Enantioselective synthesis of 1,2,5,6-tetrahydropyridines (THPs): Via proline-catalyzed direct Mannich-cyclization/domino oxidation-reduction sequence: Application for medicinally important N-heterocycles

Article abstract of DOI:10.1039/c6ra12965j

An enantioselective multi-component synthesis of 1,2,5,6-tetrahydropyridines (THPs) has been developed through a one-pot domino-process. This transformation proceeds through proline-catalyzed direct Mannich reaction-cyclization of glutaraldehyde with in s

Full text of DOI:10.1039/c6ra12965j

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Enantioselective synthesis of 1,2,5,6-tetrahydropyridines (THPs)
via proline-catalyzed direct Mannich-cyclization/domino
oxidation-reduction sequence: Application for medicinally
important N-heterocycles
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Panduga Ramaraju,a Nisar A. Mir,a Deepika Singhb and Indresh Kumar*a
www.rsc.org/
An enantioselective multi-component synthesis of 1,2,5,6-tetrahydropyridines (THPs) has been developed through a one-
pot domino-process. This transformation proceeds through proline-catalyzed direct Mannich reaction-cyclization of
glutaraldehyde with in situ generated imines, followed by site-selective oxidation-reduction sequence under mild
conditions. Chiral 1,2,5,6-THPs are obtained in good to high yields (up to 80%) and with the excellent enantioselectivity (up
to 98:2 er). The usefulness of this operationally simple method is also shown to synthesize other medicinally important
nitrogen-heterocycles.
increases the “pot economy” of the overall process.10 In
addition, multi-
Introduction
Functionalized piperidine and polyhydropyridines are an
integral part of numerous natural products.1 In particular,
1,2,5,6-tetrahydropyridine (THP) is an important structural
motif present in many biologically important synthetic
pharmaceuticals as well as natural products; such as
haouamine’s (I, II),2a,b anhydrocannabisativine (III),2c
compounds (IV, V)2d,e and (VI),3a guvacine (VII),3b (−)-205B
(VIII),3c and SKF 100330-A (IX)3d (Fig. 1). Due to the medicinal
significance of this aforementioned scaffold, several
fascinating methods found in the literature to synthesize
1,2,5,6-THPs4 which includes; hetero-Diels-Alder reaction,5
involvement of imine,6 and reduction of dihydropyridine.7
Despite of few advances for the asymmetric synthesis of
1,2,5,6-THPs,8 the development of a simple, convenient and
environmentally friendly approach for optically pure THPs is
highly desirable.
OH
Z
O
HO
O
H
N
OR
H
HO
H
N
N
N
Ar
N
H
Ar
H
R
O
(IV) Z = NHAr
(V) Z = OH
antimalarial and
C5H11
(III)
HO
(I) R = H, Haouamine A
(II) R = OH, Haouamine B
Anhydrocannabisarivine
anticancer activity
H
COOH
Me
COOH
CO2H
H
H
N
N
Ar
N
Ar
N
H
Ph
Ts
Me
Me
(VII)
Guvacine
(VI)
anticancer
Ph
(VIII)
(−)-205B
(IX)
SKF 100330-A
Fig. 1 Biologically important compounds having tetrahydropyridine (THP) moiety
The development of “one-pot domino process” for chemical
transformations that run with the ultimate aim of “to
complete an entire multi-step, multi-reaction synthesis in a
single pot” is not only considered as a sustainable strategy but
also support the basis of the green chemistry philosophy.9 One
way to achieve this task is to add substrates/reagents
sequentially at different time intervals, without workup and
product isolation at an intermediate stage, which further
component reactions (MCRs) is an alternative way to achieve
multiple bond formations in a one pot operation,11 however
the development of asymmetric MCRs are still infancy.12 In this
direction, organocatalysis13 have contributed significantly to
the recent growth of asymmetric domino14 and MCRs,15 under
mild conditions due to the increasing demand of chiral
scaffolds in pharmaceuticals. Recently, two parallel chiral
phosphoric acid catalyzed MCRs of aromatic aldehydes,
anilines, and β-ketoesters were reported by Xufeng Lin et al.16a
and Shi and Tu et al.16b to synthesize 1,2,5,6-THPs in
asymmetric fashion (eq 1, Scheme 1). A multi-component
reaction will be more cost-effective by linking through a
domino-process of three or even four consecutive steps in one
pot operation in such a way that the product of initial step
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later become the substrate for next reaction until dissolution to be best in our previous studies. However, by changing the
leads to stable product. Therefore, we present a highly reaction temperature at individual steps, we could obtain our
enantioselective synthesis of 1,2,5,6-tetrahydropyridines product with 80% yield and excellent enantioselectivity (97:3
(THPs) through proline-catalyzed multi-component Mannich er) (entry 2, Table 1). A further change in the reaction
reaction-cyclization followed by site-selective oxidation- conditions (entry 3, Table 1), and catalyst loading (entry 4,
reduction sequence as a domino-process in a single flask (eq 2, Table 1), resulted a loss in the overall yield. Thus, we choose to
Scheme 1).
perform this one pot protocol of sequential multi-component
amine catalyzed [4+2] annulation/IBX oxidation/acid mediated
NaBH4 reduction through preferred conditions (entry 2, Table
1).
