Organic Process Research & Development
Article
General Procedure for the Rh-Catalyzed Cascade
under nitrogen. After 24 h, the reaction mixture was allowed to
cool to 23 °C. A 2 L three-neck Morton flask was assembled
with a thermometer, an addition funnel, and a Claisen adapter
(one neck attached to a nitrogen line and the other neck
attached to an external bubbler). Ethanol (594 mL) was added
to the flask, which was cooled to 0 °C in an ice bath. The crude
dihydropyridine was transferred to the addition funnel via
cannula. The flask was rinsed with toluene (10 mL), and that
solution was also transferred to the addition funnel via cannula.
Sodium triacetoxyborohydride (68.0 g, 320 mmol, 3 equiv) was
added via a funnel in one portion (by temporarily removing the
thermometer) to the precooled ethanol with stirring (>750
rpm). The crude dihydropyridine was then immediately added
to the heterogeneous mixture via an addition funnel over a
period of 2 min, and at the end of the addition, the internal
temperature of the mixture had warmed to 2 °C. The addition
funnel was rinsed with toluene (10 mL), and the rinse was also
added to the reaction solution. Acetic acid (160 mL, 2.78 mol,
26 equiv) was added to the flask under nitrogen with stirring in
an ice bath over 4 min at which time the internal temperature
had increased to 7 °C. After stirring for 1 h in an ice bath, the
reaction mixture was allowed to warm to 23 °C, and the
Reaction Using [RhCl(cod)] . An oven-dried three-neck 50
2
mL flask equipped with a stir bar and reflux condenser was
charged with [RhCl(cod)] (1.0 mol %) and 4-(diethylphos-
2
phino)-N,N-dimethylaniline (2.0 mol %). The flask was purged
with nitrogen for 5 min. Toluene was added, and the resulting
mixture was stirred at 23 °C under nitrogen for 1 h. The alkyne
1.5 equiv) was added to the flask followed by the imine (1.0 g,
.0 equiv, 1.5 M final concentration). The reaction mixture was
stirred at 80 °C under nitrogen for 24 h and then was allowed
to cool to 23 °C before being taken on to the reduction step.
General Dihydropyridine Reduction Procedure for an
Internal Alkyne Coupling Partner. To a separate oven-dried
(
1
2
50 mL round-bottom flask equipped with a stir bar were
added NaBH(OAc) (3.0 equiv) and ethanol. The flask was
3
placed in a 0 °C ice bath, and within 10 min, the crude
dihydropyridine solution (from the Rh reaction) was added via
cannula or syringe transfer. Acetic acid was added to the flask,
and the reaction mixture was stirred at 0 °C for 3 h. The
reaction mixture was allowed to warm to 23 °C and then was
evaporated to dryness. EtOAc (20 mL) and H O (10 mL) were
2
added to the flask. 2 M NaOH was added to the mixture until
the pH of the aqueous layer was >11. The mixture was
extracted with EtOAc (3 × 30 mL). The combined organic
layers were washed with brine (100 mL), dried over Na SO ,
volatiles were evaporated. EtOAc (50 mL) and H O (25 mL)
2
were added to the flask. 2 M NaOH was added to the mixture
until the pH of the aqueous layer was >11. The mixture was
extracted with EtOAc (4 × 150 mL). The combined organic
layers were washed with brine (300 mL), dried over Na SO ,
2
4
and concentrated under reduced pressure. The crude residue
was purified by flash chromatography to afford the desired
tetrahydropyridine.
2
4
and concentrated under reduced pressure. The crude product
General Dihydropyridine Reduction Procedure for a
Silyl Alkyne as a Coupling Partner. To a separate oven-
dried 250 mL round-bottom flask was added tetramethylam-
monium triacetoxyborohydride (3.0 equiv). The flask was
submersed in a 23 °C water bath, and CH Cl was added under
was filtered over a plug of 450 mL of silica (400:25:3 hexanes−
EtOAc−Et N eluent) and concentrated under reduced pressure
3
to yield tetrahydropyridine 14 as a yellow oil (27.5 g, 95%
yield). Spectral data describing the product purity after crude
work up and after silica gel filtration can be found in the
Supporting Information.
