Organic Syntheses, Vol. 89, p.44 (2012).
A. 2-(4-Chlorophenyl)-N-methylacetamide (2).
A three-necked, 500-mL round-bottomed flask is equipped with a 4-cm magnetic stir bar, a temperature probe, a 50-mL addition funnel, and a reflux condenser with a nitrogen gas inlet adaptor (Note 1)
. The apparatus is flushed with nitrogen for a minimum of 15 min and charged with 4-chlorophenyl acetic acid (50.0 g, 293 mmol)
and 100 mL of anhydrous toluene (Note 2)
under nitrogen. Anhydrous DMF (2.28 mL, 2.15 g, 29.3 mmol, 0.1 equiv) (Note 2)
is added and the mixture is heated to 35 °C with a heating mantle. SOCl2 (25.6 mL, 41.9 g, 352 mmol, 1.2 equiv) (Note 2)
is added through the addition funnel over 30 min at such a rate that the internal temperature is maintained at <40 °C (Note 3)
. The resulting light brown solution is stirred at 40 °C and monitored by HPLC until the reaction is complete (Notes 4
, and 6
A three-necked, 1-L round-bottomed flask is equipped with an 8-cm mechanical stirrer, a temperature probe, a 250-mL addition funnel, and a nitrogen gas inlet adaptor. The flask is charged with methylamine solution (40 wt% in water or 11.5M, 128 mL, 114 g, 1470 mmol, 5.0 equiv) (Note 7)
and cooled to 5 °C with an ice bath.
The acid chloride solution is transferred from the 500-mL flask to the 250-mL addition funnel. The solution is added to the 1-L flask containing the methylamine solution over 45 min while maintaining the internal temperature at <25 °C with an ice bath (Note 8)
. Caution! The reaction is exothermic (Note 9)
. The resulting white suspension is stirred at ambient temperature for a minimum of 30 min and filtered through a Büchner funnel. The filter cake is washed with water (2 × 100 mL)
and dried under vacuum (30 mmHg) at 40 °C for a minimum of 24 h to afford 50.9-51.5 g (95-96%) of the desired product 2
as a white crystalline solid (Notes 4
B. 7-Chloro-2-methyl-1,4-dihydro-2H-isoquinolin-3-one (3).
A three-necked, 500-mL round-bottomed flask is equipped with a 3-cm magnetic stir bar, a temperature probe, a 50-mL addition funnel, and a reflux condenser with a nitrogen gas inlet adaptor (Note 1)
. The apparatus is flushed with nitrogen for a minimum of 15 min and charged with 50 mL of Eaton's reagent (Note 11)
. 2-(4-Chlorophenyl)-N-methylacetamide (10.0 g, 54.5 mmol)
is charged in portions, resulting in an exotherm from 23 °C to 29 °C (Note 12)
. Paraformaldehyde (1.98 g, 65.3 mmol, 1.2 equiv)
) is added and the reaction mixture is heated at 80 °C with a heating mantle for 2 h to afford a brown solution [Caution! The reaction is exothermic (Note 15)
], at which point HPLC analysis indicates complete consumption of starting material 2
). The reaction mixture is cooled to 5 °C with an ice bath and water (50 mL)
is added through the addition funnel over 30 min while maintaining the internal temperature at <25 °C. Caution! The addition of water is exothermic. Isopropyl acetate (IPAc) (50 mL)
is added and the mixture is cooled to 5 °C with an ice bath. The pH of the mixture is adjusted to 8–8.5 using 19M NaOH solution (~48-49 mL) while maintaining the internal temperature at <25 °C with an ice bath. Caution! The addition of NaOH is exothermic.
The solid precipitate is filtered off with a Büchner funnel. The filter cake is washed with IPAc (10 mL)
. The filtrate mixture is transferred to a 500-mL separatory funnel and the phases are separated. The aqueous phase is extracted with IPAc (50 mL)
and the organic phases are combined. The combined organic phases are concentrated by rotary evaporation (35 °C, 30 mmHg) to afford a brown residue. The residue is dissolved in EtOAc (50 mL)
and charged on a column (5 × 20 cm) of 200 g of silica gel (Note 17)
. The column is eluted with 1 L of EtOAc and fraction collection (50-mL fractions) is begun after 500 mL of solvent is eluted. Elution is continued with 1 L of 10% MeOH/EtOAc and the desired product is obtained in fractions 12-22 (Notes 18
), which are concentrated by rotary evaporation (35 °C, 30 mmHg) to afford a yellow oil. The oil is dried under vacuum (30 mmHg) at ambient temperature (20–25 °C) for a minimum of 24 h to afford 9.00-9.07 g (85%) of a light yellow solid (Notes 4
, and 21
The glassware was oven-dried at 80 °C for a minimum of 24 h.
