Hydrogenation of dihydrobenzodiazepines
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 7, July, 2019
1433
(d, 1 H, H(4), J = 8.4 Hz); 7.90 (d, 1 H, H(5), J = 7.8 Hz); 8.15
(d, 1 H, H(8), J = 8.4 Hz). 13С NMR (CDCl3), : 14.97
(s, CH2CH3); 43.94 (s, CH2CH3); 50.97 (s, NHCH2); 123.54
(s, C(8)); 125.44 (s, C(3)); 125.69 (s, C(6)); 126.24 (s, C(7));
126.35 (s, C(2)); 127.94 (s, C(4)); 128.79 (s, C(5)); 131.82
(s, C(8a)); 133.93 (s, C(4a)); 135.20 (s, C(1)).
tained for the novel substrate 3e (run 6). Moderate conver-
sion in this case is probably connected with limited solu-
bility of the substrate in CH2Cl2. Sterically unhindered
and very soluble substrate 3f showed quantitative conver-
sion, and product 4f had ee 62% (run 7). The highest
enantiomeric excess (74% ee) was achieved for the novel
substrate 3g bearing an additional methyl substituent in
the aromatic ring (run 8).
Тo summarize, we have synthesized a novel phos-
phoramidite ligand, which was tested in asymmetric Ir-
catalyzed hydrogenation of a series of 4-substituted
1,3-dihydro-2H-1,5-benzodiazepin-2-ones. We succeeded
in hydrogenating of these substrates with good enantio-
selectivity in the absence of chiral phosphines thereby
simplifying the procedure and also demonstrated the
possibility to develop a high-efficient catalyst based on
phosphoramidite ligands.
(Sa)-2-[N-Ethyl-N-(1-naphthylmethyl)amino]dinaphtho-
[2,1-d:1´,2´-f][1,3,2]dioxaphosphepane (L). To a stirred solution
of (Sa)-2-chlorodinaphtho[2,1-d:1´,2´-f][1,3,2]dioxaphosph-
epane (2) (0.5 g, 1.4 mmol) in CH2Cl2 (10 mL) N-(1-naphth-
ylmethyl)ethylamine (1) (0.26 g, 1.4 mmol) and NEt3 (0.22 mL,
1.6 mmol) in CH2Cl2 (10 mL) were added. The resulting mixture
was stirred for 20 min at rt and washed with water (20 mL) to
remove [HNEt3]Cl. The organic layer was separated, dried over
Na2SO4, passed through a layer of silica gel, and the solvent was
20
removed in vacuo. Yield 0.503 g (72%), white powder. []D
=
= –307.5 (c 0.5, CH2Cl2). Found (%): C, 79.61; H, 5.52; N, 2.64.
C33H26NO2P. Calculated (%): C, 79.34; H, 5.25; N, 2.80.
1H NMR (CDCl3), : 1.13 (t, 3 H, CH2CH3, J = 7.2 Hz); 2.65—2.80
(m, 1 H, CH2CH3); 3.01—3.15 (m, 1 H, CH2CH3); 4.41 (dd, 1 H,
NCH2, 2JН,Н = 15.6 Hz, 3JН,Р = 8.8 Hz); 4.76 (dd, 1 H, NCH2,
2JН,Н = 15.6 Hz, 3JН,Р = 7.2 Hz); 7.24—7.32 (m, 2 H, СНarom);
7.36 (d, 1 H, СНarom, J = 8.8 Hz); 7.37—7.55 (m, 8 H, СНarom);
7.56—7.61 (m, 1 H, СНarom); 7.63 (d, 1 H, СНarom, J = 8.4 Hz);
7.81 (d, 1 H, СНarom, J = 8.0 Hz); 7.85—7.94 (m, 3 H, СНarom);
7.96 (d, 1 H, СНarom, J = 8.0 Hz); 8.03 (d, 1 H, СНarom, J = 8.4 Hz).
13С NMR (CDCl3), : 14.68 (d, CH2CH3, 3JC,P = 2.2 Hz); 39.37
(d, CH2CH3, 2JC,P = 22.0 Hz); 45.35 (d, NCH2, 2JC,P = 20.5 Hz);
121.85 (s, Carom); 122.22 (d, Carom, JC,P = 1.5 Hz); 122.68
(d, Carom, JC,P = 2.1 Hz); 123.48 (d, Carom, JC,P = 2.2 Hz);
124.12 (d, Carom, JC,P = 5.1 Hz); 124.65 (s, Carom); 124.89
(s, Carom); 125.29 (s, Carom); 125.72 (s, Carom); 126.07 (s, Carom);
126.16 (br.s, Carom); 126.45 (s, Carom); 127.05 (s, Carom); 127.10
(br.s, Carom); 128.01 (s, Carom); 128.29 (s, Carom); 128.43
(s, Carom); 128.76 (s, Carom); 130.06 (s, Carom); 130.37 (s, Carom);
130.77 (s, Carom); 131.49 (s, Carom); 131.76 (s, Carom); 132.68
(s, Carom); 132.92 (d, Carom, JC,P = 1.4 Hz); 133.41 (s, Carom);
133.45 (s, Carom); 133.86 (s, Carom); 149.53 (br.s, POC); 150.08
(d, POC, 2JC,P = 5.1 Hz). 31P NMR (CDCl3), : 149.3.
