Organic Process Research & Development
Article
the reaction mixture. The argon flow to the system was shut off
and the pressure set to 50 bar on the BPR. A 1.5 L conical flask
containing aqueous HCl (2 M, 300 mL) was placed at the
outlet pipe with an argon flow to keep the outlet pipe under
argon. The pump was set to 10 mL min−1 and the reaction
mixture flowed through the system. After 65 min the receiver
flask was switched and the reactor washed through with
anhydrous THF, until no more active reagent mixture remained
in the reactor or pump. The collected amide product 2 was
separated and the aqueous fraction extracted with dichloro-
methane (2 × 150 mL). The combined organic fractions were
dried over MgSO4, filtered and the solvent removed in vacuo.
The solid was triturated with pentane to yield the model amide
2 was isolated as a yellow solid (54.8 g, 92% based on material
collected after an initial 2 min equilibration).
General Procedure for the Coupling of Nitriles with
Primary Amines. To a flame-dried 10 mL microwave tube
under argon containing a small stirrer bar was added DABAL-
Me3 1 (205 mg, 0.8 mmol), the desired nitrile (1 mmol), and
the desired amine (1 mmol) followed by THF (1 mL). The
flask was sealed with a microwave cap and placed in the
microwave for 12 min (130 °C, 290 W). Once the microwave
system had completed its cooling program to ambient
temperature, the microwave tube was cooled further to 0 °C
in an ice bath. The reaction was quenched with Rochelle’s salt
(5 mL) and then extracted three times with dichloromethane
(5 mL). The organic fraction was washed three times with
aqueous 2 M HCl (5 mL). The aqueous fractions are then
combined and neutralized with aqueous 2 M NaOH (ca. 20
mL) and extracted three times with dichloromethane (10 mL).
The combined organic fractions were washed with water, dried
over MgSO4 and the solvent removed in vacuo to yield the
desired amidine without any need for further purification. In
the case of coupling of benzonitrile to aniline (10b) the
coupling was carried in toluene to prevent undesired side
reactions (seen in THF).
N-Benzyl-2-(methylthio)benzimidamide (9d). Clear pale
yellow oil (76%); 1H NMR (400 MHz; CDCl3) δ 2.44 (s, 3H),
4.53 (br s, 2H), 7.12−7.16 (m, 1H), 7.22−7.34 (m, 7H), 7.39−
7.41 (m, 1H), the NH signals at ca. δH 3.5 are very broadened;
13C NMR (100 MHz, CDCl3) δ 16.0 (CH3), 46.6 (CH2), 125.0
(CH), 126.0 (CH), 126.8 (CH), 127.1 (CH), 127.3 (CH),
127.8 (CH), 128.0 (CH), 128.6 (CH), 129.7 (CH), 136.2 (C),
139.0 (C), 143.4 (C), 163.4 (CN), compound 9d is
conformationally locked; HRMS (ESI) m/z: [M + Na]+
Calcd for C15H16N2SNa 279.0926; Found 279.0922.
N-Benzylpropionimidamide (9e).26 Clear yellow oil (85%);
1H NMR (400 MHz; MeOD) δ 1.20 (t, J = 7.6 Hz, 3H), 2.24
(q, J = 7.6 Hz, 2H), 4.28 (s, 2H), 5.13 (br s, NH × 2), 7.21−
7.26 (m, 1H), 7.29−7.35 (m, 4H), NH signals apparent in
concentrated samples; 13C NMR (100 MHz, MeOD) δ 12.4
(CH3), 30.4 (CH2), 47.6 (CH2), 127.9 (CH), 128.6 (CH × 2),
129.4 (CH × 2), 140.7 (C), 168.6 (CN); HRMS (EI+) m/z:
[M]+ Calcd for C10H14N2 162.1157; Found 162.1155.
N-Benzyl-2-fluorobenzimidamide (9f). Clear yellow oil
1
(98%); H NMR (400 MHz; MeOD) δ 4.47 (s, 2H), 4.99
(br s, NH × 2), 7.15−7.26 (m, 3H), 7.31−7.35 (m, 2H), 7.39−
7.47 (m, 3H), 7.51−7.55 (m, 1H), NH signals apparent in
concentrated samples; 13C NMR (100 MHz, MeOD) δ 48.0
2
3
(CH2), 117.0 (d, JC−F = 22.0 Hz, CH), 125.4 (d, JC−F = 4.0
Hz, CH), 127.2 (d, 2JC−F = 24 Hz, C), 127.9 (CH), 128.6 (CH
× 2), 129.4 (CH × 2), 130.8 (d, 4JC−F = 3.0 Hz, CH), 132.4 (d,
3JC−F = 8.0 Hz, CH), 140.5 (C), 159.8 (d, 1JC−F = 247.0 Hz, C),
160.7 (C); 19F NMR (376 MHz, CDCl3) δ −155.61 (s);
HRMS (ESI) m/z: [M + H]+ Calcd for C14H14FN2 229.1136;
Found 229.1140. [M + Na]+ Calcd for C14H13FN2Na
251.0955; Found 251.0967.
