Jiang et al.
SCHEME 3a
crystallography, and models predictive of the stereo-
chemical outcome of the additions have been applied. In
addition, the resulting products can be efficiently depro-
tected selectively to allow for further manipulations.
Experimental Section
a Key: (a) trifluoroacetic anhydride, CH2Cl2, 0 °C (95%); (b) 0.1
N HCl(aq)., EtOH, rt, 1 h (85%)
General Procedure for the Preparation of 2-Piperazi-
nylbenzaldehydes (3a-h, Table 1). A solution containing
the corresponding 2-fluorobenzaldehyde, N-Boc-piperazine,
and K2CO3 in either DMF, DMA, or 1,4-dioxane was heated
to the temperatures and times listed in Table 1. After
consumption of the starting material, the reaction mixture was
cooled to room temperature and filtered, and the solids were
rinsed EtOAc. The filtrate was concentrated in vacuo, and the
residue was diluted with EtOAc and washed with 0.1 N HCl,
saturated aqueous NaHCO3 solution, and brine. The organic
extracts were dried over anhydrous MgSO4 and filtered,
followed by concentration at reduced pressure. The residue was
triturated with hexanes to afford the desired products as
yellow solids, unless stated otherwise.
SCHEME 4a
General Procedure for the Condensation Reaction
between 2-Piperazinylbenzaldehydes 3a-h and N-tert-
Butanesulfinamides 4, using Ti(OEt)4 (Table 2). A solu-
tion containing the corresponding 2-piperazinylbenzaldehyde
3 and N-tert-butanesulfinamide 4 in THF was treated with
Ti(OEt)4 (tech. grade, Ti ∼20%, contains excess ethanol) at
ambient temperature. The resulting homogeneous mixture was
stirred, under N2, for the times indicated in Table 2. The
reaction mixture was cautiously poured onto a saturated NaCl
aqueous solution, with vigorous stirring. The resulting suspen-
sion was filtered through a pad of Celite and rinsed thoroughly
with EtOAc and CH2Cl2, until no more product could be
detected by TLC. The organic layer was separated, dried over
anhydrous MgSO4, and filtered. The solvents were removed
in a rotary evaporator at reduced pressure. The resulting solids
were either triturated or recrystallized from hexanes to give
the final product in analytically pure form, unless otherwise
stated.
General Procedure for the Condensation Reaction
between 2-Piperazinylbenzaldehydes 3a-h and N-tert-
Butanesulfinamides 4, using Cs2CO3 (Table 2). A solution
of the corresponding 2-piperazinylbenzaldehyde 3 and N-tert-
butanesulfinamide 4 in CH2Cl2 was treated with Cs2CO3. The
resulting suspension was heated to reflux and the reaction
progress was monitored by TLC and HPLC/MS. The reactions
were allowed to proceed for the times indicated in Table 2 and
then cooled to ambient temperature. The solids were removed
by filtration, and the filtrate was concentrated in vacuum. The
residue was purified by crystallization from EtOAc.
a Key: (a) mCPBA, CH2Cl2, rt, 1 h (95%); (b) TFA (3 equiv),
CH2Cl2, rt, 1 h (95%); (c) anisole, trifluoromethanesulfonic acid,
CH2Cl2, rt, 3 h (90%)
ketones and aldehydes. We are currently investigating
the generality of this approach.
To avoid the formation of byproducts and to maximize
the yields of the benzylamine deprotections, we decided
to oxidize the N-tert-butylsulfinamide group to the cor-
responding sulfonamide, with the knowledge that the
N-tert-butylsulfonamide (Bus) would tolerate TFA.15
Other groups have also utilized a similar strategy.16
Thus, compound Ss,S-9h was oxidized by mCPBA in CH2-
Cl2, at room temperature, in nearly quantitative yield.
The resulting sulfonamide 17h, when treated with TFA
in CH2Cl2, was smoothly converted to the secondary
amine 18h in 95% yield. Alternatively, the sulfonamide
group in 17h could be selectively removed by treatment
with trifluoromethane sulfonic acid in CH2Cl2, in the
presence of 2 equiv of anisole, to give benzylamine 12h
(Scheme 4).
General Procedure for the Organolithium Additions
to N-tert-Butanesulfinyl Imines 5 (Table 3). A round-
bottom flask equipped with a magnetic stirring bar, thermom-
eter, and an inert gas inlet was flame-dried under N2. Upon
cooling, the flask was charged with the corresponding N-tert-
butanesulfinyl imine 5 and THF. The resulting solution was
cooled to -72 °C (dry ice/acetone bath) and the desired
organolithium reagent was introduced via syringe in a drop-
wise fashion, to keep the internal temperature below -68 °C.
After the addition, the reaction was kept at low temperature
for another hour and then quenched with saturated NH4Cl
aqueous. Upon warming to room temperature, the mixture was
transferred to a separatory funnel and the reaction was
partitioned between EtOAc and H2O. The organic layer was
separated, washed with brine, and dried over anhydrous
MgSO4. Filtration and concentration under vacuum gave a
residue that was purified by silica gel chromatography or
crystallization.
Conclusion
We have demonstrated the practical conversion of
2-fluorobenzaldehydes to protected chiral (arylpiperazi-
nyl)benzylamines, which are key intermediates for the
preparation of MC4R ligands. The synthetic route pre-
sented herein utilizes chiral N-tert-butanesulfinamide as
both an activating agent for the addition or organome-
tallics reagents to the CdN bond and a powerful stereo-
directing group. The diastereoselectivities obtained are
good to excellent, and in many cases the major product
can be isolated in pure form by a simple recrystallization.
The stereochemical assignments were effected via X-ray
(14) Davis, F. A.; Slegeir, W. A. R.; Evans, S.; Schwartz, A.; Goff,
D. L.; Palmer, R. J. Org. Chem. 1973, 38, 2809-2813.
(15) Sun, P.; Weinreb, S. M.; Shang, M. J. Org. Chem. 1997, 62,
8604-8608.
(16) (a) Borg, G.; Chino, M.; Ellman, J. A. Tetrahedron Lett. 2001,
42, 1433-1436. (b) Kells, K. W.; Chong, J. M. J. Am. Chem. Soc. 2004,
126, 15666-15667.
General Procedure for the Me3Al-Mediated Organo-
lithium Additions to N-tert-Butanesulfinyl Imines 5
(Table 3). A three-necked round-bottom flask equipped with
a magnetic stirring bar, thermometer, a dropping funnel, and
8930 J. Org. Chem., Vol. 70, No. 22, 2005
Jiang, Wanlong
