New route for the synthesis of chiral hydrazine SADP

Article abstract of DOI:10.2174/157017812801264674

A convenient route for the synthesis of (S)-1-amino-2-(1-methoxy-1- methylethyl)pyrrolidine (SADP) was established. The route involved three key steps viz. the Grignard addition to the N-Boc-proline ester (1), nitrosation to the aminoalcohol hydrochloride (3) and O-methylation to the alcohol group of N-nitrosopyrrolidine (4). (S)-1,1-dimethyl-tetrahydropyrrolo[1,2-c]oxazol-3-one (6) was also obtained via the reaction of (S)-1-Boc-2-(1-hydroxy-1-methylethyl) pyrrolidine (2) with sodium hydride.

Full text of DOI:10.2174/157017812801264674

Letters in Organic Chemistry, 2012, 9, 325-328
325
New Route for the Synthesis of Chiral Hydrazine SADP
Tao Jia*
School of Pharmaceutical Sciences, Wuhan University, Wuhan 430072, P.R. China
Received November 17, 2011: Revised February 15, 2012: Accepted March 09, 2012
Abstract: A convenient route for the synthesis of (S)-1-amino-2-(1-methoxy-1-methylethyl)pyrrolidine (SADP) was
established. The route involved three key steps viz. the Grignard addition to the N-Boc-proline ester (1), nitrosation to the
aminoalcohol hydrochloride (3) and O-methylation to the alcohol group of N-nitrosopyrrolidine (4). (S)-1,1-dimethyl–
tetrahydropyrrolo[1,2-c]oxazol-3-one (6) was also obtained via the reaction of (S)-1-Boc-2-(1-hydroxy-1-
methylethyl)pyrrolidine (2) with sodium hydride.
Keywords: Chiral hydrazine, Grignard addition, nitrosation, O-methylation, SADP.
INTRODUCTION
introduced to pyrrolidine, to enable the following Grignard
reaction and methylation under strong basic conditions.
However, the deproctecting step of N-benzyl group, which
was performed by catalytic hydrogenolysis with 10 % Pd/C
under high pressure, makes this reaction difficult to operate.
Furthermore, the usage of expensive, instable and toxic t-
BuONO as nitrite source limits the large scale preparation of
SADP.
Chiral hydrazones have been proven to be powerful tools
in the formation of carbon-carbon or carbon-heteroatom
bonds adjacent to a carbonyl group in a regio-, stereo-
selective manner [1]. The vast demands of chiral hydrazones
have prompted the progresses on synthesis of their key
precursors, chiral auxiliary hydrazines. One of examples is
(S)-1-amino-2-methoxymethylpyrrolidine (SAMP), a chiral
hydrazine that has been widely used to prepare its
corresponding hydrazones [2]. Then one analogue of SAMP,
(S)-1-amino-2-(1-methoxy-1-methylethyl)pyrrolidine
In this paper, we report a new route for the preparation of
chiral hydrazine SADP. The total synthesis for target
compound SADP is achieved in six steps as outlined in
Scheme 1, which is low-cost, operation-convenient.
(SADP), has been explored. The existence of the sterically-
OH
OH
a
b
c
CO2CH3
CO2CH3
HCl
N
N
N
N
H
H
HCl
Boc
Boc
1
2
3
OH
OCH3
OCH3
d
e
f
N
N
N
NO
NO
NH2
4
5
SADP
Scheme 1. Reagents and Conditions (a) (Boc)2O, Et3N, CH2Cl2. (b) CH3MgI, Et2O. (c) HCl-EtOAc. (d) NaNO2, HCl. (e) NaH, CH3I, THF.
(f) LiAlH4, THF.
demanding side chain at the pyrrolidine moiety of SADP
enhances stereochemical control in the asymmetric synthesis
of chiral hydrazones [3]. This is particularly useful because
SADP hydrazones as chiral ligands have been employed in
asymmetric catalysis, for example, palladium-catalyzed
allylic alkylation [4], addition of diethylzinc to aryl aldehyde
[5].
