol),
AgNO3 (0.02 g, 0.09 mmol) and dichloromethane (9.1 mL). The flask was wrapped with aluminum foil, and the
reaction was allowed to stir at room temperature under N2 overnight. The reaction mixture was concentrated and
purified via flash chromatography using 5% MeOH in CH2Cl2 to give 15 as a light yellow foam (0.43 g, 87%). Rf
= 0.28 (5% MeOH in CH2Cl2); 1H NMR (CDCl3, 300 MHz): δ 7.46ꢀ7.20 (m, 8H), 6.97 (d, J = 8.7 Hz, 2H), 6.94 ꢀ
6.87 (m, 4H), 6.74 (d, J = 4.3 Hz, 2H), 6.71 (d, J = 4.0 Hz, 2H), 5.39 (s, 1H), 4.99 (s, 2H), 4.92 (d, J = 11.5 Hz,
1H), 4.29 (d, J = 12.0 Hz, 1H), 4.08 (dd, J = 4.2, 6.6 Hz, 1H), 3.77 (s, 3H), 3.08 (s, 3H), 2.99 (dd, J = 4.2, 13.7
Hz, 1H), 2.73 (dd, J = 7.3, 13.7 Hz, 1H) ppm. 13C NMR (CDCl3, 125 MHz): δ 158.7, 157.9, 154.0, 151.2, 137.1,
134.2, 131.1, 129.5, 128.8, 128.7, 128.5, 128.4, 128.3, 128.1, 127.5, 114.8, 113.8, 113.4, 70.0, 68.6, 65.0, 55.4,
37.8 ppm. IR (thin film) 2923, 2851, 1734, 1607, 1510, 1454, 1382, 1299, 1247, 1178, 1033, 830, 738, 698 cmꢀ1.
HRMS (ESI+) Calculated for C34H34N3O4 m/z (M+H) 548.2549, Obsd. 548.2555.
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4-((2-Amino-4-(4-methoxybenzyl)-1-methyl-1H-imidazol-5-yl)methyl)phenol (naamine A, 8). To a 10 mL
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round bottom flask equipped with a stir bar was added 15 (0.25 g, 0.46 mmol), Pd(OH)2 on carbon (20% wt,
0.032 g, 0.046 mmol) and MeOH (4.6 mL). A H2 balloon was attached, and the reaction was allowed to stir
overnight. The reaction mixture was filtered through Celite and rinsed with dichloromethane. The reaction
mixture was concentrated to a pale yellow solid (0.12 g, 84%, mp = 182 ºC) and used without further purification
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to give 8 as naamine A. H NMR (CD3OD, 500 MHz): δ 7.08 (d, J = 8.3 Hz, 2H), 6.84 (d, J = 8.3 Hz, 2H), 6.76
(d, J = 8.3 Hz, 2H), 6.64 (d, J = 8.8 Hz, 2H), 3.76 (s, 2H), 3.72 (s, 3H), 3.69 (s, 2H), 3.08 (s, 3H) ppm. 13C NMR
(DMSOꢀd6, 125 MHz): δ 168.5, 157.8, 156.2, 148.9, 134.5, 132.4, 130.6, 130.1, 129.5, 120.3, 115.8, 114.0, 55.6,
32.7, 29.4, 28.6 ppm. IR (thin film) 2923, 2852, 1610, 1511, 1457, 1369, 1245, 1175, 1035, 814, 773, 668, 652
cmꢀ1. HRMS (ESI+) Calculated for C19H22N3O2 m/z (M+H) 324.1712, Obsd. 324.1714.
Preparation of naamidine A (6). To a 50 mL round bottom, 2ꢀneck flask equipped with a stir bar and
reflux condenser was added 1ꢀmethylparabanic acid (2.04 g, 15.9 mmol) and acetonitrile (14.5 mL).
Bis(trimethylsilyl)acetamide (4.9 mL, 20.0 mmol) was added via syringe, and the reaction mixture was allowed to
reflux for 2 hours. Without exposing reaction flask to the open atmosphere, the solvent was removed under
reduced pressure. The reaction mixture was placed under N2 and diluted with PhMe (10.5 mL). The solution was
transferred via cannula to a 50 mL round bottom, 2ꢀneck flask equipped with a stir bar and reflux condenser
containing 8 (1.03 g, 3.2 mmol, mp = 188 ºC) under a N2 atmosphere. The reaction mixture was allowed to reflux
for 16 hours. The reaction was allowed to cool to room temperature, diluted with EtOAc (10 mL), then
transferred to a 100 mL round bottom flash to be concentrated. The mixture was purified via flash
chromatography using 85:15 PhMe/MeOH with 1% Et3N to give 6 as a bright yellow solid (1.10 g, 76%). Rf =
0.4 (85:15 PhMe/MeOH with 1% NEt3); 1H NMR (CDCl3, 500 MHz): δ 7.11 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 7.8
Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 8.8 Hz, 2H), 3.87 (s, 4H), 3.77 (s, 3H), 3.40 (s, 3H), 3.17 (s, 3H)
ppm. 13C NMR (CDCl3, 125 MHz): δ 163.3, 158.5, 157.0, 155.2, 146.7, 134.7, 131.3, 129.5, 129.3, 128.7, 127.0,
115.0, 114.3, 55.5, 32.1, 30.0, 28.8, 25.0 ppm. IR (thin film) 3335, 1789, 1736, 1665, 1612, 1569, 1512, 1486,
1445, 1392, 1303, 1247, 1174, 1153, 1035, 821, 776, 727, 606 cmꢀ1. HRMS (ESI+) Calculated for C23H24N5O4
m/z (M+H) 434.1828, Obsd. 434.1840.
General Procedure A: Acylation of 15 to give 16aꢀf. Benzyl-2-(benzoylimino)-4-(4-(benzyloxy)benzyl)-
5-((Z)-4-methoxybenzylidene)-3-methylimidazolidine-1-carboxylate (16a). To a 25 mL round bottom flask
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equipped with a stir bar was added 15 (498 mg, 0.91 mmol), Et3N (0.25 mL, 1.8 mmol, 2.0 equiv.), benzoyl
chloride (0.16 mL, 1.4 mmol, 1.5 equiv.) and dichloromethane (9.1 mL). The reaction was allowed to stir for 1
hour. The reaction mixture was concentrated and purified via flash chromatography using 1:1 hexanes/EtOAc to
give 16a as a light yellow foam (545 mg, 92%). Rf = 0.43 (1:1 hexanes/EtOAc); 1H NMR (CDCl3, 300 MHz): δ
8.12 (d, J = 7.0 Hz, 2H), 7.51ꢀ7.11 (m, 13H), 7.08 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 8.7
Hz, 2H), 6.75 (d, J = 8.9 Hz, 2H), 5.45 (s, 1H), 5.01 (s, 2H), 4.80 (d, J = 19.8 Hz, 1H), 4.42 (d, J = 19.8 Hz, 1H),
4.08 (dd, J = 4.2, 6.6 Hz, 1H), 3.77 (s, 3H), 3.14 (s, 3H), 3.03 (dd, J = 4.2, 13.5 Hz, 1H), 2.78 (dd, J = 7.6, 13.5
Hz, 1H) ppm. 13C NMR (CDCl3, 75 MHz): δ 175,6, 158.7, 157.9, 151.9, 149.1, 137.3, 137.0, 134.5, 131.4, 131.1,
129.7, 129.3, 128,7, 128.6, 128.2, 128.1, 128.0, 127.8, 127.5, 127.1, 117.4, 114.8, 113.7, 70.0, 68.7, 64.6, 55.3,
37.9, 31.0 ppm. IR (thin film) 3033, 2933, 1746, 1647, 1607, 1511, 1455, 1379, 1315, 1282, 1248, 1178, 1075,
1037, 1024, 866, 826, 739, 713, 697 cmꢀ1. HRMS (ESI+) Calculated for C41H37N3O5Na m/z (M+Na) 674.2631,
Obsd. 674.2632.
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Benzyl-4-(4-(benzyloxy)benzyl)-2-((2-fluorobenzoyl)imino)-5-((Z)-4-methoxybenzylidene)-3-
methylimidazolidine-1-carboxylate (16b). Prepared according to the general procedure A with 2ꢀfluorobenzoyl
chloride, with purification on silica gel eluting with 1:1 hexanes/EtOAc to give 16b as a yellow oil (540 mg, 89%
1
yield). Rf = 0.42 (1:1 hexanes/EtOAc); H NMR (CDCl3, 300 MHz): δ 7.91 (dt, J = 2.0, 7.8 Hz, 1H), 7.44ꢀ7.01
(m, 11H), 6.97 (d, J = 8.8 Hz, 4H), 6.85 (t, J = 8.8 Hz, 2H), 6.77 (d, J = 8.8 Hz, 2H), 6.66 (d, J = 8.8 Hz, 2H),
5.46 (s, 1H), 5.00 (s, 2H), 4.82 (d, J = 19.5 Hz, 1H), 4.33 (d, J = 19.5 Hz, 1H), 4.11 (dd, J = 3.4, 7.5 Hz, 1H),
3.76 (s, 3H), 3.15 (s, 3H), 3.00 (dd, J = 4.4, 13.7 Hz, 1H), 2.78 (dd, J = 7.5, 13.7 Hz, 1H) ppm. 13C NMR (CDCl3,
75 MHz): δ 172.7, 161.3 (d, JCF = 253.8 Hz), 158.7, 158.0, 151.8, 149.1, 137.0, 134.4, 132.6, 132.3 (d, JCF = 9.0
Hz), 131.0, 129.5, 128.7, 128.7, 128.2, 128.2, 127.7, 127.5, 127.0, 123.6 (d, JCF = 3.5 Hz), 117.3, 116.4 (d, JCF
=
23.0 Hz), 114.9, 113.6, 70.1, 68.9, 64.6, 55.3, 37.9, 31.0 ppm. IR (thin film) 3033, 2930, 1743, 1598, 1510, 1483,
1452, 1407, 1379, 1314, 1282, 1246, 1177, 1116, 1029, 909, 862, 817, 756, 733, 696 cmꢀ1. HRMS (ESI+)
Calculated for C41H36N3O5FNa m/z (M+Na) 692.2537, Obsd. 692.2545.
