An efficient procedure for the preparation of 4-substituted 5-aminoimidazoles

Article abstract of DOI:10.1021/jo026257s

The preparation of O-methylimidates from α-aminonitriles and their subsequent co-cyclization with primary amines to afford 4-substituted 5-aminoimidazoles was studied. It was found that the mildly acidic pyridinium p-toluenesulfonate efficiently catalyzed each stage of the reaction sequence: (a) the formation of the O-methylimidates, (b) their co-cyclization with a variety of primary amines, and (c) certain derivatizations of the resultant heterocycles. The developed reaction conditions tolerate a wide variety of α-aminonitriles and primary amine co-reactants. Thus, it is possible to easily prepare a diverse array of substituted heterocyclic compounds in good yield. The requisite α-aminonitriles were synthesized either from amino acids or by phase-transfer alkylation of a glycine anion equivalent. The unstable free 5-aminoimidazoles were normally protected in situ to provide derivatives (methyl imidates or N,N-dimethylamidines) that were amenable to characterization.

Full text of DOI:10.1021/jo026257s

Supporting Information
An Efficient Procedure for the Preparation of 4-
Substituted-5-aminoimidazoles
Mark McLaughlin,* Rafat M. Mohareb and Henry Rapoport
Department of Chemistry
University of California, Berkeley
mark_mcl@uclink.berkeley.edu
Contents: Experimental procedures and analytical data for the following compounds are presented – 9,
10, 11, 12, 13a, 13b, 14a, 14b, 15a, 15b, 17, 21, 22, 23, 24, 26, 27a-h, 28a-g, 29a-l, 30, 31a-f, 32a-j.
Experimental Section
General Methods. Diethyl ether and tetrahydrofuran were distilled from sodium/benzophenone
immediately before use. Dichloromethane, acetonitrile, N,N-dimethylformamide, pyridine, triethylamine
and benzylamine were distilled from calcium hydride before use. Methanol was distilled from
magnesium turnings. All reactions were performed under an atmosphere of nitrogen in standard
glassware unless otherwise noted. Following aqueous work-ups organic solutions were dried over
anhydrous magnesium sulfate before the solvent was removed under reduced pressure on a rotary
evaporator. Thin layer chromatography was conducted using aluminum-backed silica plates and column
chromatography was performed using silica gel (230-400 mesh). Melting points were obtained on an
S1

open capillary apparatus and are uncorrected. NMR spectra were recorded in CDCl3 (unless otherwise
noted) at 300 MHz for 1H NMR and 100 MHz for 13C NMR. Chemical shifts are reported relative to the
13
standard ppm value for the solvent used. DEPT experiments were used to assign C NMR spectra.
Elemental analyses were performed by the Analytical Laboratory, College of Chemistry, University of
California, Berkeley, CA.
Compounds 8a,1 8b,2 19,3, 4 20,5 and 266 were prepared according to literature procedures and
provided analytical data that were in agreement with those already published.
(S)-2-[(tert-Butoxycarbonyl)amino]-3-methanesulfonyloxypropionamide (9). A mixture of alcohol
8a (167 mg, 0.82 mmol) and triethylamine (0.17 mL, 1.23 mmol, 150 mol%) in CH2Cl2 (10 mL) was
cooled to 0 °C. To this mixture was added, dropwise, methanesulfonyl chloride (64 µL, 0.82 mmol, 100
mol%) and the mixture was then stirred for 15 min before it was diluted with EtOAc and filtered
through a pad of silica. The filtrate was carefully (water bath temperature < 20 °C) concentrated to
1
afford the mesylate as a white solid (208 mg, 90%): mp 111-115 °C; H NMR δ 1.46 (s, 9H), 3.06 (s,
3H), 4.35-4.40 (dd, 1H, J = 10.2, 4.4 Hz), 4.47-4.57 (br, 1H), 4.62-4.66 (dd, 1H, J = 10.2, 4.2 Hz), 5.50-
13
5.56 (br, 1H), 5.86-5.92 (br, 1H), 6.46-6.55 (br, 1H); C NMR δ 28.2 (CH3), 37.4 (CH3), 68.8 (CH),
73.8 (C), 93.5 (CH2), 155.4 (C), 171.0 (C). Anal. Calcd for C9H18N2O6S: C, 38.29; H, 6.43; N, 9.92.
Found: C, 38.46; H, 6.57; N, 9.80.
(S)-2-[(tert-Butoxycarbonyl)amino]-3-azidopropionamide (10). To a solution of mesylate 9 (17
mg, 60 µmol) in DMF (3 mL) was added sodium azide (8 mg, 0.12 mmol, 200 mol%) and the mixture
was stirred at room temperature for 24 h. After this time, the solvent was evaporated to leave a white
solid residue, which was extracted with CH2Cl2 (20 mL). The mixture was then filtered and the filtrate
was evaporated to afford the azide as a white solid (13 mg, 95%): mp 68-69 °C; 1H NMR δ 1.45 (s, 9H),
3.52-3.58 (dd, 1H, J = 12.3, 5.6 Hz), 3.81-3.87 (dd, 1H, J = 12.3, 4.7 Hz), 4.29-4.35 (br, 1H), 5.37-5.41
(d, 1H, J = 7.1 Hz), 5.85-5.94 (br, 1H) and 6.38-6.44 (br, 1H); 13C NMR δ 28.2 (CH3), 53.2 (CH), 53.6
(CH2), 80.8 (C), 155.5 (C) and 174.1 (C). Anal. Calcd for C8H15N5O3: C, 41.92; H, 6.60; N, 30.55.
Found: C, 42.31; H, 6.75; N, 30.19.
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General Procedure A. Dehydration of Amides to Nitriles. To a solution of the primary amide (100
mol%) and para-toluenesulfonyl chloride (200 mol%) in CH2Cl2 (0.4 M) was added pyridine (500
mol%). After complete reaction as judged by TLC sat. aq. NaHCO3 was carefully added. The resultant
two-phase mixture was stirred vigorously for 2 h before the layers were separated and the organic phase
was washed with 1 M aq. HCl and then another portion of sat. aq. NaHCO3. The aqueous phases were
back extracted with CH2Cl2 and the combined organic phase was dried, filtered and concentrated to
leave a crude product. This crude product was purified by column chromatography using an
EtOAc/hexanes gradient as the eluent.
(S)-2-[(tert-Butoxycarbonyl)amino]-3-azidopropanenitrile (11). Prepared according to General
Procedure A. Primary amide 10 (500 mg, 2.18 mmol) afforded the nitrile as a white solid (456 mg,
99%): mp 64-65 °C; 1H NMR δ 1.45 (s, 9H), 3.57-3.63 (dd, 1H, J = 12.5, 5.1 Hz), 3.69-3.75 (dd, 1H, J
13
= 12.5, 4.9 Hz), 4.70-4.82 (br, 1H) and 5.37-5.40 (br d, 1H, J = 8.7 Hz). C NMR δ 28.2 (CH3), 42.2
(CH2), 52.4 (CH), 81.9 (C), 116.8 (C) and 154.1 (C). Anal. Calcd for C8H13N5O2: C, 45.49; H, 6.20; N,
33.16. Found: C, 45.86; H, 6.46; N, 32.91.
General Procedure B. Deprotection of N-Boc α-Aminonitriles. Trifluoroacetic acid (1000 mol%)
was cooled to –15 °C and then the protected α-aminonitrile (100 mol%) was added neat. The mixture
was then stirred at –15 °C for 5 h. After this time, the mixture was transferred slowly using a cannula
into a mixture of conc. NH4OH/water cooled to –10 °C. The mixture was then extracted with CH2Cl2
and the combined organic phase was dried, filtered and concentrated to leave a crude oil. This oil was
purified by column chromatography using an EtOAc/hexanes gradient as the eluent.
(S)-2-Amino-3-azidopropanenitrile (12). Prepared according to General Procedure B. Protected
1
compound 11 (10.50 g, 49.7 mmol) afforded the α-aminonitrile as a colorless oil (2.32 g, 42%): H
13
NMR δ 1.68-1.80 (br, 2H), 3.53-3.67 (m, 2H), 3.84-3.87 (t, 1H, J = 5.4 Hz); C NMR δ 43.4 (CH2),
54.2 (CH), 120.1 (C). Anal. Calc. For C3H5N5: C, 32.43; H, 4.54; N, 63.03. Found: C, 32.63; H, 4.74; N,
62.80.
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(S)-2-[(tert-Butoxycarbonyl)amino]-3-[(tert-butyldimethylsilyl)oxy]propionamide (13a). To a
solution of serine amide 8a (1.07 g, 5.2 mmol) and imidazole (0.71 g, 10.4 mmol, 200 mol%) in CH2Cl2
(30 mL) was added a solution of TBSCl (0.79 g, 5.2 mmol, 100 mol%) in CH2Cl2 (20 mL) and then
DMAP (6 mg, 52.0 µmol, 1 mol%). The mixture was stirred for 48 h before it was quickly washed with
0.5 M aq. HCl (50 mL). The combined organic phase was then dried, filtered and concentrated to leave
a colorless oil, which was purified by column chromatography using 40% EtOAc/hexanes as the eluent.