RESULTS AND DISCUSSION
In order to prevent any side reactions during the Grignard
addition to the proline ester functionality, we focused on the
N-Boc (tert-butyloxycarbonyl) protecting group, which is
easily cleaved off in quantitative yield in acid solution. After
reacted with (Boc)2O under basic condition, the starting
material L-proline ester was readily converted to its
corresponding N-Boc protected L-proline ester 1 in an
almost quantitative yield. Addition of methyl Grignard
reagent to 1 afforded the tertiary alcohol 2, in which N-Boc
group was not affected.
In the routine preparation of SADP reported by Enders
[3], a common N protecting group, benzyl group was
*Address correspondence to this author at the School of Pharmaceutical
Sciences, Wuhan University, Wuhan 430072, P.R. China; Tel: 86-27-
68759947; Fax: 86-27-68759850; E-mail: jiat@whu.edu.cn
Interestingly, the alcohol group was not converted to the
methyl ether by treatment with sodium hydride and
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

326 Letters in Organic Chemistry, 2012, Vol. 9, No. 5
Tao Jia
methyliodide in tetrahydrofuran as expected. The main
product separated was characterized by 1H NMR and HRMS
as oxazolidinone 6. Oxazolidinones can be prepared from N-
Boc derivations of β-amino alcohols by an intramolecular
attack of toluene-p-sulfonate intermediate [6], and can be
prepared from N-alkoxycarbonyl proline derivations by an
intramolecular attack in basic hydrolysis [7]. We hypothesize
that a similar cyclic esterification occurred on N-Boc tertiary
alcohol 2 based on an intramolecular cyclization mechanism
under the strong basic conditions.
points were uncorrected. All reaction solvents were dried
according to standard procedures.
(S)-1-Boc-Proline Methyl Ester (1)
To a vigorously stirred mixture of L-proline methyl ester
hydrochloride (102.7 g, 0.62 mol) and (Boc)2O (130.8 g, 0.6
mol) in CH2Cl2 (500 mL) was added dropwise Et3N (251
mL, 2.4 moL) at 0 oC. After the addition, the reaction
mixture was stirred at rt overnight. The solvent and
excessive Et3N were evaporated, the residue was partitioned
between EtOAc (500 mL) and water (500 mL). The resulting
EtOAc solution was washed with 0.5 M HCl (100 mL×3),
saturated NaHCO3 (100 mL×3), brine (100 mL). The EtOAc
layer was dried with anhydrous Na2SO4 and remove in
vacuo. Further drying afforded the compound 1 as a
colorless liquid in 96.5 % yield (132.8 g). Rf = 0.58 (EtOAc-
petroleum ether, 1:3). [α]D20= -57.9o (c=1.65, CH2Cl2). IR
OCH3
N
Boc
OH
N
Boc
(film, cm-1) 2977, 1750, 1701, 1397, 1366, 1201, 1162. H
N
1
2
O
NMR (CDCl3) δ 4.20-4.33 (m, 1H, NCH), 3.72 (s, 3H,
OCH3), 3.35-3.60 (m, 2H, NCH2), 2.14-2.28 (m, 1H,
NCHCH2CH2), 1.81-2.00 (m, 3H, CH2CH2), 1.46 and 1.41
(s, Boc rotamers 9H). HRMS (ESI) m/z calcd for C11H20NO4
[M+H]+ 230.1392, found 230.1384. Identical IR and 1H
NMR spectra were observed previously by Han et al. [8].
O
6
Deprotection of N-Boc tertiary alcohol 2 in HCl - ethyl
acetate solution made the aminoalcohol hydrochloride 3 in
quantitative yield. Compared with deprotection of N-benzyl,
the process is suitable for large scale preparation because of
convenient operation, mild reaction condition and high yield.