Benzyl-4-(4-(benzyloxy)benzyl)-2-((4-methoxybenzoyl)imino)-5-((Z)-4-methoxybenzylidene)-3-
methylimidazolidine-1-carboxylate (16c). Prepared according to the general procedure A with 4ꢀmethoxybenzoyl
chloride, with purification on silica gel eluting with 2:1 hexanes/EtOAc to give 16c as a yellow oil (78 mg, 88%
1
yield). Rf = 0.48 (2:1 EtOAc/hexanes); H NMR (CDCl3, 300 MHz): δ 8.08 (d, J = 8.7 Hz, 2H), 7.44ꢀ7.28 (m,
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5H), 7.24ꢀ7.04 (m, 5H), 6.98 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H), 6.83ꢀ6.71 (m, 6H), 5.44 (s, 1H), 5.00
(s, 2H), 4.80 (d, J = 20.0 Hz, 1H), 4.43 (d, J = 20.0 Hz, 1H), 4.06 (dd, J = 4.1, 7.1 Hz, 1H), 3.84 (s, 3H), 3.76 (s,
3H), 3.12 (s, 3H), 3.02 (dd, J = 4.1, 13.5 Hz, 1H), 2.77 (dd, J = 7.1, 13.5 Hz, 1H); 13C NMR (CDCl3, 75 MHz): δ
175.3, 162.5, 158.9, 158.0, 151.6, 149.3, 137.1, 134.7, 133.7, 131.8, 131.2, 130.2, 129.8, 129.5, 128.8, 128.7,
128.3, 128.2, 128.0, 127.6, 127.4, 117.4, 114.9, 113.8, 70.1, 68.6, 64.7, 55.6, 55.4, 38.1, 31.1; IR (thin film) 3033,
2933, 2837, 1743, 1598, 1509, 1454, 1378, 1281, 1236, 1176, 1163, 1110, 1074, 1027, 907, 861, 844, 826, 726,
696 cmꢀ1. HRMS (ESI+) Calculated for C42H39N3O6Na m/z (M+Na) 704.2737, Obsd. 704.2742.
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Benzyl-4-(4-(benzyloxy)benzyl)-5-((Z)-4-methoxybenzylidene)-3-methyl-2-((3-(trifluoromethyl)benzoyl
)imino) imidazolidine-1-carboxylate (16d). Prepared according to the general procedure A with 3ꢀ
trifluoromethylbenzoyl chloride, with purification on silica gel eluting with 2:1 EtOAc/hexanes to give 16d as a
yellow oil (61 mg, 94% yield). Rf = 0.66 (2:1 EtOAc/hexanes); 1H NMR (CDCl3, 300 MHz): δ 8.41 (s, 2H), 8.35
(d, J = 7.5 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.72 (t, J = 7.5 Hz, 2H), 7.50 (t, J = 8.0 Hz,
1H), 7.42ꢀ7.29 (m, 4H), 7.22ꢀ7.11 (m, 4H), 7.00 (d, J = 8.5 Hz, 2H), 6.80 (d, J = 9.0 Hz, 2H), 6.77 (d, J = 8.0 Hz,
2H), 5.53 (s, 1H), 5.00 (s, 2H), 4.78 (d, J = 12.0 Hz, 1H), 4.41 (d, J = 12.0 Hz, 1H), 4.13 (dd, J = 4.5, 7.3 Hz,
1H), 3.77 (s, 3H), 3.18 (s, 3H), 3.04 (dd, J = 4.5, 13.8 Hz, 1H), 2.84 (dd, J = 7.3, 13.8 Hz, 1H); 13C NMR (CDCl3,
75 MHz): δ 173.9, 160.9, 158.9, 158.0, 152.9, 149.0, 138.0, 137.0, 134.2, 133.8, 132.9, 131.9 (q, JCF = 33.4 Hz),
131.3 (q, JCF = 3.8 Hz), 131.0, 130.4, 130.2 129.9, 129.5, 129.7 (q, JCF = 3.8 Hz), 129.2, 128.7, 128.5, 128.2,
128.1 127.5, 126.8, 125.4, 124.4, 123.2, 122.3, 117.7, 114.8, 113.7, 70.0, 68.9, 64.6, 55.2, 37.8, 30.9; IR (thin
film) 2935. 1797, 1743, 1606, 1511, 1455, 1379, 1332, 1313, 1300, 1275, 1249, 1226, 1167, 1124, 1070, 1033,
996, 908, 858, 818, 789, 729, 693 cmꢀ1. HRMS (ESI+) Calculated for C42H37N3O5F3 m/z (M+H) 720.2685, Obsd.
720.2689.
Benzyl-4-(4-(benzyloxy)benzyl)-2-(isobutyrylimino)-5-((Z)-4-methoxybenzylidene)-3-
methylimidazolidine-1-carboxylate (16e). Prepared according to the general procedure A with isobutyryl chloride,
with purification on silica gel eluting with 1:1 EtOAc/hexanes to give 16e as a yellow oil (49 mg, 87% yield). Rf
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= 0.32 (1:1 hexanes/EtOAc); H NMR (CDCl3, 500 MHz): δ 7.64ꢀ7.37 (m, 10H), 7.28 (d, J = 8.8 Hz, 2H), 7.15
(d, J = 8.8 Hz, 2H), 7.08 (d, J = 7.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 5.60 (s, 1H), 5.21 (s, 2H), 5.07 (d, J = 19.5
Hz, 1H), 4.71 (d, J = 19.5 Hz, 1H), 4.20 (dd, J = 4.2, 7.1 Hz, 1H), 3.97 (s, 3H), 3.24 (s, 3H), 3.18 (dd, J = 4.2,
13.5 Hz, 1H), 2.93 (dd, J = 7.1, 13.5 Hz, 1H), 2.84 (sept, J = 6.8 Hz, 1H), 1.44 (d, J = 6.8 Hz, 3H), 1.39 (d, J =
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6.8 Hz, 3H) ppm. 13C NMR (CDCl3, 75 MHz): δ 188.0, 158.7, 157.9, 150.3, 149.2, 137.0, 134.6, 131.0, 129.5,
129.4, 128.7, 128.6, 128.2, 128.0, 127.9, 127.4, 127.2, 117.0, 114.8, 113.7, 70.0, 68.6, 64.6, 55.2, 38.6, 37.9,
30.8, 20.1 ppm. IR (thin film) 3033, 2964, 2929, 1745, 1663, 1607, 1455, 1379, 1273, 1249, 1179, 1123, 1077,
1037, 923, 864, 826, 738, 697 cmꢀ1. HRMS (ESI+) calculated for C38H39N3O5Na m/z (M+Na) 640.2787, Obsd.
640.2775.
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Benzyl-4-(4-(benzyloxy)benzyl)-5-((Z)-4-methoxybenzylidene)-3-methyl-2-((2-methylbutanoyl)imino)
imidazolidine-1-carboxylate (16f). Prepared according to the general procedure A with 2ꢀmethylbutyryl chloride,
with purification on silica gel eluting with 1:1 EtOAc/hexanes to give 16f as a yellow oil (28 mg, 85% yield). Rf
= 0.44 (1:1 hexanes/EtOAc); 1H NMR (CDCl3, 500 MHz): δ 7.44ꢀ7.17 (m, 8H), 7.08 (d, J = 8.7 Hz, 2H), 6.94 (d,
J = 8.5 Hz, 2H), 6.86 (d, J = 7.3 Hz, 2H), 6.75 (d, J = 8.4 Hz, 2H), 5.39 (d, J = 5.8 Hz, 1H), 5.00 (s, 2H), 4.88 (dd
, J = 4.0 Hz, 20.5 Hz, 1H), 4.51 (dd , J = 4.0 Hz, 20.5 Hz, 1H), 3.99 (p, J = 3.7, 1H), 3.75 (s, 3H), 3.03 (s, 3H),
2.97 (dd, J = 4.4, 13.5 Hz, 1H), 2.72 (m, 1H), 2.46 (ddq, J = 6.9, 5.6, 7.0 Hz, 1H), 1.83 (m, 1H), 1.51 (m, 1H),
1.18 (dd, J = 6.9, 7.0, 3H), 0.97 (dt, J = 4.0, 7.6 Hz, 3H) ppm; 13C NMR (CDCl3, 75 MHz): δ 187.5, 158.9,
158.0, 151.1, 150.7, 149.4, 137.2, 134.7, 131.2, 129.7, 128.8, 128.7, 128.4, 128.2, 128.0, 127.6, 127.4, 127.3,
117.2, 114.9, 113.8, 70.1, 68.8, 64.8, 55.4, 45.9, 45.5, 38.1, 31.1, 27.7, 27.5, 17.2, 16.4, 12.2, 12.0. IR (thin film)
2963, 2931, 2873, 1746, 1653, 1607, 1511, 1456, 1378, 1249, 1179, 1119, 1077, 1039, 827, 741, 696 cmꢀ1.