Procedure for the Rh-Cascade Reaction Using [RhCl(cod)]2
Precatalyst and Reduction Sequence at >100 mmol Scale
for the Synthesis of 1-Benzyl-5,6-diethyl-2,3,4-trimethyl-
1,2,3,6-tetrahydropyridine (14). An oven-dried three-neck
250 mL flask equipped with a stir bar and reflux condenser
2
2
nitrogen. The resulting mixture was stirred until homogeneous.
The crude dihydropyridine solution (from the Rh reaction) was
added to the flask via cannula or syringe transfer with the aid of
CH Cl , and the solution was vigorously stirred (>1000 rpm).
2
2
Diphenyl phosphate (2.2 equiv) in CH Cl was added over 10
2
2
min. The homogeneous mixture was stirred at 23 °C under
nitrogen for 12 h. The reaction was quenched with 1 M NaOH
was charged with [RhCl(cod)] (527 mg, 1.07 mmol, 1 mol %)
2
(
100 mL), and the mixture was stirred vigorously until gas
and 4-(diethylphosphino)-N,N-dimethylaniline (447 mg, 2.14
mmol, 2 mol %). The flask was purged with nitrogen for 5 min.
Toluene (72 mL) was added, and the resulting mixture was
stirred at 23 °C under nitrogen for 1 h. 3-Hexyne (13) (18.2
mL, 160 mmol, 1.5 equiv) was added to the flask followed by
the imine 12 (20.0 g, 107 mmol, 1 equiv). The reaction mixture
was stirred at 80 °C under nitrogen. After 24 h, the reaction
mixture was allowed to cool to 23 °C. A 2 L three-neck Morton
flask was assembled with a thermometer, an addition funnel,
and a Claisen adapter (one neck attached to a nitrogen line and
the other neck attached to an external bubbler). Ethanol (594
mL) was added to the flask and cooled to 0 °C in an ice bath.
The dihydropyridine solution was transferred to the addition
funnel via cannula. The flask was rinsed with toluene (10 mL),
and that solution was transferred to the addition funnel via
cannula. Sodium triacetoxyborohydride (68.0 g, 320 mmol, 3
equiv) was added via funnel in one portion (by temporarily
removing the thermometer) to the precooled ethanol with
stirring (>750 rpm). The dihydropyridine solution was then
immediately added to the heterogeneous mixture via addition
funnel over a period of 2 min, and at the end of the addition,
the internal temperature of the mixture had warmed to 2 °C.
The addition funnel was rinsed with toluene (10 mL), and the
evolution ceased (approximately 20 min). The mixture was
transferred to a separatory funnel, and the layers were
separated. The aqueous layer was extracted with CH Cl (2
2
2
×
50 mL). The combined organic layers were washed with
brine (150 mL) followed by a final extraction of the aqueous
phase with CH Cl (50 mL). The organic layers were dried
over MgSO and evaporated to dryness. The crude product was
purified by flash chromatography to deliver the product
tetrahydropyridine.
2
2
4
Procedure for the Rh-Cascade Reaction Using [RhCl-
2 2
(
coe) ] Precatalyst, and Reduction Sequence at >100 mmol
Scale for the Synthesis of 1-Benzyl-5,6-diethyl-2,3,4-trimeth-
yl-1,2,3,6-tetrahydropyridine (14). A 20 mL vial was charged
with [RhCl(coe) ] (192 mg, 0.267 mmol, 0.25 mol %), 4-
(
0
mixture was transferred to an oven-dried 250 mL three-neck
flask equipped with a stir bar and a reflux condenser. Toluene
2
2
diethylphosphino)-N,N-dimethylaniline (112 mg, 0.534 mmol,
.5 mol %), and toluene (12 mL), all in a glovebox. This
(
60 mL) was added to the flask. 3-Hexyne (13) (18.2 mL, 160
mmol, 1.5 equiv) was added to the flask followed by the imine
2 (20.0 g, 107 mmol, 1 equiv). The flask was removed from
the glovebox, and the reaction mixture was stirred at 80 °C
1
1
108
dx.doi.org/10.1021/op500225c | Org. Process Res. Dev. 2014, 18, 1105−1109