Vigorous off-gassing was observed during and after SOCl2
was added. Sufficient ventilation should be employed to avoid pressure accumulation during the reaction. On large scale (e.g. >300 g scale) a caustic scrubber was used to sequester acidic off-gas.
Reaction progress and product purity were evaluated by HPLC analysis using a Waters Sunfire C18 3.5 µm column (150 mm × 4.6 mm) with mobile phases A (water + 0.05% TFA) and B (acetonitrile + 0.05% TFA) and detection at 220 nm; flow: 1.0 mL/min; temp. 25 °C; and gradient: 0 min: A = 95%, B = 5%; 20 min: A = 5%, B = 95%; 20.1 min: A = 95%, B = 5%; and 22 min: A = 95%, B = 5%.
The reaction conversion samples were prepared as follows: A sample of reaction mixture (25 μL) was quenched into 50 μL of 40 wt% aqueous MeNH2
and shaken for 5 min. It was diluted with 1:1 acetonitrile/water to 2 mL and 5 μL of the resulting solution was injected on HPLC. The retention time for starting material 1
was 12.3 min, and the retention time of product 2
was 10.5 min under the HPLC conditions in Note 4
. Alternatively, the reaction can be monitored by TLC. Silica plates with glass backing were used. The plates were developed in 3:1 EtOAc/Hexanes and visualized with UV light. The RF
value for starting material 1
was 0.47. The RF
value for product 2
Generally the reaction should be complete within 30 min.
Methylamine solution (40 wt% in water or 11.5M) was purchased from Sigma Aldrich and used as received. A total of five equiv of MeNH2
were used to quench excess SOCl2
and acids generated during the reaction.
The methylamine solution was diluted with an equal volume of water in cases when a thick suspension formed and became difficult to stir.
Significant exotherm was observed during the addition of acid chloride solution to methylamine solution. The exotherm was controlled by the addition rate of acid chloride. As confirmed by safety assessment evaluated by RC1 calorimetry, the heat output of the amide formation stayed constant during the addition of the acyl chloride, characteristic of a fast reaction with no potential for latent reaction.2
Physical properties and spectral data for 2
are as follows:
mp 106-107 °C; 1
H NMR pdf
(600 MHz, CDCl3
) δ: 2.77 (d, J
= 4.9 Hz, 3 H), 3.53 (s, 2 H), 5.43 (bs, 1 H), 7.20 (d, J
= 8.4 Hz, 2 H), 7.33 (d, J
= 8.4 Hz, 2 H); 13
C NMR pdf
(150 MHz, CDCl3
) δ: 26.5, 42.9, 129.1, 130.8, 133.3, 133.4, 170.9; IR (film) [cm-1
]: 3281, 1646, 1557, 1492, 1408, 1260, 1085, 1017, 806, 734; HRMS (ES+) calculated for C9
NOCl 184.05292, found 184.05252; HPLC >99% (tR
= 10.5 min).
Eaton's reagent was purchased from Aldrich (7.7 wt% of P2
in MsOH) and used as received. Alternatively, fresh Eaton's reagent was prepared in-house at a concentration of 7.5 wt% by adding P2O5 (12 g)
to methanesulfonic acid (100 mL)
at <25 °C. A slight exotherm occurred which was easily controlled by the rate of P2
addition. Once the addition was complete, the solution was stirred at ambient temperature for 18 h and then stored in airtight containers under nitrogen. Cleaner reaction profile was obtained when freshly prepared Eaton's reagent was used.