HRMS (ESI+) calculated for C39H41N3O5Na m/z (M+Na) 654.2944, Obsd. 654.2941.
General Procedure B: deprotection with isomerization of 16 to 17. N-(5-(4-Hydroxybenzyl)-4-(4-
methoxybenzyl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide (17a). To a 5 mL round bottom flask
equipped with a stir bar was added 16a (52 mg, 0.08 mmol), PdCl2 (25 mg, 0.18 mmol) and methanol (0.9 mL).
The reaction was allowed to stir until completion under an H2 atmosphere balloon. The reaction mixture was
filtered through 0.45 µM PTFE syringe filter and rinsed with additional methanol and CH2Cl2. The solvent was
removed and the product was triturated with diethyl ether. The solid was isolated to give 17a as an offꢀwhite
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solid (34 mg, 92%, mp = 135 ºC). Rf = 0.40 (5% MeOH in CH2Cl2); H NMR (DMSOꢀd6, 500 MHz): δ 9.41 (s,
1H), 8.10 (d, J = 7.3 Hz, 2H), 7.63 (t, J = 7.33 Hz, 1H), 7.53 (t, J = 7.8 Hz, 2H), 7.20 (d, J = 8.8 Hz, 2H), 6.88 (d,
J = 8.3 Hz, 2H) 6.86 (d, J = 8.8 Hz, 2H), 6.69 (d, J = 6.4 Hz, 2H) 4.03 (s, 2H), 4.00 (s, 2H), 3.69 (s, 3H), 3.15 (s,
3H) ppm. 13C NMR (DMSOꢀd6, 125 MHz): δ 158.5, 156.7, 133.3, 130.4, 130.0, 129.5, 129.0, 128.9, 127.0, 116.0,
114.4, 55.6, 49.0, 31.7, 28.7, 27.4 ppm. IR (thin film) 3926, 2932, 1688 1612, 1510, 1474, 1453, 1408, 1363,
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1301, 1246, 1174, 1104, 1033, 908, 818, 731, 706 cmꢀ1. HRMS (ESI+) calculated for C26H26N3O3 m/z (M+H)
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428.1974, Obsd. 428.1973.
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2-Fluoro-N-(5-(4-hydroxybenzyl)-4-(4-methoxybenzyl)-1-methyl-1,3-dihydro-2H-imidazol-2-
ylidene)benzamide (17b). Prepared according to the general procedure B with 16b, with purification via
trituration with diethyl ether to give 17b as a waxy solid (23 mg, 88% yield). Rf = 0.30 (1:1 hexanes/EtOAc); 1H
NMR (DMSOꢀd6, 300 MHz): δ 9.29 (s, 1H), 7.80 (s, 1H), 7.43 (s, 1H), 7.19 (d, J = 8.1 Hz, 4H), 6.89 (d, J = 8.1
Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 8.1 Hz, 2H), 3.89 (s, 4H), 3.71 (s, 3H), 3.20 (s, 3H) ppm. 13C NMR
(DMSOꢀd6, 125 MHz): δ 157.8, 155.9, 131.3, 129.9, 129.7, 129.4, 128.3, 116.7 (d, JCF = 22.8 Hz), 115.8, 114.2,
55.4, 29.5, 27.7 ppm. IR (thin film) 1686, 1581, 1512, 1478, 1441, 1305, 1247, 1173, 1156, 1105, 904 cmꢀ1.
HRMS (ESI+) calculated for C26H24N3O3FNa m/z (M+Na) 468.1699, Obsd. 468.1700.
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N-(5-(4-Hydroxybenzyl)-4-(4-methoxybenzyl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)-4-
methoxybenzamide (17c). Prepared according to the general procedure B with 16c, with purification via
trituration with diethyl ether to give 17c as an offꢀwhite solid (50 mg, 95% yield, mp = 178 ºC). Rf = 0.30 (1:1
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hexanes/EtOAc); H NMR (DMSOꢀd6, 300 MHz): δ 9.44 (s, 1H), 8.07 (d, J = 9.3 Hz, 2H), 7.21 (d, J = 8.8 Hz,
2H), 7.10 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.3 Hz, 2H), 6.87 (d, J = 8.3 Hz, 2H), 6.69 (d, J = 8.3 Hz, 2H), 4.06 (s,
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2H), 4.01 (s, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 3.43 (s, 3H) ppm. C NMR (DMSOꢀd6, 75 MHz): δ 162.8, 157.8,
155.9, 130.4, 129.6, 129.2, 128.8, 126.2, 115.2, 113.7, 64.6, 55.3, 54.8, 31.5, 27.8, 26.6, 14.9 ppm. IR (thin film)
2929, 1605, 1585, 1569, 1510, 1465, 1367, 1303, 1248, 1166, 1101, 1030, 906, 843, 815, 770, 728, 692, 668 cmꢀ
1. HRMS (ESI+) calculated for C27H28N3O4 m/z (M+H) 458.2080, Obsd. 458.2083.
N-(5-(4-Hydroxybenzyl)-4-(4-methoxybenzyl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)-3-
(trifluoromethyl)benzamide (17d). Prepared according to the general procedure B with 16d, with purification via
trituration with diethyl ether to give 17d as an offꢀwhite solid (58 mg, 92% yield, mp = 237 ºC). Rf = 0.40 (2:1
EtOAc/hexanes); 1H NMR (DMSOꢀd6, 300 MHz): δ 9.32 (s, 2H), 8.38 (s, 2H), 7.79 (d, J = 7.8 Hz, 1H), 7.64 (t, J
= 7.5 Hz, 2H), 7.21 (d, J = 8.7 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 6.69 (d, J = 8.4 Hz,
2H), 3.93 (s, 4H), 3.71 (s, 3H), 3.29 (s, 3H) ppm. 13C NMR (DMSOꢀd6, 75 MHz): δ 157.8, 155.9, 132.2, 129.5,
129.0, 124.5, 115.4, 113.9, 55.1, 28.9, 27.1 ppm. IR (thin film) 1564, 1532, 1512, 1483, 1383, 1322, 1277, 1248,
1170, 1153, 1113, 916 cmꢀ1. HRMS (ESI+) calculated for C27H25N3O3F3 m/z (M+H) 496.1848, Obsd. 496.1850.
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N-(5-(4-Hydroxybenzyl)-4-(4-methoxybenzyl)-1-methyl-1,3-dihydro-2H-imidazol-2-
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ylidene)isobutyramide (17e). Prepared according to the general procedure B with 16e, with purification via
trituration with diethyl ether to give 17e as an offꢀwhite solid (20 mg, 98% yield, mp = 196 ºC). Rf = 0.17 (1:1
hexanes/EtOAc); 1H NMR (DMSOꢀd6, 300 MHz): δ 7.09 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.3 Hz, 2H), 6.75 (d, J
= 8.8 Hz, 2H), 6.64 (d, J = 8.3 Hz, 2H), 3.86 (s, 2H), 3.80 (s, 2H), 3.72 (s, 3H), 3.16 (s, 3H), 2.63 (sep, J = 6.8
Hz, 1H), 1.19 (d, J = 6.8 Hz, 6H) ppm; 13C NMR (DMSOꢀd6, 75 MHz): δ 176.3, 157.6, 155.8, 136.3, 130.0,
129.1, 128.7, 126.3, 125.5, 115.1, 113.5, 54.7, 33.5, 31.0, 28.0, 26.5, 18.6, ppm. IR (thin film) 3274, 2968, 2472,
1670, 1611, 1510, 1465, 1404, 1301, 1244, 1174, 1102, 1032, 973, 816 cmꢀ1. HRMS (ESI+) calculated for
C23H28N3O3 m/z (M+H) 394.2147, Obsd. 394.2138.
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N-(5-(4-Hydroxybenzyl)-4-(4-methoxybenzyl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)-2-
methylbutanamide (17f). Prepared according to the general procedure B with 16f, with purification via trituration
with diethyl ether to give 17f as an offꢀwhite solid (16 mg, 99%, mp = 102 ºC). Rf = 0.33 (1:1 hexanes/EtOAc);
1H NMR (DMSOꢀd6, 300 MHz): δ 9.40 (s, 1H), 7.17 (d, J = 8.7 Hz), 6.87 (d, J = 8.2 Hz, 2H), 6.84 (d, J = 8.7 Hz,
2H), 6.67 (d, J = 8.5 Hz, 2H), 3.98 (s, 2H), 3.94 (s, 2H), 3.71 (s, 3H), 3.36 (s, 3H), 2.89 (sextet, J = 6.6 Hz, 1H),
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1.61 (m, J = 7.4 Hz, 1H), 1.43 (m, J = 6.8 Hz, 1H), 1.10 (d, J = 6.8 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H) ppm; C
NMR (DMSOꢀd6, 75 MHz): δ 176.1, 157.9, 156.1, 136.7, 130.5, 129.5, 129.1, 126.8, 125.9, 115.4, 113.9, 55.1,
31.3, 28.5, 26.9, 26.4, 16.9, 11.5 ppm. IR (thin film) 3357, 2965, 2483, 2076, 1670, 1653, 1635, 1612, 1558,
1510, 1458, 1405, 1301, 1245, 1175, 1118, 1033, 971, 816 cmꢀ1. HRMS (ESI+) calculated for C24H30N3O3 m/z
(M+H) 408.2303, Obsd. 408.2286.
