Regioselective Base-Mediated Cyclizations of Mono-N-acylpropargylguanidines

Article abstract of DOI:10.1021/acs.joc.7b00639

A regioselective base-mediated cyclization of mono-N-acylpropargylguanidines is reported. A related Ag(I)-catalyzed hydroamination strategy was recently employed to yield N³-Cbz-protected ene-guanidines, which found utility in the synthesis of

Full text of DOI:10.1021/acs.joc.7b00639

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Note
Regioselective base-mediated cyclizations
of mono-N-acylpropargylguanadines.
Justin Michael Salvant, Anne Victoria Edwards, Daniel Zachary Kurek, and Ryan E. Looper
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 30 May 2017
Downloaded from http://pubs.acs.org on May 31, 2017
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The Journal of Organic Chemistry
Regioselective baseꢀmediated cyclizations of monoꢀNꢀacylpropargylguanadines.
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Justin M. Salvant, Anne V. Edwards, Daniel Z. Kurek and Ryan E. Looper*
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Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, UT, 84112
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Abstract: A regioselective baseꢀmediated cyclization of monoꢀNꢀacylpropargylguanidines is reported. A related
Ag(I)ꢀcatalyzed hydroamination strategy was recently employed to yield N3ꢀCbzꢀprotected eneꢀguanidines which
found utility in the synthesis of naamidine A. Herein we report the baseꢀcatalyzed hydroamination of monoꢀNꢀ
acylpropargylguanidines which proceeds with the opposite regiochemistry to deliver isomerized N2ꢀacylꢀ2ꢀ
aminoimidazoles with broad substrate scope, circumventing the problematic regiospecific acylation of free 2ꢀ
aminoimidazoles.
2ꢀaminoimidazoles’ abundance in marine natural product cores has motivated the development of methodology to
access these nitrogenꢀrich heterocycles with robust chemistry.1 Tailoring of the heterocycle to the 2ꢀ
monoacylaminoimidazole scaffold has yielded a class of pharmacologically privileged compounds that include
transforming growth factor β1 receptor (TGFβ1) inhibitors,2 glial inflammation suppressors,3 antiꢀhepatitis C
agents,4 and Pgpꢀmultidrug resistance reversal agents.5
We were particularly inspired by the unique EGFꢀdependent cytotoxicological profile of naamidine A, a
2ꢀaminoimidazole alkaloid originally isolated from the marine sponge Leucetta chagosensis, and its applications
in breast cancer therapy.6,7 Extending our methodology for the synthesis of naamidine A, we reported a number of
first generation analogs.8 Initial screening of these compounds identified a compound dubbed zinaamidole A
(ZNA, 4a) as a promising lead due to its antiꢀproliferative activity (EC50 = 8.8 µM) against drugꢀresistant pleural
effusion cells (PE1005339) derived from patients with breast cancer as well as immortalized, cancerous MCFꢀ7
cells (EC50 = 3.3 µM).9 In additional assays, ZNA showed negligible cytotoxicity against normal primary
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epithelial cells or the untransformed breast cancer cell line MCFꢀ10A, and was significantly more selective than
its natural product inspiration naamidine A.10,11 This selectivity of growth inhibition against cancerous tissue
necessitated efforts towards a scalable, modular synthesis of ZNA and structurally related compounds.
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Initial efforts to generate simplified naamidine A analogs focused on the treatment of a free 2ꢀ
aminoimidazole with an acid chloride, yielding a problematic 1:2 mixture of mono and bisꢀN2ꢀacylated products
respectively; a similar phenomenon was reported by Jiang and coworkers.7 Our solution relied on treatment of
monoꢀCbz protected propargylguanidines with AgNO3, yielding a N3ꢀCbzꢀeneꢀguanidine bearing an exoꢀcyclic
alkene as a single regioisomer.8 This allowed for the selective acylation of N2, followed by Cbz deprotection of N3
to yield N2ꢀacylꢀ2ꢀaminoimidazoles such as ZNA. We reasoned that deprotonation of the monoꢀNꢀ
acylpropargylguanidine might allow for preferential cyclization through the more reactive, nonꢀacylated,
guanidine nitrogen to directly give N2ꢀacylꢀ2ꢀaminoimidazoles without the need for this protection/deꢀprotection
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sequence. Examples of diverse metalꢀcatalyzed and baseꢀmediated hydroaminations exist in the literature12,13
,
including the synthesis of imidazoleꢀ2ꢀthiones from propargylthioureas14; however, the reactivity and
regioselectivity of monoꢀNꢀacylpropargylguanidines hydroaminations has not been explored. If this reactivity
were realized, it would greatly facilitate the preparation of ZNA analogues for biological evaluation.
To evaluate this hypothesis, we treated propargylamine 1a with potassium Nꢀcyanoꢀ2ꢀfluorobenzamide 2a
activated by TMSCl to deliver monoꢀNꢀacylpropargylguanidines 3a (Scheme 1). To our delight, addition of one
equivalent of NaH to compound 3a in THF afforded a material that was identical to ZNA, indicating that not only
had the cyclization occurred exclusively through the nonꢀacylated nitrogen, but subsequent double bond
isomerization directly yielded the
N
2ꢀacylꢀ2ꢀaminoimidzole. These results were confirmed by spectroscopic
methods, and permitted the multiꢀgram synthesis of ZNA in four transformations. A crystal structure of 4a has
been reported previously.8
Scheme 1. Second generation synthesis of ZNA.
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The Journal of Organic Chemistry
Further exploration of the efficiency and selectivity of this transformation began with the preparation of
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monoꢀNꢀacylpropargylguanidines from potassium salts of Nꢀcyanobenzamides activated by TMSCl and
respective secondary propargylic amines (Table 1). All of the performed reactions proceeded in good yield at
room temperature, usually reaching completion within 20 minutes. Generally, more electronꢀdeficient Nꢀ
cyanobenzamides performed better in the guanidinylation step, presumably due to the increased reactivity of their
Nꢀsilylcarbodiimide intermediates. Initial investigation into the scope of the NaH mediated hydroamination of
monoꢀNꢀacylpropargylguandidines revealed that the reaction is amenable to electronꢀdonating and withdrawing
aryl substituents at the R1 and R4 positions. Introduction of a cyclopropyl group at the R3 position gave
comparable yields to aryl substituents (e.g. 4i-4l). Carbamoyl guanidines also cyclize selectively under these
conditions as illustrated by 4m. The regiochemistry is further supported by the Xꢀray structure of 4m (Figure 1).
Interestingly this N2ꢀcarbamoyl derivative exists as the endocyclic N3ꢀimino tautomer in contrast to structures of
the amides at N2, previously obtained in our laboratory, which exist predominantly as the exocyclic N2ꢀimino
tautomers.
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Table 1. Substrate scope of the synthesis of N2ꢀacylꢀ2ꢀaminoimidazoles.
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Figure 1. Crystal structure of 4m (ellipsoids are shown at 35% probability level).
Cyclization of substrates in which the R1 position was unsubstituted or alkylꢀsubstituted failed to undergo
cyclization with our initial conditions. This was surprising, as we have never observed a reaction dependence on
this substituent in the metalꢀcatalyzed cyclizations (AgI or RhII).13 For example, when we attempted the
cyclization of 3p (R1 = iPr) under the same conditions as the arylꢀsubstituted propargylguanidines in Table 1 we
observed only starting material accompanied by decomposition products, as evidenced by NMR spectroscopy of
the crude material (Table 2).
After optimization of this reaction, it was found that treatment of 3p with NaH in DMF at 60 °C with molecular
sieves proceeded cleanly to give the desired N2ꢀacylꢀ2ꢀaminoimidazole with minimal byproducts as judged by
1Hꢀ NMR. It appears that the intermediate cyclic eneꢀguanidine is prone to decomposition if strict anhydrous
conditions are not maintained. Since the isomerization of the cyclic eneꢀguanidine to the N2ꢀacylꢀ2ꢀ
aminoimidazole is facilitated by the aromatic group at R1, we presume that the increased lifetime of the cyclic
eneꢀguanidine when R1 = alkyl leads to decomposition and lowers the efficiency of the transformation in those
substrates. Under these optimized conditions, a variety of alkyl substituted substrates can be cyclized including
the dialkyl substrate 3q to give 4q and the unsubstituted substrates 3r-t to give 4r-t.
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Table 2. Optimized conditions for synthesis C5 alkyl and C5 unsubstituted 2ꢀacylaminoimidazoles from monoꢀNꢀ
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acylpropargylguanidines.
In summary, we have reported a synthetically useful and broadly applicable means of generating N2ꢀacylꢀ
2ꢀacylaminoimidazoles with high regiochemical fidelity through the baseꢀmediated hydroamination of monoꢀNꢀ
acylpropargylguanidines. This provides a robust 4ꢀstep synthesis of highly substituted N2ꢀacylꢀ2ꢀaminoimidazoles
from commercially available starting materials, contrasted to the lengthy methods used in other procedures, and
avoids the use of a protecting group strategy when furnishing the N2ꢀacylꢀ2ꢀacylaminoimidazoles.
Experimental Section:
General Experimental Considerations: 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 flameꢀdried glassware. Silver
nitrate was purchased from SigmaꢀAldrich. Dichloromethane (CH2Cl2), acetonitrile (CH3CN), tetrahydrofuran
(C4H8O), dimethylformamide (C3H7NO), 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 on Merk silica gel Kieselgel 60 (230ꢀ400 mesh) from EM science with the
indicated solvent. 1H NMR spectra were recorded on Varian Unityꢀ300, Inovaꢀ400, or VXRꢀ500 MHz
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spectrometers as indicated. The chemical shifts (δ) of proton resonances are reported relative to CDCl3 or CD3OD,
using the following format: chemical shift [multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, app = apparent, br = broad), coupling constant(s) (J in Hz), integral].15,16 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. Mass spectra were obtained at the University of Utah CIF on a LCT XE premier (ESI/APCIꢀTOF)
for HRMS.
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General Procedure for the 3-component coupling: N-(1-(4-Methoxyphenyl)-3-phenylprop-2-yn-1-yl)-N-
methylprop-2-en-1-amine (s1). In a 250 mL high pressure flask containing a magnetic stir bar were added pꢀ
anisaldehyde (10 g, 73.4 mmol), phenylacetylene (7.5 g, 73.4 mmol), Nꢀallylmethylamine (4.75 g, 66.7 mmol),
ovenꢀdried 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 24h. The reaction flask was removed from the oil bath and
allowed to cool to room temperature. CuBr (0.95 g, 6.67mmol) was then added and the flask was sealed and
returned to the preheated 80˚C oil bath for 48h. The reaction tube was removed from the oil bath and allowed to
cool to room temperature. The mixture was filtered through diatomaceous earth and rinsed with EtOAc (50 mL).
The filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography,
eluting with 9:1 hexanes/EtOAc to give a dark orange oil (12.7 g, 65%). Rf = 0.78 (2:1 hexanes/EtOAc); 1H 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 (ESIꢀTOF) m/z: [M + H]+ Calcd for C20H21NO 292.1701; Found 292.1699.