Earlier work: (organocatalytic asymmetric multicomponent approach) ref (16)
NHAr2O
O
O
Ar1
Ar2
chiral
OR
(1)
+
2
+
2
Table 1 Optimization of reaction conditions for pyrrole-3-methanols
CHO
NH2
phosphoric acid
OR
Ar1
N
Ar1
Ar2
Present work: (organocatalytic asymmetric multicomponent one-pot domino process)
OMe
O
CH2OH
R
L-proline 1 (20 mol %)
CHO
CHO
DMSO
+
+
(2)
R
H
IBX
H+, NaBH4
N
2
PMP
4
R= Ar, HetAr
NH2
One-pot process
5
(25% aq sol)
3
chiral 1,2,5,6-THPs
Scheme 1 Overview of present work for pyrrole-3-methanols synthesis
Results and discussion
Linear dialdehydes have recently being shouted as suitable
bifunctionalized substrates for amine catalyzed asymmetric
and non-asymmetric transformations.17 In this direction, Xu
and co-workers have earlier utilized glutaraldehyde and imines
for the asymmetric synthesis of 1,2,3,4-tetrahydropyridines
(THPs).18 Our group has independently developed proline-
catalyzed [4+2] annulation between glutaraldehyde and imines
for the asymmetric synthesis of piperidines,19 and 1,2-
dihydropyridines (DHPs).20 Next, we become fascinated to
extend our idea of the synthesis of 1,2,5,6-THPs and that is
quite feasible if we selectively reduce the in situ generated 1,2-
DHPs without isolation so that a one pot domino process will
be realized. Although the use of preformed imines was an
option, the whole process will be greener and more
economical if imines could be generated in situ. This reaction
could conveniently follow multi-component pathway through
in situ formation of imine (step 1), proline-catalytic Mannich
reaction-cyclization (step 2), in situ site-selective oxidation
with IBX (step 3) and finally acid mediated selective NaBH4
reduction (step 4) as one pot domino-approach to furnish
1,2,5,6-THPs with high stereoselectivity without any isolation
at intermediate stage. By keeping this idea in mind and the
previous experience in this direction, we quickly established
the reaction conditions by taking p-nitrobenzaldehyde 2c as a
aUnless otherwise indicated, the reaction was carried out with: (step 1) 2c (0.3
mmol), 3 (0.3 mmol), DMSO (3.0 mL), (step 2) glutaraldehyde 4 (25% aqueous
sol., 0.9 mmol), L-Proline 1 (20 mol %), (step 3) IBX (120 mol %), and (step 4)
MeOH (3.0 mL), NaBH4 (excess), CH3CO2H (200 mol %). bIsolated yield of 5c.
cDetermined using stationary chiral columns. dCH3CO2H (200 mol %), and MeOH
(3.0 mL) were not added during step 4. eCatalyst 1 (10 mol %).
Once we established the reaction conditions for this one pot
domino sequence, we turn our attention to check the
substrate scope with respect to
aldehydes having various substituents. This one pot protocol
advance well in almost all cases when aromatic aldehydes
a variety of aromatic
2
2
were decorated with electron withdrawing groups (EWG) (e.g.
−NO2, −F, −Cl, −Br and –CN) at the ortho-, meta-, or para-
positions, and furnished corresponding 1,2,5,6-DHPs 5a
(Table 2) with good yields and high enantioselectivity’s. In all
the cases, aromatic aldehyde was stirred with p-anisidine
-5p
2
3
at rt for about 3 h (step 1) for in situ generation of imine,
which subsequently used for further steps. The amine
catalyzed Mannich reaction-cyclization (step 2) was rather
slow in case of imines generated from aldehydes substituted at
ortho-position
(5a, 5d, 5g, and 5i, Table 2). A similar
observation of slow reaction was made for 5q (Table 2) when
benzaldehyde 2q was used for this one-pot sequence.
model substrate along with p-anisidine
3 and glutaraldehyde 4
Pleasantly, compound 5r-5v (Table 2) were also obtained in
as shown in Table 1.
good yields and high enantiomeric ratio, when hetero-
aromatic aldehydes were employed under standardized
conditions. This reaction failed to give desired product 5w
(Table 2) when electronically rich aryl-aldehydes was
employed.