Preparation of Compound 18a. N-(1,3-diphenylprop-2-yn-1-yl)-N-methylprop-2-en-1-amine (S1a). In a
250 mL high pressure flask containing a magnetic stir bar were added benzaldehyde (3.1 g, 29.0 mmol),
phenylacetylene (2.95 g, 28.9 mmol), Nꢀallylmethylamine (1.88 g, 26.3 mmol), oven dried molecular sieves
(Grade 564, 3 Å, 8ꢀ12 mesh) (ca. 2 g) and acetonitrile (200 mL). The flask was sealed and placed in a preheated
80˚C oil bath for 24 h. The reaction flask was removed from the oil bath and allowed to cool to room temperature.
CuBr (0.38 g, 2.6 mmol) was added and the flask was sealed and returned to the preheated 80 ˚C oil bath for 48 h.
The reaction tube was removed from the oil bath and allowed to cool to room temperature. The reaction mixture
was filtered through Celite and rinsed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure.
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The crude product was purified via flash chromatography, eluting with 9:1 hexanes/EtOAc to give S1a as a dark
orange oil (5.3 g, 88%). Rf = 0.78 (2:1 hexanes/EtOAc); 1H NMR (CDCl3, 300 MHz): δ 7.65 (d, J = 6.9 Hz, 2H),
7.56ꢀ7.53 (m, 2H), 7.40ꢀ7.26 (m, 6H), 5.93 (ddt, J = 6.6 Hz, 10.4 Hz, 17.1 Hz, 1H), 5.32 (dd, J = 17.1 Hz, 1.5
Hz, 1H), 5.18 (dd, J = 10.4 Hz, 1.2 Hz, 1H), 4.99 (s, 1H), 3.89 (s, 3H), 3.19 (d, J = 5.1 Hz, 2H), 2.23 (s, 3H).
13C NMR (CDCl3, 75 MHz): δ 138.9, 136.3, 131.9, 128.5, 128.4, 128.3, 127.7, 123.4, 117.8, 88.5, 84.9,
59.8, 57.9 ppm. IR (thin film): 3061, 3030, 2978, 2945, 2844, 2788, 1598, 1489, 1448, 1324, 1273, 1196, 1155,
1127, 1070, 1023, 994, 963, 917, 754, 726, 689 cmꢀ1. HRMS (ESI+) Calculated for C19H19N m/z 262.1590
(M+H), Obsd. 262.1572.
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N-methyl-1,3-diphenylprop-2-yn-1-amine (S2a). In a 250 mL round bottom flask containing a magnetic
stir bar were added Pd(PPh3)4 (1.3 g, 1.1 mmol), thiosalicylic acid (7.0 g, 45.0 mmol) and CH2Cl2 (100 mL). A
solution of S1a (5.3 g, 22.7 mmol) in 15 mL in CH2Cl2 was added, and the reaction mixture was allowed to stir at
room temperature under N2 for 12 h. The solvent was then removed under reduced pressure and the crude product
was reꢀdissolved in Et2O (10 mL). The organic layer was washed with aqueous solutions of saturated NaHCO3
(50 mL) and brine (50mL), then dried and filtered over Na2SO4. The crude product was purified via flash
chromatography, eluting with 4:1 hexanes/EtOAc to give S2a as a dark orange oil (3.1 g, 73%). Rf = 0.22 (2:1
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hexanes/EtOAc); H NMR (CDCl3, 300 MHz): δ 7.61ꢀ7.31 (m, 10H), 4.76 (s, 1H), 2.57 (s, 3H), 1.47 (s, 1H)
ppm. 13C NMR (CDCl3, 75 MHz): δ 140.3, 131.8, 128.6, 128.4, 128.2, 127.9, 127.7, 123.2, 89.1, 85.7, 56.4, 33.9
ppm. IR (thin film) 3060, 3029, 2933, 2850, 2793, 1653, 1598, 1559, 1540, 1489, 1473, 1449, 1306, 1214, 1177,
1098, 1071, 1027, 915, 755, 691 cmꢀ1. HRMS (ESI+) Calculated for C16H16N m/z 222.1259 (M+H), Obsd.
222.1288.
Benzyl (Z)-5-benzylidene-2-imino-3-methyl-4-phenylimidazolidine-1-carboxylate (S3a). In a 100 mL
round bottom flask containing a magnetic stir bar were added potassium benzyloxycarbonylcyanamide (0.65 g,
3.0 mmol), TMSCl (0.34 g, 3.1 mmol) and acetonitrile (15 mL). The solution was stirred at room temperature for
10 minutes. A solution of S2a (0.46 g, 2.4 mmol) in acetonitrile (3.5 mL) was then added, and the reaction
mixture was allowed to stir at room temperature for 1 h. The solvent was removed under reduced pressure and the
crude product was dissolved in EtOAc (150 mL). The organic layer was washed aqueous solutions of saturated
NaHCO3 (50 mL) and brine (50 mL), then dried and filtered over Na2SO4. The crude product was purified via
flash chromatography, eluting with 1:1 hexanes/EtOAc to give S3a as a dark brown oil (0.75 g, 85%). Rf = 0.48
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(1:1 hexanes/EtOAc); H NMR (CDCl3, 300 MHz): δ 7.58ꢀ7.23 (m, 15H), 5.18 (s, 2H), 2.83 (s, 3H) ppm. 13C
NMR (CDCl3, 75 MHz): δ 164.3, 161.3, 158.0, 137.2, 132.1, 128.9, 128,8, 128.6, 128.3, 128.2, 127.9, 127.6,
122.7, 87.0, 85.1, 67.1, 51.4, 30.1 ppm. IR (thin film) 3331, 3031, 2939, 1736, 1646, 1596, 1534, 1491, 1450,
1379, 1153, 1050, 1028, 801, 757, 696 cmꢀ1. HRMS (ESI+) Calculated for C25H24N3O2 m/z 398.1869 (M+H),
Obsd. 398.1877.
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(Z)-Benzyl 5-benzylidene-2-imino-3-methyl-4-phenylimidazolidine-1-carboxylate (18a). In a 50 mL foilꢀ
wrapped round bottom flask containing a magnetic stir bar were added S3a (0.75, 2.0 mmol), AgNO3 (35 mg,
0.20 mmol), and CH2Cl2 (20 mL). The solution was stirred at room temperature for 6 h. The solvent was then
removed under reduced pressure and the crude product was reꢀdissolved in EtOAc (50 mL). The organic layer
was washed with aqueous solutions of saturated NaHCO3 (15 mL) and brine (15 mL), then dried and filtered over
Na2SO4. The crude product was purified via flash chromatography, eluting with 1:1 hexanes/EtOAc to give 18a
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as a dark brown oil (0.53 g, 71%). Rf = 0.31 (1:1 hexanes/EtOAc); H NMR (CDCl3, 300 MHz): δ 7.43ꢀ7.12 (m,
11H), 7.08 (d, J = 7.0 Hz, 2H), 6.90 (d, J = 7.5 Hz, 2H), 5.52 (d, J = 3.0 Hz, 1H), 5.00 (d, J = 3.0 Hz, 1H), 4.79 (d
, J = 19.5 Hz, 1H), 4.37 (d, J = 19.5 Hz, 1H), 2.81 (s, 3H) ppm. 13C NMR (CDCl3, 75 MHz): δ 154.1, 151.4,
137.6, 136.3, 34.4, 129.2, 129.1, 128.7, 128.5, 128.4, 128.2, 127.4, 127.1, 113.4, 68.4, 67.6, 30.2 ppm. IR (thin
film) 3346, 3031, 1734, 1684, 1652, 1495, 1426, 1386, 1303, 1249, 1197, 1161, 1047, 1026, 957, 797, 696 cmꢀ1.
HRMS (ESI+) Calculated for C25H24N3O2 m/z 398.1869 (M+H), Obsd. 398.1876.
