A synthesis of pseudoconhydrine and its epimer via hydroformylation and dihydroxylation

Article abstract of DOI:10.1021/jo2008912

A synthesis of the alkaloid pseudoconhydrine and its epimer has been achieved using tandem hydroformylation-condensation to form the six-membered ring and stereoselective dihydroxylation to introduce oxygenation. The stereoselectivity of dihydroxylation can be explained by lipophilic and electrostatic effects, supported by DFT calculations. The alkaloids can be obtained either by regioselective dehydroxylation or by rearrangement, followed by reduction.

Full text of DOI:10.1021/jo2008912

NOTE
pubs.acs.org/joc
A Synthesis of Pseudoconhydrine and Its Epimer via Hydroformylation
and Dihydroxylation
Roderick W. Bates,*,† K. Sivarajan,† and Bernd F. Straub‡
†Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371
‡Organisch-Chemisches Institut der Universit€at Heidelberg, Im Neuenheimer Feld 270, D-69120, Heidelberg, Germany
S Supporting Information
b
ABSTRACT: A synthesis of the alkaloid pseudoconhydrine and its epimer
has been achieved using tandem hydroformylationÀcondensation to form
the six-membered ring and stereoselective dihydroxylation to introduce
oxygenation. The stereoselectivity of dihydroxylation can be explained by lipophilic and electrostatic effects, supported by DFT
calculations. The alkaloids can be obtained either by regioselective dehydroxylation or by rearrangement, followed by reduction.
n terms of tons of product per year, hydroformylation is
probably the largest transition metal-catalyzed process in
Scheme 1. Pseudoconhydrine Retrosynthesis
I
current operation.1À3 The reaction is used for the synthesis of
huge amounts of bulk chemicals but has received less attention
from synthetic organic chemists.4 Notable exceptions are found
in the work of Ojima5 and, more recently, Breit,6 as well as
Taddei and Mann,7 and Tan.8 An advantage of hydroformylation
for the synthesis of complex molecules is the good tolerance of
other functional groups by the reaction. In the case of amine
derivatives, this permits the design of tandem reactions, combin-
ing hydroformylation with condensation, to give enamine
derivatives.7,9À11 We became interested in employing the tan-
dem hydroformylationÀcondensation chemistry, combined
with oxidation of the resulting enamine derivative, to synthesize
pseudoconhydrine 1,12À18 one of the alkaloids from hemlock
(Conium maculatum).19 A simple retrosynthetic analysis led to
homoallylic amine derivative 3 (Scheme 1). A tosyl group was
chosen for N-protection in part due to the clarity of NMR spectra
compared to carbamates at the piperidine stage but also due to
the robustness of this protecting group under many conditions.
The Vilaivan imine asymmetric allylation was chosen for the
preparation of 3 on the grounds of requiring readily available
starting materials, and simple operation.20 The unstable imine 4
of butyraldehyde and (S)-phenylglycinol was prepared and
treated with allyl bromide and indium (Scheme 2). Under
carefully controlled conditions, the allylation product 5 was
obtained in 80% yield and good diastereoselectivity. Control of
temperature during addition of indium was found to be essential
for obtaining this degree of stereoselectivity. Vilaivan has attrib-
uted the stereoselectivity to delivery of the allylating reagent
through indiumÀoxygen coordination. Zinc will also coordinate
effectively to oxygen. Interestingly, treatment of the imine with
allylzinc bromide,21À23 prepared by the method of Knochel,24
yielded the same allylation product 5 in slightly higher dr. The
phenylethanol moiety was cleaved according to the method
of Vilaivan, and the free amine was tosylated. The ee of the
Scheme 2. Synthesis and Hydroformylation of the Homo-
allylic Amine (L = ligand: triphenyl phosphite or
BIPHEPHOS)
sulfonamide 3 resulting from the zinc procedure, determined by
chiral HPLC, was found to be 90%. The indium procedure gave,
at best, an ee of 88% but was capricious.