Evaporation of the solvent afforded the silylated serine amide as a white solid (1.57 g, 94%): mp 82-84
°C; 1H NMR δ 0.09 (s, 6H), 0.86 (s, 9H), 1.42 (s, 9H), 3.60-3.65 (t, 1H, J = 9.8 Hz), 3.95-4.00 (dd, 1H,
J = 9.8, 4.0 Hz), 4.05-4.20 (br, 1H), 5.40-5.42 (d, 1H, J = 6.6 Hz), 6.12-6.28 (br, 1H), 6.46-6.58 (br,
1H); 13C NMR δ -5.6 (CH3), -5.5 (CH3), 18.2 (C), 25.8 (CH3), 28.3 (CH3), 55.2 (CH), 63.2 (CH2), 80.0
(C), 155.5 (C), 173.3 (C). Anal. Calc. For C14H30N2O4Si: C, 52.80; H, 9.49; N, 8.80. Found: C, 52.82;
H, 9.48; N, 8.81.
(2S,3R)-2-[(tert-Butoxycarbonyl)amino]-3-[(tert-butyldimethylsilyl)oxy]butyramide (13b). To a
solution of threonine amide 8b (3.36 g, 15.4 mmol) and imidazole (2.10 g, 30.8 mmol, 200 mol%) in
CH2Cl2 (60 mL) was added a solution of TBSCl (2.32 g, 15.4 mmol, 100 mol%) in CH2Cl2 (20 mL)
then DMAP (2 mg, 15 µmol, 1 mol%). The mixture was stirred for 48 h before it was quickly washed
with 0.5 M aq. HCl (70 mL). The combined organic phase was then dried, filtered and concentrated to
leave a colorless oil, which was purified by column chromatography using 40% EtOAc/hexanes as the
eluent. Evaporation of the solvent afforded the silylated threonine amide as a colorless oil (4.78 g,
1
96%): H NMR δ 0.07 (s, 3H), 0.09 (s, 3H), 0.89 (s, 9H), 1.15-1.17 (d, 3H, J = 6.3 Hz), 1.49 (s, 9H),
4.09-4.18 (br, 1H), 4.38-4.41 (m, 1H), 5.42-5.55 (br, 2H), 6.59-6.69 (br, 1H); 13C NMR δ -5.0 (CH3), -
4.7 (CH3), 17.6 (CH3), 18.6 (C), 25.8 (CH3), 28.3 (CH3), 59.1 (CH), 68.1 (CH), 79.9 (C), 155.7 (C),
172.6 (C). Anal. Calc. For C15H32N2O4Si: C, 54.18; H, 9.70; N, 8.42. Found: C, 54.21; H, 9.80; N, 8.15.
(S)-2-[(tert-Butoxycarbonyl)amino]-3-[(tert-butyldimethylsilyl)oxy]propanenitrile (14a).
Prepared according to General Procedure A. Primary amide 13a (1.01 g, 3.17 mmol) afforded the nitrile
1
as a colorless oil (0.91 g, 96%): H NMR δ 0.09 (s, 3H), 0.10 (s, 3H), 0.90 (s, 9H), 1.45 (s, 9H), 3.74-
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3.79 (dd, 1H, J = 10.3, 4.3 Hz), 3.84-3.88 (dd, 1H, J = 10.3, 3.4 Hz), 4.58-4.66 (br, 1H), 5.18-5.25 (br,
1H); 13C NMR δ -5.2 (CH3), -5.1 (CH3), 18.3 (C), 25.7 (CH3), 28.2 (CH3), 44.5 (CH), 63.3 (CH2), 81.2
(C), 117.8 (C), 154.4 (C). Anal. Calc. For C14H28N2O2Si: C, 55.96; H, 9.39; N, 9.32. Found: C, 55.91;
H, 9.14; N, 9.52.
(2S,3R)-2-[(tert-Butoxycarbonyl)amino]-3-[(tert-butyldimethylsilyl)oxy]butanenitrile
(14b).
Prepared according to General Procedure A. Primary amide 13b (1.15 g, 3.6 mmol) afforded the nitrile
as a colorless oil (1.02 g, 94%): 1H NMR δ 0.11 (s, 3H), 0.16 (s, 3H), 0.91 (s, 9H), 1.20-1.22 (d, 3H, J =
6.0 Hz), 1.47 (s, 9H), 4.11-4.18 (m, 1H), 4.46-4.53 (br, 1H), 4.97-5.06 (br, 1H); 13C NMR δ -4.9 (CH3),
-4.6 (CH3), 18.0 (C), 19.9 (CH3), 25.7 (CH3), 28.2 (CH3), 48.7 (CH), 68.5 (CH), 81.2 (C), 118.3 (C),
154.8 (C). Anal. Calc. For C15H30N2O3Si: C, 57.29; H, 9.61; N, 8.91. Found: C, 56.95; H, 9.70; N, 8.64.
(S)-2-Amino-3-[(tert-butyldimethylsilyl)oxy]propanenitrile (15a). Prepared according to General
Procedure B. Protected compound 14a (9.75 g, 32.4 mmol) afforded the α-aminonitrile as a colorless oil
(2.86 g, 44%): 1H NMR δ 0.10 (s, 3H), 0.12 (s, 3H), 0.92 (s, 9H), 1.71-1.84 (br, 2H), 3.76-3.86 (m, 3H);
13C NMR δ -5.5 (CH3), 18.3 (C), 25.8 (CH3), 45.6 (CH), 64.8 (CH2), 120.8 (C). Anal. Calc. For
C9H20N2OSi: C, 53.95; H, 10.06; N, 13.98. Found: C, 53.78; H, 10.21; N, 13.72.
(2S,3R)-2-Amino-3-[(tert-butyldimethylsilyl)oxy]-butanenitrile (15b).7 Prepared according to
General Procedure B. Protected compound 14b (10.00 g, 31.8 mmol) afforded the α-aminonitrile as a
colorless oil (3.51 g, 51%): 1H NMR δ 0.11 (s, 3H), 0.13 (s, 3H), 0.90 (s, 9H), 1.26-1.28 (d, 3H, J = 6.3
Hz), 1.54-1.66 (br, 2H), 3.51-3.64 (br, 1H), 3.98-4.06 (m, 1H); 13C NMR δ -4.9 (CH3), -4.5 (CH3), 17.9
(C), 19.6 (CH3), 25.7 (CH3), 50.2 (CH), 69.4 (CH), 121.0 (C). Anal. Calc. For C10H22N2OSi: C, 56.03;
H, 10.34; N, 13.07. Found: C, 55.66; H, 10.52; N, 12.99.
(S)-2-Amino-3-phenylpropanenitrile (17).8 Prepared according to General Procedures A and B from
the known9 (S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionamide. The desired α-aminonitrile was
1
obtained as a white solid (8.55 g, 72% from the amide): mp 60-61 °C; H NMR δ 1.57-1.66 (br, 2H),
3.03-3.05 (d, 2H, J = 6.3 Hz), 3.93-3.97 (t, 1H, J = 6.3 Hz), 7.26-7.60 (m, 5H); 13C NMR δ 41.1 (CH2),
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44.7 (CH), 121.6 (C), 127.7 (CH), 128.9 (CH), 129.6 (CH), 134.9 (C). Anal. Calc. For C9H10N2: C,
73.94; H, 6.89; N, 19.16. Found: C, 73.71; H, 6.86; N, 19.12.
(S)-Methyl 2-[(tert-butoxycarbonyl)amino]-4-azido-butanoate (21). Acetyl chloride (35.0 mL,
0.49 mol, 1000 mol%) was added dropwise to anhydrous MeOH (260 mL) at 0 °C. Upon completion of
the addition, the mixture was allowed to warm to room temperature and was stirred for 30 min before
the carboxylic acid 20 (12.95 g, 49.2 mmol) was added as a solid. The mixture was then stirred for a
further 24 h before the solvent was evaporated to afford the methyl ester as an off-white solid (12.8 g,
94%). Analytical data were in agreement with those previously published:10 mp 128-130 ºC; 1H NMR δ
(CD3OD) 2.30-2.39 (m, 1H), 2.41-2.57 (m, 1H), 3.58-3.63 (t, 2H, J = 6.8 Hz), 3.85 (s, 3H), 4.20-4.24 (t,
1H, J = 6.4 Hz), 4.86-4.91 (br, 3H).