Safety assessment evaluated by RC1 calorimetry indicated that a mild thermal event took place upon addition of the phenyl acetamide (ΔH
= −35 kJ/mol, ΔTad
= 14 K) which rapidly subsided.2
Paraformaldehyde (95%) and sodium hydroxide solution (19M or 50 wt%) were purchased from Aldrich
and used as received.
RC1 study revealed that addition of paraformaldehyde was marked by an initial endothermic event devoid of any significant thermal activity until the system was heated.2
The thermal profile observed during heating resulted in a net output of −120 kJ/mol (ΔTad
= 43 K). Upon completion of the heat cycle, a decaying heat flow was observed which ended within an hour, indicating that no rapid temperature spike or uncontrollable heat accumulation occurred.2
The reaction progress was monitored using the HPLC method described in Note 4
. The reaction conversion samples were prepared as follows: A sample of reaction mixture (25 μL) was quenched into 1 mL of water. It was diluted with acetonitrile to 2 mL and 5 μL of the resulting solution was injected on HPLC. The retention time for starting material 2
was 10.5 min, and the retention time of product 3
was 11.3 min under the HPLC conditions in Note 4
Silica gel SiliaFlash® F60 (40–63 μm/230–400 mesh) was purchased from Silicycle.
The starting material 2
co-elutes with the product during column chromatography purification, thus it is necessary to ensure complete consumption of the starting material before work up.
The fractions were monitored by HPLC analysis for purity using the HPLC method described in Note 4
. HPLC samples were prepared as follows: A sample of each fraction (100 μL) was evaporated under a flow of nitrogen to a residue and dissolved in 2 mL of 1:1 acetonitrile/water. The typical injection volume was 10 μL, but the volume was adjusted for some fractions based on the concentration of each fraction.
Physical properties and spectral data for 3
are as follows: mp 51-54 °C; 1
H NMR pdf
(600 MHz, CDCl3
) δ: 3.11 (s, 3 H), 3.58 (s, 2 H), 4.47 (s, 2 H), 7.09 (d, J
= 8.2 Hz, 1 H), 7.17 (d, J
= 1.9 Hz, 1 H), 7.23 (dd, J
= 8.2 Hz, 1 H); 13
C NMR pdf
(150 MHz, CDCl3
) δ: 34.4, 36.3, 52.4, 125.2, 127.7, 128.7, 130.7, 132.3, 132.6, 168.2; IR (film) [cm-1
]: 1626, 1488, 1389, 1331, 1244, 1085, 902, 810; HRMS (ES+) calculated for C10
NOCl 196.05292, found 196.05257; HPLC 97.6-98.3% (tR
= 11.3 min).
The product needs to be stored under nitrogen at −20 °C as slow decomposition was observed when it was stored at ambient temperature (20–25 °C).
All hazardous materials should be handled and disposed of in accordance with "Prudent Practices in the Laboratory"; National Academies Press; Washington, DC, 2011.
The present procedure is a simple, efficient, and economical method for the preparation of tetrahydroisoquinoline-3-ones that can be easily scaled up. The safety concerns are minimized with the use of Eaton's reagent since the resultant mixtures are more mobile solutions with temperature requirements much lower than that of PPA. Although the use of Eaton's reagent as a dehydrating agent in various reactions is well documented, Eaton's reagent-mediated cyclization of phenyl acetamide derivatives with formaldehyde was not available in the literature7-15
. Cyclization of phenyl acetamides using Eaton's reagent was broadened to understand the scope and limitation of the process. Some representative examples of tetrahydroisoquinoline-3-ones prepared by this method are compiled in Table 1. For the phenyl acetamides with electron-withdrawing groups on 2- or 4- positions, the desired cyclized products were isolated in excellent yield by neutralization of the reaction to pH 8.0 – 8.5 with sodium hydroxide (NaOH), followed by extraction of the product with isopropyl acetate (IPAc) and isolation by concentration. A ~2:1 mixture favoring 6-chloro-2-methyl-1,4-dihydro-2H
-isoquinolin-3-one was obtained when 2-(3-chlorophenyl)-N
-methylacetamide was subjected to this condition, as the formation of 8-chloro-2-methyl-1,4-dihydro-2H
-isoquinolin-3-one was more hindered by the chloro group. Complicated results were afforded when phenyl acetamides with electron-donating groups were treated with Eaton's reagent under the same conditions.
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