Hydroformylation of alkene 5 (Scheme 2) was carried out
using rhodium acetate (1 mol %) in THF under a mixture of CO
and H2 (30 psi of each gas). With triphenyl phosphite as the
Received: May 4, 2011
Published: June 13, 2011
r
2011 American Chemical Society
6844
dx.doi.org/10.1021/jo2008912 J. Org. Chem. 2011, 76, 6844–6848
|

The Journal of Organic Chemistry
NOTE
Scheme 3. Synthetic Routes to Pseudoconhydrine and Its
Epimer
Figure 1. Transition state leading to 8.
Six-membered ring ene-carbamates have been shown to
undergo hydroborationÀoxidation16À18 and epoxidation26
with trans selectivity. As substituents R to the ring nitrogen
of N-acyl and N-sulfonyl piperidines are known to occupy
an axial position,27 this corresponds to the reagent approaching
the less-hindered face. To our surprise, dihydroxylation of ene-
sulfonamide 2 under Tsuji conditions28 gave the cis product
as the major isomer (Scheme 3).29 The diols were obtained in
90% yield as an inseparable 7:1 mixture. Surprisingly, addition of
either (DHQ)2PHAL or (DHQD)2PHAL to the reaction mix-
ture resulted in lower stereoselectivity (4.7:1 and 3.6:1,
respectively).30,31 The stereochemistry was not apparent from
the 1H NMR spectrum but was subsequently confirmed by X-ray
analysis of the bis(3,5-dinitrobenzoyl) derivative,32 and also by
the eventual conversion to epi-pseudoconhydrine.
DFT calculations attheB3LYP/LACV3P** level of theory33À38
indicate that the two most favored gas-phase transition states
leading to the diastereoisomeric trans-propyl and all-cis products
feature very similar Gibbs free energies of activation 61.4 and
57.0 kJ molÀ1, respectively. This translates into a predicted cis/
trans ratio of 6:1 at room temperature, which is in good agreement
with the experimentally obtained 7:1 ratio. The analogous free
Gibbs activation energy of the reaction of ethylene with OsO4 is
predicted to amount to 69.7 kJ molÀ1 at the same level of theory.39
In the calculated all-cis transition state (Figure 1) which leads to
the observed product 8, the angle sum of 359.7° at the nitrogen
atom reflects a planar bonding environment. The tolyl group is
directed toward the osmium tetroxide moiety with a distance
between the ortho-proton and the OsO4 oxygen of 234 À236 pm
in both diastereomeric transition states. The tosyl orientation thus
originates from the electrostatic attraction between the partially
positive tolyl group and the negatively polarized oxygen atoms
on osmium, and an electrostatic repulsion of the latter with the
negatively polarized sulfonyl fragment.
Table 1. Hydroformylationa
ligand, loading,
(mol %)
acetals 7,
alkene 6,
entry
2 yield (%)
yield (%)
yield (%)
1
2
3
4
5
6
7
(PhO)3P, 2
56
10
20
trace
0
15
4
(PhO)3P, 6
67
(PhO)3P, 12
(PhO)3P, 18
(PhO)3P, 26
(PhO)3P, 50
BIPHEPHOS, 2
78
8
82
15
12
17
0
79
0
80
0
quant
0
a Conditions Rh2(OAc)4 1 mol %, THF, CO (30 psi), H2 (30 psi) at
65 °C.
ligand, the product of linear hydroformylation, ene-sulfonamide
2, with tandem cyclo-dehydration was obtained in 56À82%
yield (Table 1). A small amount of the products of branched
hydroformylationÀcyclization were always obtained. While
the linear product was always obtained in its dehydrated form
as a cyclic ene-sulfonamide, the branched product was usually
obtained as a mixture of dehydrated form 6 and the cyclic
N,O-acetal 7, itself, a complex mixture of stereoisomers. Inter-
estingly, increasing the loading of the phosphite ligand resulted,
at first, in an increased yield of the desired ene-sulfonamide 2.
This increase leveled off at about 12 mol % (P:Rh ratio = 6:1).
