PAPER
Synthesis of a Substituted Benzazepin-2-one Dihydrate
1985
alanine (6; 2.29 g, 0.0110 M) and DMF (13 mL, 5.68 vol). The slur-
ry was stirred for 20–25 min at r.t. under a nitrogen atmosphere to
obtain a clear solution, then cooled to between –48 °C and –50 °C.
NMM (0.03 mL, 0.0003 M) and ClCO2(i-Bu) (1.40 mL, 0.0107 M)
were added sequentially, while maintaining the temperature at
–48 °C during addition [ClCO2(i-Bu) addition caused an exother-
mic reaction]. The reaction was stirred at –48 °C for an additional
30 min then used immediately as described below.
since silyl protection of the alcohol moiety would not pre-
dispose this site to side reactions.
Compound 9 was converted into its corresponding bis-tri-
methylsilyloxy-protected derivative 15 by heating in the
presence of hexamethyldisilazane (HMDS) and catalytic
ammonium sulfate, followed by distillation. Conversion
of 15 with oxalyl chloride in the presence of catalytic N,N-
dimethylformamide, in either dichloromethane or tetrahy-
drofuran, resulted in the formation of acid chloride 16.
Coupling of 3a with 16 led to the formation of intermedi-
ate 17, which was converted into 4 by hydrolysis in situ.
Since compound 4 can be crystallized from acetone–
water, the solvent was exchanged with acetone after the
acylation reaction and before deprotection. Finally, com-
pound 4 was crystallized in 82% yield from the acetone
solvent by addition of water.
Preparation of Free Amine 5
To a 25 mL round-bottomed flask equipped with a thermocouple
and magnetic bar, was added 1 (2.26 g, 0.01 M) and CH2Cl2 (10
mL). The contents were stirred for 10 min and then cooled to
–10 °C, NMM (1.01 g, 0.01 M) was added and the reaction was
stirred for 10 min and then cooled to –20 °C.
Preparation of Enamine 8
The free base slurry of 5 (prepared as described above) at –48 °C,
was added to a pre-cooled solution of the mixed anhydride 7 at
–48 °C as soon as possible. CH2Cl2 (4 mL) was used to rinse the
flask. The reaction temperature rose to –39 °C. The temperature of
the reaction mixture was allowed to slowly rise to r.t. over 4.5 h to
give a thick slurry. CH2Cl2 was removed at atmospheric pressure
using a rotary evaporator and then DMF was removed under vacu-
um. CH2Cl2 (40 mL) and H2O (30 mL) were added to the reaction
mixture and the contents were stirred at r.t. to dissolve the solids.
The organic layer was taken and concentrated to obtain a white sol-
id, which was suspended in acetone (9.5 mL), filtered and dried in
a vacuum oven.
In conclusion, a streamlined, cost-effective and environ-
mentally friendly process for the synthesis of 4 has been
developed, as shown in Scheme 4.
(NH4)2SO4
(cat.)
DMF (cat.)
THF or CH2Cl2
9
Cl
OTMS
HMDS
120 °C, 5 h
distillation
OTMS
(COCl)2, r.t.
OTMS
15
O
O
16
Yield: 93%; white solid; mp 212–214 °C.
IR (KBr): 3299, 1647, 1597 cm–1.
+
O
1H NMR (300 MHz, DMSO-d6): d = 1.3 (d, J = 6.9 Hz, 3 H, CH3),
1.95 (s, 3 H, CH3), 2.93 (s, 3 H, NCH3), 3.3–3.6 (m, 3 H, 3 × CH),
3.7 (s, 3 H, COOCH3), 4.19 (m, 1 H, CH), 4.4 (s, 2 H, CH, =CH),
4.6 [m, 1 H, CH(CH3)], 6.2 (d, J = 6.3 Hz, 1 H, CH), 7.2 (m, 4 H,
ArH), 8.6 (d, J = 7.7 Hz, 1 H, NH), 8.8 (d, J = 7.7 Hz, 1 H, NH).
NMM
r.t.
3
H2N
N
H
Me
N
O
Me
3a
HRMS: m/z calcd for C19H25N3O4: 359.4288; found: 359.4283.
Preparation of 3
The enamine 8 obtained above, was dissolved in CH2Cl2 (70 mL)
under reflux conditions. Solvent exchange with acetone (70 mL)
was performed. The reaction mixture was cooled to 12–15 °C, and
MsOH (0.85g, 0.0088M) and H2O (0.16 mL) were added. After stir-
ring for 10 min, white solids appeared. The contents were stirred for
3–4 h then filtered and washed with acetone (18 mL). The product
was dried in a vacuum oven at 50 °C.
add water,
O
distill CH2Cl2 or THF
add acetone–water
cool and filter
H
N
OTMS
N
H
4
O
Me
17
N
O
Me
Scheme 4 Alternate synthesis of 4 using TMS protection
Yield: 93.56%; white solid; mp >260 °C; chiral purity 99.5% (de-
termined by chiral HPLC).
IR (KBr): 3274, 3077–2803, 1646 cm–1.
HMDS, methyl acetoacetate, ClCO2(i-Bu), (S)-alanine, Boc-(S)-
alanine, (S)-2-hydroxy-3-methybutyric acid, EDC, HOBT, N-meth-
ylmorpholine (NMM), methanesulfonic acid (MsOH), DMF, THF,
CH2Cl2 and NaOH pellets were all used as received from commer-
cial suppliers without purification.
1H NMR spectra were recorded on a 300 MHz Bruker Avance spec-
trometer. Chemical shifts (d) are reported in ppm downfield from
TMS. HPLC analysis was performed using an Agilent HPLC 1100
series instrument. Melting points were measured on Buchi R-535
apparatus and are uncorrected. HRMS were recorded using a Wa-
ters LCT instrument with electrospray ionization. IR spectra were
recorded using a Nicolet Magna 550-FTIR spectrophotometer.
1H NMR (300 MHz, DMSO-d6): d = 1.39 (d, J = 6.9 Hz, 3 H, CH3),
2.28 (s, 3 H, OSO2CH3), 2.92 (s, 3 H, NCH3), 2.91 (m, 2 H,
2 × CH), 3.81 (m, 1 H, CH), 4.23 (m, 2 H, 2 × CH), 6.21 (d, J = 7.9
Hz, 1 H, CH), 7.18 (m, 4 H, ArH), 8.10 (br, 3 H, NH3), 8.94 (d,
J = 7.7 Hz, 1 H, CONH).
+
HRMS: m/z calcd for C14H20N3O2: 262.1556; found: 262.1556.
Preparation of 15
To a 250 mL 3-necked round-bottomed flask equipped with a mag-
netic stir bar, condenser, thermocouple, and nitrogen purge, was
added 9 (20.2 g, 0.171 M), HMDS (80 mL, 0.3836 M), and NH4SO4
(80 mg). Upon addition of the HMDS, the reaction mixture became
a solid mass. The mass was heated to 124–126 °C whereupon the
solids dissolved to form a homogeneous solution. The solution was
refluxed for 6 h and then allowed to cool to r.t. Excess HMDS was
Preparation of Mixed Anhydride 7
To a 100 mL 3-necked round-bottomed flask fitted with a mechan-
ical stirrer and temperature probe, was added the Dane salt of (S)-
Synthesis 2009, No. 12, 1983–1986 © Thieme Stuttgart · New York