N-(1-(4-Chlorophenyl)-3-phenylprop-2-yn-1-yl)-N-methylprop-2-en-1-amine (s2). Prepared from the 3ꢀ
component coupling of 4ꢀchlorobenzaldehyde (5 g, 35.57 mmol), phenylacetylene (3.9 mL, 35.57 mmol), Nꢀ
allylmethylamine (3.07 mL, 32.34 mmol), oven dried molecular sieves (Grade 564, 3 Å, 8ꢀ12 mesh) (ca. 2 g), and
acetonitrile (200 mL), with flash chromatography purification using silica gel eluting with 9:1 hexanes/EtOAc to
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The Journal of Organic Chemistry
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yield a dark orange oil (5.84 g, 61%). Rf = 0.75 (6:4 hexanes/EtOAc); H NMR (CDCl3, 500 MHz): δ 7.65ꢀ7.61
(m, 2H), 7.59ꢀ7.56 (m, 2H), 7.40ꢀ7.34 (m, 5H), 5.90ꢀ5.91 (m, 1H), 5.35 (dd, J = 17.0 Hz, 2.0 Hz, 1H), 5.23 (dd, J
= 10.5 Hz, 2.0 Hz, 1H), 4.98 (s, 1H), 3.21 (d, J = 6.0 Hz, 2H), 2.26 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ 137.5,
135.9, 133.3, 131.8, 129.8, 128.4, 128.3 (2), 122.9, 117.9, 88.7, 84.2, 59.1, 57.8, 37.6 ppm. IR (thin film): 1487,
1442, 1402, 1089, 1014, 994, 962, 920, 853, 796, 689, 592, 582 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for
C19H19NCl 296.1026; Found 296.1206.
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N-(3-Cyclopropyl-1-(4-methoxyphenyl)prop-2-yn-1-yl)-N-methylprop-2-en-1-amine (s3). Prepared from the 3ꢀ
component coupling of pꢀanisaldehyde (500 mg, 4.12 mmol), cyclopropylacetylene (0.35 mL, 4.12 mmol), Nꢀ
allylmethylamine (0.36 mL, .38 mmol), oven dried molecular sieves (Grade 564, 3 Å, 8ꢀ12 mesh) (ca. 2 g), CuBr
(0.46 g, 3.23 mmol), and acetonitrile (100 mL), with flash chromatography purification using silica gel eluting
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with 9:1 hexanes/EtOAc to yield a dark orange oil (226 mg, 22%). Rf = 0.68 (6:4 hexanes/EtOAc); H NMR
(CDCl3, 500 MHz): δ 7.43 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 5.84ꢀ5.81 (m, 1H), 5.23 (dd, J = 17.0 Hz,
1.5 Hz, 1H), 5.12 (d, J = 6.5 Hz, 1H), 4.62 (s, 1H), 3.04 (t, J = 7.5 Hz, 2H), 2.10 (s, 3H), 1.40ꢀ1.32 (m, 1H), 0.84ꢀ
0.80 (m, 2H), 0.75ꢀ0.71 (m, 2H) ppm. 13C NMR (CDCl3, 125 MHz): δ 159.1, 136.6, 131.7, 129.7, 117.5, 113.5,
91.7, 77.5, 59.0, 57.7, 55.5, 37.8, 8.8, 0.2 ppm. IR (thin film): 1610, 1507, 1361, 1243, 1109, 1035, 1016, 999,
918, 982, 850, 808, 777, 584 cm ꢀ1. HRMS (ESIꢀTOF) [M + H]+ m/z: Calcd for C17H22NO 256.1701; Found
256.1701.
N-Allyl-N-(1-(4-methoxyphenyl)-3-phenylprop-2-yn-1-yl)prop-2-en-1-amine (s4). Prepared from the 3ꢀcomponent
coupling of pꢀanisaldehyde (4.0 mL, 33 mmol), phenylacetylene (3.55 mL, 33 mmol), nꢀdiallylamine (3.7 mL, 30
mmol), CuBr (430 mg, 3 mmol), oven dried molecular sieves (Grade 564, 3 Å, 8ꢀ12 mesh) (ca. 1 g), and
acetonitrile (100 mL), with flash chromatography purification using silica gel eluting with 9:1 hexanes/EtOAc to
yield a light yellow oil (3.55 g, 38%). Rf = 0.75 (6:4 hexanes/EtOAc); 1H NMR (CDCl3, 500 MHz): δ 7.59 (d, J =
8.5 Hz, 2H), 7.55ꢀ7.54 (m, 2H), 7.53ꢀ7.51 (m, 3H), 6.89 (d, J = 8.5 Hz, 2H), 5.90ꢀ5.83 (m, 1H), 5.27 (d, J = 17.0
Hz, 1H), 5.14 (d, J = 10.0 Hz, 1H), 5.05 (s, 1H), 3.82 (s, 3H), 3.28 (dd, J = 14.0 Hz, 2.0 Hz, 2H), 3.04 (dd, J =
14.0 Hz, 8.0 Hz, 2H) ppm. 13C NMR (CDCl3, 125 MHz): δ 159.1, 136.8, 132.1, 132.0, 131.6, 129.6, 128.5,
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128.3, 123.6, 117.5, 113.7, 88.9, 85.9, 56.2, 55.5, 53.7 ppm. IR (thin film): 1609, 1508, 1489, 1447, 1301, 1246,
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1170, 1108, 1036, 995, 971, 919, 848, 811, 759, 691 cm . HRMS (ESIꢀTOF) [M + H]+ m/z: Calcd for
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C22H24NO 318.1858; Found 318.1867.
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N-Allyl-1-cyclopropyl-N,4-dimethylpent-1-yn-3-amine (s5). Prepared from the 3ꢀcomponent coupling of
isobutyraldehyde, cyclopropylacetylene, nꢀallylmethylamine.17
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N-Allyl-N,4-dimethyl-1-phenylpent-1-yn-3-amine (s6). Prepared from the 3ꢀcomponent coupling of
isobutyraldehyde, phenylacetylene, nꢀallylmethylamine, CuBr, oven dried molecular sieves (Grade 564, 3 Å, 8ꢀ12
mesh) (ca. 1 g), and acetonitrile (100 mL), with flash chromatography purification using silica gel eluting with
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9:1 hexanes/EtOAc to yield a light yellow oil (3.5 g, 46%). Rf = 0.74 (6:4 hexanes/EtOAc); H NMR (CDCl3, 500
MHz): δ 7.47ꢀ7.44 (m, 2H), 7.32ꢀ7.29, (m, 3H), 5.88 (ddt, J = 6.0 Hz, 10.5 Hz, 17.0 Hz, 1H), 5.27 (d, J = 17.0
Hz, 2H), 5.17 (d, J = 10.5 Hz, 2H), 3.23 (dd, J = 5.0 Hz, 13.5 Hz, 1H), 3.19 (d, J = 9.0 Hz, 1H), 2.91 (dq, J =
16.5 Hz, 6.5 Hz, 1H), 1.13 (d, J = 6.5 Hz, 3H), 1.05 (d, J = 6.5 Hz, 3H) ppm. 13C NMR (CDCl3, 125 MHz): δ
136.2, 131.7, 128.4, 128.2, 127.8, 123.6, 117.4, 86.4, 63.2, 58.2, 37.8, 31.0, 20.8, 19.9 ppm. IR (thin film) 1952,
1643, 1598, 1488, 1443, 1412, 1383, 1364, 1326, 1261, 1208, 1163, 1096, 1069, 1027, 995, 917, 753, 689, 595,
545 cmꢀ1. HRMS (ESIꢀTOF) [M + H]+ m/z: Calcd for C16H22N 228.1752; Found 228.1751.
N-Allyl-N-(2,4-dimethoxybenzyl)non-4-yn-3-amine (s7). Prepared from the 3ꢀcomponent coupling of
propionaldehyde, 1ꢀhexyne, nꢀallyldimethoxybenzylamine.17
N-Methyl-N-(3-(p-tolyl)prop-2-yn-1-yl)prop-2-en-1-amine (s8). Prepared from the 3ꢀcomponent coupling of
formaldehyde, 1ꢀethynylꢀ4ꢀmethylbenzene, nꢀallylmethylamine, CuBr, oven dried molecular sieves (Grade 564, 3
Å, 8ꢀ12 mesh) (ca. 1 g) and acetonitrile (100 mL), with flash chromatography purification using silica gel eluting
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with 9:1 hexanes/EtOAc to yield a light yellow oil (78%). Rf = 0.44 (6:4 hexanes/EtOAc); H NMR (CDCl3, 500
MHz): δ 7.33 (d, J = 8.3 Hz, 2H), 7.09 (d, J = 8.3 Hz, 2H), 5.89 (ddt, J = 4.0 Hz, 6.5 Hz, 10.3 Hz, 1H), 5.25 (d, J
= 17.5 Hz, 1H), 5.17 (d, J = 10.3 Hz, 1H), 3.54 (s, 1H), 3.14 (d, J = 6.5 Hz, 2H), 2.38 (s, 3H), 2.33 (s, 3H) ppm.
13C NMR (CDCl3, 125 MHz): δ 138.1, 135.1, 131.6, 129.0, 120.1, 118.3, 85.6, 83.3, 59.1, 46.0, 41.6, 21.4 ppm.
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IR (thin film) 2918, 1787, 1643, 1509, 1449, 1359, 1325, 1254, 1193, 1128, 1107, 1032, 994, 968, 921, 814, 677,
629, 566 cmꢀ1. HRMS (ESIꢀTOF) [M + H]+ m/z: Calcd for C14H18N 200.1439; Found 200.1440.
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N-Methyl-N-(3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-yl)prop-2-en-1-amine (s9). Prepared from the 3ꢀ
component coupling of formaldehyde, 1ꢀethynylꢀ4ꢀtrifluoromethylbenzene, nꢀallylmethylamine.13
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General Procedure for the deallylation of amines: 1-(4-Methoxyphenyl)-N-methyl-3-phenylprop-2-yn-1-amine
(1a). In a 250 mL round bottom flask containing a magnetic stir bar were added Pd(PPh3)4 (0.22 g, 0.19 mmol),
N,Nꢀdimethylbarbituric acid (9.0 g, 57.69 mmol) and CH2Cl2 (100 mL). A solution of Nꢀ(1ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀ
phenylpropꢀ2ꢀynꢀ1ꢀyl)ꢀNꢀmethylpropꢀ2ꢀenꢀ1ꢀamine (s1) (5.6 g, 19.23 mmol) in 25 mL in CH2Cl2 was added, and
the reaction mixture was allowed to stir at room temperature under N2 for 12h. The solvent was then removed
under reduced pressure and the crude product was reꢀdissolved in Et2O (75 mL). The organic layer was washed
with NaHCO3 (20 mL) and then acidified with 2M HCl (5 mL). The aqueous layer was collected and neutralized
with 10% NaOH, and partitioned with CH2Cl2 (70 mL). The organic layer was collected, and the aqueous layer
was extracted with additional CH2Cl2 (2 x 50 mL). The organic extracts were combined, and then dried and
1
filtered over Na2SO4 to give a dark orange oil (2.13 g, 44%). Rf = 0.22 (2:1 hexanes/EtOAc); H NMR (CDCl3,
300 MHz): δ 7.54ꢀ7.48 (m, 4H), 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 (ESIꢀTOF) [M + Na]+ m/z:
Calcd for C17H17NONa 274.1208; Found 274.1213.
1-(4-Chlorophenyl)-N-methyl-3-phenylprop-2-yn-1-amine (1b). Prepared from the deallylation of s2 (8.0 g, 26.29
1
mmol) as a dark orange oil (3.29 g, 49%). Rf = 0.29 (6:4 hexanes/EtOAc); H NMR (CDCl3, 500 MHz): δ 7.54ꢀ
7.61 (m, 2H), 7.50ꢀ7.48 (m, 2H), 7.36ꢀ7.29 (m, 5H), 4.72 (s, 1H), 2.54 (s, 3H), 1.43 (s, 1H) ppm. 13C NMR
(CDCl3, 125 MHz): δ 139.9, 133.4, 132.0, 129.3, 128.8, 128.6, 128.5, 123.1, 88.7, 86.3, 55.8, 33.9 ppm. IR (thin
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film) 1488, 1442, 1264, 1090, 1015, 732, 703, 691, 579, 543 cmꢀ1. HRMS (ESIꢀTOF) [M + H]+ m/z: Calcd for
C16H15NCl 256.0893; Found 256.0890.