Preparation of compound 18b. N-(1-(4-Methoxyphenyl)-3-phenylprop-2-yn-1-yl)-N-methylprop-2-en-1-
amine (S1b). Prepared according to the A3ꢀcoupling procedure of S1a using pꢀanisaldehyde, nꢀallylmethylamine,
and phenylacetylene with purification on silica gel eluting with 2:1 hexanes/EtOAc to give a dark orange oil (12.7
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g, 65%). Rf = 0.78 (2:1 hexanes/EtOAc); H NMR (CDCl3, 300 MHz): δ 7.59ꢀ7.53 (m, 4H), 7.37ꢀ7.26 (m, 3H),
6.49 (d, J = 8.7 Hz, 2H), 5.92 (ddt, J = 6.6 Hz, 10.5 Hz, 17.4 Hz, 1H), 5.33 (dd, J = 17.4 Hz, 2.0 Hz, 1H), 5.19
(dd, J = 9.3 Hz, 2.0 Hz, 1H), 4.94 (s, 1H), 3.83 (s, 3H), 3.19 (d, J = 6.6 Hz, 2H), 2.24 (s, 3H). 13C NMR (CDCl3,
75 MHz): δ 159.1, 136.3, 131.9, 131.1, 129.7, 128.4, 128.2, 123.4, 117.7, 113.6, 88.3, 85.3, 59.3, 57.8,
55.4, 37.8 ppm. IR (thin film) 2948, 2834, 2786, 1642, 1609, 1583, 1507, 1488, 1441, 1301, 1244, 1169, 1126,
1107, 1033, 994, 962, 916, 850, 807, 778, 754, 689, 583, 524 cmꢀ1. HRMS (ESI+) Calculated for C20H21NO m/z
292.1701 (M+H), Obsd. 292.1699.
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1-(4-Methoxyphenyl)-N-methyl-3-phenylprop-2-yn-1-amine (S2b). Prepared according to the Pd(0)ꢀ
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deallylation procedure with S1b, with purification on silica gel eluting with 2:1 hexanes/EtOAc to give S2b a
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dark orange oil (2.1 g, 44%). Rf = 0.22 (2:1 hexanes/EtOAc); H NMR (CDCl3, 300 MHz): δ 7.54ꢀ7.48 (m, 4H),
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7.33ꢀ7.31 (m, 3H), 6.9 (d, J = 8.7 Hz, 2H), 5.18 (s, 1H), 3.81 (s, 3H), 2.56 (s, 3H), 1.81 (s, 1H) ppm. 13C NMR
(CDCl3, 75 MHz): δ 159.2, 132.4, 131.7, 128.8, 128.3, 128.1, 123.1, 113.8, 89.2, 85.5, 55.6, 55.3, 33.7
ppm. IR (thin film) 2953, 2834, 2790, 1609, 1584, 1508, 1488, 1462, 1440, 1301, 1243, 1171, 1095, 1031, 956,
913, 829, 754, 727, 703, 689, 573, 547, 524 cmꢀ1. HRMS (ESI+) Calculated for C17H17NONa m/z 274.1208
(M+Na), Obsd. 274.1213.
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Benzyl (Z)-5-benzylidene-2-imino-4-(4-methoxyphenyl)-3-methylimidazolidine-1-carboxylate (S3b).
Prepared according to the guanylation procedure of S2b, with purification on silica gel eluting with 1:1
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hexanes/EtOAc to give a dark orange oil (2.97 g, 82%). Rf = 0.48 (1:1 hexanes/EtOAc); H NMR (CDCl3, 300
MHz): δ 7.51ꢀ7.43 (m, 6H), 7.36ꢀ7.25 (m, 7H), 6.9 (d, J = 6.3 Hz, 2H), 5.18 (s, 2H), 3.80 (s, 3H), 2.80 (s, 3H).
13C NMR (CDCl3, 75 MHz): δ 164.1, 160.9, 159.4, 137.6, 131.9, 129.0, 128.7, 128.6, 128.4, 128.0, 127.7, 122.2,
113.9, 86.6, 85.2, 66.9, 55.3, 50.6, 29.7 ppm. IR (thin film) 3403, 2932, 1646, 1584, 1532, 1508, 1488, 1440,
1376, 1273, 1246, 1121, 1150, 1110, 1027, 908, 845, 799, 775, 755, 729, 690, 647, 586, 552 cmꢀ1. HRMS (ESI+)
Calculated for C26H26N3O3 m/z 428.1974 (M+Na), Obsd. 428.1979.
(Z)-Benzyl 5-benzylidene-2-imino-4-(4-methoxyphenyl)-3-methylimidazolidine-1-carboxylate (18b).
Prepared according to the Ag(I)ꢀcyclization procedure, with purification by silica gel eluting with 1:1
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hexanes/EtOAc to give a dark brown oil (1.2 g, 87%). Rf = 0.18 (1:1 hexanes/EtOAc); H NMR (CDCl3, 300
MHz): δ 7.28ꢀ7.16 (m, 9H), 7.10ꢀ7.08 (m, 2H), 6.92ꢀ6.88 (m, 4H), 5.47 (d, J = 2.1 Hz, 1H), 4.92 (d, J = 2.1 Hz,
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1H), 4.82 (d, J = 19.5 Hz, 2H), 4.33 (d, J = 19.5 Hz, 2H), 3.81 (s, 3H), 2.75 (s, 3H) ppm. C NMR (CDCl3, 75
MHz): δ 106.1, 153.5, 151.4, 136.5, 135.1, 134.4, 129.7, 129.6, 128.7, 128.4, 127.4, 127.0, 114.5, 113.0, 62.2,
67.0, 55.4, 30.1 ppm. IR (thin film) 3404, 2932, 1646, 1548, 1532, 1508, 1488, 1440, 1376, 1273, 1246, 1171,
1150, 1110, 1027, 908, 845, 799, 779, 755, 728, 690, 647, 586, 552 cmꢀ1. HRMS (ESI+) Calculated for
C26H26N3O3 m/z 428.1974 (M+Na), Obsd. 428.1979.
General Procedure C: Acylation of 18 to give 19. Benzyl-2-(benzoylimino)-5-((Z)-benzylidene)-3-
methyl-4-phenylimidazolidine-1- carboxylate (19a). In a 10 mL roundꢀbottomed flask containing a magnetic stir
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bar were added 18a (73 mg, 0.18 mmol), benzoyl chloride (0.032 mL, 0.28 mmol, 1.5 equiv.), triethylamine
(0.051 mL, 0.37 mmol, 2.0 equiv.), and dichloromethane (2 mL) under N2. The reaction was stirred at room
temperature for 2 h. The solution was concentrated under reduced pressure and the crude material was dissolved
in EtOAc (20 mL). The organic layer was washed with aqueous solutions of saturated NaHCO3 (15 mL) and
brine (15 mL). The organic layer was dried over Na2SO4, and the resulting material was purified via flash
chromatography (3:2 hexanes/EtOAc) to yield 19a as a light brown foam (86 mg, 93%). Rf = 0.22 (3:2
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hexanes/EtOAc) H NMR (CDCl3, 300 MHz): δ 8.21ꢀ8.18 (m, 2H), 7.51ꢀ7.32 (m, 8H), 7.25ꢀ7.11 (m, 8H), 6.8ꢀ
6.78 (m, 2H), 5.77 (d J = 2.0 Hz, 1H), 5.16 (d , J = 2.0 Hz, 1H), 4.70 (d, J = 12.0 Hz, 2H), 4.63 (d, J = 12.0 Hz,
2H), 2.93 (s, 3H) ppm. 13C NMR (CDCl3, 75 MHz): δ 178.8, 151.8, 149.3, 137.1, 136.8, 135.4, 134.5, 133.9,
131.6, 129.7, 129.4, 129.3, 127.8, 127.5, 116.9, 68.8, 67.0, 30.6 ppm. IR (thin film) 3060, 3029, 1744, 1557,
1494, 1448, 1404, 1377, 1315, 1277, 1226, 1173, 1144, 1080, 1036, 1020, 976, 909, 856, 794, 752, 727, 696, 668
cmꢀ1. HRMS (ESI+) calculated for C32H27N3NaO3 m/z (M+Na) 524.1950, Obsd. 524.1963.
Benzyl (2-(benzoylimino)-5-((Z)-benzylidene)-4-(4-methoxyphenyl)-3-methylimidazolidine- 1-carboxylate
(19b). Prepared according to general procedure C using 18b and benzoyl chloride, with purification using silica
gel eluting with 3:2 hexanes/EtOAc to give 19b as a light brown foam (96 mg, 80%). Rf = 0.22 (3:2
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hexanes/EtOAc); H NMR (CDCl3, 500 MHz): δ 8.18 (d, J = 8.0 Hz, 2H), δ 7.50ꢀ7.21 (m, 14H), δ 6.91 (d, J =
8.5 Hz, 2H), δ 6.80 (d, J = 7.0 Hz, 2H), δ 5.74 (d, J = 1.8 Hz, 1H), δ 5.13 (d, J = 1.8 Hz, 1H), δ 4.72 (d, J =
13
12.0 Hz, 1H), δ 4.24 (d, J = 12.0 Hz, 1H), δ 3.82 (s, 3H), δ 2.90 (s, 3H) ppm. C NMR (CDCl3, 125 MHz): δ
175.2, 160.5, 151.9, 149.4, 137.3, 135.6, 134.7, 134.6, 134.4, 131.7, 129.8, 129.4, 128.7, 128.5, 128.4, 128.3,
128.2, 127.6, 116.8, 114.9, 69.0, 66.8, 55.6, 30.7 ppm. IR (thin film) 3404, 2932, 1646, 1548, 1532, 1508, 1488,
1440, 1376, 1273, 1246, 1171, 1150, 1110, 1027, 908, 845, 799, 779, 755, 728, 690 cmꢀ1. HRMS (ESI+)
calculated for C33H29N3NaO4 m/z (M+Na) 554.2056, Obsd. 554.2066.