A mixture of the methyl ester prepared above (11.70 g, 42.2 mmol), di-tert-butyl dicarbonate (9.68 g,
44.4 mmol, 105 mol%) and 1,4-dioxane (80 mL) was cooled to 0 °C. To this mixture was added,
dropwise, a solution of NaHCO3 (14.20 g, 0.169 mol, 400 mol%) in water (80 mL) (slow addition of the
base minimized formation of an azetidine side-product) and the mixture was stirred at 0 °C for a further
16 h. After this time, the mixture was diluted with water (200 mL) then extracted with CH2Cl2 (3 × 200
mL). The combined organic phase was dried, filtered and concentrated to leave a crude brown oil. This
oil was purified by column chromatography using a 10-30% EtOAc/hexanes gradient as the eluent.
Evaporation of the solvent afforded the N-protected compound as a colorless oil (12.30 g, 98%).
Analytical data were in agreement with those previously published:11 1H NMR δ 1.43 (s, 9H), 2.08-2.25
(m, 1H), 2.36-2.43 (m, 1H), 3.40-3.44 (t, 1H, J = 7.2 Hz), 3.69 (s, 3H), 4.45-4.56 (br, 1H), 5.07-5.18
(br, 1H).
To a solution of the N-protected compound prepared above (5.90 g, 19.9 mmol) in acetone (200 mL)
was added sodium iodide (5.97 g, 39.8 mmol, 200 mol%) and the mixture was heated under reflux for 2
h. After this time, the mixture was filtered and then concentrated to leave a crude yellow oil. This oil
was purified by column chromatography using 10% EtOAc/hexanes as the eluent. Evaporation of the
solvent afforded the iodide as a pale yellow oil (6.15 g, 90%). Analytical data were in agreement with
S6

those previously published:11 1H NMR δ 1.43 (s, 9H), 2.08-2.21 (m, 1H), 2.29-2.47 (m, 1H), 3.13-3.18
(t, 1H, J = 7.8 Hz), 3.74 (s, 3H), 4.28-4.37 (br, 1H), 5.09-5.15 (br, 1H).
A mixture of the iodide (6.10 g, 17.8 mmol), sodium azide (2.00 g, 30.8 mmol, 170 mol%) in
anhydrous DMF (100 mL) was heated at 90 °C for 2 h. After this time, the solvent was evaporated to
leave a yellow, semi-solid residue, which was partitioned between brine (100 mL) and EtOAc (3 × 100
mL). The combined organic phase was dried, filtered and then concentrated to leave a crude yellow oil.
This oil was purified by column chromatography using 10% EtOAc/hexanes as the eluent. Evaporation
of the solvent afforded the azide as a colorless oil (4.45 g, 97%): 1H NMR δ 1.44 (s, 9H), 1.86-1.98 (m,
1H), 2.04-2.16 (m, 1H), 3.38-3.43 (t, 2H, J = 6.9 Hz), 3.77 (s, 3H), 4.36-4.46 (m, 1H) and 5.11-5.23 (m,
1H); 13C NMR δ 28.2 (CH3), 31.8 (CH2), 47.7 (CH), 51.2 (CH2), 52.6 (CH3), 80.2 (C), 155.3 (C), 172.5
(C). Anal. Calc. For C10H18N4O4: C, 46.50; H, 7.03; N, 21.69. Found: C, 46.39; H, 7.07; N, 21.84.
(S)-2-[(tert-Butoxycarbonyl)amino]-4-azido-butyramide (22). In a glass pressure tube, a solution of
methyl ester 21 (193 mg, 0.75 mmol) in anhydrous MeOH (10 mL) was cooled to 0 °C and then
saturated with ammonia gas. The tube was then sealed and the stirred mixture was heated at 50 °C for
24 h. After this time, the solvent was evaporated to afford the primary amide as a white solid requiring
no further purification (182 mg, 99%): mp 95-96 °C; 1H NMR δ 1.46 (s, 9H), 1.91-2.05 (m, 1H), 2.11-
2.18 (m, 1H), 3.43-3.48 (t, 2H, J = 6.6 Hz), 4.37-4.46 (m, 1H), 5.22-5.24 (d, 1H, J = 7.5 Hz) and 5.30-
13
5.80 (br, 2H); C NMR δ 28.3 (CH3), 31.7 (CH2), 48.1 (CH), 51.7 (CH2), 80.4 (C), 155.8 (C), 174.3
(C). Anal. Calc. For C9H17N5O3: C, 44.43; H, 7.04; N, 28.79. Found: C, 44.30; H, 7.05; N, 29.00.
(S)-2-[(tert-Butoxycarbonyl)amino]-4-azido-butanenitrile (23). Prepared according to General
Procedure A. Primary amide 22 (19.6 g, 80.6 mmol) afforded the nitrile as a white solid (18.0 g, 99%):
1
mp 74-75 °C; H NMR δ 1.47 (s, 9H), 1.98-2.13 (dt, 2H, J = 12.7, 6.4 Hz), 3.52-3.74 (dt, 2H, J = 1.9,
6.4 Hz), 4.69-4.76 (br, 1H) and 5.07-5.16 (br, 1H); 13C NMR δ 28.2 (CH3), 32.2 (CH2), 40.2 (CH), 47.3
(CH2), 81.4 (C), 118.2 (C), 154.4 (C). Anal. Calc. For C9H15N5O2: C, 47.99; H, 6.71; N, 31.09. Found:
C, 48.00; H, 6.73; N, 31.37.
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(S)-2-Amino-4-azido-butanenitrile (24). Prepared according to General Procedure B. Protected
compound 23 (4.00 g, 17.8 mmol) afforded the α-aminonitrile as a colorless oil (1.64 g, 74%): 1H NMR
δ 1.58-1.69 (br, 2H), 1.89-2.07 (m, 2H), 3.49-3.68 (m, 2H), 3.79-3.88 (br, 1H); 13C NMR δ 34.3 (CH2),
40.7 (CH), 47.3 (CH2), 121.6 (C). Anal. Calc. For C4H7N5: C, 38.39; H, 5.64; N, 55.97. Found: C,
38.44; H, 6.00; N, 55.61.
General Procedure C. Phase-transfer Alkylation of 2-[(Diphenylmethylene)amino]acetonitrile
26. To a solution of 2-[(diphenylmethylene)amino]acetonitrile 26 (100 mol%) in CH2Cl2 (0.6 M) was
added the alkyl halide (105 mol%), 11 M aq. NaOH (1800 mol%) and then benzyltriethylammonium
chloride (10 mol%). The resultant two-phase mixture was stirred vigorously until complete reaction as
judged by TLC. The mixture was then diluted with water and extracted with CH2Cl2. The organic phase
was dried, filtered and concentrated to leave a crude product, which was purified by column
chromatography using an EtOAc/hexanes gradient containing 1% Et3N.
2-[(Diphenylmethylene)amino]-3-(4-methoxyphenyl)propanenitrile (27a). Starting with 2-
[(diphenylmethylene)amino]acetonitrile 26 (6.84 g, 31.0 mmol) the alkylated product was obtained as a
1
yellow oil (8.70 g, 82%): H NMR δ 3.13-3.28 (m, 2H), 3.81 (s, 3H), 4.36-4.41 (t, 1H, J = 7.2 Hz),
6.80-6.83 (d, 2H, J = 8.7 Hz), 6.87-6.90 (m, 2H), 7.03-7.06 (d, 2H, J = 8.7 Hz), 7.38-7.48 (m, 6H), 7.63-
13
7.67 (d, 2H, J = 8.1 Hz); C NMR δ 40.3 (CH2), 55.2 (CH), 55.3 (CH3), 113.9 (CH), 119.4 (C), 127.3
(CH), 127.6 (C), 128.3 (CH), 128.8 (CH), 129.0 (CH), 130.8 (CH), 131.2 (CH), 135.1 (C), 138.4 (C),
158.8 (C), 173.2 (C). Anal. Calc. For C23H20N2O: C, 81.15; H, 5.92; N, 8.23. Found: C, 80.99, H, 5.99;
N, 8.19.
2-[(Diphenylmethylene)amino]-3-(4-nitrophenyl)propanenitrile (27b). Starting with 2-
[(diphenylmethylene)amino]acetonitrile 26 (6.84 g, 31.0 mmol) the alkylated product was obtained as a
yellow oil (10.26 g, 93%): 1H NMR δ 3.32-3.35 (d, 2H, J = 9.0 Hz), 4.44-4.49 (t, 1H, J = 9.0 Hz), 6.92-
6.94 (d, 2H, J = 6.0 Hz), 7.31-7.38 (m, 4H), 7.45-7.50 (m, 4H), 7.59-7.62 (d, 2H, J = 9.0 Hz), 8.14-8.17
(d, 2H, J = 9.0 Hz); 13C NMR δ 40.7 (CH2), 53.9 (CH), 118.6 (C), 123.7 (CH), 127.1 (CH), 128.4 (CH),
129.0 (CH), 129.1 (CH), 129.6 (CH), 130.7 (CH), 131.6 (CH), 134.8 (C), 137.9 (C), 143.1 (C), 146.9
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(C), 174.0 (C). Anal. Calc. For C22H17N3O2: C, 74.35; H, 4.82; N, 11.82. Found: C, 74.22, H, 5.04; N,
11.70.