Further increases in the phosphite loading, up to 50 mol %, did
not result in any noticeable inhibition of the reaction but did
cause an increase in the yield of the five-membered ring ene-
carbamate 6 at the expense of the N,O-acetal mixture 7. The
optimum conditions for the formation of the desired six-mem-
bered ring ene-carbamate appear to be with 18 mol % of the
phosphite. On the other hand, use of the bulky bisphosphite
BIPHEPHOS25 resulted in complete selectivity for the linear
isomer 2.
The cis-relationship between the 2-substituent and the 5-hy-
droxyl group is seen in natural products such as 5-hydroxyseda-
mine, azimic acid, carpamic acid, cassine, and others.40
The diol 8 was further converted to both pseudoconhydrine
and its epimer (Scheme 3). When an attempt was made to carry
out an exchange of the hydroxy group R to the nitrogen under
acidic conditions, it was found that facile rearrangement occurred
to give the ketopiperidine 9 in good yield. There appear to
be few reports of general routes to such potentially versatile
building blocks.41À44 On the basis that the n-propyl side chain
would adopt an axial position,27 the ketone was reduced with
K-selectride.15 A single diastereoisomer, expected to be trans
isomer 10, was obtained in 95% yield. This isomer was depro-
tected in 70% yield under Carpino’s conditions45 with the modifi-
cation of using ultrasound, yielding, after acidification, pseudo-
conhydrine 1 as its hydrochloride, with spectroscopic data and
optical rotation in excellent agreement with that reported.12,13
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The Journal of Organic Chemistry
NOTE
On the other hand, reduction with sodium borohydride gave a 3:1
mixture of alcohols. Deprotection of the major alcohol 12 yielded
epi-pseudoconhydrine 13. epi-Pseudoconhydrine could also be
prepared from the diol 8 without going through ketopiperidine 9.
To prevent rearrangement, the hydroxy groups were acetylated.
KursanovÀParnes reduction46 of diacetate 11 with triethylsilane
and trifluoroacetic acid removed the acetoxy group R to nitrogen.
Methanolysis of the remaining acetate group gave hydroxypiper-
idine 12 as a single diastereoisomer after chromatography,
identical to the major isomer from sodium borohydride reduction
of ketopiperidine 9.
While hydroformylation of homoallylic amine derivatives
provides a facile route to six-membered ring ene-carbamates,
dihydroxylation subsequently gives access to the cis-hydroxy
piperidines. Facile rearrangement of the diol to the ketopiper-
idine, on the other hand, provides access to both stereochemical
series. Pseudoconhydrine and its epimer are obtained in 37% and
30% yields, respectively, from propionaldehyde.
magnesium sulfate, filtered, and evaporated. The crude product was
purified by silica gel flash column chromatography to give 179 mg
(78% yield) of the sulfonamide product 3 as a colorless solid: FTIR
(neat, cmÀ1): νmax 1359, 1165; 1H NMR (400 MHz, CDCl3) δ 0.80 (t,
3H, J = 7.3 Hz), 1.09À1.44 (m, 4H), 2.09 (approx t, 2H, J = 6.9 Hz), 2.42
(s, 3H), 3.20À3.34 (m, 1H), 4.32À4.44 (m, 1H), 4.88À5.06 (m, 2H),
5.48À5.62 (m, 1H), 7.29 (d, 2H, J = 8.2 Hz), 7.74 (d, 2H, J = 7.8 Hz);
13C NMR (100 MHz, CDCl3) δ 13.9, 18.8, 21.7, 36.9, 39.2, 53.2, 119.1,
127.3, 129.8, 133.5, 138.4, 143.4; MS (ESI+) m/z 268 (M+ + 1, 100);
HRMS Calcd for C14H21NO2S (M++H) 268.1371, found 268.1366;
[R]22.3D = 19.1 (c = 2, CHCl3).