Benzyl 5-((Z)-benzylidene)-2-((4-methoxy benzoyl)imino)-3-methyl-4- phenylimidazolidine-1-carboxylate
(19c). Prepared according to general procedure C using 18a and 4ꢀmethoxybenzoyl chloride, with purification
using silica gel eluting with 3:2 hexanes/EtOAc to give 19c as a light brown foam (0.12 g, 95%). Rf = 0.19 (3:2
hexanes/EtOAc); 1H NMR (CDCl3, 500 MHz): δ 8.16 (d, J = 9.0 Hz, 2H), 7.41ꢀ7.37 (m, 3H), 7.33ꢀ7.30 (m, 2H),
7.26ꢀ7.12 (m, 8H), 6.93 (d, J = 9.0 Hz, 2H), 6.81 (d, J = 7.5 Hz, 2H), 5.72 (d, J = 2.0 Hz, 1H), 5.13 (s, 1H), 4.71
13
(d , J = 12.3 Hz), 4.65 (d , J = 12.3 Hz), 3.86 (s, 3H), 2.92 (s, 3H) ppm. C NMR (CDCl3, 125 MHz): δ 175.0,
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162.6, 151.5, 149.5, 137.1, 135.6, 134.8, 134.2, 131.8, 130.1, 129.5, 129.4, 1283, 127.9, 127.6, 116.9, 113.4,
68.9, 67.2, 55.6, 30.8 ppm. IR (thin film) 3058, 2951, 1745, 1652, 1597, 1507, 1456, 1427, 1249, 1227, 1177,
1162, 1022, 974, 863, 843, 731, 693 cmꢀ1. HRMS (ESI+) calculated for C33H29N3NaO4 m/z (M+Na) 554.2056,
Obsd. 554.2061.
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5
6
7
8
9
Benzyl-5-((Z)-benzylidene)-3-methyl-4-phenyl-2-((3-(trifluoromethyl)benzoyl)imino)imidazolidine-1-
carboxylate (19d). Prepared according to general procedure C using 18a and 3ꢀtrifluoromethylbenzoyl chloride,
with purification using silica gel eluting with 3:2 hexanes/EtOAc to give 19d as a light brown foam (0.12 g,
87%). Rf = 0.31 (3:2 hexanes/EtOAc); 1H NMR (CDCl3, 500 MHz): δ 8.47 (s, 1H), 8.37 (d, J = 8.0 Hz, 1H), 7.74
(d, J = 8.0 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.42 (m, 4H), 7.34 (m, 2H), 7.26 (m, 3H), 7.19 (d, J = 7.0 Hz, 2H),
7.15 (t, J = 7.5 Hz, 2H), 6.78 (d, J = 7.0 Hz, 2H), 5.80 (s, 1H), 5.20 (s, 1H), 4.69 (d , J = 11.8 Hz), 4.64 (d , J =
11.8 Hz), 2.95 (s, 3H) ppm. 13C NMR (CDCl3, 125 MHz): δ 173.6, 155.1, 144.3, 138.1, 136.7, 135.4, 134.4,
133.9, 133.1, 130.6 (q, JCF = 32.4 Hz), 128.8, 128.7, 128.5, 128.5, 128.4, 128.3, 128.2 (q, JCF = 2.8 Hz), 128.0,
127.7, 126.8 (q, JCF = 3.6 Hz), 124.3 (q, JCF = 270.5 Hz), 117.4, 69.2, 67.3, 30.8 ppm. IR (thin film) 1699, 1652,
1616, 1325, 1259, 1166, 1121, 1070, 998, 920, 855, 817, 758, 692 cmꢀ1. HRMS (ESI+) calculated for
C33H26F3N3NaO3 m/z (M+Na) 592.1824, Obsd. 592.1821.
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11
12
13
14
15
16
17
18
19
20
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22
23
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Benzyl 5-((Z)-benzylidene)-2-(isobutyrylimino)-3-methyl-4-phenylimidazolidine-1- carboxylate (19e).
Prepared according to general procedure C using 18a and isobutyryl chloride, with purification using silica gel
eluting with 3:2 hexanes/EtOAc to give 19e as a light brown foam (38 mg, 92%). Rf = 0.34 (3:2 hexanes/EtOAc);
1H NMR (CDCl3, 500 MHz): δ 7.42ꢀ7.35 (m, 3H), 7.29ꢀ 7.15 (m, 10H), 6.86 (d, J = 7.0 Hz, 2H), 5.72 (d, J = 2.0
Hz, 1H), 5.07 (d, J = 2.0 Hz, 1H), 4.74 (d , J = 12.3 Hz), 4.69 (d , J = 12.3 Hz), 2.81 (s, 3H), 2.71 (m, 1H), 1.26
(d, J = 7.0 Hz, 6H) ppm. 13C NMR (CDCl3, 125 MHz): δ 187.6, 150.2, 149.5, 137.1, 135.6, 134.7, 134.1, 129.5,
128.6, 128.4, 128.3, 127.8, 127.6, 116.6, 68.8, 67.1, 38.8, 30.6, 20.0 ppm. IR (thin film) 3030, 2966, 2360, 2340,
1743, 1653, 1598, 1494, 1455, 1403, 1378, 1345, 1261, 1175, 1121, 1080, 1023, 977, 919, 847, 820, 752, 730,
695, 668, 634, 598, 557 cmꢀ1. HRMS (ESI+) calculated for C29H29N3NaO3 m/z (M+Na) 490.2107, Obsd. 490.2103
(M+Na).
Benzyl-5-((Z)-benzylidene)-3-methyl-2-((2-methylbutanoyl)imino)-4- phenylimidazolidine-1-carboxylate
(19f). Prepared according to general procedure C using 18a and 2ꢀmethylbutyryl chloride, with purification using
silica gel eluting with 3:2 hexanes/EtOAc to give 19f as a light brown foam Light brown foam (57 mg, 70%). Rf =
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1
0.39 (3:2 hexanes/EtOAc); H NMR (CDCl3, 500 MHz): δ 7.42ꢀ7.12 (m, 13H), δ 6.86 (d, J = 7.5 Hz, 2H), 5.72
(d, J = 2.0 Hz, 1H), 5.08 (d, J = 2.0 Hz, 1H), 4.77ꢀ4.66 (m, 2H), 2.81 (s, 3H), 2.53 (m, 1H), 1.87 (m, 1H), 1.55
(m, 1H), 1.23 (d, J = 7 Hz, 3H), 1.01 (t, J = 6.5 Hz, 3H) ppm. 13C NMR (CDCl3, 125 MHz): δ 186.8, 150.6,
149.6, 137.3, 137.1, 135.6, 134.7, 134.3, 134.1, 129.5, 129.4, 128.5, 128.4, 128.3, 127.9, 127.8, 127.5, 116.4,
68.8, 45.8, 30.7, 27.6, 16.8, 12.1 ppm. IR (thin film) 3031, 2963, 2931, 2873, 1744, 1653, 1597, 1494, 1456,
1403, 1375, 1264, 1175, 1113, 1080, 1039, 978, 908, 752, 730, 695, 668, 633, 588 cmꢀ1. HRMS (ESI+) calculated
for C30H31N3NaO3 m/z (M+Na) 504.2263, Obsd. 504.2275.
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2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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26
27
28
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31
32
33
34
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37
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39
40
41
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44
45
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52
53
54
55
56
57
58
59
60
Benzyl-5-((Z)-benzylidene)-2-((2-fluorobenzoyl)imino)-3-methyl-4-phenylimidazolidine-
1-carboxylate
(19g). Prepared according to general procedure C using 18a and 2ꢀfluorobenzoyl chloride, with purification using
silica gel eluting with 3:2 hexanes/EtOAc to give 19g as a light brown foam (120 mg, 95%). Rf = 0.28 (3:2
1
hexanes/EtOAc); H NMR (CDCl3, 500 MHz): δ 7.99 (t, J = 8.0 Hz, 1H), 7.50ꢀ7.34 (m, 4H), 7.34ꢀ7.29 (m, 2H),
7.21ꢀ7.07 (m, 8H), 6.99 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 7.0 Hz) 5.71 (d, J = 2.0 Hz, 1H), 5.17 (d, J = 2.0 Hz,
1H), 4.75 (d , J = 11.8 Hz), 4.54 (d , J = 11.8 Hz), 2.93 (s, 3H) ppm. 13C NMR (CDCl3, 125 MHz): δ 172.3, 161.3
(d, JCF = 423.0 Hz), 151.5, 149.3, 136.7, 135.2, 134.4, 133.9, 132.6, 132.5, 134.4, 129.4, 128.7, 128.4, 128.3,
128.0, 127.9, 127.5, 125.9 (d, JCF = 16.6 Hz), 123.8 (d, JCF = 6.6 Hz), 117.2, 116.5 (d, JCF = 38.4 Hz), 69.0, 67.9,
30.5 ppm. IR (thin film) 3031, 1745, 1596, 1483, 1404, 1378, 1316, 1280, 1263, 1223, 1179, 1157, 1111, 1081,
1023, 974, 909, 866, 782, 755, 732, 696, 655 cmꢀ1. HRMS (ESI+) calculated for C32H26FN3NaO3 m/z (M+Na)
542.1856, Obsd. 542.1865.