2-[(Diphenylmethylene)amino]octanenitrile
(27c).
Starting
with
2-
[(diphenylmethylene)amino]acetonitrile 26 (6.84 g, 31.0 mmol) the alkylated product was obtained as a
1
yellow oil (8.29 g, 88%): H NMR δ 0.91−0.96 (t, 3H, J = 7.2 Hz), 1.31-1.35 (m, 6H), 1.48 (m, 2H),
1.99-2.03 (m, 2H, J = 7.2 Hz), 4.26-4.31 (t, 1H, J = 6.6 Hz), 7.27-7.30 (m, 2H), 7.43-7.48 (m, 2H),
7.54-7.73 (m, 4H), 7.87-7.90 (d, 2H, J = 8.1 Hz); 13C NMR δ 14.0 (CH3), 22.5 (CH2), 25.5 (CH2), 28.6
(CH2), 31.5 (CH2), 34.9 (CH2), 53.1 (CH), 119.8 (C), 127.4 (CH), 128.2 (CH), 129.0 (CH), 130.1 (CH),
131.1 (CH), 132.4 (CH), 135.3 (C), 137.6 (C), 173.6 (C). Anal. Calc. For C21H24N2: C, 82.85; H, 7.95;
N, 9.20. Found: C, 83.18, H, 7.59; N, 8.84.
2-[(Diphenylmethylene)amino]-3-methylbutanenitrile
(27d).12
Starting
with
2-
[(diphenylmethylene)amino]acetonitrile 26 (6.84 g, 31.0 mmol) the alkylated product was obtained as a
yellow oil (6.78 g, 83%): 1H NMR δ 1.01-1.03 (d, 3H, J = 6.9 Hz), 1.13-1.14 (d, 3H, J = 6.6 Hz), 2.12-
2.19 (m, 1H), 3.98-4.00 (d, 1H, J = 6.3 Hz), 7.21-7.25 (m, 2H), 7.27-7.32 (m, 2H), 7.33-7.55 (m, 4H),
13
7.63-7.66 (d, 2H, J = 8.1 Hz); C NMR δ 18.6 (CH3), 19.0 (CH3), 33.6 (CH) 59.5 (CH), 119.0 (C),
127.3, 128.3, 129.0, 129.7, 131.1 (CH), 132.5 (CH), 135.4 (C), 137.6 (C), 173.0 (C). Anal. Calc. For
C18H18N2: C, 82.41; H, 6.92; N, 10.68. Found: C, 82.53; H, 6.89; N, 10.48.
Ethyl
4-cyano-4-[(diphenylmethylene)amino]butanoate
(27e).
Starting
with
2-
[(diphenylmethylene)amino]acetonitrile 26 (13.68 g, 62.1 mmol) the alkylated product was obtained as
a yellow oil (19.68 g, 99%): 1H NMR δ 1.23-1.28 (t, 3H, J = 7.2 Hz), 2.20-2.30 (m, 2H), 2.41-2.64 (m,
2H), 4.00-4.08 (q, 2H, J = 7.2 Hz), 4.32-4.36 (t, 1H, J = 6.3 Hz), 7.20-7.22 (m, 2H), 7.29-7.36 (m, 2H),
7.38-7.54 (m, 4H), 7.59-7.69 (m, 2H); 13C NMR δ 14.1 (CH3), 29.9 (CH2), 30.0 (CH2), 51.9 (CH), 60.7
(CH2), 119.4 (C), 127.3 (CH), 128.2 (CH), 129.1 (CH), 129.5 (CH), 130.1 (CH), 131.3 (CH), 135.1 (C),
138.3 (C), 172.1 (C), 178.0 (C). Anal. Calc. For C20H20N2O2: C, 74.98; H, 6.29; N, 8.74. Found: C,
74.67, H, 6.50; N, 8.36.
S9

Ethyl
5-cyano-5-[(diphenylmethylene)amino]pentanoate
(27f).
Starting
with
2-
[(diphenylmethylene)amino]acetonitrile 26 (13.68 g, 62.1 mmol) the alkylated product was obtained as
a yellow oil (19.64 g, 95%): 1H NMR δ 1.22-1.27 (t, 3H, J = 7.2 Hz), 1.71-1.81 (m, 2H), 1.87-2.03 (m,
2H), 2.28-2.33 (t, 2H, J = 7.2 Hz), 4.08-4.15 (q, 2H, J = 7.2 Hz), 4.21-4.25 (t, 1H, J = 7.2 Hz), 7.20-
13
7.23 (m, 2H), 7.33-7.38 (m, 2H), 7.42-7.54 (m, 4H), 7.63-7.66 (d, 2H, J = 7.2 Hz); C NMR δ 14.2
(CH3), 21.0 (CH2), 33.5 (CH2), 34.2 (CH2), 52.7 (CH), 60.5 (CH2), 119.4 (C), 127.4 (CH), 128.3 (CH),
128.9 (CH), 129.1 (CH), 129.4 (CH), 131.2 (CH), 135.2 (C), 138.4 (C), 172.9 (C), 173.2 (C). Anal.
Calc. For C21H22N2O2: C, 75.42; H, 6.63; N, 8.38. Found: C, 75.65, H, 6.89; N, 8.35.
2-[(Diphenylmethylene)amino]-5-chloropentanenitrile
(27g).
Starting
with
2-
[(diphenylmethylene)amino]acetonitrile 26 (0.684 g, 3.1 mmol) the alkylated product was obtained as a
yellow oil (0.843 g, 92%): 1H NMR δ 1.89-2.14 (m, 4H), 3.53-3.59 (t, 2H, J = 6.6 Hz), 4.26-4.30 (t, 1H,
J = 6.0 Hz), 7.20-7.23 (m, 2H), 7.33-7.39 (m, 2H), 7.41-7.57 (m, 4H) and 7.63-7.66 (m, 2H); 13C NMR
δ 28.5 (CH2), 32.2 (CH2), 44.2 (CH2), 52.4 (CH), 119.3 (C), 127.4 (CH), 128.3 (CH), 129.1 (CH), 129.2
(CH), 129.5 (CH), 131.4 (CH), 135.1 (C), 138.3 (C), 173.4 (C). Anal. Calc. For C18H17N2Cl: C, 72.84;
H, 5.77; N, 9.44. Found: C, 72.85, H, 5.91; N, 9.20.
2-[(Diphenylmethylene)amino]-5-azidopentanenitrile (27h). To a solution of alkyl chloride 63 (650
mg, 2.19 mmol) in anhydrous DMF (10 mL) was added sodium azide (285 mg, 4.38 mmol, 200 mol%)
and the mixture was then heated at 80 °C for 24 h. After this time, the solvent was evaporated to leave a
yellow, semi-solid residue. This residue was partitioned between Et2O (40 mL) and water (10 mL). The
separated organic phase was then washed with more water (10 mL), then brine (10 mL) before it was
dried, filtered and concentrated to leave a yellow oil. This oil was purified by column chromatography
using 10%EtOAc/hexanes containing 1% Et3N as the eluent. Evaporation of the solvent afforded the
azide as a yellow oil (635 mg, 95%): 1H NMR δ 1.69-1.83 (m, 2H), 1.93-2.09 (m, 2H), 3.30-3.34 (t, 2H,
J = 6.7 Hz), 4.26-4.30 (t, 1H, J = 6.4 Hz), 7.20-7.23 (m, 2H), 7.33-7.39 (m, 2H), 7.41-7.55 (m, 4H) and
13
7.63-7.66 (m, 2H); C NMR δ 28.5 (CH2), 32.2 (CH2), 44.2 (CH2), 52.4 (CH), 119.3 (C), 127.4 (CH),
S10

128.3 (CH), 129.1 (CH), 129.2 (CH), 129.5 (CH), 131.4 (CH), 135.1 (C), 138.3 (C), 173.4 (C). Anal.
Calc. For C18H17N5: C, 71.27; H, 5.65; N, 23.09. Found: C, 71.35, H, 5.79; N, 22.99.
General Procedure D. Hydrolysis of Alkylated Benzophenone Imines. To a solution of the imine
(100 mol%) in THF (0.25 M) was added 1 M aq. HCl (105 mol%) over a 1 h period using a syringe
pump. After complete reaction as judged by TLC, sat. aq. NaHCO3 was added and then the THF was
evaporated. The residue was partitioned between dil. aq. NH4OH and CH2Cl2. The organic phase was
dried, filtered and concentrated to leave a crude product, which was purified by column chromatography
using an EtOAc/hexanes gradient containing 1% Et3N as the eluent. Evaporation of the solvent afforded
the α-aminonitriles.