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N-(3-Cyclopropyl-1-(4-methoxyphenyl)prop-2-yn-1-yl)-N-methylprop-2-en-1-amine (1c). Prepared from the
deallylation of s3 as a dark orange oil (1.07 g, 42%). Rf = 0.23 (6:4 hexanes/EtOAc); 1H NMR (CDCl3, 500 MHz):
δ 7.38 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 4.40 (s, 1H), 2.42 (s, 3H), 1.31ꢀ1.25 (m, 1H), 0.79ꢀ0.73 (m,
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2H), 0.70ꢀ0.66 (m, 2H) ppm. C NMR (CDCl3, 125 MHz): δ 159.3, 133.0, 132.3, 128.9, 113.9, 89.2, 75.0, 55.5,
33.7, 8.5, 0.2 ppm. IR (thin film) 1609, 1508, 1463, 1440, 1301, 1243, 1171, 1029, 892, 831, 810, 779, 722, 585,
541 cmꢀ1. HRMS (ESIꢀTOF) [M + H]+ m/z: Calcd for C14H18NO 216.1388; Found 216.1393.
N-(1-(4-Methoxyphenyl)-3-phenylprop-2-yn-1-yl)prop-2-en-1-amine (1d). Prepared from the deallylation of s4
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(3.55 g, 11.2 mmol) as a dark orange oil (0.96 g, 31%). Rf = 0.59 (6:4 hexanes/EtOAc); H NMR (CDCl3, 500
MHz): δ 7.52 (d, J = 8.5 Hz, 2H), 7.49ꢀ7.47 (m, 2H), 7.33ꢀ7.31 (m, 3H), 6.92 (d, J = 8.5 Hz, 2H), 5.97 (ddt, J =
7Hz, 10.5 Hz, 6.5 Hz, 1H), 5.27 (dd, J = 17 Hz, 1.5 Hz), 5.14 (dd, J =10.5 Hz, 1.5 Hz), 4.70 (s, 1H), 3.82 (s, 3H),
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3.44 (dqt, J = 6 Hz, 13.5 Hz, 1.5 Hz, 2H), 1.67 (s, 1H) ppm. C NMR (CDCl3, 125 MHz): δ 159.4, 136.6, 132.8,
131.9, 129.0, 128.5, 128.4, 116.7, 114.1, 89.7, 85.6, 55.6, 53.5, 30.1 ppm. IR (thin film) 2834, 1609, 1585, 1508,
1489, 1442, 1417, 1302, 1245, 1171, 1094, 1070, 1033, 995, 917, 832, 788, 756, 691, 579, 548 cmꢀ1. HRMS (ESIꢀ
TOF) [M + H]+ m/z: Calcd for C19H20NO 278.1545; Found 278.1537.
1-Cyclopropyl-N,4-dimethylpent-1-yn-3-amine (1e). Prepared from the deallylation of s5.17
N,4-Dimethyl-1-phenylpent-1-yn-3-amine (1f). Prepared from the deallylation of s6 (1.36 g, 6.0 mmol) as a dark
orange oil (0.78g, 70%). Rf = 0.35 (6:4 hexanes/EtOAc); 1H NMR (CDCl3, 500 MHz): δ 7.44ꢀ7.40 (m, 2H), 7.30ꢀ
7.24 (m, 3H), 3.31 (s, 1H), 2.56 (s, 3H), 1.61 (br.s., 1H), 1.06ꢀ1.04 (m, 6H) ppm. 13C NMR (CDCl3, 125 MHz): δ
131.7, 128.2, 127.8, 123.5, 89.2, 84.7, 59.0, 24.6, 32.7, 19.8, 17.9 ppm. IR (thin film) 2958, 2870, 1597, 1489,
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1467, 1442, 1383, 1366, 1343, 1322, 1131, 1106, 1070, 1028, 990, 914, 754, 689, 580, 545 cmꢀ1. HRMS (ESIꢀ
TOF) [M + H]+ m/z: Calcd for C13H18N 188.1439; Found 188.1447.
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N-(2,4-Dimethoxybenzyl)non-4-yn-3-amine (1g). Prepared from the deallylation of s7.17
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N-Methyl-3-(p-tolyl)prop-2-yn-1-amine (1h). Prepared from the deallylation of s8 as a dark orange oil (226 mg,
35%). Rf = 0.18 (6:4 hexanes/EtOAc); 1H NMR (CDCl3, 500 MHz): δ 7.31 (d, J = 8Hz, 2H), 7.09 (d, J = 8.5 Hz,
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2H), 3.60 (s, 2H), 2.53 (s, 3H), 2.33 (s, 3H), 1.15 (br.s.,1H) ppm. C NMR (CDCl3, 125 MHz): δ 128.2, 131.5,
129.0, 85.9, 84.1, 40.5, 35.0, 21.4 ppm. IR (thin film) 2919, 2791, 1792, 1675, 1548, 1508, 1427, 1407, 1379,
1345, 1257, 1180, 1107, 1077, 1020, 948, 815, 753, 722, 696, 541 cmꢀ1. HRMS (ESIꢀTOF) [M + H]+ m/z: Calcd
for C11H13N 160.1126 ; Found 160.1135.
N-methyl-3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-amine (1i). Prepared from the deallylation of s9.13
N-benzylprop-2-yn-1-amine (1j). Prepared according to Merlic et al.18
General Procedure for the preparation of potassium N-cyanobenzamides: (2a). Potassium N-cyano-2-
fluorobenzamide: A oneꢀnecked 500 mL round bottom flask open to the atmosphere, equipped with a magnetic
stirring bar is charged with cyanamide (6.3 g, 0.15 mol) and distilled water (200 mL). Sodium hydroxide pellets
(12.3 g, 0.308 mol) are then added in portions (~3 x 4 g) over a 15 minute period. The mixture is then stirred for
30 min. at room temperature and then cooled to 0 °C. The flask is fitted with a 1000 mL addition funnel and the
addition funnel charged with 2ꢀfluorobenzoyl chloride (23.5 g, 0.15 mol). The 2ꢀfluorobenzoyl chloride is then
added dropwise over a span of 20 min. After addition of the benzoyl chloride the reaction is stirred for an
additional 3 hours at room temperature. The mixture is transferred to a 500 mL separatory funnel and washed with
diethyl ether (1 x 50 mL). The aqueous layer is then transferred to a 1ꢀL Erlenmeyer flask equipped with a
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magnetic stirring bar and acidified to pH = 2 with conc. HCl (approx. 15 mL). Dichloromethane (200 mL) is then
added to dissolve the solids and the mixture transferred to a 500 mL separatory funnel. After separation of the
layers, the aqueous fraction is extracted with dichlormethane (2 x 100 mL) and the combined organics dried over
anhydrous Na2SO4. The organics were filtered through a sintered glass funnel and the resultant sodium sulfate
was washed with dichloromethane (2 x 50 mL). The solvent was removed on a rotary evaporator and then the
flask transferred to a highꢀvac line for 3 hours. The resulting white solid was then dissolved in MeOH (50 mL)
and added dropwise to a 500 mL round bottom flask equipped with a stir bar containing potassium hydroxide
(8.0g, 0.143 mol) dissolved in MeOH (200 mL) at 0 °C. The flask is stoppered and allowed to stand in a ꢀ20 °C
freezer overnight. The crude solid is collected on a Buchner funnel and washed with cold MeOH (2 x 50 mL) to
give a fine white powder after sufficient drying under vacuum (19.8 g, 65%). Mp: 276ꢀ278 °C. NMR (d6ꢀDMSO,
500 MHz): δ 7.63 (td, J = 7.7, 1.9 Hz, 1H), 7.32 (tdd, J = 7.3, 4.9, 2.0 Hz, 1H), 7.10 – 7.02 (m, 2H) ppm. 13C
NMR (d6ꢀDMSO, 125MHz): δ 173.2, 160.0 (d, JCF = 250.0 Hz), 130.7 (d, JCF = 3.1 Hz), 130.6 (d, JCF = 8.4 Hz),
128.1 (d, JCF = 11.8 Hz), 123.4 (d, JCF = 2.6 Hz), 121.9, 116.0 (d, JCF = 22.7 Hz) ppm. IR (solid) 2160, 1626,
1612, 1612, 1591, 1547, 1485, 1450, 1360, 1293, 1220, 1108, 1098, 1039, 897 cmꢀ1. HRMS (ESIꢀTOF) [M ꢀ H]ꢀ
m/z: Calc. C8H4N2OF 163.0308; Found 163.0308.
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Potassium N-cyano-4-methoxybenzamide (2b). Prepared according to the general procedure for the preparation of
potassium cyanobenzamides using 4ꢀmethoxybenzoyl chloride to yield a white solid (47% yield). Mp: 328ꢀ330 °C
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(decomposition). H NMR (d6ꢀDMSO, 500 MHz): δ 7.86 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 3.76 (s,
3H) ppm. 13C NMR (d6ꢀDMSO, 125MHz): δ 174.5, 160.8, 131.1, 129.8, 123.2, 112.6, 55.1 ppm. IR (solid) 2154,
1593, 1550, 1508, 1344, 1308, 1241, 1169, 1157, 1117, 1105, 1037, 1021, 1001, 951, 886 cmꢀ1. HRMS (ESIꢀ
TOF) [M ꢀ H]ꢀ m/z: Calc. C9H7N2O2 175.0508; Found 175.0513.
Potassium N-cyano-4-chlorobenzamide (2c). Prepared according to the general procedure for the preparation of
potassium cyanobenzamides using 4ꢀchlorobenzoyl chloride to yield a white solid (62% yield). Mp: >350 °C. 1H
NMR (d6ꢀDMSO, 500 MHz): δ 7.91 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H) ppm. 13C NMR (d6ꢀDMSO,
125MHz): δ 173.6, 137.3, 134.7, 130.0, 127.5, 122.5 ppm. IR (solid) 2154, 1588, 1548, 1487, 1402, 1340, 1283,
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1193, 1173, 1094, 1019, 1007, 885 cmꢀ1. HRMS (ESIꢀTOF) [M ꢀ H]ꢀ m/z: Calc. C8H4N2OCl 179.0012; Found
179.0017.
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Potassium N-cyanobenzamide (2d). Prepared according to the general procedure for the preparation of potassium
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cyanobenzamides using benzoyl chloride to yield a white solid (65% yield). Mp: 345ꢀ347 °C. H NMR (d6ꢀ
DMSO, 500 MHz): δ 7.93 (d, J = 6.9 Hz, 2H), 7.38 (t, J = 7.3 Hz, 1H), 7.31 (d, J = 6.9 Hz, 2H) ppm. 13C NMR
(d6ꢀDMSO, 125MHz): δ 175.0, 138.4, 129.9, 128.1, 127.5, 123.1 ppm. IR (solid) 2160, 1595, 1556, 1492, 1446,
1344, 1300, 1103, 1028, 1012, 934, 890 cmꢀ1. HRMS (ESIꢀTOF) [M ꢀ H]ꢀ m/z: Calc. C8H5N2O 145.0402; Found
145.0398.