During our experimental studies, we initially carried out all
steps of the multi-component/domino-reaction at room
temperature with proline
1 (20 mol %) in DMSO as preferred
solvent and obtained 1,2,5,6-THP 5c exclusively in moderate
yield (65%) and enantioselectivity (88:12 er) (entry 1, Table 1).
We did not alter the amine catalyst or solvent as they turn out
2 | J. Name., 2012, 00, 1-3
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Table 2 Substrate scope with respect to various iminonitriles 2
aUnless otherwise indicated, the reaction was carried out with (step 1) 2 (0.3
mmol), 3 (0.3 mmol), DMSO (3.0 mL), 3 h, (step 2) glutaraldehyde 4 (25%
aqueous sol., 0.9 mmol), L-Proline 1 (20 mol %), btime required (h), (step 3) IBX
(120 mol %), 40 °C, 4 h, and (step 4) NaBH4 (excess), MeOH (3.0 mL), CH3CO2H
(200 mol %) in single flask. cisolated yield of 5. dDetermined using stationary
chiral columns.
OMe
O
CH2OH
R
proline 1
DMSO
CHO
+
+
R
H
IBX
H+, NaBH4
N
CHO
2
PMP
4
R= Ar, HetAr
NH2
One-pot process
5, time (h)b
(%)c, erd
(25% aq sol)
3
conditionsa
Synthetic applications
OH
OH
OH
NO2
1,2,5,6-THPs
5, carrying a double bond and alcohol
NO2
N
N
N
functionality as well as some functional groups at the aromatic
ring, are interesting scaffolds for further functionalization.
Therefore, we
PMP
PMP
PMP
NO2
5a, 10 h, 63%
5b, 8 h, 74%
5c, 6 h, 80%
er = 97:3
er = 97:3
er = 94:6
initially developed
a rapid synthesis of chromeno-[4,3-
b]pyridine 7 from compound 5j to demonstrate the synthetic
OH
F
OH
OH
potential of these compounds. Pd-catalyzed intramolecular C-
O coupling reaction of in situ generated syn-alcohol (Scheme
2a) via Pd/C reduction of 5j, furnished polycyclic alkaloid-type
F
N
N
N
PMP
PMP
PMP
F
product
Subsequent PMP-cleavage (PMP = p-methoxyphenyl) resulted
highly functionalized hexahydrochromeno[4,3-b]pyridine
This polycyclic chromeno-[4,3-b]pyridine compound and
similar ring systems are present as core skeletons in many
interesting bioactive compounds, like- Moreover,
and 9 21
6 having syn-stereochemistry at two chiral centers.
5d, 9 h 61%
er = 98:2
5e, 7 h, 66%
er = 81:19
5f, 7 h, 68%
er = 83:17
7.
OH
Cl
OH
OH
7
Cl
N
N
N
8
.
PMP
PMP
PMP
Cl
derivatization of the double-bond present in the ring through
diastereoselective epoxidation/dihydroxylation reactions could
lead to saturated piperidines. Initially, 5c underwent
diastereoselective epoxidation with m-CPBA (meta-
chloroperbenzoic acid) in CH2Cl2 at rt to corresponding epoxy-
5h, 8 h, 68%
5g, 10 h, 65%
er = 97:3
5i, 8 h, 70%
er = 86:14
er = 85:15
OH
Br
OH
OH
Br
N
N
N
compound 10
.
Whereas, corresponding dihydroxylated
PMP
PMP
PMP
Br
compound 11 was obtained with good yield and selectivity (dr
≥95:5) under standard dihydroxylation conditions (Scheme 2b).