2-Amino-3-(4-methoxyphenyl)propanenitrile (28a). Imine 27a (8.70 g, 25.6 mmol) afforded the α-
aminonitrile as a colorless oil (3.91 g, 87%): 1H NMR δ 1.53-1.62 (br, 2H), 2.96-2.99 (dd, 2H, J = 6.0,
2.1 Hz), 3.80 (s, 3H), 3.83-3.94 (br, 1H), 6.88-6.91 (d, 2H, J = 8.7 Hz), 7.20-7.23 (d, 2H, J = 8.7 Hz);
13C NMR δ 40.2 (CH2), 44.8 (CH), 55.3 (CH3), 114.2 (CH), 121.7 (C), 126.8 (C), 130.7 (CH), 159.1
(C). Anal. Calc. For C10H12N2O: C, 68.16; H, 6.86; N, 15.90. Found: C, 67.94, H, 6.94; N, 15.86.
2-Amino-3-(4-nitrophenyl)propanenitrile (28b). Imine 27b (8.00 g, 22.5 mmol) afforded the α-
1
aminonitrile as a yellow solid (3.84 g, 89%): mp 81-82 °C; H NMR δ 1.66-1.69 (d, 2H, J = 7.5 Hz),
3.13-3.16 (dd, 2H, J = 6.3, 1.5 Hz), 3.94-4.04 (m, 1H), 7.48-7.51 (d, 2H, J = 8.7 Hz), 8.22-8.25 (d, 2H, J
= 8.7 Hz); 13C NMR δ 40.9 (CH2), 44.2 (CH), 120.9 (C), 124.0 (CH), 130.6 (CH), 142.4 (C), 147.5 (C).
Anal. Calc. For C9H9N3O2: C, 56.54; H, 4.74; N, 21.98. Found: C, 56.50, H, 4.75; N, 22.07.
2-Aminooctanenitrile (28c).29 Imine 27c (6.85 g, 22.5 mmol) afforded the α-aminonitrile as a
1
colorless oil (2.97 g, 94%): H NMR δ 0.87-0.91 (t, 3H, J = 6.6 Hz), 1.24-1.42 (m, 6H), 1.43-1.55 (m,
2H), 1.56-1.67 (m, 2H), 1.70-1.78 (m, 2H), 3.61-3.72 (br, 1H); 13C NMR δ 13.9 (CH3), 22.4 (CH2), 25.3
(CH2), 28.6 (CH2), 31.5 (CH2), 35.2 (CH2), 43.3 (CH), 122.4 (C). Anal. Calc. For C8H16N2: C, 68.52; H,
11.50; N, 19.98. Found: C, 68.28, H, 11.18; N, 19.62.
S11

2-Amino-3-methylbutanenitrile (28d). Imine 27d (6.35 g, 24.2 mmol) afforded the α-aminonitrile
as a colorless oil (2.18 g, 92%): 1H NMR δ 1.06-1.07 (d, 3H, J = 2.7 Hz), 1.09-1.10 (d, 3H, J = 2.7 Hz),
13
1.76-1.86 (br, 2H), 1.87-2.02 (m, 1H), 3.53-3.55 (d, 1H, J = 5.7 Hz); C NMR δ 17.5 (CH3), 18.8
(CH3), 32.8 (CH), 49.7 (CH), 121.3 (C). Anal. Calc. For C5H10N2: C, 61.19; H, 10.27; N, 28.54. Found:
C, 61.35, H, 10.07; N, 28.32.
Ethyl 4-amino-4-cyanobutanoate (28e). Imine 27e (19.90 g, 62.1 mmol) afforded the α-aminonitrile
as a colorless oil (7.50 g, 77%): 1H NMR δ 1.24-1.29 (t, 3H, J = 7.2 Hz), 1.69-1.80 (br, 2H), 2.03-2.10
(q, 2H, J = 7.1 Hz), 2.51-2.58 (m, 2H), 3.80-3.84 (t, 1H, J = 7.1 Hz), 4.11-4.18 (q, 2H, J = 7.2 Hz); 13C
NMR δ 14.1 (CH3), 29.9 (CH2), 30.2 (CH2), 42.5 (CH), 60.8 (CH2), 121.8 (C), 172.3 (C). Anal. Calc.
For C7H12N2O2: C, 53.83; H, 7.74; N, 17.94. Found: C, 53.77, H, 7.75; N, 17.65.
Ethyl 5-amino-5-cyanopentanoate (28f). Imine 27f (8.40 g, 25.1 mmol) afforded the α-aminonitrile
as a colorless oil (3.33 g, 78%): 1H NMR δ 1.23-1.28 (t, 3H, J = 6.9 Hz), 1.81-1.84 (m, 4H), 2.25-2.31
13
(br, 2H), 2.34-2.40 (m, 2H), 3.74-3.78 (t, 1H, J = 6.6 Hz), 4.10-4.17 (q, 2H, J = 6.9 Hz); C NMR δ
14.2 (CH3), 20.8 (CH2), 33.4 (CH2), 34.6 (CH2), 43.1 (CH), 60.5 (CH2), 122.0 (C), 172.8 (C). Anal.
Calc. For C8H14N2O2: C, 56.45; H, 8.29; N, 16.46. Found: C, 56.49, H, 8.24; N, 16.25.
2-Amino-5-azidopentanenitrile (28g). Imine 27h (245 mg, 0.81 mmol) afforded the α-aminonitrile
as a colorless oil (90 mg, 80%): 1H NMR δ 1.52-1.69 (br, 2H), 1.74-1.89 (m, 4H), 3.36-3.40 (t, 2H, J =
13
6.3 Hz), 3.64-3.77 (br, 1H); C NMR δ 25.0 (CH2), 32.5 (CH2), 42.9 (CH), 50.6 (CH2), 122.0 (C).
Anal. Calc. For C5H9N5: C, 43.15; H, 6.52; N, 50.33. Found: C, 43.64, H, 6.76; N, 49.94.
General Procedure E. Conversion α-Aminonitriles to Methyl Imidates. To a solution of the α-
aminonitrile (100 mol%) in trimethylorthoformate (0.1 M) was added PPTS (0.2 mol%) and the mixture
was heated at 65 °C for 1 h. The mixture was then concentrated to afford microanalytically pure methyl
imidate, normally as a colorless oil, in near quantitative yield.
2-[(Methoxymethylene)amino]-3-phenylpropanenitrile (29a). α-Aminonitrile 17 (292 mg, 2.00
mmol) gave the imidate as a colorless oil (374 mg, 99%): 1H NMR δ 3.10-3.12 (d, 2H, J = 6.6 Hz), 3.74
S12

13
(s, 3H), 4.41-4.46 (t, 1H, J = 6.6 Hz), 7.21-7.36 (m, 5H), 7.54 (s, 1H); C NMR δ 41.5 (CH2), 53.5
(CH), 54.0 (CH3), 118.7 (C), 127.5 (C), 128.6 (CH), 129.8 (CH), 135.2 (CH), 158.7 (CH). Anal. Calc.
For C11H12N2O: C, 70.19; H, 6.43; N, 14.88. Found: C, 70.21; H, 6.10; N, 15.04.
2-[(Methoxymethylene)amino]-3-azidopropanenitrile (29b). α-Aminonitrile 12 (222 mg, 2.00
1
mmol) gave the imidate as a colorless oil (306 mg, 99%): H NMR δ 3.57-3.59 (d, 2H, J = 5.7 Hz),
3.79 (s, 3H), 4.42-4.46 (dt, 1H, J = 5.7, 0.9 Hz), 7.85 (s, 1H). This compound was too unstable for
further characterization and was used directly in the attempted preparation of the imidazole.
2-[(Methoxymethylene)amino]-3-[(tert-butyldimethylsilyl)oxy]propanenitrile
(29c).
α-
1
Aminonitrile 15a (401 mg, 2.00 mmol) gave the imidate as a colorless oil (484 mg, 99%): H NMR
δ 0.08 (s, 6H), 0.89 (s, 9H), 3.74 (s, 3H), 3.81-3.83 (d, 2H, J = 6.0 Hz), 4.31-4.34 (t, 1H, J = 6.0 Hz),
7.76 (s, 1H); 13C NMR δ -5.4 (CH3), -5.3 (C), 18.2 (C), 25.7 (CH3), 53.9 (CH3), 54.2 (CH), 64.4 (CH2),
117.9 (C), 159.5 (CH). Anal. Calc. For C11H22N2O2Si: C, 54.51; H, 9.15; N, 11.56. Found: C, 54.28; H,
9.11; N, 11.64.
2-[(Methoxymethylene)amino]-3-[(tert-butyldimethylsilyl)oxy]butanenitrile
(29d).