Potassium benzyloxycarbonylcyanamide (2e). Prepared according to Looper et al.19
Preparation of mono-N-acylguanidines from propargylamines: 2-Fluoro-N-(N-(1-(4-methoxyphenyl)-3-
phenylprop-2-yn-1-yl)-N-methylcarbamimidoyl)benzamide (3a). In a 50 mL round bottom flask containing a
magnetic stir bar were added 2a (97 mg, 0.48 mmol), chlorotrimethylsilane (64 µL, 0.50 mmol) and acetonitrile
(10 mL) under N2. The solution was stirred at room temperature for 10 minutes. A solution of 1a (100 mg, 0.40
mmol) in acetonitrile (5 mL) was then added, and the reaction mixture was allowed to stir at room temperature for
1h. The solvent was then removed under reduced pressure and the crude product was reꢀdissolved in EtOAc (50
mL). The organic layer was washed with NaHCO3 (20 mL) and brine (20 mL) and dried and filtered over
Na2SO4. The crude product was purified via flash chromatography, eluting with 6:4 hexanes/EtOAc to give a
foamy white oil (124 mg, 75% yield). (3a) was prepared by guanylation of 1a (100 mg, 0.40 mmol) with 2a (89
1
mg, 0.48 mmol) as a foamy white oil (124 mg, 75%). Rf = 0.16 (6:4 hexanes/EtOAc); H NMR (CDCl3, 500
MHz): δ 8.06 (t, J = 12.5 Hz, 1H), 7.65 (s, 1H), 7.58ꢀ7.51 (m, 4H), 7.38ꢀ7.32 (m, 4H), 7.18 (t, J = 13.0 Hz, 1H),
7.07 (t, J = 13.0 Hz, 1H), 6.92 (d, J = 14.5 Hz, 2H), 3.81 (s, 3H), 2.86 (s, 3H) ppm. 13C NMR (CDCl3, 125 MHz):
δ 175.5, 162.0 (d, JCF = 254.3 Hz), 160.7. 159.7. 148.0. 138.4. 132.2. 132.1 (2), 129.0, 128.8 (d, JCF = 24.6 Hz),
128.6, 123.6 (d, JCF = 3.9 Hz), 122.6, 116.8 (d, JCF = 23.2 Hz), 114.7, 114.2 , 87.0, 75.4, 55.6, 50.9, 29.3 ppm. IR
(thin film) 1673, 1588, 1560, 1533, 1509, 1452, 1423, 1355, 1304, 1247, 1218, 1173, 1153, 1030, 897, 845, 758,
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732, 691, 590, 550 cmꢀ1. HRMS (ESIꢀTOF) [M + Na]+ m/z: Calcd for C25H22N3O2NaF 438.1594; Found
438.1599.
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4-Methoxy-N-(N-(1-(4-methoxyphenyl)-3-phenylprop-2-yn-1-yl)-N-methylcarbamimidoyl)benzamide
(3b).
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Prepared by guanylation of 1a (100 mg, 0.40 mmol) with 2b (103 mg, 0.48 mmol), with flash chromatography
purification eluting with 6:4 hexanes/EtOAc to yield a foamy white oil (119.8 mg, 70% yield). Rf = 0.13 (6:4
hexanes/EtOAc); 1H NMR (CDCl3, 500 MHz): δ 8.25 (d, J = 9.5 Hz, 2H), 7.65 (s, 1H), 7.58 (d, J = 9.0 Hz, 2H),
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7.55ꢀ7.52 (m, 2H), 7.37ꢀ7.35 (m, 3H), 6.92ꢀ6.91 (m, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 2.87 (s, 3H) ppm. C NMR
(CDCl3, 125 MHz): δ 176.9, 162.3, 160.7, 159.7, 132.1, 131.8, 131.3, 129.0, 128.6, 122.7, 114.3, 113.3, 87.0,
85.5, 55.6, 55.5, 50.8, 29.4 ppm. IR (thin film) 1583, 1558, 1528, 1508, 1464, 1424, 1351, 1305, 1263, 1248,
1173, 1155, 1032, 893, 788, 730, 701, 653, 554 cmꢀ1. HRMS (ESIꢀTOF) [M + Na]+ m/z: Calcd for
C26H25N3O3Na 450.1794; Found 450.1799.
4-Chloro-N-(N-(1-(4-methoxyphenyl)-3-phenylprop-2-yn-1-yl)-N-methylcarbamimidoyl)benzamide (3c). Prepared
by guanylation of 1a (100 mg, 0.40 mmol) with 2c (105 mg, 0.48 mmol), with flash chromatography purification
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eluting with 6:4 hexanes/EtOAc to yield a foamy white oil (140 mg, 81%). Rf = 0.22 (6:4 hexanes/EtOAc); H
NMR (CDCl3, 500 MHz): δ 8.20 (d, J = 8.5 Hz, 2H), 7.65 (s, 1H), 7.57ꢀ7.51 (m, 4H), 7.38ꢀ7.33 (m, 5H), 6.92 (d,
J = 8.5 Hz, 2H), 3.82 (s, 3H), 2.89 (s, 3H) ppm. 13C NMR (CDCl3, 125 MHz): δ 176.1, 160.9, 159.8, 137.5, 137.4,
132.1, 130.8, 129.4, 129.0, 128.9, 128.6, 128.3, 122.6, 114.3, 87.2, 85.2, 55.6, 50.9, 29.5 ppm. IR (thin film)
1583, 1582, 1528, 1508, 1488, 1464, 1421, 1350, 1304, 1246, 1171, 1116, 1111, 1086, 1058, 1034, 1012, 996,
974, 893, 853, 801, 772, 755, 733, 710, 689, 621, 587, 553 cmꢀ1. HRMS (ESIꢀTOF) [M + H]+ m/z: Calcd for
C25H23N3O2Cl 432.1479; Found 432.1489.
N-(N-(1-(4-Methoxyphenyl)-3-phenylprop-2-yn-1-yl)-N-methylcarbamimidoyl)benzamide (3d). ). Prepared by
guanylation of 1a (100 mg, 0.40 mmol) with 2c (81 mg, 0.48 mmol), with flash chromatography purification
eluting with 6:4 hexanes/EtOAc to yield a foamy white oil (121.3 mg, 76% yield). Rf = 0.22 (6:4
hexanes/EtOAc); 1H NMR (CDCl3, 500 MHz): δ 8.28 (d, J = 7 Hz, 2H), 7.71 (s, 1H), 7.58 (d, J = 9 Hz, 2H), 7.55ꢀ
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The Journal of Organic Chemistry
13
7.52 (m, 2H), 7.47ꢀ7.33 (m, 7H), 6.92 (d, J = 8 Hz, 2H), 3.82 (s, 3H), 2.89 (s, 3H) ppm. C NMR (CDCl3, 125
MHz): δ 177.2, 160.9, 159.7, 139.0, 132.1, 131.3, 129.6, 129.4, 129.0, 128.9, 128.6, 128.1, 122.6, 114.2, 87.1,
85.4, 55.6, 50.9, 29.4 ppm. IR (thin film) 1587, 1556, 1530, 1508, 1489, 1448, 1422, 1353, 1299, 1247, 1171,
1067, 1026, 891, 756, 733, 710, 689, 621, 587, 553 cmꢀ1. HRMS (ESIꢀTOF) [M + Na]+ m/z: Calcd for
C25H23N3O2Na 420.1688; Found 420.1697.
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N-(N-(1-(4-Chlorophenyl)-3-phenylprop-2-yn-1-yl)-N-methylcarbamimidoyl)-2-fluorobenzamide (3e). Prepared
by guanylation of 1b (100 mg, 0.39 mmol) with 2a (81 mg, 0.47 mmol), with flash chromatography purification
eluting with 6:4 hexanes/EtOAc to yield a foamy white oil (90 mg, 62% yield). Rf = 0.32 (6:4 hexanes/EtOAc);
1H NMR (CDCl3, 500 MHz): δ 8.03 (t, J = 7.5 Hz, 1H), 7.69 (s, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.53ꢀ7.51 (m, 2H),
7.39ꢀ7.33 (m, 6H), 7.14 (t, J = 8.0, 1H), 7.13ꢀ7.05 (m, 1H), 2.87 (s, 3H) ppm. 13C NMR (CDCl3, 125 MHz): δ
175.6, 162.0 (d, JCF = 254.6 Hz), 160.7, 136.1, 134.3, 132.2 (d, JCF = 8.8 Hz), 132.0 (3), 128.1, 129.0 (2), 128.6,
126.6 (d, JCF = 15.2 Hz), 122.3, 116.8 (d, JCF = 23.3 Hz), 87.5, 84.5, 50.9, 29.4 ppm IR (thin film) 1683, 1589,
1560, 1531, 1488, 1452, 1426, 1353, 1327, 1290, 1263, 1218, 1175, 1152, 1130, 1091, 1062, 1032, 1014, 897,
844, 791, 756, 737, 691, 669, 539 cmꢀ1. HRMS (ESIꢀTOF) [M + Na]+ m/z: Calcd for C24H19N3OFNaCl 442.1098;
Found 442.1099.
N-(N-(1-(4-Chlorophenyl)-3-phenylprop-2-yn-1-yl)-N-methylcarbamimidoyl)-4-methoxybenzamide (3f). Prepared
by guanylation of 1b (100 mg, 0.39 mmol) with 2b (101 mg, 0.47 mmol), with flash chromatography purification
eluting with 6:4 hexanes/EtOAc to yield a foamy white oil (94 mg, 56% yield). Rf = 0.21 (6:4 hexanes/EtOAc); 1H
NMR (CDCl3, 500 MHz): δ 8.21 (d, J = 9.0 Hz, 2H), 7.73 (s, 1H), 7.59 (d, J = 8.5 Hz, 2H), 7.53ꢀ7.51 (m, 2H),
7.36ꢀ7.33 (m, 5H), 6.89 (d, J = 9.0 Hz, 2H), 3.83 (s, 3H), 2.86 (s, 3H) ppm. 13C NMR (CDCl3, 125 MHz): δ
177.0, 162.4, 160.7, 136.3, 134.3, 132.1, 131.6, 131.3, 129.1, 128.7, 122.4, 113.3, 87.5, 84.7, 50.6, 50.8, 29.5
ppm. IR (thin film) 1654, 1603, 1455, 1383, 1300, 1273, 1257, 1169, 1125, 1069, 1035, 1011, 932, 914, 855, 769,
685, 639, 612 cmꢀ1. HRMS (ESIꢀTOF) [M + Na]+ m/z: Calcd for C25H22N3O2NaCl 454.1298; Found 454.1296.
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4-Chloro-N-(N-(1-(4-chlorophenyl)-3-phenylprop-2-yn-1-yl)-N-methylcarbamimidoyl)benzamide (3g). Prepared
by guanylation of 1b (100 mg, 0.39 mmol) with 2c (102 mg, 0.47 mmol), with flash chromatography purification
eluting with 6:4 hexanes/EtOAc to yield a foamy white oil (80 mg, 47% yield). Rf = 0.37 (6:4 hexanes/EtOAc); 1H
NMR (CDCl3, 500 MHz): δ 8.17 (d, J = 8.5 Hz, 2H), 7.68 (s, 1H), 7.57 (d, J = 8.5 Hz, 2H), 7.54ꢀ7.52 (m, 2H),
7.39ꢀ7.35 (m, 7H), 2.89 (s, 3H) ppm. 13C NMR (CDCl3, 125 MHz): δ 176.2, 173.2, 160.9, 137.5, 137.3, 136.0,
134.5, 132.1, 130.8, 129.2, 129.1, 129.0, 128.7, 128.3, 122.3, 87.7, 84.4, 51.0, 29.6 ppm. IR (thin film) 3310,
3169, 1684, 1586, 1556, 1523, 1488, 1469, 1422, 1358, 1323, 1290, 1242, 1159, 1031, 1089, 1064, 1015, 997,
978, 896, 856, 792, 779, 755, 689, 629, 548 cmꢀ1. HRMS (ESIꢀTOF) [M + H]+ m/z: Calcd for C24H20N3OCl2
436.0983; Found 436.0988.