Benzyl-5-((Z)-benzylidene)-2-((2-fluorobenzoyl)imino)-4-(4-methoxyphenyl)-3- methylimidazolidine-1-
carboxylate (19h). Prepared according to general procedure C using 18b and 2ꢀfluorobenzoyl chloride, with
purification using silica gel eluting with 3:2 hexanes/EtOAc to give 19h a light brown foam (0.98 g, 83%). Rf =
1
0.25 (3:2 hexanes/EtOAc); H NMR (CDCl3, 300 MHz): δ 7.99 (t, J = 6 Hz, 1H), 7.44 (m, 1H), 7.24ꢀ7.05 (m,
10H), 6.99ꢀ6.83 (m, 5H) 5.69 (d, J = 1.8 Hz, 1H), 5.15 (d, J = 1.8 Hz, 1H), 4.77 (d J = 19.8 Hz), 4.64 (d , J =
19.8 Hz), 3.82 (s, 3H), 2.89 (s, 3H) ppm. 13C NMR (CDCl3, 125 MHz): δ 161.3 (d, JCF = 253.4 Hz), 160.4, 151.5,
149.4, 135.3, 134.4, 134.3, 132.7, 132.6, 129.4, 128.8, 128.4, 128.3, 128.0, 127.5, 123.8 (d, JCF = 4.0 Hz), 117.1,
116.5 (d, JCF = 23.0 Hz), 114.8, 69.0, 66.6, 55.4, 30.4 ppm. IR (thin film) 2933, 2834, 2790, 109, 1584, 1508,
1488, 1462, 1440, 1301, 1243, 1171, 1095, 1031, 956, 913, 829, 783, 754, 727, 689, 660, 634, 618, 573, 547, 524
cmꢀ1. HRMS (ESI+) calculated for C33H28FN3NaO4 m/z (M+Na) 572.1962, Obsd. 572.1980.
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The Journal of Organic Chemistry
Benzyl-5((Z)-benzylidene)-4-(4-methoxyphenyl)-3-methyl-2-((3-
1
2
3
4
5
(trifluoromethyl)benzoyl)imino)imidazolidine-1-carboxylate (19i). Prepared according to general procedure C
using 18b and 3ꢀtrifluoromethylbenzoyl chloride, with purification using silica gel eluting with 3:2
6
7
1
hexanes/EtOAc to give 19i as a light brown foam (95%). Rf = 0.25 (3:2 hexanes/EtOAc); H NMR (CDCl3, 1
8
MHz): δ 8.46 (s, 1H), 8.36 (d, J = 9.5 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.55 (t, J = 10.0 Hz, 1H), 7.27ꢀ7.10 (m,
10), 6.93 (d, J = 10.5 Hz, 2H), 6.78 (d, J = 9.5 Hz, 2H), 5.77 (s, 1H), 5.18 (s, 1H), 4.70 (d , J = 14.5 Hz), 4.62 (d ,
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18
19
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60
13
J = 14.5 Hz), 3.89 (s, 3H), 2.92 (s, 3H) ppm. C NMR (CDCl3, 125 MHz): δ 173.3, 160.4, 152.8, 149.1, 137.9,
135.3, 134.0, 132.8, 130.3 (q, JCF = 24.7 Hz), 129.3, 128.5, 128.3, 128.3, 128.2, 128.1, 127.9, 127.5, 126.5 (q, JCF
= 2.9 Hz), 124.2 (q, JCF = 203.2 Hz), 117.0, 114.7, 68.9, 66.7, 55.4, 30.4 ppm. IR (thin film) 1775, 1739, 1670,
1608, 1514, 1383, 1323, 1252, 1172, 1127, 1072, 1030, 770 cmꢀ1. HRMS (ESI+) calculated for C34H28F3N3NaO4
m/z (M+Na) 622.1930, Obsd. 622.1927.
General Procedure D: deprotection with isomerization of 19 to 20. N-(4-Benzyl-1-methyl-5-phenyl-
1H-imidazol-2(3H)-ylidene)benzamide (20a). In a 5 mL test tube containing a magnetic stir bar were added 19a
(84 mg, 0.17 mmol), Pd/C (10% w/w, 9 mg), and distilled MeOH (2 mL) under a stream of N2. The reaction tube
was then sealed in a pressure vessel and purged with H2 three times. The pressure vessel was then charged with
H2 at 60 psi, and the reaction was stirred at room temperature for 24 h. After releasing the H2 from the pressure
vessel, the solution was filtered with a nonꢀpolar syringe filter followed by addition of 5 mL of hot methanol to
wash the filter. The filtrate was concentrated via rotary evaporation under reduced pressure, and the resulting
material was purified via flash chromatography (3:2 hexanes/EtOAc) to yield 20a as a light brown foam (44 mg,
1
72%). Rf = 0.47 (3:2 hexanes/EtOAc); H NMR (CDCl3, 500 MHz): δ 8.28 (d, J = 8.5 Hz, 2H), 7.51ꢀ7.46 (m,
8H), 7.36ꢀ7.26 (m, 2H), 7.18ꢀ7.09 (m, 3H), 3.80 (s, 2H), 3.50 (s, 3H) ppm. 13C NMR (CDCl3, 125 MHz): δ 170.9,
137.9, 137.2, 132.8, 132.6, 130.6, 130.2, 129.7, 129.4, 129.2, 128.9, 128.6, 128.5, 127, 34.6, 31 ppm. IR (thin
film) 1695, 1653, 1601, 1560, 1494, 1472, 1452, 1379, 1314, 1269, 1025, 765, 742, 700, 658 cmꢀ1. HRMS (ESI+)
calculated for C24H22N3O m/z (M+H) 368.1763, Obsd. 368.1768.
N-(4-Benzyl-5-(4-methoxyphenyl)-1-methyl-1H-imidazol-2(3H)-ylidene)benzamide
(20b).
Prepared
according to general procedure D using 19b, with purification using silica gel eluting with 3:2 hexanes/EtOAc to
1
give 20b as a light brown foam (9.7 mg, 84%). Rf = 0.47 (3:2 hexanes/EtOAc); H NMR (CDCl3, 500 MHz): δ
8.27 (d, J = 7.0 Hz, 2H), 7.45ꢀ7.40 (m, 3H), 7.32ꢀ7.27 (m, 4H), 7.22 (m, 1H), 7.15 (d, J = 7.5 Hz, 2H), 7.01 (d, J
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= 9.0 Hz, 2H), 3.86 (s, 3H), 3.83 (s, 2H), 3.49 (s, 3H) ppm. 13C NMR (CDCl3, 125 MHz): δ 160.5, 138.7, 131.9,
130.8, 129.2, 128.9, 128.4, 128.1, 127.2, 124.5, 120.0, 114.8, 55.7, 32.4, 31.0 ppm. IR (thin film) 3061, 2933,
1675, 1636, 1566, 1541, 1494, 1464, 1453, 199, 1350, 1288, 1246, 1174, 1108, 1025, 1004, 906, 832, 718, 709,
645, 593 cmꢀ1. HRMS (ESI+) calculated for C25H23N3NaO2 m/z (M+Na) 420.1688, Obsd. 420.1698.
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9
N-(4-Benzyl-1-methyl-5-phenyl-1,3-dihydro-2H-imidazol-2-ylidene)-4-methoxybenzamide
(20c).
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18
19
20
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Prepared according to general procedure D using 19c, with purification using silica gel eluting with 3:2
1
hexanes/EtOAc to give 20c as a light brown foam (46 mg, 62%). Rf = 0.29 (3:2 hexanes/EtOAc); H NMR
(CDCl3, 500 MHz): δ 8.30 (d, J = 9.0 Hz, 2H), 7.48ꢀ7.44 (m, 3H), 7.31ꢀ7.27 (m, 2H), 7.10ꢀ7.02 (m, 3H), 7.00ꢀ
13
6.95 (m, 4H), 3.85 (s, 3H), 3.60 (s, 2H), 3.48 (s, 3H) ppm. C NMR (CDCl3, 125 MHz): δ 163.3 137.8, 131.4,
130.5, 129.7, 129.3, 128.9, 128.4, 127.3, 126.9, 113.9, 55.7, 32.9, 30.8 ppm. IR (thin film) 2858, 1678, 1603,
1573, 1514, 1494, 1453, 1401, 1348, 1311, 1176, 1027, 846, 766 cmꢀ1. HRMS (ESI+) calculated for
C25H23N3NaO2 m/z (M+Na) 420.1688, Obsd. 420.1688.