(S)-1-Boc-2-(1-hydroxy-1-methylethyl)pyrrolidine (2)
N-Nitrosamines usually arise from the reaction of nitrite
sources with secondary amine compounds. The most
common reagent of nitrite sources is nitrous acid, which is
produced from sodium nitrite and mineral acid in water. We
then used this method to prepare the nitrosopyrrolidine 4
successfully by reacting aminoalcohol hydro chloride 3 with
nitrous acid. Compared with t-BuONO as nitrite source in
Enders’ preparation[3], nitrous acid method is of great
significance due to low-cost and considerate yield.
A solution of the compound 1 (91.8 g, 0.40 mol) in dry
ether (200 mL) was added dropwise to a vigorously stirred
solution of CH3MgI (1.00 mol) in dry ether (400 mL) cooled
o
to 0 C, which was freshly prepared in the usual way. After
o
stirring at 0 C for 1 h, the reaction mixture was warmed to
room temperature and stirred an additional 2 h. The reaction
was cooled to 0 oC and quenched by adding dropwise a
saturated NH4Cl solution. After separation of the organic
layer, the aqueous phase was extracted with ether (300
mL×2). The combined organic layer was washed with
saturated NaHCO3 (200 mL×3), brine (200 mL), dried with
anhydrous Na2SO4. The solvent was removed to afford the
compound 2 as a white solid in 93.1 % yield (85.4 g). mp 72-
73 oC. Rf = 0.51 (EtOAc-petroleum ether, 1:3). [α]D20= -86.5o
(c=1.11, CH2Cl2). IR (KBr, cm-1) 3412, 2973, 1654, 1404,
The alcohol group of the nitrosopyrrolidine 4 was thus
readily converted to the methylether 5 by treatment with
sodium hydride and methyliodide in tetrahydrofuran, while
nitroso group was preserved. The final desired product,
SADP, was obtained by reduction of methylether 5 with
LiAlH4 at a high yield.
1
1384, 1170. H NMR (CDCl3) δ 5.94 (br, 1H, OH), 3.87 (t,
In conclusion, we have provided a new low-cost,
operation-convenient route for synthesis of chiral hydrazine
SADP. This synthesis is potentially useful for the large scale
preparation of SADP. Moreover, since variability of
Grignard reagent, more stereochemically controlling chiral
hydrazine analogues can be produced in a similar manner.
1H, J = 7.2 Hz, NCH), 3.67 (m, 1H, NCH2), 3.18 (m, 1H,
NCH2), 2.07 (m, 1H, CH2), 1.59-1.88 (m, 3H, CH2), 1.47 (s,
9H, CH3), 1.17 (s, 3H, CH3), 1.08 (s, 3H, CH3). HRMS (ESI)
m/z calcd for C12H24NO3 [M+H]+ 230.1756, found 230.1744.
1
Identical H NMR spectrum was observed in supplementary
content of literature [9].
EXPERIMENTAL
(S)-2-(1-Hydroxy-1-methylethyl)pyrrolidine Hydrochlo-
IR spectra (cm-1) were recorded on Thermo Nexus 470
FT-IR. 1H NMR (300 or 400 MHz) spectra were recorded on
a Varian VX-300 or a Bruker AV400 spectrometer. High
resolution electrospray ionization (ESI) mass spectra were
recorded on an Agilent Accurate-Mass Q-TOF 6520 LC/MS
system. Optical rotation values were measured with a Perkin
Elmer 341 polarimeter. TLC analysis was performed on
GF254 chromatographic plates. All melting points and boiling
ride (3)
To a stirred solution of the compound 2 (84.0 g, 0.366
mol) in EtOAc (300 mL) was added dropwise the solution of
HCl (0.55 mol) in EtOAc (200 mL). After stirring at rt
overnight, the solution was purged with nitrogen and
evaporated under reduced pressure to afford the compound 3
as a white solid in near-quantitative yield. mp 146-147 oC.