These polyhydroxyl-piperidines and similarly functionalized
compounds are important glycosidase inhibitors categorized as
iminosugars.22
5j, 10 h, 58%
er = 98:2
5k, 9 h, 67%
er = 90:10
5l, 9 h, 69%
er = 92:8
OH
OH
OH
Br
CN
N
N
N
PMP
PMP
PMP
CN
F
5o, 9 h, 78%
er = 90:10
5m, 8 h, 71%
er = 87:13
5n, 9 h, 74%
er = 88:12
OH
OH
OH
N
Cl
Cl
N
N
N
PMP
PMP
PMP
5p, 9 h, 70%
er = 93:7
5r, 10 h, 63%
5q, 10 h, 58%
er = 91:9
er = 85:15
OH
OH
OH
S
N
N
N
N
PMP
PMP
N
PMP
5u, 10 h, 53%
er = 86:14
5s, 11 h, 72%
er = 81:19
5t, 10 h, 76%
er = 96:4
OH
O
OH
N
N
NO2
PMP
PMP
5w, 24 h, nr
Scheme 2 Applications for the synthesis of hexahydrochromeno[4,3-b]pyridine
OMe
and important polyfunctionalized piperidines
5v, 8 h, 63%
er = 86:14
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Interestingly, direct oxidation of primary alcohol functionality Synthetic application of this method was also shown to
of 5q to corresponding carboxylic acid provide a rapid access synthesize structural analog 19 of (–)-CP-99 994 20 as this
to guvacine derivatives 12 (Scheme 3a). Further, we also compound carries interesting biological activity.24 In this
showed the synthetic utility of our approach to synthesize ent- context, firstly Pd/C catalyzed hydrogenation of THP-
5q by just changing the stereochemistry of catalyst used under compound 5q gave syn-2,3-substituted-piperidine 16 in 90%
standardized
conditions
with
similar
yields
and yield and with high diastereoselectivity (dr ≥95:5). The
enantioselectivity (18:82 er). The resulting product ent-5q was alcoholic group was converted into –OTs under standard
next used for the synthesis of syn-nipecotic acid derivative 14 condition, the crude 17 was further subjected to nucleophilic
with 66% yield (after two steps, Scheme 3b) through substitution with 2-methoxyaniline 18 under heating condition
reduction-oxidation sequence. Nipecotic acid 15, a cyclic resulted in compound 19 (68% yield from 20, Scheme 4).
amino acid and considered as a conformationally restricted β-
alanine analog, shows high in vitro activity as an inhibitor of
[3H]GABA uptake.23
Conclusions
In summary, we have developed an efficient multi-component
domino-sequence for the asymmetric synthesis of
functionalized 1,2,5,6-tetrahydropyridines (THPs) in a single
flask. This method proceeds through proline-catalyzed
Mannich reaction-cyclization of glutaraldehyde with in situ
generated imines, followed by sequential selective IBX-
oxidation/NaBH4-reduction under mild conditions, without any
isolation at intermediate stages. Further applications of this
developed method were also shown for the synthesis of; (i)
hexahydrochromeno[4,3-b]pyridine (ii) polyhydroxy-piperidine
(iii) guvacine and nipecotic acid derivatives, and (iv) structural
analog of (–)-CP 99 994, as medicinally important scaffolds.
Further efforts are underway to synthesize other important
polyhydropyridines through this one-pot method and results
will be presented later.
Experimental
General Remarks: Unless otherwise stated, all reagents were
purchased from commercial suppliers and used without
further purification. All solvents employed in the reactions
were distilled from appropriate drying agents prior to use. All
reactions under standard conditions were monitored by thin-
layer chromatography (TLC) on Merck silica gel 60 F254 pre-
coated plates (0.25 mm). The column chromatography was
Scheme 3 Quick synthesis of guvacine and nipecotic acid derivative
performed on silica gel (100-200) using
a mixture of
hexane/EtOAc. Chemical yields refer to pure isolated
substances. 1H-NMR spectra were recorded on a BRUKER-
AV400 (400 MHz) spectrometer. Chemical shifts are reported
in ppm from tetramethylsilane with the solvent resonance as
1
the internal standard (CDCl3= δ 7.26 for H, and 77.00 for 13C-
NMR). Data are reported as follows: chemical shift, multiciplity
(s = singlet, d = doublet, dd = doublet of doublet, t = triplet, q =
quartet, br = broad, m = multiplet), coupling constants (Hz)
and integration. 13C-NMR spectra were recorded on a BRUKER-
AV400 (75 MHz) spectrometer with complete proton
decoupling. High-resolution mass spectra were recorded using
the quadrupole electrospray ionization (ESI) technique. HPLC
was performed on Water-2998-instrument with CHIRALPAK-IA
and IB columns using hexane/2-propanol.
Scheme 4 Synthesis of structural analog 19 of (–)-CP-99 994 20
Typical procedure for the synthesis of THPs (5)
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To a stirred solution of aryl aldehyde
2
(0.3 mmol) in DMSO
(0.3 mmol) and stirred tetrahydropyridin-3-yl)methanol (5c).