(R)-1,2,3,4-Tetrahydro-2-propyl-1-tosylpyridine (2). Amine
3 (100 mg, 0.375 mmol), Rh2(OAc)4 (1.8 mg, 3.75 Â 10À3 mmol), and
47
P(OPh)3 (20 μL, 0.075 mmol) were dissolved in THF (3 mL) in a
Fisher-Porter tube. The Fisher-Porter tube was purged (three times)
with H2/CO (1:1) and finally charged with H2 (30 psi)/CO (30 psi).
The reaction mixture was stirred vigorously at 65 °C for 18 h. The
solvent was removed under reduced pressure and the residue was
purified by silica gel flash column chromatography to give 83 mg (80%
yield) of the ene-sulfonamide 2 as a colorless oil: FTIR (neat, cmÀ1):
νmax 1359, 1165, 1645; 1H NMR (400 MHz, CDCl3) δ 0.81À0.99 (m,
1H), 0.93 (t, 3H, J = 7.32), 1.22À1.99 (m, 8H), 2.41 (s, 3H), 3.91 (br s,
1H), 5.02 (t, 6.4 Hz), 6.58 (d, 1H, J = 8.2 Hz), 7.28 (d, 2H, J = 8.2 Hz),
7.66 (d, 2H, J = 8.2 Hz); 13C NMR (100 MHz, CDCl3) δ 14.1, 17.5,
19.3, 21.8, 23.0, 33.9, 53.0, 109.6, 123.8, 127.2, 129.8, 136.4, 143.4; MS
(ESI+) m/z 280 (M+ + 1, 100); HRMS Calcd for C15H21NO2S (M+ +
H) 280.1371, found 280.1376; [R]22.5D = À311.6 (c = 1, CHCl3).
(2S,3S,6R)-6-Propyl-1-tosylpiperidine-2,3-diol (8). MeSO2-
NH2 (120 mg, 1.25 mmol) was added to a solution of ene-sulfonamide 2
(350 mg, 1.25 mmol) in THF (4 mL), and the mixture was stirred until it
was completely dissolved. To the resulting solution were added NMO
(0.77 mL, 3.76 mmol), H2O (0.44 mL), and K2OsO4 (46 mg, 0.125
mmol), and the mixture was stirred overnight. The reaction mixture was
quenched with sat. aq Na2S2O3, washed with water and brine, dried over
MgSO4, filtered, and evaporated to give 353 mg (90% yield) of the diol 8
as a yellowish oil and as an inseparable mixture of diastereoisomers:
FTIR (neat, cmÀ1): νmax 1329, 1161, 3503; 1H NMR (400 MHz,
CDCl3) δ 0.92 (t, 3H, J = 7.3 Hz), 1.20À2.00 (m, 6H), 2.21 (t, 1H, J =
7.8 Hz), 2.42 (s, 3H), 3.00À3.12 (m, 1H), 3.22À3.36 (m, 1H),
3.82À3.92 (m, 1H), 5.37 (t, 1H, J = 3.2 Hz), 7.29 (d, 2H, J = 8.2 Hz),
7.69 (d, 2H, J = 8.2 Hz); 13C NMR (100 MHz, CDCl3) δ 14.1, 20.8,
21.7, 22.6, 26.5, 36.7, 52.5, 69.4, 78.4, 127.0, 130.0, 138.3, 143.7; MS
(ESI+) m/z 314 (M+ + 1, 9), 296 (M+ À OH, 100); HRMS Calcd for
C15H23NO4S (M+ + H) 314.1426, found 314.1436.