[α]D20= -11.3o (c=2.02, MeOH). IR (KBr, cm-1) 3410, 2975,
1
1579, 1451, 1390, 1306, 1221, 1137. H NMR (D2O) δ 3.40

New Route for the Synthesis of Chiral Hydrazine SADP
Letters in Organic Chemistry, 2012, Vol. 9, No. 5
327
(m, 1H, J = 7.8 Hz, NCH), 3.15 (m, 2H, NCH2), 1.78-2.03
(m, 3H, CH2), 1.62-1.75 (m, 1H, CH2), 1.16 (s, 3H, CH3),
1.13 (s, 3H, CH3). HRMS (ESI) m/z calcd for C7H16NO [M-
Cl]+ 130.1232, found 130.1219.
followed again by suction filtration. The combined filtrates
were dried with anhydrous MgSO4, filtered and concentrated
under reduced pressure. This concentrate was distilled to
afford SADP as a colorless liquid in 80.9 % yield (26.0 g).
bp 59-61oC/3mmHg. [α]D20= -16.3o (c=1.01, CH2Cl2). IR
(film, cm-1) 3347, 2971, 2826, 1608, 1465, 1382, 1366,
(S)-1-Nitroso-2-(1-hydroxy-1-methylethyl)pyrrolidine (4)
To a stirred solution of the compound 3 (0.366 mol) in
1
1181, 1146, 1067. H NMR (CDCl3) δ 3.43 (br, 2H, NH2),
3.20-3.27 (m, 1H, NCH), 3.23 (s, 3H, OCH3), 2.33-2.45 (m,
2H, NCH2), 1.85-1.95 (m, 1H, CH2), 1.63-1.71 (m, 2H,
CH2), 1.50-1.57 (m, 1H, CH2), 1.19 (s, 3H, CH3), 1.11 (s, 3
H, CH3). HRMS (ESI) m/z calcd for C8H19N2O [M+H]+
159.1497, found 159.1485. The spectroscopic data are in
conformity with literature [3].
o
water (400 mL) at 70 C was added dropwise the solution of
NaNO2 (51.0 g, 0.732 mol) in water (200 mL). During the
addition, the reaction was acidified with 3 M hydrochloride
acid to pH = 4-5. The reaction was stirred an additional 3 h
o
o
at 70 C. The reaction was cooled to 20 C, saturated with
NaCl, and extracted with EtOAc (400 mL×3). The combined
organic layer was washed with saturated NaHCO3 (200 mL),
brine (200 mL), dried with anhydrous Na2SO4. The solvent
was removed to afford the compound 4 as a yellow liquid in
82.6 % yield (47.8 g). Rf = 0.22 (EtOAc-petroleum ether,
1:3). [α]D20= -290.9o (c=1.06, CH2Cl2). IR (film, cm-1) 3415,
2978, 1452, 1403, 1299, 1242, 1171, 1144. 1H NMR
(CDCl3) δ 4.36-4.42 (m, 1H, NCH), 3.96-4.05 (m, 1H,
NCH2), 3.29-3.40 (m, 1H, NCH2), 2.90 (br, 1H, OH), 2.18-
2.27 (m, 1H, CH2), 2.05-2.11 (m, 1H, CH2), 1.75-1.95 (m,
2H, CH2), 1.30 (s, 3H, CH3), 1.20 (s, 3H, CH3). HRMS (ESI)
m/z calcd for C7H15N2O2 [M+H]+ 159.1134, found 159.1125.
(S)-1,1-Dimethyl-tetrahydropyrrolo[1,2-c]oxazol-3-one
(6)
Sodium hydride (0.78 g of a 55 % suspension in mineral
oil, 0.0327 mol) was slowly added to a stirred solution of the
compound 2 (5.0 g, 0.0218 mol) and iodomethane (2.0 mL,
0.0327 mol) in dry THF (40 mL). The reaction was stirred
for 1 h at room temperature and refluxed for an additional 3
h. The reaction was quenched by adding dropwise a
saturated NH4Cl solution. After separation of the organic
layer, the aqueous phase was extracted with EtOAc (10
mL×3). The combined organic layer was dried with
anhydrous Na2SO4 and the solvent was removed.