for additional 3 hr at same temperature. To this mixture, was Yellowish viscous oil, (82 mg, 80% yield), 1H NMR (400 MHz,
added glutaraldehyde (25 % sol. in water, 0.360 mL, 0.9 CDCl3) δ 2.32–2.47 (m, 2H), 3.11–3.22 (m, 2H), 3.74 (s, 3H),
mmol), and L-proline (6.9 mg, 0.06 mmol) and taken to 10 °C. 3.85 (d, J = 12.7 Hz, 1H), 3.99 (d, J = 12.8 Hz, 1H), 5.18 (s, 1H),
(R)-(1-(4-Methoxyphenyl)-2-(4-nitrophenyl)-1,2,5,6-
(3.0 mL) at rt was added p-anisidine
3
4
1
This reaction mixture was further stirred at the same 6.14 (t, J = 3.2 Hz, 1H), 6.75 (d, J = 9.1 Hz, 2H), 6.83 (d, J = 9.1
temperature until the in situ generated imine was consumed Hz, 2H), 7.31 (d, J = 8.8 Hz, 2H), 8.07 (d, J = 8.8 Hz, 2H); 13C
completely as monitored by TLC. IBX (2-Iodoxybenzoic acid) NMR (75 MHz, CDCl3) δ 24.79, 42.96, 55.32, 61.74, 66.59,
(1.2 equiv, 0.36 mmol) was added into the same flask and 114.15 (2C), 121.20 (2C), 122.98 (2C), 124.84, 129.48 (2C),
further heated to 40 °C for 4 hrs. This reaction mixture was 136.81, 143.68, 146.82, 147.80, 154.28; IR (KBr)/cm-1 3446,
then cooled to 0 °C and methanol (3.0 mL) was added followed 2925, 2854,1522, 1468, 1350, 1241, 1180, 1034; HRMS (ESI
25
by NaBH4 (in excess and portion wise) along with CH3CO2H Calcd for C19H20N2O4 (MH+) 341.1501; Found: 341.1495. [α]D
(200 mol %) until the dark red color of the solution turned into = – 198 (c 1.0, CH2Cl2). HPLC analysis: 97:3 er [Daicel Chiralpak-
pale reddish yellow. The reaction was quenched slowly with IA, n-hexane/2-propanol = 80/20), flow rate (1.0 mL/min), t
saturated NaHCO3 (5.0 mL, 20% sol.) and stirred with ethyl (minor) = 17.932 min, t (major) = 22.037 min].
acetate (10 mL) for 10 min. at rt and organic layer was
(S)-(2-(2-Fluorophenyl)-1-(4-methoxyphenyl)-1,2,5,6-
separated out. The aqueous layer was further extracted with tetrahydropyridin-3-yl)methanol (5d).
ethyl acetate (10 mL) and the combined organic extracts were Reddish viscous oil, (57 mg, 61% yield), 1H NMR (400 MHz,
washed with brine solution, dried over anhydrous Na2SO4 and CDCl3) δ 2.17–2.22 (m, 1H), 2.27–2.32 (m, 1H), 3.28–3.31 (m,
concentrated under reduced pressure after filtration. 2H), 3.74 (s, 3H), 3.94 (s, 2H), 5.48 ( s, 1H), 6.11 (t, J = 3.9 Hz,
Purification was performed by a silica gel column and eluted 1H), 6.77 (d, J = 8.9 Hz, 2H), 7.02 (d, J = 9.0 Hz, 2H), 7.17–7.22
with hexane/EtOAc to give product
enantiomeric ratios (er) of the products were determined by MHz, CDCl3) δ 23.38, 44.79, 55.37, 57.34, 64.71, 114.08 (2C),
5
(58-80% yields). The (m, 2H), 7.32–7.34 (m, 1H) 7.39–7.41(m, 1H); 13C NMR (75
stationary chiral phase HPLC analysis.
120.67 (2C), 124.84, 126.43, 128.51, 129.81, 129.96, 135.32,
137.64, 138.39, 144.27, 153.89; IR (KBr)/cm-1 3140, 2916,
(R)-(1-(4-Methoxyphenyl)-2-(2-nitrophenyl)-1,2,5,6-
tetrahydropyridin-3-yl)methanol (5a).
Yellow viscous oil, (64 mg, 63% yield), 1H NMR (400 MHz, C19H20FNO2 (MH+) 314.1556; Found: 314.1559. [α]D = – 46.1
CDCl3) δ 1.77–1.79 (bs, 1H), 2.18–2.23 (m, 1H), 2.25-2.32 (m, (c 0.8, CH2Cl2). HPLC analysis: 98:2 er [Daicel Chiralpak-IB, n-
1H), 3.00–3.07 (m, 1H), 3.15–3.19 (m, 1H), 3.73 (s, 3H), 4.06 (s, hexane/2-propanol = 90/10), flow rate (0.5 mL/min), t (minor)
2H), 5.80 (s, 1H), 6.16 (t, J = 4.2 Hz, 1H), 6.72 (d, J = 9.1 Hz, = 11.835 min, t (major) = 14.871 min].
2850,1660, 1508, 1246, 1178; HRMS (ESI): Calcd for
25
2H), 6.84 (d, J = 9.1 Hz, 2H), 7.32–7.36 (m, 1H), 7.50–7.51 (m,
(R)-(2-(3-Fluorophenyl)-1-(4-methoxyphenyl)-1,2,5,6-
2H), 7.63 (d, J = 8.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 23.70, tetrahydropyridin-3-yl)methanol (5e).