(2S,3S,6R)-6-Propyl-1-tosylpiperidine-2,3-acetate (11). Acetic
anhydride (0.07 mL, 0.702 mmol), triethylamine (0.11 mL, 0.798 mmol),
and DMAP (4 mg, 0.032 mmol) were added to a solution of diol 8(100mg,
0.320 mmol) in CH2Cl2 (5 mL). The mixture was stirred for 3 h. The
reaction mixture was diluted with sat. aq NH4Cl, extracted with CH2Cl2,
washed with water, dried over MgSO4, filtered, and evaporated. The crude
product was purified by silica gel flash column chromatography to give a
quantitative yield of the diacetate 11 as a colorless oil and as an inseparable
mixture of diastereoisomers:48 FTIR (neat, cmÀ1): νmax 1738, 1732, 1339,
1163; 1H NMR (400 MHz, CDCl3) δ 0.91 (t, 3H, J = 7.32 Hz), 1.18À1.40
(m, 2H), 1.47À1.81 (m, 6H), 1.97 (s, 3H), 2.03 (s, 3H), 2.42 (s, 3H), 3.95
(approx q, 1H, J = 6.4 Hz), 4.61 (approx dt, 1H, J = 11.9, 4.1 Hz), 6.79 (d,
1H, J= 3.7 Hz), 7.30 (d, 2H, J= 8.2 Hz), 7.72 (d, 2H, J=8.2 Hz);13CNMR
(100 MHz, CDCl3) δ 14.2, 19.4, 20.5, 21.0, 21.2, 21.8, 26.4, 35.5, 52.6, 69.9,
76.1, 127.3, 130.0, 137.9, 144.0, 169.3, 170.1; MS (ESI+) m/z 314 (M+ À
OAc, 100), 296 (M+ À C3H6, 14); HRMS Calcd for C19H27NO6SNa
(M+ + Na) 420.1457, found 420.1461.
’ EXPERIMENTAL SECTION
(S)-2-((R)-Hept-1-en-4-ylamino)-2-phenylethanol (5). (a)
Indium powder (240 mg, 2.09 mmol) was added portionwise to a
solution of imine 4 (200 mg, 1.05 mmol) and allyl bromide (0.27 mL,
3.14 mmol) in methanol (10 mL) at À10 °C. The resulting mixture was
stirred at À10 °C for 6 h. The reaction mixture was diluted with 10%
aqueous NaHCO3, extracted with ethyl acetate, dried over magnesium
sulfate, filtered, and evaporated. The residue was purified by silica gel
flash column chromatography to give 195 mg (80% yield) of the
allylation product 4 as a colorless oil.
(b) 1,2-Dibromoethane (0.01 mL, 0.12 mmol) was added to a
suspension of zinc dust (226 mg, 3.45 mmol) in THF (20 mL). The
mixture was heated gently until ebullition of the solvent and stirred for 5
min. After the heating and stirring process was repeated three times,
chlorotrimethylsilane (0.02 mL, 0.136 mmol) was added and the
mixture was stirred for another 15 min. Allyl bromide (0.1 mL, 1.15
mmol) was added dropwise and stirring was continued for 1 h.
The mixture was added via cannula to a solution of imine 4 (200 mg,
1.05 mmol) in THF (10 mL) at À20 °C and stirred for 6 h. The reaction
mixture was then poured into a water and ethyl acetate mixture and
stirred vigorously. The mixture was then filtered, and the water layer
was extracted with ethyl acetate, dried over magnesium sulfate, and
evaporated. The product was then purified by silica gel flash column
chromatography to give 195 mg (80% yield) of the allylation product 4
as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.79 (t, 3H, J = 6.8 Hz),
1.41À1.14 (m, 4H), 2.10À2.28 (m, 2H), 2.48À2.60 (m, 1H), 3.47 (dd,
1H, J = 10.5, 8.7 Hz), 3.66 (dd, 1H, J = 10.5, 4.6 Hz), 3.88 (dd, 1H,
J = 8.7, 4.6 Hz), 5.04À5.14 (m, 2H), 5.74À5.86 (m, 1H), 7.24À7.38 (m,
5H); 13C NMR (100 MHz, CDCl3) δ 14.3, 19.2, 37.2, 38.1, 53.7, 61.7,
67.0, 117.4, 127.4, 127.7, 128.8, 135.5, 141.5; MS (ESI+) m/z 243.1
(100).