α-
1
Aminonitrile 15b (429 mg, 2.00 mmol) gave the imidate as a colorless oil (513 mg, 99%): H NMR δ
0.06 (s, 3H), 0.08 (s, 3H), 0.88 (s, 9H), 1.28-1.30 (d, 3H, J = 6.3 Hz), 3.74 (s, 3H), 3.95-4.03 (m, 1H),
13
4.13-4.15 (dd, 1H, J = 6.0, 0.6 Hz), 7.70 (s, 1H); C NMR δ –4.9 (CH3), -4.6 (CH3), 17.9 (C), 19.7
(CH3), 25.6 (CH3), 53.9 (C), 59.5 (CH), 69.3 (CH), 117.8 (C), 159.2 (CH). Anal. Calc. For
C12H24N2O2Si: C, 56.21; H, 9.43; N, 10.92. Found: C, 55.94; H, 9.23; N, 11.09.
2-[(Methoxymethylene)amino]-4-azidobutanenitrile (29e). α-Aminonitrile 24 (250 mg, 2.00 mmol)
1
gave the imidate as a colorless oil (333 mg, 99%): H NMR δ 1.98-2.16 (m, 2H), 3.42-3.54 (m, 2H),
3.76 (s, 3H), 4.39-4.43 (t, 1H, J = 6.6 Hz), 7.80 (s, 1H); 13C NMR δ 34.4 (CH2), 47.0 (CH2), 48.6 (CH),
54.8 (CH3), 118.5 (C), 159.2 (CH). Anal. Calc. For C6H9N5O: C, 43.11; H, 5.43; N, 41.89. Found: C,
42.89; H, 5.61; N, 41.79.
S13

2-[(Methoxymethylene)amino]-3-(4-methoxyphenyl)propanenitrile (29f). α-Aminonitrile 28a
(352 mg, 2.00 mmol) gave the imidate as a colorless oil (432 mg, 99%): 1H NMR δ 3.04-3.06 (d, 2H, J
= 6.9 Hz), 3.75 (s, 3H), 3.78 (s, 3H), 4.37-4.41 (t, 1H, J = 6.9 Hz), 6.84-6.87 (d, 2H, J = 8.7 Hz), 7.13-
7.16 (d, 2H, J = 8.7 Hz), 7.53 (s, 1H); 13C NMR δ 40.6 (CH2), 53.7 (CH), 54.0 (CH3), 55.2 (CH3), 114.0
(CH), 118.8 (C), 127.2 (C), 130.8 (CH),158.7 (C), 158.9 (CH). Anal. Calc. For C12H14N2O2: C, 66.04;
H, 6.47; N, 12.84. Found: C, 66.29; H, 6.55; N, 13.10.
2-[(Methoxymethylene)amino]-3-(4-nitrophenyl)propanenitrile (29g). α-Aminonitrile 28b (382
mg, 2.00 mmol) gave the imidate as a colorless oil (466 mg, 99%): 1H NMR δ 3.21-3.23 (d, 2H, J = 6.6
Hz), 3.73 (s, 3H), 4.51-4.55 (t, 1H, J = 6.6 Hz), 7.41-7.44 (d, 2H, J = 8.7 Hz), 7.61 (s, 1H), 8.17-8.19 (d,
13
2H, J = 8.7 Hz); C NMR δ 41.0 (CH2), 52.4 (CH), 54.2 (CH3), 117.9 (C), 123.7 (CH), 130.8 (CH),
142.7 (C), 147.4 (C), 159.1 (CH). Anal. Calc. For C11H11N3O3: C, 56.65; H, 4.75; N, 18.02. Found: C,
56.70; H, 5.03; N, 17.83.
2-[(Methoxymethylene)amino]octanenitrile (29h). α-Aminonitrile 28c (280 mg, 2.00 mmol) gave
1
the imidate as a colorless oil (364 mg, 99%): H NMR δ 0.86-0.91 (t, 3H, J = 6.6 Hz), 1.23-1.49 (m,
8H), 1.77-1.84 (m, 2H), 3.75 (s, 3H), 4.21-4.26 (t, 1H, J = 6.9 Hz), 7.76 (s, 1H); 13C NMR δ 14.0 (CH3),
22.5 (CH2), 25.3 (CH2), 28.6 (CH2), 31.5 (CH2), 35.4 (CH2), 51.8 (CH), 53.9 (CH3), 119.2 (C), 158.2
(CH). Anal. Calc. For C10H18N2O: C, 65.90; H, 9.95; N,15.37. Found: C, 66.04; H, 9.84; N,15.42.
2-[(Methoxymethylene)amino]-3-methylbutanenitrile (29i). α-Aminonitrile 28d (196 mg, 2.00
1
mmol) gave the imidate as a colorless oil (214 mg, 76%): H NMR δ 1.02-1.04 (d, 3H, J = 3.9 Hz),
1.05-1.06 (d, 3H, J = 3.9 Hz), 1.97-2.12 (m, 1H), 3.75 (s, 3H), 4.07-4.10 (d, 1H, J = 5.7 Hz), 7.74 (s,
1H). This compound was too volatile/unstable for further characterization.
Ethyl 4-cyano-4-[(methoxymethylene)amino]butanoate (29j). α-Aminonitrile 28e (312 mg, 2.00
mmol) gave the imidate as a colorless oil (395 mg, 99%): 1H NMR δ 1.24-1.29 (t, 3H, J = 7.2 Hz), 2.05-
2.22 (m, 2H), 2.48-2.53 (t, 2H, J = 7.1 Hz), 3.74 (s, 3H), 4.11-4.17 (q, 2H, J = 7.2 Hz), 4.38-4.43 (t, 1H,
13
J = 7.1 Hz), 8.07 (s, 1H); C NMR δ 14.1 (CH3), 29.6 (CH2), 30.4 (CH2), 50.5 (CH), 53.9 (C), 60.7
S14

(CH2), 118.6 (C), 158.8 (CH), 172.2 (C). Anal. Calc. For C9H14N2O3: C, 54.53; H, 7.12; N, 14.13.
Found: C, 54.59; H, 6.99; N, 14.41.
Ethyl 5-cyano-5-[(methoxymethylene)amino]pentanoate (29k). α-Aminonitrile 28f (340 mg, 2.00
mmol) gave the imidate as a colorless oil (424 mg, 99%): 1H NMR δ 1.23-1.28 (t, 3H, J = 7.2 Hz), 1.73-
1.90 (m, 4H), 2.35-2.39 (t, 2H, J = 6.9 Hz), 3.74 (s, 3H), 4.10-4.17 (q, 2H, J = 7.2 Hz), 4.25-4.29 (t, 1H,
J = 6.3 Hz), 7.77 (s, 1H); 13C NMR δ 14.2 (CH3), 20.7 (CH2), 33.4 (CH2), 34.6 (CH2), 51.3 (CH), 53.9
(CH3), 60.4 (CH2), 118.8 (C), 158.5 (CH), 172.8 (C). Anal. Calc. For C10H16N2O3: C, 56.59; H, 7.60; N,
13.20. Found: C, 56.48; H, 7.59; N, 13.12.
2-[(Methoxymethylene)amino]-5-azidopentanenitrile (29l). α-Aminonitrile 28g (278 mg, 2.00
mmol) gave the imidate as a colorless oil (359 mg, 99%): 1H NMR δ 1.72-1.84 (m, 2H), 1.87-1.96 (m,
13
2H), 3.36-3.40 (t, 2H, J = 6.6 Hz), 3.75 (s, 3H), 4.29-4.33 (dt, 1H, J = 6.3, 0.6 Hz), 7.78 (s, 1H); C
NMR δ 24.8 (CH2), 32.6 (CH2), 50.7 (CH2), 51.1 (CH), 54.0 (CH3), 118.7 (C), 158.5 (CH). Anal. Calc.
For C7H11N5O: C, 46.40; H, 6.12; N, 38.65. Found: C, 46.59; H, 6.23; N, 39.02.
General Procedure F. Cyclization of Imidates to 5-Aminoimidazoles and Derivatizations. To a
solution of the imidate in anhydrous CHCl3 (0.1 M) was added the amine (100 mol%) and PPTS (1
mol%). The mixture was then heated under reflux for 16 h before it was concentrated to afford the crude
1
5-aminoimidazoles that were usually > 95% pure as judged by H NMR spectroscopy. The unstable
crude 5-aminoimidazoles were then immediately derivatized (compound 30 was the only free
aminoimidazole that was partially characterized) as either methyl imidates or N, N-dimethylamidines by
heating in trimethylorthoformate (0.1 M) or N, N-dimethylformamide dimethylacetal (0.1 M) at 80 °C
for 24 h.