44.50, 55.35, 55.57, 64.91, 114.20 (2C), 121.40 (2C), 124.16, Yellow viscous liquid, (62 mg, 66% yield), 1H NMR (400 MHz,
125.61, 128.02, 130.13, 131.66, 135.19, 136.73, 143.78, CDCl3) δ 2.26–2.31 (m, 1H), 2.39–2.47 (m, 1H), 3.18–3.21 (m,
150.57, 154.65; IR (KBr)/cm-1 3448, 2924, 2854, 1520, 1466, 2H), 3.74 (s, 3H), 3.91 (d, J = 12.4 Hz, 1H), 3.99 (d, J = 12.7 Hz,
1350, 1242, 1180, 1034; HRMS (ESI): Calcd for C19H20N2O4 1H), 5.08 (s, 1H), 6.10 (t, J = 4.3 Hz, 1H), 6.76 (d, J = 9.1 Hz, 2H),
25
(MH+) 341.1501; Found: 341.1504. [α]D = – 81.4 (c 0.1, 6.86 (d, J = 9.2 Hz, 3H), 6.90–6.92 (m, 2H), 7.14–7.20 (m, 1H);
CH2Cl2). HPLC analysis: 97:3 er [Daicel Chiralpak-IB, n- 13C NMR (75 MHz, CDCl3) δ 24.62, 42.63, 55.44, 61.87, 64.97,
hexane/2-propanol = 94/06), flow rate (0.8 mL/min), t (minor) 114.15 (2C), 114.33, 115.41, 115.62, 120.88 (2C), 124.39,
= 15.224 min, t (major) = 22.808 min].
124.67, 129.27, 129.35, 137.59, 144.24, 153.99; IR (KBr)/cm-1
3420, 2924, 2848, 1655, 1589, 1247, 1170; HRMS (ESI Calcd
(R)-(1-(4-Methoxyphenyl)-2-(3-nitrophenyl)-1,2,5,6-
tetrahydropyridin-3-yl)methanol (5b).
25
for C19H20FNO2 (MH+) 314.1556; Found: 314.1562. [α]D = –
Pale yellow viscous liquid, (75 mg, 74% yield), 1H NMR (400 41.3 (c 0.6, CH2Cl2). HPLC analysis: 81:19 er [Daicel Chiralpak-
MHz, CDCl3) δ 2.33–2.47 (m, 2H), 3.10–3.22 (m, 2H), 3.73 (s, IA, n-hexane/2-propanol = 90/10), flow rate (0.5 mL/min), t
3H), 3.86 (d, J = 12.8 Hz, 1H), 4.01 (d, J = 12.8 Hz, 1H), 5.20 (s, (minor) = 17.480 min, t (major) = 20.078 min].
1H), 6.16 (t, J = 3.1 Hz, 1H), 6.75 (d, J = 9.1 Hz, 2H), 6.85 (d, J =
(R)-(2-(4-Fluorophenyl)-1-(4-methoxyphenyl)-1,2,5,6-
9.0 Hz, 2H), 7.37 (t, J = 7.9 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), tetrahydropyridin-3-yl)methanol (5f).
8.02–8.08 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 24.68, 43.00, Yellowish viscous liquid, (64 mg, 68% yield), 1H NMR (400 MHz,
55.40, 61.64, 64.78, 114.24 (2C), 121.24 (2C), 122.41, 123.23, CDCl3) δ 2.25–2.26 (m, 1H), 2.39–2.47 (m, 1H), 3.14–3.17 (m,
125.30, 128.76, 135.14, 136.77, 141.61, 143.76, 147.90, 2H), 3.74 (s, 3H), 3.93 (m, 2H), 5.07 (s, 1H), 6.09 (t, J = 4.4 Hz,
154.34; IR (KBr)/cm-1 3418, 2924, 2847, 1605, 1520, 1458, 1H), 6.75 (d, J = 9.2 Hz, 2H), 6.84 (d, J = 9.1 Hz, 2H), 6.89 (t, J =
1342, 1250, 1188, 1034; HRMS (ESI): Calcd for C19H20N2O4 8.7 Hz, 2H), 7.07 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 24.76,
25
(MH+) 341.1501; Found: 341.1508. [α]D = – 173 (c 0.5, 42.35, 55.43, 61.80, 65.02, 114.10 (2C), 114.62, 114.83, 121.16
CH2Cl2). HPLC analysis: 94:6 er [Daicel Chiralpak-IA, n- (2C), 124.14, 130.35, 130.43, 134.74, 137.93, 144.31, 154.04,
hexane/2-propanol = 90/10), flow rate (0.5 mL/min), t (minor) 160.83; IR (KBr)/cm-1 3426, 2924, 2854, 1643, 1597, 1512,
= 29.538 min, t (major) = 33.207 min].