Synthesis of benzodiazepines 3d,e (general procedure). To
a boiling solution of о-phenylenediamine (0.54 g, 5 mmol) in
о-xylene (1.5 mL) a solution of ethyl 3-(4-fluorophenyl)-3-
oxopropanoate16 (1.345 g, 6.4 mmol) or ethyl 3-(1,3-benzodi-
oxol-5-yl)-3-oxopropanoate17 (1.511 g, 6.4 mmol) in xylene
(2 mL) for 20 min was added dropwise. The mixture was heated
under reflux for 2 h, cooled to rt and kept for 2 h. The precipi-
tated crystals of the product were filtered, rinsed with cold
о-xylene, and recrystallized from ethyl acetate.
4-(4-Fluorophenyl)-1,3-dihydro-2H-1,5-benzodiazepin-2-one
(3d). Yield 0.648 g (51%). Yellowish crystals. Found (%):
C, 71.05; H, 4.58; N, 10.87. C15H11FN2O. Calculated (%):
C, 70.86; H, 4.36; N, 11.02.
4-(1,3-Benzodioxol-5-yl)-1,3-dihydro-2H-1,5-benzodiaz-
epin-2-one (3е). Yield 0.868 g (62%). White crystals. Found (%):
C, 68.80; H, 4.54; N, 9.81. C16H12N2O3. Calculated (%):
C, 68.56; H, 4.32; N, 9.99.
Synthesis of 4,7-dimethyl-1,3-dihydro-2H-1,5-benzodiazepin-
2-one (3g). To a stirred solution of acetyl chloride (7.8 g, 0.1 mol)
in diethyl ether (100 mL) cooled using an ice bath in argon at-
mosphere, trimethylamine (16.7 mL, 0.12 mol) was added
dropwise during 30 min, and this mixture was stirred for 1 h. To
Experimental
31Р, 1H, and 13С NMR spectra were recorded on Bruker
Avance 400 (161.98, 400.13, and 100.61 MHz) and Bruker Avance
III 600 (242.94, 600.13, and 150.90 MHz) instruments relative
to 85% Н3РО4 solution in D2О and Me4Si respectively. Enan-
tiomeric analysis of products of catalytic reactions was performed
by chiral HPLC on an Agilent HP-1100 chromatograph. Optical
rotation was measured on an AP-300 polarimeter. Phosphoryl-
ating agent (Sa)-2-chlorodinaphtho[2,1-d:1´,2´-f][1,3,2]dioxa-
phosphepane (2)13, 4-phenyl-1,3-dihydro-2H-1,5-benzodiaze-
pin-2-one (3a)14, 4-(4-methoxyphenyl)-1,3-dihydro-2H-1,5-
benzodiazepin-2-one (3b)10, 4-(3-methoxyphenyl)-1,3-dihydro-
2H-1,5-benzodiazepin-2-one (3c)10, 4-methyl-1,3-dihydro-2H-
1,5-benzodiazepin-2-one (3f)9, [Ir(COD)Cl]2 were obtained
15
according to the known procedures. Spectral characteristics of
hydrogenation products: 4-phenyl-1,3,4,5-tetrahydro-2H-1,5-
benzodiazepin-2-one (4a)14, 4-(4-methoxyphenyl)-1,3,4,5-
tetrahydro-2H-1,5-benzodiazepin-2-one (4b)10, 4-(3-meth-
oxyphenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one
(4с)10, 4-methyl-1,3,4,5-tetrahydro-2H-1,5- benzodiazepin-2-
one (4g)14 correspond to the literature data.
Synthesis of N-(1-naphthylmethyl)ethylamine (1). To a stirred
solution of 1-naphthaldehyde (0.6 g, 3.8 mmol) in methanol
(2 mL), 70% aqueous ethylamine was added ( 2 mL, an excess).
The reaction mixture was stirred for 2 h, the product was ex-
tracted with CH2Cl2 (4 mL), the solvent was removed in vacuo.
The residue was diluted with methanol (6 mL) and NaBH4 was
added portionwise (0.433 g, 11.4 mmol, 3 equiv. based on
1-naphthaldehyde) The mixture was heated under reflux for 2 h
with a reflux condenser equipped with a calcium chloride tube.
To this mixture water was added (5 mL); the product was ex-
tracted with ethyl acetate and dried over sodium sulfate. The
resulting solution was filtered and evaporated. Yield 0.436 g
(62%), yellow oil. Found (%): C, 84.47; H, 8.44; N, 7.27.
C
13H15N. Calculated (%): C, 84.28; H, 8.16; N, 7.56. 1H NMR
(CDCl3), : 1.23 (t, 3 H, CH2CH3, J = 7.2 Hz); 2.81 (br.s, 1 H,
NH); 2.83 (q, 2 H, CH2CH3, J = 7.2 Hz); 4.29 (s, 2 H, NHCH2);
7.46 (t, 1 H, H(3), J = 7.5 Hz); 7.50—7.54 (m, 1 H, H(6)); 7.54
(d, 1 H, H(2), J = 7.2 Hz); 7.55—7.59 (m, 1 H, H(7)); 7.81