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N-(N-(1-(4-Chlorophenyl)-3-phenylprop-2-yn-1-yl)-N-methylcarbamimidoyl)benzamide (3h). Prepared by
guanylation of 1b (100 mg, 0.39 mmol) with 2d (81 mg, 0.47 mmol), with flash chromatography purification
eluting with 6:4 hexanes/EtOAc to yield a foamy white oil (90 mg, 57% yield). Rf = 0.27 (6:4 hexanes/EtOAc); 1H
NMR (CDCl3, 500 MHz): δ 8.26 (d, J = 8.0 Hz, 2H), 7.55 (s, 1H), 7.60 (d, J = 8.5 Hz, 2H), 7.58ꢀ7.52 (m, 2H),
7.48ꢀ7.33 (m, 8H), 2.88 (s, 3H) ppm. 13C NMR (CDCl3, 125 MHz): δ 177.3, 160.9, 138.8, 136.2, 134.4, 132.1,
131.4, 129.4, 129.1, 128.7, 128.1, 122.3, 87.6, 84.6, 50.9, 29.5 ppm. IR (thin film) 1585, 1580, 1509, 1490, 1456,
1356, 1329, 1250, 1172, 1156, 1101, 1032, 892, 850, 788, 758, 692 cmꢀ1. HRMS (ESIꢀTOF) [M + H]+ m/z: Calcd
for C24H21N3OCl 402.1373; Found 402.1374.
N-(N-(3-Cyclopropyl-1-(4-methoxyphenyl)prop-2-yn-1-yl)-N-methylcarbamimidoyl)-2-fluorobenzamide
(3i).
Prepared by guanylation of 1c (100 mg, 0.46 mmol) with 2a (93 mg, 0.46 mmol), with flash chromatography
purification eluting with 6:4 hexanes/EtOAc to yield a foamy white oil (74% yield). Rf = 0.21 (6:4
hexanes/EtOAc); 1H NMR (CDCl3, 500 MHz): δ 8.02 (dt, J = 1.8, 7.8 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.38ꢀ7.33
(m, 1H), 7.18 (t, J = 7.8 Hz, 1H), 7.06 (dd, J = 1.0, 8.3 Hz, 1H), 6.87 (d, J = 7.3 Hz, 2H), 3.79 (s, 3H), 2.76 (s,
3H), 1.39ꢀ1.31 (m, 1H), 0.85ꢀ0.80 (m, 2H), 0.78ꢀ0.73 (m, 2H) ppm. 13C NMR (CDCl3, 125 MHz): δ 175.4, 162.9
(d, JCF = 254.4 Hz), 160.5, 159.4, 132.2 (d, JCF = 9.8 Hz), 132.0, 131.9, 128.8, 127.8 (d, JCF = 9.0 Hz), 123.5 (d,
JCF = 3.8 Hz), 116.8 (d, JCF = 23.2 Hz), 113.9, 90.7, 71.2, 55.5, 50.4, 8.5 (2) ppm. IR (thin film) 3336, 2933,
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1588, 1559, 1536, 1509, 1453, 1425, 1353, 1248, 1173, 1031, 897 cmꢀ1. HRMS (ESIꢀTOF) [M + Na]+ m/z: Calcd
for C22H22N3O2NaF 402.1594; Found 402.1601.
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N-(N-(3-Cyclopropyl-1-(4-methoxyphenyl)prop-2-yn-1-yl)-N-methylcarbamimidoyl)-4-methoxybenzamide
(3j).
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Prepared by guanylation of 1c (100 mg, 0.46 mmol) with 2b (100 mg, 0.46 mmol), with flash chromatography
purification eluting with 6:4 hexanes/EtOAc to yield a foamy white oil (83% yield). Rf = 0.16 (6:4
hexanes/EtOAc); 1H NMR (CDCl3, 500 MHz): δ 8.2 (d, J = 6.0 Hz, 2H), 7.47 (d, J = 7.5 Hz, 2H), 6.87 (t, J = 7.5
Hz, 4H), 3.83 (s, 3H), 3.78 (s, 3H), 2.77 (s, 3H), 1.40ꢀ1.32 (m, 1H), 0.86ꢀ0.80 (m, 2H), 0.79ꢀ0.73 (m, 2H) ppm.
13C NMR (CDCl3, 125 MHz): δ 176.7, 173.1 162.1, 160.5, 159.4, 131.7, 131.1, 130.1, 128.8, 113.9, 113.1, 90.6,
71.2, 55.4, 50.3, 29.1 8.6, 8.5 ppm. IR (thin film) 2933, 1585, 1528, 1507, 1462, 1349, 1346, 1152, 1029 cmꢀ1.
HRMS (ESIꢀTOF) [M + H]+ m/z: Calcd for C23H26N3O3 392.1974; Found 392.1974.
4-Chloro-N-(N-(3-cyclopropyl-1-(4-methoxyphenyl)prop-2-yn-1-yl)-N-methylcarbamimidoyl)benzamide
(3k).
Prepared by guanylation of 1c (100 mg, 0.46 mmol) with 2c (100 mg, 0.46 mmol), with flash chromatography
purification eluting with 6:4 hexanes/EtOAc to yield a foamy white oil (80% yield). Rf = 0.35 (6:4
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hexanes/EtOAc); H NMR (CDCl3, 500 MHz): δ 8.17 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 7.9 Hz, 2H), 7.43 (d, J =
9.1 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 3.79 (s, 3H), 2.78 (s, 3H), 1.40ꢀ1.33 (m, 1H), 0.86ꢀ0.82 (m, 2H), 0.79ꢀ0.74
(m, 2H) ppm. 13C NMR (CDCl3, 125 MHz): δ 175.9, 173.1, 160.7, 159.5, 137.5, 137.2, 130.7, 129,8, 128.7,
128.1, 114.0, 90.8, 71.0, 55.4, 50.5, 29.2, 8.6, 8.5 ppm. IR (thin film) 3355, 2932, 1552, 1530, 1508, 1422, 1349,
1246, 1172, 1087, 1030, 1013 cmꢀ1. HRMS (ESIꢀTOF) [M + Na]+ m/z: Calcd for C22H22N3O2NaCl 418.1303;
Found 418.1300.
N-(N-(3-Cyclopropyl-1-(4-methoxyphenyl)prop-2-yn-1-yl)-N-methylcarbamimidoyl)benzamide (3l). Prepared by
guanylation of 1c (100 mg, 0.46 mmol) with 2d (85 mg, 0.46 mmol), with flash chromatography purification
eluting with 6:4 hexanes/EtOAc to yield a foamy white oil (65% yield). Rf = 0.26 (6:4 hexanes/EtOAc); 1H NMR
(CDCl3, 500 MHz): δ 8.25 (d, J = 7.2 Hz, 2H), 7.48 (d, J = 9.7 Hz, 2H), 7.44 (d, J = 7.9 Hz, 1H), 7.39 (d, J = 7.9
Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 3.79 (s, 3H), 2.78 (s, 3H), 1.4ꢀ1.33 (m, 1H), 0.86ꢀ0.81 (m, 2H), 0.79ꢀ0.75 (m,
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2H). 13C NMR (CDCl3, 125 MHz): δ 176.9, 160.7, 159.4, 139.0, 131.2, 132.2, 131.1, 130.0, 129.2, 128.8
K, 127.9,
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114.0, 90.7, 71.2, 55.4, 29.2, 8.6, 8.5 ppm. IR (thin film) 3346, 2962, 1588, 1552, 1536, 1467, 1423, 1353, 1329,
1168, 1066, 893 cmꢀ1. HRMS (ESIꢀTOF) [M + Na]+ m/z: Calcd for C22H23N3O2Na 384.1688; Found 384.1693.
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Benzyl (Z)-5-benzylidene-2-imino-4-(4-methoxyphenyl)-3-methylimidazolidine-1-carboxylate (3m). Prepared by
guanylation of 1a with 2e, with purification on silica gel eluting with 1:1 hexanes/EtOAc to give a dark orange oil
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(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), 6.90 (d, J = 6.3 Hz, 2H), 5.18 (s, 2H), 3.80 (s, 3H), 2.80 (s, 3H). 13C NMR (CDCl3, 300MHz): 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 (ESIꢀTOF) [M + Na]+ m/z: Calcd for
C26H26N3O3 428.1974; Found 428.1979.
N-(N-Allyl-N-(1-(4-methoxyphenyl)-3-phenylprop-2-yn-1-yl)carbamimidoyl)-2-fluorobenzamide (3n). Prepared
by guanylation of 1d with 2a, with flash chromatography purification eluting with 6:4 hexanes/EtOAc to yield a
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foamy white oil (54% yield). H NMR (CDCl3, 500 MHz): δ 8.08 (dt, J = 8.0 Hz, 2.0 Hz, 1H), 7.64 (s, 1H), 7.61
(d, J = 9.0 Hz, 2H), 7.40ꢀ7.3 (m, 2H), 7.15 (t, J = 7.5 Hz, 1H), 7.08 (dd, J = 11.0 Hz, 8.5 Hz, 1H), 6.91 (d, J = 9.0
Hz, 2H), 5.77ꢀ5.72 (m, 1H), 5.32 (d, J = 17.0 Hz, 1H), 5.25 (dd, J = 10.0 Hz, 1.5 Hz, 1H), 3.95 (ABq, J = 15 Hz,
38 Hz, 2H), 3.82 (s, 3H) ppm. 13C NMR (CDCl3, 125 MHz): δ 175.8, 162.0 (d, JCF = 254.6 Hz), 161.0, 159.8,
134.0, 132.2 (d, JCF = 8.3 Hz), 132.1 (d, JCF = 1.5 Hz), 132.0, 129.7, 129.2, 128.9, 128.6, 127.8 (d, JCF = 3.8 Hz),
123.6 (d, JCF = 3.8 Hz), 122.6, 118.5, 114.2, 87.1, 85.7, 55.6, 50.8, 47.1 ppm. IR (thin film) 1586, 1560, 1510,
1452, 1327, 1248, 1219, 1173, 1152, 1096, 1031, 906, 836, 757, 726, 690, 668, 646 cmꢀ1. HRMS (ESIꢀTOF) [M +
H]+ m/z: Calcd for C27H25N3O2F 442.1931; Found 442.1925.
2-Fluoro-N-(N-methyl-N-(4-methyl-1-phenylpent-1-yn-3-yl)carbamimidoyl)benzamide
(3o).
Prepared
by
guanylation of 1e (100mg, 0.53 mmol) with 2a (128 mg, 0.64 mmol), with flash chromatography purification
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eluting with 6:4 hexanes/EtOAc to yield a foamy white oil (136 mg, 75%). Rf = 0.29 (6:4 hexanes/EtOAc); H
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NMR (CDCl3, 500 MHz): δ 8.00 (dt, J = 2 Hz, 7.5 Hz, 1H), 7.44ꢀ7.41 (m, 2H), 7.39ꢀ7.34 (m, 1H), 7.32ꢀ7.28 (m,
3H), 7.16ꢀ7.13 (m, 1H), 7.09ꢀ7.05 (m, 1H), 5.94 (br.s., 1H), 3.05 (s, 3H), 2.11ꢀ2.05 (m, 1H), 1.17 (d, J = 7.0 Hz,
3H), 0.98 (d, J = 7.0 Hz, 3H) ppm. 13C NMR (CDCl3, 125 MHz): δ 175.0, 161.7 (d, JCF = 254.5 Hz), 160.7, 132.8
(d, JCF = 9.2 Hz), 131.7 (d, JCF = 3.4 Hz), 128.4, 128.3, 127.7 (d, JCF = 8.9 Hz), 123.3 (d, JCF = 3.8 Hz), 122.7,
116.7 (d, JCF = 23.2 Hz), 86.4, 85.5, 34.8, 32.8, 29.8, 19.5, 19.1 ppm IR (thin film) 1587, 1554, 1534, 1467, 1451,
1421, 1359, 1330, 1277, 1260, 1217, 1184, 1155, 1098, 1062, 1032, 985, 896, 754, 731, 690, 626 cmꢀ1. HRMS
(ESIꢀTOF) [M + H]+ m/z: Calcd for C21H23N3OF 352.1825; Found 352.1830.