1242, 1034, 825, 725; HRMS (ESI): Calcd for C19H20FNO2 (MH+)
25
314.1556; Found: 314.1549. [α]D = – 101 (c 0.2, CH2Cl2).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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DOI: 10.1039/C6RA12965J
ARTICLE
Journal Name
HPLC analysis: 83:17 er [Daicel Chiralpak-IA, n-hexane/2- 7.55 (m, 1H), 7.59–7.61 (m, 1H); 13C NMR (75 MHz, CDCl3) δ
propanol = 90/10), flow rate (0.5 mL/min), t (minor) = 18.826 23.36, 45.13, 55.36, 59.75, 64.72, 114.04 (2C), 121.06 (2C),
min, t (major) = 20.510 min].
124.97, 126.17, 127.03, 128.78, 130.19, 133.18, 137.67,
140.09, 144.35, 153.98; IR (KBr)/cm-1 3317, 3055, 2916, 2847,
(S)-(2-(2-Chlorophenyl)-1-(4-methoxyphenyl)-1,2,5,6-
tetrahydropyridin-3-yl)methanol (5g).
1512, 1450, 1242, 1180, 1034; HRMS (ESI): Calcd for
1
25
Dark red viscous liquid, (64 mg, 65% yield), H NMR (400 MHz, C19H20BrNO2 (MH+) 374.0755; Found: 374.0759. [α]D = – 32.3
CDCl3) δ 2.16–2.23 (m, 1H), 2.25–2.34 (m, 1H), 3.28–3.31 (m, (c 0.6, CH2Cl2). HPLC analysis: 98:2 er [Daicel Chiralpak-IB, n-
2H), 3.74 (s, 3H), 3.93 (s, 2H), 5.48 (s, 1H), 6.11 (t, J = 3.8 Hz, hexane/2-propanol = 90/10), flow rate (0.5 mL/min), t (minor)
1H), 6.77 (d, J = 9.1 Hz, 2H), 7.02 (d, J = 9.0 Hz, 2H), 7.15–7.22 = 10.465 min, t (major) = 13.302 min].
(m, 2H), 7.32–7.34 (m, 1H), 7.37–7.41 (m, 1H); 13C NMR (75
(R)-(2-(3-Bromophenyl)-1-(4-methoxyphenyl)-1,2,5,6-
MHz, CDCl3) δ 23.35, 44.76, 55.38, 57.30, 64.75, 114.07 (C), tetrahydropyridin-3-yl)methanol (5k).
120.64 (2C), 124.90, 126.44, 128.53, 129.83, 129.96, 153.33, Yellow viscous liquid, (75 mg, 67% yield), 1H NMR (400 MHz,
137.62, 138.38, 144.25, 153.87; IR (KBr)/cm-1 3418, 2924, CDCl3) δ 2.27–2.28 (m, 1H), 2.41–2.48 (m, 1H), 3.19–3.22 (m,
2862, 1659, 1512, 1458, 1250, 1188, 1095, 1034; HRMS (ESI): 2H), 3.77 (s, 3H), 3.92 (d, J = 12.9 Hz, 1H), 4.01 (d, J = 12.8 Hz,
Calcd for C19H20ClNO2 (MH+) 330.1261; Found : 330.1255. 1H), 5.07 (s, 1H), 6.12 (t, J = 4.2 Hz, 1H), 6.79 (d, J = 9.2 Hz, 2H),
25
[α]D = – 76.6 (c 0.3, CH2Cl2,). HPLC analysis: 97:3 er [Daicel 6.88 (d, J = 9.1 Hz, 2H), 7.05–7.12 (m, 2H), 7.34–7.37 (m, 2H);
Chiralpak-IB, n-hexane/2-propanol = 90/10), flow rate (0.6 13C NMR (75 MHz, CDCl3) δ 24.44, 42.35, 55.40, 61.75, 64.69,
mL/min), t (minor) = 8.278 min, t (major) = 11.601 min].
(R)-(2-(3-Chlorophenyl)-1-(4-methoxyphenyl)-1,2,5,6-
tetrahydropyridin-3-yl)methanol (5h).