(R)-N-Tosylhept-1-en-4-amine (3). Lead tetraacetate (456 mg,
1.03 mmol) was added to a solution of amino alcohol 5 (200 mg, 0.857
mmol) in dry CH2Cl2/MeOH (1:1) at 0 °C and stirred (30 min) until
confirmed complete by TLC. Hydroxylamine hydrochloride (596 mg,
8.57 mmol) was added to the resulting mixture and stirred for another
30 min. The residue remaining after removal of the solvents was washed
with hexane and suspended in CH2Cl2 followed by filtration of the
lead precipitates. The organic solvent was evaporated and the residue
was dried in vacuo. The residue was taken up in dry CH2Cl2 (10 mL),
and Et3N (0.25 mL, 1.77 mmol) and TsCl (168 mg, 0.883 mmol) were
added and stirred overnight. The reaction mixture was then diluted with
sat. aq ammonium chloride, extracted with ethyl acetate, dried over
(R)-6-Propyl-1-tosylpiperidin-3-one (9). Trifluoroacetic acid
(10 μL, 0.128 mmol) was added to a solution of diol 8 (100 mg,
0.320 mmol) in CH2Cl2 (3 mL), and the mixture was stirred for 2 h.
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The Journal of Organic Chemistry
NOTE
The reaction mixture was evaporated, taken up in CH2Cl2, washed with
water and brine, dried over MgSO4, filtered, and evaporated. The crude
product was purified by silica gel flash column chromatography to give
quantitative yield of the ketone 9 as a colorless oil: FTIR (neat, cmÀ1):
[R]22.7D = À8.1 (c = 0.2, EtOH) {lit.12 [R]20D = À10.2 (c = 1.0, EtOH)};
mp 120À121 °C [lit.12 mp 148 °C].
1
’ ASSOCIATED CONTENT
νmax 1730, 1342, 1160; H NMR (400 MHz, CDCl3) δ 0.94 (t, 3H,
J = 7.1 Hz), 1.30À1.76 (m, 6H), 1.94À2.06 (m, 1H), 2.14À2.26 (m,
1H), 2.41 (s, 3H), 3.64 (d, 1H, J = 18.8 Hz), 4.01 (approx quin, 1H,
J = 14.2, 7.3 Hz), 4.16 (d, 1H, J = 18.3 Hz), 7.76 (d, 2H, J = 7.8 Hz), 7.65
(d, 2H, J = 8.2 Hz); 13C NMR (100 MHz, CDCl3) δ 14.1, 19.2, 21.7,
26.1, 35.6, 36.1, 51.1, 52.9, 127.2, 130.2, 136.7, 144.0, 206.7; MS (ESI+)
m/z 296 (M+ + 1, 100); HRMS Calcd for C15H21NO3S (M+ + H)
296.1320, found 296.1320; [R]22.3D = 71.3 (c = 0.5, CHCl3).
(3S,6R)-6-Propyl-1-tosylpiperidin-3-ol (12). NaBH4 (0.02 mg,
0.51 mmol) was added to a solution of ketone 9 (100 mg, 0.339 mmol) in
MeOH and the mixture was stirred at room temperature for 2 h. The
reaction mixture was evaporated, taken up in CH2Cl2, washed with water
and brine, dried over MgSO4, filtered, and evaporated to give 93 mg (93%
yield) of the hydroxypiperidine 12 as a yellowish oil and as a 3:1 mixture
of diastereoisomers.
Supporting Information. 1H NMR and 13C NMR spec-
S
b
tra for compounds 1, 2, 3, 5, 6, 8, 9, 10, 11, 12, and 13. ORTEP
and CIF files for compound 8-bis(dinitrobenzoate ester) and
details of DFT calculations. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: roderick@ntu.edu.sg.
’ ACKNOWLEDGMENT
Trifluoroacetic acid (19 μL, 0.252 mmol) was added to a solution
of the diacetate 11 (100 mg, 0.252 mmol) and Et3SiH (0.40 mL,
2.52 mmol) in CH2Cl2,. The resulting mixture was stirred (3 h) at room
temperature until confirmed complete by TLC. The reaction mixture
was diluted with water, extracted with CH2Cl2, dried over MgSO4,
filtered, and evaporated. The residue was taken up in MeOH (3 mL).