N-(Furan-2-ylmethyl)benzimidamide (10a). Orange oil
1
(95%); H NMR (400 MHz; CDCl3) δ 4.47 (s, 2H), 5.48
(br s, NH × 2), 6.24 (dd, J = 3.2, 0.8 Hz, 1H), 6.30 (dd, J = 3.2,
1.6 Hz, 1H), 7.31−7.39 (m, 4H), 7.52−7.54 (m, 2H), NH
signals apparent in concentrated samples; 13C NMR (100 MHz,
CDCl3) δ 40.5 (CH2), 107.0 (CH), 110.4 (CH), 126.2 (CH ×
2), 128.6 (CH × 2), 130.1 (CH), 137.3 (C), 141.9 (CH), 152.5
(C), 162.8 (CN); HRMS (ESI) m/z: [M + H]+ Calcd for
C12H13N2O 201.1022; Found 201.1016.
N-Benzylbenzimidamide (9a).24 Yellow oil (98%); 1H
NMR (500 MHz; DMSO-d6) δ 4.35 (s, 2H), 6.59 (br s, 2 ×
NH), 7.19−7.22 (m, 1H), 7.30−7.33 (m, 2H), 7.37−7.43 (m,
5H), 7.83−7.84 (m, 2H); 13C NMR (126 MHz, DMSO-d6) δ
49.3 (CH2), 126.0 (CH), 126.5 (CH × 2), 127.5 (CH × 2),
127.9 (CH × 2), 128.0 (CH × 2), 129.3 (CH), 137.2 (C),
141.9 (C), 156.7 (CN); HRMS (ESI) m/z: [M + H]+ Calcd
for C14H15N2 211.1230; Found 211.1239.
N-Phenylbenzimidamide (10b).24 pale yellow solid (98%);
mp 115−118 °C (Lit. mp 117−118 °C24a); H NMR (400
1
MHz; CDCl3) δ 4.92 (br s, NH × 2), 6.97−7.00 (m, 2H), 7.07
(tt, J = 7.6, 1.2 Hz, 1H), 7.33−7.37 (m, 2H), 7.42−7.51 (m,
3H), 7.84 (d, J = 6.8 Hz, 2H), NH signals apparent in
concentrated samples; 13C NMR (100 MHz, CDCl3) δ 121.9
(CH × 2), 123.3 (CH), 127.0 (CH × 2), 128.6 (CH × 2),
129.6 (CH × 2), 130.8 (CH), 135.5 (C), 149.0 (C), 155.6
(CN); HRMS (ESI) m/z: [M + H]+ Calcd for C13H13N2
197.1073; Found 197.1082.
N-Benzyl-4-bromobenzimidamide (9b).25 Clear yellow oil
1
(64%); H NMR (400 MHz; MeOD) δ 4.44 (s, 2H), 7.21−
7.27 (m, 1H), 7.30−7.35 (m, 2H), 7.36−7.40 (m, 2H), 7.50−
7.66 (m, 4H), NH signals not apparent due to exchange; 13C
NMR (100 MHz, MeOD) δ 48.7 (CH2), 125.3 (C), 127.9
(CH), 128.6 (CH × 2), 129.5 (CH × 2), 129.8 (CH × 2),
132.6 (CH × 2), 137.4 (C), 140.7 (C), 163.1 (CN); HRMS
(ESI) m/z: [M + H]+ Calcd for C14H14BrN2 289.0335; Found
289.0334 (79Br).
N-(4-Methylbenzyl)benzimidamide (10c).25 pale green
1
solid (97%); mp 65−68 °C (lit. mp. 65−66 °C25); H NMR
(400 MHz; CDCl3) δ 2.35 (s, 3H), 4.51 (s, 2H), 7.17 (d, J =
8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.36−7.42 (m, 3H),
7.57−7.60 (m, 2H), NH signals not apparent due to exchange;
13C NMR (100 MHz, CDCl3) δ 21.2 (CH3), 46.6 (CH2), 126.1
(CH × 2), 127.8 (CH × 2), 128.7 (CH × 2), 129.4 (CH × 2),
130.1 (CH), 135.9 (C), 137.0 (C), 137.8 (C), 163.7 (CN);
HRMS (ESI) m/z: [M + H]+ Calcd for C15H17N2 225.1386;
Found 225.1398.
N-Benzylcyclohex-1-ene-1-carboximidamide (9c). Orange
oil (98%); 1H NMR (400 MHz; MeOD) δ 1.60−1.74 (m, 4H),
2.14−2.19 (m, 2H), 2.26−2.30 (m, 2H), 4.37 (s, 2H), 6.32 (tt,
J = 3.8, 1.7 Hz, 1H), 7.21−7.26 (m, 1H), 7.29−7.33 (m, 4H),
NH signals not apparent due to exchange; 13C NMR (100
MHz, MeOD) δ 22.8 (CH2), 23.5 (CH2), 26.2 (CH2), 26.6
(CH2), 47.1 (CH2), 128.0 (CH), 128.4 (CH × 2), 129.5 (CH
× 2), 131.5 (CH), 135.2 (C), 140.1 (C), 166.6 (CN);
HRMS (ESI) m/z: [M + H]+ Calcd for C14H19N2 215.1543;
Found 215.1546.
N-(1-(Naphthalen-2-yl)ethyl)benzimidamide (10d). Yellow
oil (60%); 1H NMR (400 MHz; MeOD) δ 1.62 (d, J = 6.8 Hz,
H
Org. Process Res. Dev. XXXX, XXX, XXX−XXX