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N-(N-(1-Cyclopropyl-4-methylpent-1-yn-3-yl)-N-methylcarbamimidoyl)benzamide (3p). Prepared by guanylation
of 1e (111 mg, 0.66 mmol) with 2d (100 mg, 0.66 mmol), with flash chromatography purification eluting with 6:4
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hexanes/EtOAc to yield a foamy white oil (78% yield). Rf = 0.64 (6:4 hexanes/EtOAc); H NMR (CDCl3, 500
MHz): δ 8.18 (d, J = 9 Hz, 1H), 7.46ꢀ7.35 (m, 2H), 5.51 (bs, 2H), 2.97 (s, 3H), 1.96 (sextet, J = 7.3 Hz, 1H), 1.3ꢀ
1.22 (m, 1H), 1.09 (d, J = 7.7 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H), 0.8ꢀ0.75 (m, 2H), 0.7ꢀ0.65 (m, 2H) ppm. 13C
NMR (CDCl3, 125 MHz): δ 176.7, 139.1, 131.0, 129.1, 127.8, 89.2, 77.4, 54.8, 33.0, 19.6, 19.3, 8.5, 8.4 ppm. IR
(thin film) 3337, 2961, 1588, 1556, 1469, 1450, 1425, 1354, 1239, 1154, 1046 cmꢀ1. HRMS (ESIꢀTOF) [M +
Na]+ m/z: Calcd for C18H22N3OFNa 338.1645; Found 338.1635.
N-(N-(2,4-Dimethoxybenzyl)-N-(non-4-yn-3-yl)carbamimidoyl)-2-fluorobenzamide (3q). Prepared by guanylation
of 1f (500 mg, 1.72 mmol) with 2a (420 mg, 2.07 mmol), with flash chromatography purification eluting with 6:4
hexanes/EtOAc to yield a foamy white oil (446 mg, 63%). Rf = 0.41 (6:4 hexanes/EtOAc); 1H NMR (CDCl3, 500
MHz): δ 7.99 (dt, J = 2.0 Hz, 8.0 Hz, 1H), 7.37ꢀ7.28 (m, 2 H), 7.14ꢀ7.11 (m, 1H), 7.07ꢀ7.03 (m, 1H), 6.49ꢀ6.45
(m, 2H), 5.98 (br.s., 1H), 4.54 (s, 1H), 3.86 (s, 3H), 3.80 (s, 3H), 2.13 (dt, J = 2.0 Hz, 6.5 Hz, 2H), 1.82ꢀ1.66 (m,
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2H), 1.38ꢀ1.24 (m, 4H), 1.01 (t, J = 7.0 Hz, 3H), 0.84 (t, J = 7.5 Hz, 3H) ppm. C NMR (CDCl3, 125 MHz): δ
175.1, 161.7 (d, JCF = 254.5 Hz), 160.4, 157.2, 131.8 (d, JCF = 1.7 Hz), 131.6 (d, JCF = 8.8 Hz), 129.1, 127.8 (d,
JCF = 8.9 Hz), 123.2 (d, JCF = 3.8 Hz), 116.6 (d, JCF = 23.3 Hz), 116.0, 104.5, 98.2, 86.2, 77.9, 55.4 (2), 50.8,
41.3, 30.6, 28.3, 21.8, 18.3, 13.6, 10.8 ppm. IR (thin film) 2957, 2933, 1587, 1666, 1524, 1504, 1452, 1373, 1333,
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1291, 1256, 1206, 1177, 1155, 1135, 1116, 1092, 1033, 958, 907, 894, 833, 759, 730, 669, 646, 564 cmꢀ1. HRMS
(ESIꢀTOF) [M + H]+ m/z: Calcd for C26H33N3O3F 454.2506; Found 454.2509.
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2-Fluoro-N-(N-methyl-N-(3-(p-tolyl)prop-2-yn-1-yl)carbamimidoyl)benzamide (3r). Prepared by guanylation of
1g (150 mg, 0.94 mmol) with 1a (228 mg, 1.13 mmol), with flash chromatography purification eluting with 6:4
hexanes/EtOAc to yield a foamy white oil (207 mg, 68%). Rf = 0.21 (6:4 hexanes/EtOAc); 1H NMR (CDCl3, 500
MHz): δ 8.04 (t, J = 10.5Hz, 1H), 7.39ꢀ7.32 (m, 3H), 7.16ꢀ7.02 (m, 4H), 4.66 (s, 2H), 3.11 (s, 3H), 2.32 (s, 3H)
ppm. 13C NMR (CDCl3, 125 MHz): δ 175.4kk, 161.7 (d, JCF = 254.4 Hz), 160.6, 138.7, 131.9 (3), 131.7, 127.6 (d,
JCF = 8.8 Hz), 123.4 (d, JCF = 3.8 Hz), 116.6 (d, JCF = 22.8 Hz), 84.8, 82.6, 39.1, 33.7, 21.5 ppm. IR (thin film)
1587, 1546, 1509, 1431, 1423, 1333, 1261, 1215, 1178, 1153, 1134, 1098, 1065, 1021, 946, 896, 816, 758, 729,
654, 569 cmꢀ1. HRMS (ESIꢀTOF) [M + H]+ m/z: Calcd for C19H19N3OF 324.1512; Found 324.1519.
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N-(N-methyl-N-(3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-yl)carbamimidoyl)benzamide (3s). Prepared by
guanylation of 1h with 2d, with flash chromatography purification eluting with 6:4 hexanes/EtOAc to yield a
foamy white oil (1.23g, 58%). Rf = 0.24 (6:4 hexanes/EtOAc); 1H NMR (CDCl3, 500 MHz): δ 8.26ꢀ8.24 (m, 2H),
7.55ꢀ7.26 (m, 7H), 4.76 (s, 2H), 3.13 (s, 3H) ppm. 13C NMR (CDCl3, 125 MHz): δ 177.3, 160.9, 138.9, 132.3,
131.4, 130.5 (q, JCF = 32.5 Hz), 129.3, 128.1, 125.5 (q, JCF = 3.7 Hz), 124.0 (q, JCF = 270.6 Hz), 86.6, 83.3, 39.4,
34.0 ppm. IR (thin film) 1589, 1555, 1424, 1318, 1163, 1120, 1064, 1016, 907 cmꢀ1. HRMS (ESIꢀTOF) [M + H]+
m/z: Calcd for C19H17N3OF3 360.1324; Found 360.1324.
N-(N-benzyl-N-(prop-2-yn-1-yl)carbamimidoyl)benzamide (3t). Prepared by guanylation of 1i with 2d, with flash
chromatography purification eluting with 6:4 hexanes/EtOAc to yield a foamy white oil (127.2 mg, 35%). Rf =
1
0.43 (6:4 hexanes/EtOAc); H NMR (CDCl3, 500 MHz): δ 8.25 (d, J = 7.0 Hz, 2H), 7.47ꢀ7.29 (m, 8H), 4.83 (s,
2H), 4.36 (s, 2H), 2.34 (t, J = 2.5 Hz, 1H) ppm. 13C NMR (CDCl3, 125 MHz): δ 177.6, 161.2, 138.9, 136.2, 131.4,
129.4, 12.3, 128.2, 128.1, 127.5, 78.4, 73.7, 50.8, 37.0 ppm. IR (thin film) 1588, 1553, 1530, 1450, 1418, 1367,
1332, 1298, 1202, 1166, 1118, 1068, 1027, 1001, 958, 907 cmꢀ1. HRMS (ESIꢀTOF) [M + H]+ m/z: Calcd for
C18H18N3O 292.1450; Found 292.1448.
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NaH-mediated
Cyclizations:
N-(4-Benzyl-5-(4-methoxyphenyl)-1-methyl-1H-imidazol-2(3H)-ylidene)-2-
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fluorobenzamide (4a). In a 25 mL round bottom flask containing a magnetic stir bar were added 3a (402.5 mg,
0.97 mmol) and THF (30 mL) under N2. The solution was stirred at room temperature, and NaH (22.5 mg, 0.97
mmol) was added, resulting in a bright yellow solution. The reaction was stirred for 30 minutes, after which the
solvent was removed under reduced pressure and the crude product was reꢀdissolved in EtOAc (25 mL). The
organic layer was washed with saturated aqueous NH4Cl (10 mL) and brine (10 mL), dried over Na2SO4, filtered,
and concentrated. The resulting yellow solid required no further purification (330 mg, 82%). Rf = 0.41 (6:4
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hexanes/EtOAc); H NMR (CDCl3, 500 MHz): δ 8.07 (t, J = 8.0 Hz, 2H), 7.34ꢀ7.32 (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 171.8k, 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 cmꢀ1. HRMS (ESIꢀTOF) [M + Na]+ m/z: Calcd
for C25H22N3O2FNa 438.1594; Found 438.1601.
N-(4-Benzyl-5-(4-methoxyphenyl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)-4-methoxybenzamide
(4b).
Prepared via NaHꢀmediated cyclization of (3b) (31.5 mg, 0.074 mmol) in THF as a yellow foam (26.5 mg, 84%).
Rf = 0.21 (6:4 hexanes/EtOAc); 1H NMR (CDCl3, 300 MHz): δ 8.08 (d, J = 8.7 Hz, 2H), 7.30–7.21 (m, 5H), 7.14
(d, J = 8.7 Hz, 2H), 7.01 (d, J = 9.0 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.82 (s, 2H), 3.47
(s, 3H) ppm. 13C NMR (CDCl3, 125 MHz): δ 161.8, 160.2, 137.7, 131.6, 130.5, 128.5, 128.2, 126.8, 124.4, 119.9,
114.5, 113.1, 55.4, 55.3, 30.7, 30.0 ppm. IR (thin film) 1671, 1603, 1567, 1508, 1454, 1414, 1398, 1349, 1308,
1289, 1246, 1175, 1163, 1108, 1028, 1005, 882, 835, 799, 765, 733, 697, 608 cmꢀ1. HRMS (ESIꢀTOF) [M + H]+
m/z: Calcd for C26H26N3O3 428.1974; Found 428.1971.
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N-(4-Benzyl-5-(4-methoxyphenyl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)-4-chlorobenzamide
(4c).
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Prepared via NaHꢀmediated cyclization of 3c in THF as a yellow foam (42.2 mg, 82%). Rf = 0.38 (6:4
hexanes/EtOAc); 1H NMR (CDCl3, 500 MHz): δ 8.19 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.30–7.21 (m,
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7
13
5H), 7.12 (d, J = 7.5 Hz, 2H), 7.01 (d, J = 8.0 Hz, 2H), 3.86 (s, 3H), 3.82 (s, 2H), 3.47 (s, 3H) ppm. C NMR
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(CDCl3, 125 MHz): δ 173.7, 160.5, 150.6, 137.6, 137.2, 136.8, 131.8, 130.4, 129.2, 128.4, 128.2, 127.2, 124.5,
120.4, 119.8, 113.8, 55.6, 50.8, 30.1 ppm. IR (thin film) 1670, 1603, 1566, 1508, 1453, 1348, 1307, 1280, 1242,
1174, 1162, 1108, 1027, 835, 779, 733, 697, 607 cmꢀ1. HRMS (ESIꢀTOF) [M + H]+ m/z: Calcd for C25H23N3O2Cl
432.1479; Found 432.1480.
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N-(4-Benzyl-5-(4-methoxyphenyl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide (4d). Prepared via
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NaHꢀmediated cyclization of 3d in THF as a yellow foam (55.4 mg, 63%). Rf = 0.47 (6:4 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), 7.22ꢀ? (m, 1H), 7.15
(d, J = 7.5 Hz, 2H), 7.01 (d, J = 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 [M + H]+ (ESIꢀTOF) m/z: Calcd for C25H24N3O2 398.1869;
Found 398.1869.