1,4-Dibenzyl-5-aminoimidazole (30). The imidate 29a (374 mg, 1.99 mmol) gave the crude 5-
aminoimidazole (containing 5 mg PPTS cat.) as a cream solid (528 mg, 100%): mp 97-103 °C (dec.); 1H
NMR δ 2.49-2.57 (br, 2H), 3.90 (s, 2H), 5.00 (s, 2H), 7.10-7.12 (d, 2H, J = 6.3 Hz), 7.14-7.37 (m, 9H);
13C NMR δ 33.5 (CH2), 47.3 (CH2), 126.0 (C), 126.8 (CH), 127.9 (CH), 128.5 (CH), 128.7 (CH), 129.0
S15

(CH), 130.2 (C), 130.8 (CH) 131.7 (CH), 136.6 (C), 140.4 (C). This compound was too unstable for
further characterization.
1,4-Dibenzyl-5-[((N,N-dimethylamino)methylene)amino]imidazole (31a). The aminoimidazoles
was derivatized as the N, N-dimethylamidine, obtained as a brown oil (576 mg, 91% from the α-
aminonitrile): 1H NMR δ 2.79-2.87 (br, 6H), 3.90 (s, 2H), 5.00 (s, 2H), 7.12-7.19 (m, 4H), 7.22-7.33 (m,
13
8H); C NMR δ 33.9 (CH3), 34.1 (CH2), 39.9 (CH3), 47.1 (CH2), 123.0 (C), 125.7 (CH), 127.4 (CH),
127.6 (CH), 128.4 (CH), 128.5 (CH), 128.6 (CH), 131.4 (CH), 137.7 (C), 137.9 (C), 142.2 (C), 154.5
(CH). Anal. Calc. For C20H22N4: C, 75.44; H, 6.96; N, 17.60. Found: C, 75.16; H, 7.06; N, 17.65.
1-Propyl-4-benzyl-5-[((N,N-dimethylamino)methylene)amino]imidazole
(31b).
The
aminoimidazole was derivatized as the N, N-dimethylamidine, obtained as a brown solid (481 mg, 89%
1
from the α-aminonitrile): mp 57-58 °C; H NMR δ 0.88-0.91 (t, 3H, J = 7.5 Hz), 1.66-1.78 (m, 2H),
13
2.87 (br, 6H), 3.71-3.76 (t, 2H, J = 6.9 Hz), 3.87 (s, 2H), 7.10-7.17 (m, 2H), 7.22-7.28 (m, 5H); C
NMR δ 11.3 (CH3), 23.8 (CH2), 33.9 (CH3), 34.0 (CH2), 39.9 (CH3), 45.3 (CH2), 122.9 (C), 125.6 (CH),
128.3 (CH), 128.4 (CH), 131.2 (CH), 137.5 (C), 142.4 (C), 154.3 (CH). Anal. Calc. For C16H22N4: C,
71.08; H, 8.20; N, 20.72. Found: C, 71.03; H, 8.29; N, 20.78.
1-Cyclopentyl-4-benzyl-5-[((N,N-dimethylamino)methylene)amino]imidazole
(31c).
The
aminoimidazole was derivatized as the N, N-dimethylamidine, obtained as a brown solid (474 mg, 80%
from the α-aminonitrile): mp 78-81 °C; 1H NMR δ 1.61-1.85 (m, 6H), 2.10-2.12 (m, 2H), 2.85 (br, 6H),
13
3.84 (s, 2H), 4.41-4.50 (m, 1H), 7.09-7.16 (m, 2H), 7.23-7.28 (m, 5H); C NMR δ 24.9 (CH2), 33.0
(CH2), 33.9 (CH2), 34.1 (CH2), 39.8 (CH3), 55.0 (CH), 123.1 (C), 125.6 (CH), 128.3 (CH), 128.5 (CH),
128.8 (CH), 137.7 (C), 142.4 (C), 154.4 (CH). Anal. Calc. For C18H24N4: C, 72.92; H, 8.16; N, 18.90.
Found: C, 72.63; H, 8.39; N, 18.76.
1-Benzyl-4-[((tert-butyldimethylsilyl)oxy)methyl]-5-[((N,N-dimethylamino)methylene)-
amino]imidazole (31d). The aminoimidazole was derivatized as the N, N-dimethylamidine, obtained as
a yellow oil (320 mg, 43% from the α-aminonitrile): 1H NMR δ 0.08 (s, 6H), 0.89 (s, 9H), 2.97 (s, 6H),
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4.53 (s, 2H), 5.03 (s, 2H), 7.18-7.41 (m, 6H), 8.02 (s, 1H). 13C NMR δ -4.9 (CH3), 18.3 (C), 26.1 (CH3),
33.9 (CH3), 40.1 (CH3), 46.9 (CH2), 59.7 (CH2), 123.3 (C), 127.4 (CH), 127.5 (CH), 128.5 (CH), 130.7
(CH), 137.8 (C), 140.2 (C), 155.6 (CH). Anal. Calc. For C20H32N4OSi: C, 64.47; H, 8.66; N, 15.04.
Found: C, 64.17; H, 8.82; N, 14.94.
1-Benzyl-4-(3-azidopropyl)-5-[((N,N-dimethylamino)methylene)amino]imidazole (31f). The
aminoimidazole was derivatized as the N, N-dimethylamidine, obtained as a yellow oil (573 mg, 92%
1
from the α-aminonitrile): H NMR δ 1.93-2.02 (m, 2H), 2.56-2.61 (t, 2H, J = 7.2 Hz), 2.95 (s, 6H),
3.31-3.35 (t, 2H, J = 6.6 Hz), 4.97 (s, 2H), 7.14-7.17 (d, 2H, J = 6.8 Hz), 7.20-7.33 (m, 4H), 7.47 (s,
13
1H). C NMR δ 24.1 (CH2), 28.9 (CH2), 34.0 (CH3), 40.0 (CH3), 47.0 (CH2), 50.9 (CH2), 122.8 (C),
127.4 (CH), 127.8 (CH), 128.6 (CH), 131.3 (CH), 137.3 (C), 137.9 (C), 154.3 (CH). Anal. Calc. For
C16H21N7: C, 61.71; H, 6.80; N, 31.49. Found: C, 61.56; H, 7.02; N, 31.73.
1,4-Dibenzyl-5-[(methoxymethylene)amino]imidazole (32a). The aminoimidazole was derivatized
as the methyl imidate, obtained as a brown oil (550 mg, 90% from the α-aminonitrile): 1H NMR δ 3.76
(s, 3H), 3.92 (s, 2H), 5.03 (s, 2H), 7.11-7.37 (m, 11H), 7.69 (s, 1H); 13C NMR δ 33.8 (CH2), 47.6 (CH2),
53.6 (CH3), 125.3 (C), 126.0 (CH), 127.3 (CH), 127.8 (CH), 128.4 (CH), 128.5 (CH), 128.8 (CH), 132.6
(C), 133.1 (CH), 137.1 (C), 140.7 (C), 156.5 (CH). Anal. Calc. For C19H19N3O: C, 74.73; H, 6.27; N,
13.76. Found: C, 74.44; H, 6.29; N, 13.85.
1-Phenyl-4-benzyl-5-[(methoxymethylene)amino]imidazole (32b). The aminoimidazole was
1
derivatized as the methyl imidate, obtained as a yellow oil (391 mg, 67% from the α-aminonitrile): H
NMR δ 3.73 (s, 3H), 3.96 (s, 2H), 7.16-7.23 (m, 1H), 7.29-7.31 (d, 4H, J = 4.5 Hz), 7.34-7.47 (m, 5H),
13
7.57 (s, 1H), 7.74 (s, 1H); C NMR δ 32.9 (CH2), 53.5 (CH3), 125.7 (C), 126.1 (CH), 127.1 (CH),
127.6 (CH), 128.5 (CH), 128.7 (CH), 129.0 (CH), 132.4 (C), 133.3 (CH), 137.4 (C), 140.5 (C), 156.6
(CH). Anal. Calc. For C18H17N3O: C, 74.20; H, 5.88; N, 14.42. Found: C, 74.51; H, 6.02; N, 14.42.
1-Benzyl-4-(2-azidoethyl)-5-[((N,N-dimethylamino)methylene)amino]imidazole
(32d).
The
aminoimidazole was derivatized as the methyl imidate, obtained as a brown oil (512 mg, 90% from the
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1
α-aminonitrile): H NMR δ 2.74-2.78 (t, 2H, J = 6.6 Hz), 3.62-3.67 (t, 2H, J = 6.6 Hz), 3.83 (s, 3H),
13
5.02 (s, 2H), 7.14-7.16 (d, 2H, J = 6.8 Hz), 7.27-7.35 (m, 4H), 7.98 (s, 1H); C NMR δ 27.2 (CH2),
47.5 (CH2), 51.1 (CH2), 53.7 (CH3), 122.6 (C), 127.2 (CH), 127.8 (CH), 128.7 (CH), 133.3 (C), 133.5
(CH), 137.0 (C), 156.9 (CH). Anal. Calc. For C14H16N6O: C, 59.14; H, 5.67; N, 29.56. Found: C, 59.00;
H, 5.99; N, 29.91.
