Pymisyl-Protected Aziridines
FULL PAPER
action). The reaction mixture was then transferred to a precooled sepa-
rating funnel and the organic layer was drained at a reasonable rate
(faster than dropwise) into a vigorously stirred, two-phase mixture of 2-
methylaziridine (8.85 mL, 0.125 mmol) in CH2Cl2 (100 mL) and
1mK2CO3 (200 mL, 0.2 mol) at ꢀ5 to ꢀ28C. The aqueous layer in the
separating funnel was extracted with cold (ꢀ208C) CH2Cl2 (40 mL) and
the organic layer was added to the reaction mixture. After stirring for
30 min on an ice bath, the organic layer was washed with brine (100 mL),
dried with Na2SO4, and concentrated in vacuo. The residue (22.9 g) was
purified by dry column vacuum chromatography on silica (EtOAc/hep-
tane, 0:1!9:1) to afford the title compound 8 as a colorless solid after
crystallization in the freezer (17.5 g, 70%). A small sample was recrystal-
lized from EtOAc/hexane (408C). M.p. 55–568C (EtOAc/hexane).
1H NMR (300 MHz, CDCl3): d=8.98 (d, J=4.8 Hz, 2H), 7.58 (t, J=
4.9 Hz, 1H), 3.21–3.09 (m, 1H), 2.94 (d, J=6.9 Hz, 1H), 2.26 (d, J=
4.9 Hz, 1H), 1.42–1.34 ppm (m, 3H); 13C NMR (75 MHz, CDCl3): d=
164.6, 158.8, 123.9, 37.3, 35.6, 16.8; elemental analysis calcd (%) for
C7H9N3O2S (199.1): C 42.20; H 4.55; N 21.09; found: C 42.43; H 4.41; N
21.35.
Table 2 provided the pymisyl-protected amphetamine (R)-
11b. The final three steps were performed as follows: Alky-
lation with propargylic bromide, followed by deprotection
with 2-mercaptoacetic acid in the same pot, gave secondary
amine 19. After aqueous workup, the methyl group on the
nitrogen was introduced by reductive alkylation to give (R)-
selegiline (20) in 86% yield over three steps from (R)-11b.
This modular protocol is very flexible and high-yielding, al-
lowing for easy manipulation of the selegiline structure.
1
The position of the H and 13C NMR signals and the spe-
cific rotation of our product 20 differed significantly from
the data reported by Sudalai et al.[27,28] The product formed
by using the current procedure had the same sign for the
specific optical rotation, but its value was lower by a factor
of eight, even though we could only detect a single enantio-
mer by chiral HPLC. We therefore carefully compared our
data to those of an authentic sample of (R)-Selegeline[29]
General procedure for CuBr·SMe2-catalyzed ring opening of 8 with
Grignard reagents: CuBr·SMe2 (62 mg, 0.30 mmol) was added to a flame-
dried Schlenk flask under nitrogen. THF was added and the slurry was
stirred at RT for 15 min and then cooled to ꢀ558C (externally). The
Grignard reagent (3.0 mmol) in THF was added dropwise by syringe and
the mixture was stirred for 30–45 min at ꢀ508C and then cooled to
ꢀ788C. 2-(2-Methylaziridin-1-ylsulfonyl)pyrimidine (397 mg, 2.0 mmol)
in THF (3.5 mL) was added dropwise by syringe and the reaction mixture
was stirred at ꢀ788C for 0.5–4 h. The reaction was quenched at ꢀ788C
with saturated NH4Cl (8 mL) and allowed to warm to RT in open air.
The mixture was transferred to a 100 mL flask (using some THF, water
and sat. aqueous NH4Cl (4 mL)) and concentrated in vacuo to remove
THF. CH2Cl2 (15–20 mL) was added and, if undissolved solid remained
at this point, the mixture was filtered through Celite and the Celite was
washed with CH2Cl2 and water. Otherwise the aqueous layer was extract-
ed with CH2Cl2 (3ꢂ10 mL) and the combined organic phases were
washed with brine, dried over Na2SO4, filtered, and concentrated in
vacuo. Flash chromatography afforded the pure sulfonamides.
1
and found that the H and 13C NMR signals of the authentic
product were in perfect agreement. Furthermore, the specif-
ic rotation of our product also matched that of the authentic
sample. This leaves us with no doubt about the identity and
purity of our product 20 (see the Supporting Information for
further details). The reason for the large discrepancies be-
tween our data and those reported by Sudalai et al. is un-
clear.