Purification by chromatography over silica gel column using
EtOAc-petroleum ether (1:1) as an eluent to afford the
compound 6 as a white solid in 61.3 % yield (2.07 g). mp 58-
59 oC. Rf = 0.26 (EtOAc-petroleum ether, 1:3). [α]D20= -60.6o
(c=1.42, CH2Cl2). IR (KBr, cm-1) 2974, 1739, 1397, 1352,
(S)-1-Nitroso-2-(1-methoxy-1-methylethyl)pyrrolidine (5)
Sodium hydride (16.5 g of a 55 % suspension in mineral
oil, 0.380 mol) was slowly added to a stirred solution of the
compound 4 (40 g, 0.252 mol) and iodomethane (23.6 mL,
0.380 mol) in dry THF (400 mL). The reaction was stirred
for 1 h at room temperature and refluxed for an additional 3
h. The reaction was quenched by adding dropwise a
saturated NH4Cl solution. After separation of the organic
layer, the aqueous phase was extracted with EtOAc (100
mL×2). The combined organic layer was dried with
anhydrous Na2SO4 and the solvent was removed. The residue
was distilled in vacuo to afford the compound 5 as a yellow
liquid in 85.5 % yield (37.1 g). bp. 121-124oC/3mmHg. Rf =
0.53 (EtOAc-petroleum ether, 1:3). [α]D20= -159.6o (c=1.89,
CH2Cl2). IR (film, cm-1) 2978, 1460, 1422, 1292, 1250,
1
1289, 1169, 1066. H NMR (CDCl3) δ 3.05-3.14 (m, 1H,
NCH), 2.95-3.00 (m, 1H, NCH2), 2.60-2.69 (m, 1H, NCH2),
1.50-1.62 (m, 1H, CH2), 1.20-1.40 (m, 2H, CH2), 0.92-1.02
(m, 1H, CH2), 0.99 (s, 3H, CH3), 0.85 (s, 3H, CH3). HRMS
(ESI) m/z calcd for C8H14NO2 [M+H]+ 156.1025, found
156.1027.
CONFLICT OF INTEREST
Declared none.
1
1170, 1086. H NMR (CDCl3) δ 4.50-4.60 (m, 1H, NCH),
3.85-4.00 (m, 1H, NCH2), 3.29-3.40 (m, 1H, NCH2), 3.20 (s,
3H, OCH3), 2.16-2.25 (m, 1H, CH2), 2.03-2.11 (m, 2H,
CH2), 1.78-1.90 (m, 1H, CH2), 1.27 (s, 3H, CH3), 1.21 (s, 3
H, CH3). HRMS (ESI) m/z calcd for C8H17N2O2 [M+H]+
173.1290, found 173.1284.
ACKNOWLEDGEMENT
The project described was supported by the National
Natural Science Foundation of China (NO. 21002074).
SUPPLEMENTARY MATERIAL
(S)-1-Amino-2-(1-methoxy-1-methylethyl)pyrrolidine
(SADP)
Supplementary material is available on the publishers
web site along with the published article.
To a vigorously stirred mixture of LiAlH4 (15.2 g, 0.40
mol) in THF (100 mL) at 0 oC was added carefully the
solution of the compound 5 (35.0 g, 0.203 mol) in THF (100
mL). After addition, the mixture was refluxed until the
reaction was complete (TLC monitor). Excess LiAlH4 was
decomposed by cautiously adding a 20 % aqueous KOH
solution at 0 oC. After the hydrolysis was complete, the
mixture was refluxed for 15 min and the hot solution was
filtered by suction. The precipitate was extracted by
refluxing with THF (100 mL×2) and vigorously stirring,
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