N-(4-Benzyl-5-(4-chlorophenyl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)-2-fluorobenzamide (4e). Prepared
via NaHꢀmediated cyclization of 3e in THF as a yellow foam (32.7 mg, 62%). Rf = 0.38 (6:4 hexanes/EtOAc); 1H
NMR (CDCl3, 500 MHz): δ 8.08 (t, J = 2.5 Hz, 1H), 7.46 (d, J = 8 Hz, 2H), 7.40 (m, 1H), 7.30ꢀ7.25 (m, 4H),
7.22ꢀ7.10 (m, 5H), 3.84 (s, 2H), 3.43 (s, 3H) ppm. 13C NMR (CDCl3, 125 MHz): δ 171.0, 161.4 (d, JCF = 252.5
Hz), 147.9, 137.7, 135.2, 132.3 (d, JCF = 8.8 Hz), 131.7 (d, JCF = 2.5 Hz), 131.5, 129.3, 128.9, 128.2, 126.9, 126.5,
124.3, 123.8 (d, JCF = 2.5 Hz), 116.6, 116.4, 31.2, 30.5 ppm. IR (thin film) 1682, 1567, 1490, 1352, 1221, 1091,
1010, 906 cmꢀ1. HRMS (ESIꢀTOF) [M + H]+ m/z: Calcd for C24H20N3OFCl 420.1279; Found 420.1278.
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N-(4-Benzyl-5-(4-chlorophenyl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)-4-methoxybenzamide
(4f).
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Prepared via cyclization of 3f in THF as an offꢀwhite foam (25.7 mg, 74%). Rf = 0.38 (6:4 hexanes/EtOAc); H
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NMR (CDCl3, 300 MHz): δ 8.19 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.30ꢀ7.23 (m, 5H), 7.13 (d, J = 8.4
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7
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Hz, 2H), 6.90 (d, J = 9.0 Hz, 2H), 3.84 (s, 2H), 3.83 (s, 2H), 3.48 (s, 3H) ppm. C NMR (CDCl3, 125 MHz): δ
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162.0, 137.5, 135.2, 131.6, 131.4, 130.5, 129.5, 129.3, 128.9, 128.2, 128.1, 126.9, 126.5, 114.6, 113.5, 113.6,
55.3, 30.9, 30.2 ppm. IR (thin film) 1671, 1568, 1513, 1491, 1452, 1346, 1309, 1248, 1174, 1162, 1090, 881,
831, 779, 764, 728, 696, 607 cmꢀ1. HRMS (ESIꢀTOF) [M + H]+ m/z: Calcd for C25H23N3O2Cl 432.1479; Found
432.1480.
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N-(4-Benzyl-5-(4-chlorophenyl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)-4-chlorobenzamide (4g). Prepared
via NaHꢀmediated cyclization of 3g in THF as a yellow foam (35.1 mg, 64%). Rf = 0.68 (6:4 hexanes/EtOAc); 1H
NMR (CDCl3, 500 MHz): δ 8.18 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.30ꢀ7.25
13
(m, 5H), 7.12 (d, J = 7.0 Hz, 2H), 3.83 (s, 2H), 3.48 (s, 3H) ppm. C NMR (CDCl3, 125 MHz): δ 137.1, 136.7,
135.8, 131.7, 130.4, 129.7, 129.3, 128.3, 127.4, 126.2, 123.6, 30.8, 30.4 ppm. IR (thin film) 1571, 1492, 1397,
1350, 1091, 1012, 767 cmꢀ1. HRMS (ESIꢀTOF) [M + H]+ m/z: Calcd for C24H20N3OCl2 436.0983; Found,
436.0984.
N-(4-Benzyl-5-(4-chlorophenyl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide (4h). Prepared via NaHꢀ
1
mediated cyclization of 3h in THF as a white foam (39.3 mg, 77%). Rf = 0.40 (6:4 hexanes/EtOAc); H NMR
(CDCl3, 500 MHz): δ 8.24 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.45ꢀ7.39 (m, 3H), 7.30ꢀ7.20 (m, 5H),
7.12 (d, J = 7.0 Hz, 2H), 3.83 (s, 2H), 3.48 (s, 3H) ppm. 13C NMR (CDCl3, 125 MHz): δ 174.1, 149.9, 137.8,
137.7, 135.4, 131.6, 131.1, 129.6, 129.1, 128.9, 128.3, 128.1, 127.1, 126.6, 124.0, 122.6, 31.1, 30.5 ppm. IR (thin
film) 1678, 1566, 1492, 1467, 1453, 1396, 1353, 1304, 1280, 1169, 1092, 1025, 1011, 876, 831, 741, 711 cmꢀ1.
HRMS (ESIꢀTOF) [M + Na]+ m/z: Calcd for C24H20N3ONaCl 424.1193; Found 424.1203.
N-(4-(Cyclopropylmethyl)-5-(4-methoxyphenyl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)-2-fluorobenzamide
(4i). Prepared via NaHꢀmediated cyclization of 3i in THF as a yellow foam (45.6 mg, 86%). Rf = 0.3 (6:4
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1
hexanes/EtOAc); H NMR (CDCl3, 500 MHz): δ 8.09 (dt, J = 1.7, 6.1 Hz, 1H), 7.40ꢀ7.34 (m, 2H), 7.23 (d, J =
7.3 Hz, 2H), 7.16 (t, J = 8.4, 1H), 7.09 (dd, J = 3.0 Hz, 8.4 Hz, 1H), 6.99 (d, J = 9.0 Hz, 2H), 3.86 (s, 3H), 3.42
(s, 3H), 2.40 (d, J = 6.7 Hz, 2H), 0.97ꢀ0.88 (m, 1H), 0.56 (d, J = 8.3 Hz, 2H), 0.17 (d, J = 4.8 Hz, 2H) ppm. 13C
NMR (CDCl3, 125 MHz): δ 172.5, 161.5 (d, JCF = 252.5 Hz), 160.1, 149.1, 131.7, 131.6 (d, JCF = 2.5 Hz), 131.5
(d, JCF = 8.8 Hz), 127.1 (d, JCF = 8.8 Hz), 123.5 (d, JCF = 3.8 Hz), 123.3, 122.4, 120.0, 116.5 (d, JCF = 22.5 Hz),
114.3, 55.3, 29.9, 29.3, 10.2, 4.5 ppm. IR (thin film) 2934, 1566, 1510, 1480, 1353, 1247, 1174, 1031 cmꢀ1.
HRMS (ESIꢀTOF)[M + Na]+ m/z: Calcd for C22H22N3O2FNa 402.1594; Found 402.1598.
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N-(4-(Cyclopropylmethyl)-5-(4-methoxyphenyl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)-4-
methoxybenzamide (4j). Prepared via NaHꢀmediated cyclization of 3j in THF as a yellow foam (63.2 mg, 84%).
Rf = 0.27 (6:4 hexanes/EtOAc); 1H NMR (CDCl3, 500 MHz): δ 8.27 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.6 Hz, 2H),
7.00 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.2 Hz, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.45 (s, 3H), 2.39 (d, J = 6.8 Hz, 2H),
0.97ꢀ0.88 (m, 1H), 0.57 (d, J = 8.1 Hz, 2H), 0.17 (d, J = 4.7 Hz, 2H) ppm. 13C NMR (CDCl3, 125 MHz): δ 174.5,
172.8, 161.8, 160.1, 131.8, 130.6, 122.9, 120.9, 120.2, 114.4, 113.1, 94.9, 55.5, 55.4, 29.8, 29.3, 10.3, 4.6 ppm. IR
(thin film) 2931, 2836, 1568, 1509, 1463, 1348, 1290, 1246, 1163, 1100, 1030 cmꢀ1. HRMS (ESIꢀTOF) [M +
Na]+ m/z: Calcd for C23H25N3O3Na 414.1794; Found 414.1794.
4-Chloro-N-(4-(cyclopropylmethyl)-5-(4-methoxyphenyl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide
(4k). Prepared via NaHꢀmediated cyclization of 3k in THF as a yellow foam (48.2 mg, 87%). Rf = 0.48 (6:4
1
hexanes/EtOAc); H NMR (CDCl3, 500 MHz): δ 8.24 (d, J = 7.8 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 7.23 (d, J =
8.2 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 3.86 (s, 3H), 3.45 (s, 3H), 2.40 (d, J = 6.8 Hz, 2H), 0.97ꢀ0.88 (m, 1H), 0.57
(d, J = 7.1 Hz, 2H), 0.18 (d, J = 5.5 Hz, 2H) ppm. 13C NMR (CDCl3, 125 MHz): δ 173.8, 173.2, 160.3, 150.3,
137.3, 136.7, 131.8, 130.3, 128.1, 123.2, 121.7, 120.0, 114.5, 55.6, 29.9, 29.3, 10.2, 4.7 ppm. IR (thin film) 2929,
1822, 1725, 1569, 1512, 1466, 1348, 1289, 1248, 1162, 1087, 1013 cmꢀ1. HRMS (ESIꢀTOF) [M + Na]+ m/z:
Calcd for C22H22N3O2NaCl 418.1298; Found 418.1302.
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N-(4-(Cyclopropylmethyl)-5-(4-methoxyphenyl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide
(4l).
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Prepared via NaHꢀmediated cyclization of 3l in THF as a yellow foam (52.3 mg, 91%). Rf = 0.55 (6:4
hexanes/EtOAc); 1H NMR (CDCl3, 500 MHz): δ 8.31 (d, J = 7.3 Hz, 2H), 7.47ꢀ7.39 (m, 4H), 7.24 (d, J = 9.0 Hz,
3H), 7.01 (d, J = 8.7 Hz, 2H), 3.87 (s, 3H), 3.47 (s, 3H), 2.41 (d, J = 7.3 Hz, 2H), 0.97ꢀ0.89 (m, 1H), 0.58 (d, J =
7.8 Hz, 2H), 0.19 (d, J = 4.8 Hz, 2H) ppm. 13C NMR (CDCl3, 125 MHz): δ 174.9, 173.0, 160.2, 138.8, 130.7,
128.9, 128.0, 123.1, 120.2, 114.5, 55.5, 29.9, 29.3, 10.3,k 4.7 ppm. IR (thin film) 2979, 1821, 1724, 1569, 1511,
1464, 1349, 1287, 1248, 1138, 1023 cmꢀ1. HRMS (ESIꢀTOF) [M + Na]+ m/z: Calcd for C22H23N3O2Na 384.1688;
Found 384.1690.
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Benzyl (4-benzyl-5-(4-methoxyphenyl)-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)carbamate (4m). Prepared
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via NaHꢀmediated cyclization of 3m in THF as a yellow foam (3.0 g, 81 %). Rf = 0.22 (6:4 hexanes/EtOAc); H
NMR (CDCl3, 500 MHz): δ 7.41 (d, J = 6.9 Hz, 2H), 7.29ꢀ7.19 (m, 8H), 7.11 (d, J = 6.9 Hz, 2H), 6.99 (d, J = 8.9
Hz, 2H), 5.15 (s, 2H), 3.84 (s, 3H), 3.77 (s, 2H), 3.32 (s, 3H) ppm. 13C NMR (CDCl3, 125 MHz): δ 162.9, 160.3,
150.2, 137.9, 137.8, 131.8, 129.1, 128.5, 128.3, 128.1, 127.6, 127.1, 124.6, 121.2, 120.0, 114.6, 66.9, 55.6, 31.0,
30.2 ppm. IR (thin film) 1724, 1590, 1508, 1298, 1244, 1210, 1175, 1059, 906 cmꢀ1. HRMS (ESIꢀTOF) [M + H]+
m/z: Calcd for C26H26N3O3 428.1974; Found 428.1974.