Conclusion
The pymisyl sulfonyl group has been introduced as a new ni-
trogen protection group. The required sulfonyl chloride is
readily prepared from inexpensive starting materials. The
pymisyl group activates aziridines towards ring opening with
organocuprates. The resulting sulfonamide can be alkylated
with alkyl halides or alcohols by using the Mitsunobu proto-
col, and the pymisyl group can be removed under very mild
conditions by using a thiolate. The versatility of this new
protecting group was demonstrated in a convergent synthe-
sis of Selegiline, which is a drug currently marketed for the
treatment of Parkinsonꢀs disease. The sequence from the
key intermediate (R)-8, the pymisyl-protected aziridine, pro-
ceeds very efficiently to give Selegiline in 78% yield over
four steps.
Synthesis of (R)-Selegeline: (R)-2-(Pyrimidine-2-sulfonamido)propylpyr-
imidine-2-sulfonate (18): Sodium hypochlorite (72.1 mL, 1.83m in H2O,
132 mmol) was slowly added to a mechanically stirred mixture of 2-mer-
captopyrimidine (4.48 g, 40 mmol) in 2m HCl/1.5m CaCl2 (101 mL) and
CH2Cl2 (130 mL) keeping the internal temperature at ꢀ10 to ꢀ78C with
intermittent cooling in an acetone–dry-ice bath. After the addition was
complete, stirring was continued for 15 min at ꢀ108C. Excess chlorine
was quenched with cold 1m Na2SO3 (10–12 mL) at ꢀ108C. The organic
layer was separated through a Whatman phase separator 1 PS into a
250 mL two-necked flask cooled in a dry-ice–acetone bath with argon
passing through the flask as a blanketing gas. A solution of (R)-alaninol
(897 mg, 11.9 mmol), 4-dimethylaminopyridine (122 mg, 1 mmol), and
pyridine (8.05 mL, 100 mmol) in anhydrous CH2Cl2 (5 mL) was slowly
added below ꢀ358C (10 min). The reaction mixture was slowly allowed
to warm to 08C (1.5 h) and then washed with 1m NaHSO4 (5ꢂ30 mL).
The combined washings were extracted with CH2Cl2 (2ꢂ40 mL) and the
combined organic layers were washed with brine (40 mL), dried over
Na2SO4, and concentrated in vacuo. The crude product was redissolved in
CH2Cl2 and a small amount of CH3CN and concentrated in vacuo with
iPrOH (20–25 mL) until a white solid started to crystallize (ca. 18–20 g
solvent). The mixture was cooled in an ice bath for 1 h and filtered. The
white solid (2.19 g) was recrystallized from an EtOH/CH3CN (19:1) mix-
ture (ca. 32 mL) to afford 18 as a colorless solid (1.88 g, 44%). M.p.
1228C (dec.: sample melts with gas formation and yellow coloration).
Experimental Section
2-(2-Methylaziridin-1-ylsulfonyl)pyrimidine (8): Sodium hypochlorite
(298 mL, 1.55m, 0.462 mol) was slowly added to a mechanically stirred
mixture of 2m HCl (305 mL) and CH2Cl2 (400 mL) in a three-necked
flask, keeping the internal temperature below ꢀ58C by intermittent cool-
ing in an acetone–dry-ice bath. 2-Mercaptopyrimidine (15.7 g, 0.140 mol)
was added as a solid in small portions to the yellow-greenish solution,
keeping the temperature at ꢀ10 to ꢀ58C. After the addition was com-
plete, stirring was continued for 10 min keeping the internal temperature
at ꢀ10 to ꢀ58C (by then no remaining solid 2-mercaptopyrimidine
(yellow) could be seen), then excess chlorine (indicated by a yellow-
greenish color of the organic phase) was quenched by adding ice-cold
10% aqueous Na2SO3 (until KI/starch-paper no longer gave a positive re-
1
[a]2D0 =+27.5 (c 1.04, CH3CN); H NMR (300 MHz, [D6]DMSO): d=9.10
(d, J=4.9 Hz, 2H), 9.00 (d, J=4.8 Hz, 2H), 8.31 (d, J=7.5 Hz, 1H), 7.91
(t, J=4.9 Hz, 1H), 7.75 (t, J=4.8 Hz, 1H), 4.34 (dd, J=4.4, 8.9 Hz, 1H),
4.30 (dd, J=4.1, 8.9 Hz, 1H), 3.90–3.75 (m, 1H), 3.31 (s, 3H), 1.13 ppm
(d, J=6.8 Hz, 3H); 13C NMR (75 MHz, [D6]DMSO): d=165.8, 161.9,
159.4, 158.8, 125.2, 123.8, 75.6, 48.9, 17.2 ppm; HRMS (ESI): m/z calcd
for C11H13N5O5S2: 360.0436 [M+H]; found: 306.0440.
Chem. Eur. J. 2010, 16, 12474 – 12480
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
12479