K2CO3 (52 mg, 0.378 mmol) was added, and the mixture was stirred at
room temperature for 3 h. The reaction mixture was evaporated, taken
up in CH2Cl2, washed with water and brine, dried over MgSO4, filtered,
evaporated, and purified by silica gel flash column chromatography to
give 57 mg (76% yield) of the piperidinol 12 as a colorless oil: 1H NMR
(400 MHz, CDCl3) δ 0.87 (t, 3H, J = 7.3 Hz), 1.15À1.83 (m, 8H), 2.42
(s, 3H), 2.71 (dd, 1H, J = 13.3, 11.0 Hz), 3.37À3.50 (m, 1H), 3.85 (ddd,
1H, J = 13.3, 5.0, 1 Hz), 3.92À4.01 (m, 1H), 7.28 (d, 2H, J = 7.8 Hz),
7.70 (d, 2H, J = 8.2 Hz); 13C NMR (100 MHz, CDCl3) δ 14.0, 19.9,
21.7, 26.7, 28.4, 31.4, 46.4, 51.9, 66.3, 127.1, 129.9, 138.5, 143.3; MS
(GC) m/z 254 (M+ À C3H7, 100), 155 (M+ À C8H16NO, 24); HRMS
We thank Nanyang Technological University and the Singa-
pore Ministry of Education Academic Research Fund Tier 1
(grant RG62/10) and the University of Heidelberg for support of
this work. We thank Professor Tirayut Vilaivan (Chulalongkorn
University, Bangkok, Thailand) for helpful discussions about
allylation and Professor Jason Smith (University of Tasmania)
for encouragement in using the Ts protecting group.
’ REFERENCES
(1) Maitlis, P; Haynes, A. Metal-catalysis in Industrial Organic
Processes; Royal Society of Chemistry: Cambridge, 2008; p 141.
(2) Frohning, C. D.; Kohlpainter, C. W. Applied Homogeneous
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(3) Parshall, G. W.; Ittel, S. D. Applied Homogeneous Catalysis; John
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(4) Breit, B.; Seiche, W. Synthesis 2001, 1.
Calcd. for C15H23NO3S (M+ + H) 298.1477, found 298.1483; [R]21.9
À2.2 (c = 1, CHCl3).
=
D
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(3R,6R)-6-Propyl-1-tosylpiperidin-3-ol (10). K-Selectride (0.37 mL
of a 1 M solution in THF, 0.37 mmol) was added to a solution of
ketopiperidine 9 (100 mg, 0.339 mmol) in THF (3 mL) at 0 °C, and the
mixture was stirred and allowed to warm slowly to room temperature. The
reaction mixture was diluted with water, extracted with CH2Cl2, dried over
MgSO4, filtered, evaporated, and purified by silica gel flash column chroma-
tography to give 95 mg (95% yield) of the trans isomer 10 as a colorless oil. 1H
and 13C NMR spectroscopic data were in agreement with literature values.12
General Procedure for Detosylation. Mg turnings (163 mg,
6.72 mmol) were added to a solution of tosylpiperidinol (100 mg, 0.336
mmol) in MeOH (3 mL) portionwise over 3 h as the reaction mixture
was being sonicated (ultrasonic cleaning bath) or until confirmed to
be complete by TLC. The reaction mixture was acidified with 2 M
HCl, washed with CH2Cl2, neutralized with 2 M NaOH, and extracted
with CH2Cl2. The organic layer was reacidified with 2 M HCl, and
the aqueous layer was evaporated to give 42 mg (70% yield) of the
piperidinol salt as a brownish solid.
(6) Laemmerhold, K. M.; Breit, B. Angew. Chem., Int. Ed. 2010,
49, 2367.
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1
(3R,6R)-6-Propylpiperidin-3-ol Hydrochloride (1). H and
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17.8, 22.7, 27.6, 35.1, 49.1, 56.6, 61.5; MS (ESI+) m/z 144 (M+ + 1, 100);
HRMS Calcd for C8H17NO (M+ + H) 144.1388, found 144.1385;
6847
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The Journal of Organic Chemistry
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