N-(1-allyl-4-benzyl-5-(4-methoxyphenyl)-1,3-dihydro-2H-imidazol-2-ylidene)-2-fluorobenzamide
(4n)
was
obtained via NaHꢀmediated cyclization cyclization of 3n in THF as a yellow foam (42.6 mg, 54%). Rf = 0.50 (6:4
1
hexanes/EtOAc); H NMR (CDCl3, 500 MHz): δ 8.06 (dt, J = 1.5 Hz, 8.0 Hz, 1H), 7.56ꢀ7.53 (m, 1H), 7.29ꢀ7.26
(m, 4H), 7.23ꢀ7.20 (m, 1H), 7.15ꢀ7.12 (m, 2H), 7.09ꢀ7.05 (m, 1H), 6.98 (d, J = 9.0 Hz, 2H), 5.91ꢀ5.83 (m, 1H),
5.12 (dd, J = 1.0 Hz, 10.0 Hz, 1H), 4.96 (dd, J = 1.0 Hz, 17.5 Hz, 1H), 3.86 (s, 3H), 3.80 (s, 2H) ppm. 13C NMR
(CDCl3, 125 MHz): δ 161.9 (d, JCF = 252.8 Hz), 160.5, 137.9, 132.9, 132.2, 132.1, 132.0 (3), 129.1, 128.4, 127.1,
123.7 (d, JCF = 3.8 Hz), 120.0, 117.8, 116.7 (d, JCF = 23.2 Hz), 114.5 55.6, 45.5, 31.1 ppm. IR (thin film) 2924,
1567, 1512, 1364, 1290, 1252, 1176, 1032, 759, 687 cmꢀ1. HRMS (ESIꢀTOF) [M + H]+ m/z: Calcd for
C27H25N3O2F 442.1931; Found 442.1929.
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NaH-mediated cyclization of C5-alkyl or C5-unsubstituted mono-N-acylpropargylguanidines: N-(4-Benzyl-
5-isopropyl-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)-2-fluorobenzamide (4o). In a 25 mL ovenꢀdried round
bottom flask containing a magnetic stir bar were added 3o (141 mg, 0.40 mmol), oven dried molecular sieves
(Grade 564, 3 Å, 8ꢀ12 mesh) (ca. 20 mg) and DMF (10 mL) under N2. The solution was stirred at room
temperature, and NaH (5 mg, 0.25 mmol) was added, resulting in a bright yellow solution. The reaction
temperature was then elevated to 60 ˚C, and allowed to stir for 8 hours. The solvent was removed under reduced
pressure and the crude product was reꢀdissolved in EtOAc (25 mL). The organic layer was washed with saturated
aqueous NH4Cl (10 mL) and saturated aqueous LiCl (3 x 10 mL). The organics were dried over Na2SO4, filtered,
and concentrated. The resulting yellow oil was purified by column chromatography, eluting with 6:4
hexanes/EtOAc to yield an offꢀwhite foam (80.4 mg, 57%). Rf = 0.32 (6:4 hexanes/EtOAc); 1H NMR (CDCl3, 500
MHz): δ 8.03 (t, J = 8.0 Hz, 1H), 7.35ꢀ7.03 (m, 8H), 3.92 (s, 3H), 3.12ꢀ3.05 (m, 1H), 1.31 (d, J = 7.0 Hz, 6H)
ppm. . 13C NMR (CDCl3, 125 MHz): δ 172.2, 161.5 (d, JCF = 252.9), 149.3, 137.6, 131.6 (d, JCF = 1.9 Hz), 131.5
(d, JCF = 8.7 Hz), 128.9, 128.1, 127.0 (d, JCF = 6.9 Hz), 126.9, 123.4 (d, JCF = 3.7 Hz), 118.4, 116.5 (d, JCF = 23.2
Hz), 31.0, 29.5, 24.5, 24.6, 19.9 ppm. IR (thin film) 1564, 1481, 1452, 1356, 1260, 1216, 1153, 1096, 1030, 906,
870, 815, 756, 724, 694, 644, 561 cmꢀ1. HRMS (ESIꢀTOF) [M + H]+ m/z: Calcd for C21H23N3OF 352.1825;
Found 352.1832.
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N-(4-(cyclopropylmethyl)-5-isopropyl-1-methyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide (4p). Prepared via
NaHꢀmediated cyclization of 3p in DMF at 60 ˚C as a yellow foam (33.2 mg, 42%). Rf = 0.39 (6:4
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hexanes/EtOAc); H NMR (CDCl3, 500 MHz): δ 8.29 (d, J = 6.4 Hz, 2H), 7.43ꢀ7.38 (m, 3H), 3.63 (s, 3H), 3.02
(sp, J = 7.9 Hz, 1H), 2.49 (d, J = 6.8 Hz, 2H), 1.33 (d, J = 6.8 Hz, 6H), δ 0.99ꢀ0.90 (m, 1H), δ 0.63 (q, J = 4.8 Hz,
2H), δ 0.26 (q, J = 4.8 Hz, 2H) ppm. 13C NMR (CDCl3, 125 MHz): δ 174.7, 173.2, 138.7, 130.5, 128.7, 127.9,
126.4, 118.9, 29.4, 24.5, 21.8, 10.3, 4.7 ppm. IR (thin film) 3286, 2925, 1737, 1567, 1465, 1367, 1244, 1169,
1022 cmꢀ1. HRMS (ESIꢀTOF) [M + Na]+ m/z: Calcd for C18H23N3ONa 320.1739; Found 320.1743.
N-(1-(2,4-dimethoxybenzyl)-5-ethyl-4-pentyl-1,3-dihydro-2H-imidazol-2-ylidene)-2-fluorobenzamide
(4q).
Prepared obtained via NaHꢀmediated cyclization of 3q in DMF at 60° C as a colorless foam (59.2 mg, 69%). Rf =
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0.44 (6:4 hexanes/EtOAc); 1H NMR (CDCl3, 500 MHz): δ 8.04 (t, J = 7.0 Hz, 1H), 7.34ꢀ7.30 (m, 1H), 7.11ꢀ6.98
(m, 3H), 6.45 (s, 1H), 6.39 (d, J = 8.5 Hz, 1H), 5.17 (s, 2H), 3.85 (s, 3H), 3.77 (s, 3H), 2.48ꢀ2.41 (m, 4H), 1.62ꢀ
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1.58 (m, 1H), 1.36ꢀ1.29 (m, 4H), 0.99 (t, J = 8.0 Hz, 3H), 0.89 (t, J = 7.0 Hz, 3H) ppm. C NMR (CDCl3, 125
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MHz): 172.7, 161.7 (d, JCF = 253.4 Hz), 160.3, 157.3, 150.1, 131.8 (d, JCF = 2.0 Hz), 131.2 (d, JCF = 8.8 Hz),
129.1, 127.5, 123.3 (d, JCF = 3.7 Hz), 120.2, 117.5, 116.4 (d, JCF = 23.0 Hz), 110.0, 104.4, 98.2 55.4, 55.3, 39.2,
31.3, 28.8, 24.2, 22.4, 16.0, 14.5, 14.0 ppm. IR (thin film) 2931, 2858, 1611, 1587, 1563, 1500, 1482, 1460, 1420,
1356, 1287, 1264, 1208, 1157, 1119, 1034, 897, 819, 758, 734 cmꢀ1. HRMS (ESIꢀTOF) [M + H]+ m/z: Calcd for
C26H33FN3O3 454.2506; Found 454.2501.
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2-Fluoro-N-(1-methyl-4-(4-methylbenzyl)-1,3-dihydro-2H-imidazol-2-ylidene)benzamide (4r) was obtained via
NaHꢀmediated cyclization of 3r in DMF at 60° C as a colorless foam (57.6 mg, 58%). Rf = 0.24 (6:4
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hexanes/EtOAc); H NMR (CDCl3, 500 MHz): δ 8.04 (t, J = 7.5 Hz, 1H), 7.39ꢀ7.32 (m, 1H), 7.15ꢀ7.04 (m, 6H),
6.21 (s, 1H), 3.78 (s, 2H), 3.51 (s, 3H), 2.32 (s, 3H) ppm. 13C NMR (CDCl3, 125 MHz): δ 171.7, 161.4 (d, JCF
=
252.7 Hz), 149.0, 136.7, 133.7, 131.9 (d, JCF = 8.9 Hz), 131.7 (d, JCF = 2.0 Hz), 129.5, 128.5, 126.6, 126.3, 123.6
(d, JCF = 3.7 Hz), 116.5 (d, JCF = 23.3 Hz), 112.4, 31.8, 31.6, 21.0 ppm. IR (thin film) 1684, 1623, 1564, 1514,
1481, 1448, 1355, 1296, 1260, 1215, 1154, 1126, 1092, 1032, 898, 852, 802, 754, 730, 688, 644 cmꢀ1. HRMS
(ESIꢀTOF) [M + H]+ m/z: Calcd for C19H19N3OF 324.1512; Found 324.1512.
N-(1-Methyl-4-(4-(trifluoromethyl)benzyl)-1,3-dihydro-2H-imidazol-2-ylidene)benzamide (4s). Prepared via NaHꢀ
mediated cyclization of 3s in DMF at 60° C, with flash chromatography purification eluting with 6:4
hexanes/EtOAc to yield a foamy white oil (802 mg, 71% yield). Rf = 0.19 (6:4 hexanes/EtOAc); 1H NMR (CDCl3,
500 MHz): δ 8.23 (d, J = 7.5 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.47ꢀ7.36 (m, 3H), 7.27ꢀ7.24 (m, 2H), 6.22 (s,
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1H), 3.84 (s, 2H), 3.53 (s, 3H) ppm. C NMR (CDCl3, 125 MHz): δ 173.7, 149.9, 141.5, 137.8, 131.1, 129.5 (q,
JCF = 30.4 Hz), 129.1, 128.9, 128.1, 125.8 (q, JCF = 2.1 Hz), 124.3 (q, JCF = 272.0 Hz), 113.2, 32.1, 31.9 ppm. IR
(thin film) 1570, 1558, 1367, 1352, 1160, 1106, 1065 cmꢀ1. HRMS (ESIꢀTOF) [M + H]+ m/z: Calcd for
C19H17N3OF3 360.1324; Found 360.1323.
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N-(1-Benzyl-4-methyl-1,3-dihydro-2H-imidazol-2-ylidene)benzamide (4t). Prepared via NaHꢀmediated cyclization
of 3t in DMF at 60° C as a colorless foam (82.4 mg, 52%). Rf = 0.19 (6:4 hexanes/EtOAc); 1H NMR (CDCl3, 500
MHz): δ 8.30 (d, J = 8.0 Hz, 2H), 7.45ꢀ7.30 (m, 8H), 6.17 (s, 1H), 5.17 (s, 2H), 2.14 (s, 3H) ppm. 13C (CDCl3,
125 MHz): δ 174.9, 151.1, 138.8, 136.5, 130.8, 129.1 (2), 128.4, 128.0, 121.1, 110.0, 95.0, 48.1, 11.0 ppm. IR
(thin film) 3219, 1629, 1590, 1567, 1544, 1496, 1488, 1471, 1455, 1381, 1349, 1300, 1138, 1024 cmꢀ1. HRMS
(ESIꢀTOF) [M + H]+ m/z: Calcd for C18H18N3O 292.1450; Found 292.1451.
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Supporting Information:
Xꢀray crystal structure data for 4m. Copies of 1H NMR and 13C NMR spectra for all new compounds.
Acknowledgements: This work was supported by a grant from the National Institutes of Health Institute of General Medical Sciences
(2R01GM90082ꢀA1).
References:
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