1-Benzyl-4-(4-methoxybenzyl)-5-[(methoxymethylene)amino]imidazole
(32e).
The
aminoimidazole was derivatized as the methyl imidate, obtained as a brown oil (610 mg, 91% from the
α-aminonitrile): 1H NMR δ 3.76 (two overlapping s, 6H), 3.86 (s, 2H), 5.03 (s, 2H), 6.80-6.83 (d, 2H, J
= 8.7 Hz), 7.11-7.18 (m, 4H), 7.27-7.36 (m, 4H), 7.71 (s, 1H); 13C NMR δ 33.0 (CH2), 47.5 (CH2), 53.5
(CH3), 55.2 (CH3), 113.9 (CH), 125.7 (C), 127.3 (CH), 127.7 (CH), 128.7 (CH), 129.3 (CH), 132.4 (C),
132.8 (C), 133.1 (CH), 137.2 (C), 156.4 (CH), 157.9 (C). Anal. Calc. For C20H21N3O2: C, 71.62; H,
6.31; N, 12.53. Found: C, 71.34; H, 6.48; N, 12.52.
1-Benzyl-4-(4-nitrobenzyl)-5-[(methoxymethylene)amino]imidazole (32f). The aminoimidazole
was derivatized as the methyl imidate, obtained as a brown solid (651 mg, 93% from the α-
aminonitrile): mp 69-70 °C; 1H NMR δ 3.80 (s, 3H), 3.99 (s, 2H), 5.04 (s, 2H), 7.15-7.18 (d, 2H, J = 6.8
Hz), 7.29-7.40 (m, 6H), 7.67 (s, 1H), 8.12-8.15 (d, 2H, J = 8.7 Hz); 13C NMR δ 33.5 (CH2), 47.7 (CH2),
53.8 (CH3), 123.6 (C), 123.8 (CH), 127.3 (CH), 127.9 (CH), 128.8 (CH), 129.3 (CH), 133.1 (CH), 133.6
(C), 136.8 (C), 146.4 (C), 148.5 (C), 156.6 (CH). Anal. Calc. For C19H18N4O3: C, 65.13; H, 5.18; N,
15.99. Found: C, 65.08; H, 5.20; N, 15.97.
1-Benzyl-4-hexyl-5-[(methoxymethylene)amino]imidazole (32g). The aminoimidazole was
1
derivatized as the methyl imidate, obtained as a brown oil (515 mg, 86% from the α-aminonitrile): H
NMR δ 0.85-0.89 (t, 3H, J = 6.6 Hz), 1.23-1.39 (m, 8H), 1.60-1.70 (m, 2H), 2.47-2.52 (t, 1H, J = 7.8
Hz), 3.82 (s, 2H), 5.01 (s, 2H), 7.14-7.16 (d, 2H, J = 6.8 Hz), 7.28-7.34 (m, 4H), 7.86 (s, 1H); 13C NMR
δ 14.1 (CH3), 22.6 (CH2), 27.5 (CH2), 29.2 (CH2), 29.9 (CH2), 31.7 (CH2), 47.5 (CH2), 53.5 (CH3),
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127.2 (C), 127.3 (CH), 127.7 (CH), 128.7 (CH), 131.6 (C), 132.7 (CH), 137.2 (C), 156.0 (CH). Anal.
Calc. For C18H25N3O: C, 72.21; H, 8.42; N, 14.03. Found: C, 72.32; H, 8.44; N, 14.21.
1-Benzyl-4-(isopropyl)-5-[(methoxymethylene)amino]imidazole (32h). The aminoimidazole was
derivatized as the methyl imidate, obtained as a brown oil (324 mg, 85% from imidate 29i): 1H NMR δ
1.22-1.24 (d, 6H, J = 6.9 Hz), 2.69-2.84 (sept, 1H, J = 6.9 Hz), 3.77 (s, 3H), 4.94 (s, 2H), 7.09-7.12 (m,
2H), 7.17-7.29 (m, 4H), 7.77 (s, 1H); 13C NMR δ 23.0 (CH3), 26.0 (CH), 47.4 (CH2), 53.5 (CH3), 127.2
(CH), 127.6 (CH), 128.7 (CH), 130.4 (C), 132.5 (C), 132.8 (CH), 137.2 (C), 156.3 (CH). Anal. Calc.
For C15H19N3O: C, 70.01; H, 7.44; N, 16.33. Found: C, 70.21; H, 7.58; N, 16.60.
Ethyl
3-[1-benzyl-5-((methoxymethylene)amino)imidazol-4-yl]propanoate
(32i).
The
aminoimidazole was derivatized as the methyl imidate, obtained as a brown oil (530 mg, 84% from the
α-aminonitrile): 1H NMR δ 1.19-1.24 (t, 3H, J = 7.2 Hz), 2.72-2.86 (m, 4H), 3.83 (s, 3H), 4.07-4.14 (q,
2H, J = 7.2 Hz), 5.00 (s, 2H), 7.13-7.16 (d, 2H, J = 6.8 Hz), 7.28-7.34 (m, 4H), 8.03 (s, 1H); 13C NMR δ
14.2 (CH3), 22.4 (CH2), 33.6 (CH2), 47.4 (CH2), 53.5 (CH3), 60.3 (CH2), 124.7 (C), 127.2 (CH), 127.7
(CH), 128.7 (CH), 132.1 (CH), 133.0 (CH), 137.1 (C), 156.9 (CH), 173.4 (C). Anal. Calc. For
C17H21N3O3: C, 64.74; H, 6.71; N, 13.32. Found: C, 64.99; H, 6.84; N, 13.20.
Ethyl
4-[1-benzyl-5-((methoxymethylene)aminoimidazol-4-yl]butanoate
(32j).
The
aminoimidazole was derivatized as the methyl imidate, obtained as a brown oil (534 mg, 81% from the
1
α-aminonitrile): H NMR δ 1.21-1.26 (t, 3H, J = 6.9 Hz), 1.93-2.03 (m, 2H, J = 7.2 Hz), 2.35-2.40 (t,
2H, J = 7.2 Hz), 2.54-2.58 (t, 2H, J = 7.2 Hz), 3.82 (s, 3H), 4.07-4.14 (q, 2H, J = 6.9 Hz), 5.01 (s, 2H),
7.14-7.16 (d, 2H, J = 6.9 Hz), 7.29-7.34 (m, 4H), 7.92 (s, 1H); 13C NMR δ 14.2 (CH3), 24.9 (CH2), 26.6
(CH2), 33.7 (CH2), 47.4 (CH2), 53.5 (CH3), 60.2 (CH2), 125.9 (C), 127.2 (CH), 127.7 (CH), 128.7 (CH),
132.0 (C), 132.9 (CH), 137.1 (C), 156.3 (CH), 173.6 (C). Anal. Calc. For C18H23N3O3: C, 65.63; H,
7.04; N, 12.76. Found: C, 65.40; H, 7.15; N, 12.66.
References
(1)
Drenkard, S.; Ferris, J.; Eschenmoser, A. Helv. Chim. Acta 1990, 73, 1373.
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(2)
Cimarusti, C. M.; Bonner, D. P.; Breuer, H.; Chang, H. W.; Fritz, A. W.; Floyd, D. M.;
Kissik, T. P.; Koster, W. H.; Kronenthal, D.; Massa, F.; Mueller, R. H.; Pluscec, J.;
Slusarchyk, A.; Sykes, R. B.; Taylor, M.; Weaver, E. R. Tetrahedron 1983, 39, 2577.
(3)
(4)
(5)
(6)
(7)
(8)
(9)
Hofmann, K.; Johl, A.; Furlenmeir, A. E.; Kappeler, H. J. Am. Chem. Soc. 1957, 79, 1636.
Sugano, H.; Miyoshie, M. Bull. Chem. Soc. Jpn. 1973, 46, 669.
Nollet, A. J. H.; Huting, C. M.; Pandit, U. K. Tetrahedron 1969, 25, 5971.
O’Donnell, M. J.; Polt, R. L. J. Org. Chem. 1982, 47, 2663.
Cainelli, G.; Giacomini, D.; Treré, A.; Galleti, P. Tetrahedron Asym. 1995, 6, 1593.
Lipshutz, B. H.; Papa, P.; Keith, J. M. J. Org. Chem. 1999, 64, 3792.
Houssin, R.; Lohez, M.; Bernier, J. L.; Henichart, J. P. J. Org. Chem. 1985, 50, 2787.
(10) Frankel, M.; Knobler, Y. J. Am. Chem. Soc. 1958, 80, 3147.
(11) Zeng, B.; Wong, K. K.; Pompliano, D. L.; Reddy, S.; Tanner, M. E. J. Org. Chem. 1998, 63,
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(12) O’Donnell, M. J.; Eckrich, T. M. Tetrahedron Lett. 1978, 4625.
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