N-(4-Benzyl-1-methyl-5-phenyl-1,3-dihydro-2H-imidazol-2-ylidene)-3-
(trifluoromethyl)benzamide
(20d). Prepared according to general procedure D using 19d, with purification using silica gel eluting with 3:2
1
hexanes/EtOAc to give 20d a light brown foam (123 mg, 87%). Rf = 0.76 (3:2 hexanes/EtOAc); H NMR
(CDCl3, 500 MHz): δ 8.55 (s, 1H), 8.43 (d, J = 7.5 Hz, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.53ꢀ7.48 (m, 4H), 7.40ꢀ
7.37 (m, 2H), 7.32ꢀ7.29 (m, 2H), 7.26ꢀ7.24 (m, 1H), 7.15 (d, J = 8.0 Hz, 2H), 3.87 (s, 2H), 3.54 (s, 3H) ppm. 13C
NMR (CDCl3, 125 MHz): δ 173.3, 150.8, 139.5, 137.3, 132.1, 120.5, 129.5, 129.3, 129.2, 128.5, 128.4, 127.7,
127.3, 127.2 (q, JCF = 3.8 Hz), 125.9 (q, JCF = 3.8 Hz), 124.8, 120.6, 95.0, 30.8, 30.3 ppm. IR (thin film) 3062,
1598, 1568, 1471, 1362, 1315, 1276, 1216, 1162, 1117, 1084, 1067, 907, 795, 763, 726 cmꢀ1. HRMS (ESI+)
calculated for C25H21N3OF3 m/z (M+H) 436.1637, Obsd. 436.1639.
N-(4-Benzyl-1-methyl-5-phenyl-1H-imidazol-2(3H)-ylidene)isobutyramide (20e). Prepared according to
general procedure D using 19e, with purification using silica gel eluting with 3:2 hexanes/EtOAc to give 20e as a
1
light brown foam (24 mg, 74%). Rf = 0.50 (3:2 hexanes/EtOAc); H NMR (CDCl3, 500 MHz): δ 7.42ꢀ7.39 (m,
3H), 7.33 (d, J = 8.0 Hz, 2H), 7.24ꢀ7.20 (m, 3H), 7.13 (d, J = 8.0 Hz 2H), 3.83 (s, 2H), 3.31 (s, 3H), 2.49 (m, 1H),
1.13 (d, J = 7.0 Hz, 6H) ppm. 13C NMR (CDCl3, 125 MHz): δ 140.3, 130.2, 129.7, 129.0, 128.6, 128.5, 128.4,
126.2, 35.7, 32.9, 31.8, 19.8 ppm. IR (thin film) 3028, 2968, 2873, 1653, 1602, 1540, 1506, 1494, 1466, 1456,
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The Journal of Organic Chemistry
1437, 1399, 1383, 1312, 1221, 1190, 1156, 1098, 1014, 950, 910, 867, 725, 697 cmꢀ1. HRMS (ESI+) calculated
1
2
3
for C21H23N3O m/z (M+Na) 356.1739, Obsd. 356.1743 (M+H).
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5
6
N-(4-Benzyl-1-methyl-5-phenyl-1H-imidazol-2(3H)-ylidene)-2-methylbutanamide
(20f).
Prepared
7
8
according to general procedure D using 19f, with purification using silica gel eluting with 3:2 hexanes/EtOAc to
9
1
give 20f as a light brown foam (33 mg, 80%). Rf = 0.44 (3:2 hexanes/EtOAc); H NMR (CDCl3, 500 MHz): δ
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13
14
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18
19
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7.42ꢀ7.39 (m, 3H), 7.29 (d, J = 8.0 Hz, 2H), 7.24ꢀ7.20 (m, 3H), 7.05 (d, J = 8.0 Hz 2H), 3.77 (s, 2H), 3.30 (s, 3H),
2.43 (m, 1H), 1.69 (m, 1H), 1.41 (m, 1H), 1.10 (d, 7.0 Hz, 3H), 0.87 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (CDCl3,
125 MHz): δ 139.9, 130.3, 129.1, 128.8, 128.6, 128.5, 42.8, 32.3, 27.2, 17.7, 11.1 ppm. IR (thin film) 2835, 1609,
1583, 1508, 1488, 1442, 1419, 1301, 1244, 1169, 1126, 1107, 1069, 1033, 994, 962, 917, 850, 807, 778, 754,
690, 584 cmꢀ1. HRMS (ESI+) calculated for C22H25N3O m/z (M+H) 348.2076, Obsd. 348.2082 (M+H).
N-(4-Benzyl-1-methyl-5-phenyl-1H-imidazol-2(3H)-ylidene)-2-fluorobenzamide
(20g).
Prepared
according to general procedure D using 19g, with purification using silica gel eluting with 3:2 hexanes/EtOAc to
1
give a light brown (7.1 mg, 89%). Rf = 0.82 (3:2 hexanes/EtOAc); H NMR (CDCl3, 500 MHz): δ 8.08 (dt, J =
2.0, 8.0 Hz, 1H), 7.49 (m, 3H), 7.38 (m, 3H), 7.28 (m, 2H), 7.21 (m, 2H), 7.16 (m, 2H), 7.10 (m, 1H), 3.85 (s,
2H), 3.49 (s, 3H) ppm. 13C NMR (CDCl3, 125 MHz): δ 161.7 (d, JCF = 252.4 Hz), 137.8, 132.4 (d, JCF = 8.1 Hz),
131.9, 130.5, 129.4, 129.3, 129.1, 128.5, 128.0, 127.1, 125.6, 123.9 (d, JCF = 3.6 Hz), 116.7 (d, JCF = 23.2 Hz),
113.3, 31.2, 30.8 ppm. IR (thin film) 3029, 1683, 1560, 1494, 1452, 1350, 1286, 1259, 1222, 1135, 1127, 1075,
1054, 1030, 1014, 967, 817, 755, 725, 696, 643 cmꢀ1. HRMS (ESI+) calculated for C24H21FN3O m/z (M+H)
386.1669, Obsd. 386.1677.
N-(4-Benzyl-5-(4-methoxyphenyl)-1-methyl-1H-imidazol-2(3H)-ylidene)-2-fluorobenzamide (20h). Prepared
according to general procedure D using 19h, with purification using silica gel eluting with 3:2 hexanes/EtOAc to
give a light brown foam (13 mg, 81%). Rf = 0.41 (3:2 hexanes/EtOAc); 1H NMR (CDCl3, 500 MHz): δ 8.07 (t, J
= 8.0 Hz, 2H), 7.34 (m, 1H), 7.32ꢀ7.27 (m, 4H), 7.21 (t, J = 8.5 Hz, 1H), 7.19ꢀ7.16 (m, 3H), 7.08 (t, J = 9.5 Hz,
1H), 7.00 (d, J = 8.5 Hz, 2H), 3.86 (s, 3H), 3.81 (s, 2H), 3.44 (s, 3H) ppm. 13C NMR (CDCl3, 125 MHz): δ 171.8,
162.5 (d, JCF = 253.4 Hz), 160.2, 148.7, 137.8, 131.8, 131.7 (d, JCF = 1.9 Hz), 131.6, 128.8, 128.2, 126.8, 126.4,
124.8, 123.6 (d, JCF = 3.8 Hz), 119.9, 116.5 (d, JCF = 22.9 Hz), 114.5, 55.4, 31.0, 30.1 ppm. IR (thin film) 2929,
2360, 2340, 1684, 1569, 1511, 1494, 1455, 1401, 1339, 1290, 1248, 1176, 1032, 834, 815, 757, 731, 696, 667 cmꢀ
1. HRMS (ESI+) calculated for C25H22FN3NaO2 m/z (M+Na) 438.1594, Obsd. 438.1601.
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N-(4-Benzyl-5-(4-methoxyphenyl)-1-methyl-1H-imidazol-2(3H)-ylidene)-3- (trifluoromethyl)benzamide
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(20i). Prepared according to general procedure D using 19i, with purification using silica gel eluting with 3:2
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5
1
hexanes/EtOAc to give a light brown foam (99 mg, 53% yield). Rf = 0.76 (3:2 hexanes/EtOAc); H NMR
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9
(CDCl3, 300 MHz): δ 8.54 (s, 1H), 8.42 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.50 (t, J = 8.4 Hz, 1H),
7.32ꢀ7.23 (m, 5H), 7.15 (d, J = 6.9 Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 3.87 (s, 3H), 3.84 (s, 2H), 3.50 (s, 3H) ppm.
13C NMR (CDCl3, 125 MHz): δ 173.0, 160.3, 150.5, 139.4, 137.3, 131.9, 131.6, 130.1 (q, JCF = 32.2 Hz), 129.0,
128.2, 128.1, 127.0, 126.9 (q, JCF = 3.8 Hz), 125.7 (q, JCF = 3.8 Hz), 124.3 (q, JCF = 270.4 Hz), 120.0, 119.4,
114.6, 55.4, 30.5, 29.9 ppm. IR (thin film) 1569, 1512, 1466, 1363, 1317, 1278, 1249, 1217, 1165, 1121, 1069,
1034, 906, 834, 768, 725 cmꢀ1. HRMS (ESI+) calculated for C26H22F3N3NaO2 m/z (M+Na) 488.1562, Obsd.
488.1559.
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Associated Content
Supporting Information. Xꢀray crystallography data for compounds 18b and 20h. 1H and 13C NMR spectra for all
compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
Author Information:
Corresponding Author
*Eꢀmail: r.looper@utah.edu
Acknowledgments
REL thanks the NIH, General Medical Sciences (R01 GM090082, P41 GM08915), Cūrza, Amgen and Eli
Lilly for financial support. BEW thanks the NIH, National Cancer Institute (R01 CA140296) for funding. We
thank Dr. Atta Arif (U. of U. Chemistry) for help with Xꢀray crystallography studies. We thank John Sullivan and
Richard Nkansah for exploratory work on this project.
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