114.12 (2C), 120.86 (2C), 122.09, 124.34, 127.66, 129.40,
130.34, 131.49, 137.24, 141.57, 144.01, 153.98; IR (KBr)/cm-1
3302, 3055, 2916, 2839, 1566, 1512, 1458, 1242, 1180, 1034;
Pale yellow liquid, (67 mg, 68% yield), 1H NMR (400 MHz, HRMS (ESI): Calcd for C19H20BrNO2 (MH+) 374.0755; Found:
25
CDCl3) δ 2.19 (bs, 1H), 2.25–2.30 (m, 1H), 2.40–2.46 (m, 1H), 374.0762. [α]D = – 113.3 (c 1.5, CH2Cl2). HPLC analysis: 90:10
3.17–3.20 (m, 2H), 3.78 (s, 3H), 3. 89 (d, J = 12.8 Hz, 1H), 3.98 er [Daicel Chiralpak-IA, n-hexane/2-propanol = 90/10), flow
(d, J = 12.8 Hz, 1H), 5.06 (s, 1H), 6.09 (t, J = 3.2 Hz, 1H), 6.76 (d, rate (0.5 mL/min), t (minor) = 17.692 min, t (major) = 19.870
J = 9.1 Hz, 2H), 6.86 (d, J = 9.1 Hz, 2H), 6.98–7.01 (m, 1H), 7.08– min].
7.13 (m, 1H), 7.15–7.19 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
(R)-(2-(4-Bromophenyl)-1-(4-methoxyphenyl)-1,2,5,6-
24.47, 42.47, 55.42, 6180, 64.76, 114.14 (2C), 120.87 (2C), tetrahydropyridin-3-yl)methanol (5l).
124.36, 127.25, 127.46, 128.64, 129.12, 133.79, 137.33, Colorless viscous liquid, (77 mg, 69% yield), 1H NMR (400 MHz,
141.36, 144.03, 154.01; IR (KBr)/cm-1 3464, 2924, 2947, 1643, CDCl3) δ 2.25–2.30 (m, 1H), 2.38–2.46 (m, 1H), 3.13–3.16 (m,
1512, 1242, 1188, 1088, 1034; HRMS (ESI): Calcd for 2H), 3.74 (s, 3H), 3.87 (d, J = 12.0 Hz, 1H), 3.96 (d, J = 12.9 Hz,
C19H20ClNO2 (MH+) 330.1261; Found : 330.1267. [α]D25 = – 97.6 1H), 5.04 (s, 1H), 6.08 (t, J = 4.2 Hz, 1H), 6.75 (d, J = 9.1 Hz,
(c 0.8, CH2Cl2). HPLC analysis: 85:15 er [Daicel Chiralpak-IA, n- 2H), 6.83 (d, J = 9.1 Hz, 2H), 6.99 (d, J = 9.6 Hz, 2H), 7.33 (d, J =
hexane/2-propanol = 90/10), flow rate (0.5 mL/min), t (minor) 9.4 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 24.70, 42.31, 55.37,
= 17.376 min, t (major) = 19.863 min].
61.79, 64.70, 114.09 (2C), 121.05 (2C), 121.24, 124.07, 130.51
(2C), 130.91 (2C), 137.52, 137.94, 144.08, 154.01; IR (KBr)/cm-1
3418, 2916, 2908, 1659, 1504, 1242, 1188, 1026, 818; HRMS
(R)-(2-(4-Chlorophenyl)-1-(4-methoxyphenyl)-1,2,5,6-
tetrahydropyridin-3-yl)methanol (5i).
Colorless viscous liquid, (69 mg, 70% yield), 1H NMR (400 MHz, (ESI): Calcd for C19H20BrNO2 (MH+) 374.0755; Found: 374.0757.
25
CDCl3) δ 2.25–2.30 (m, 1H), 2.38–2.46 (m, 1H), 3.12–3.17 (m, [α]D = – 187.5 (c 0.8, CH2Cl2). HPLC analysis: 92:8 er [Daicel
2H), 3.74 (s, 3H), 3.87 (d, J = 13.1 Hz, 1H), 3.95 (d, J = 12.8 Hz, Chiralpak-IA, n-hexane/2-propanol = 90/10), flow rate (0.5
1H), 5.06 (s, 1H), 6.08 (t, J = 3.2 Hz, 1H), 6.75 (d, J = 9.1 Hz, 2H), mL/min), t (minor) = 21.191 min, t (major) = 25.148 min].
6.84 (d, J = 9.1 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.5
(R)-(2-(3-Bromo-4-fluorophenyl)-1-(4-methoxyphenyl)-
Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 24.71, 42.31, 55.38, 61.76, 1,2,5,6-tetrahydropyridin-3-yl)methanol (5m).
64.78, 114.08 (2C), 121.09 (2C), 124.11, 127.99 (2C), 130.16 Pale yellow viscous liquid, (83 mg, 71% yield), 1H NMR (400
(2C), 133.02, 137.42, 137.60, 144.12, 154.02; IR (KBr)/cm-1 MHz, CDCl3) δ 2.26–2.31 (m, 1H), 2.37–2.45 (m, 1H), 3.09–3.17
3418, 2916, 2847, 1651, 1597, 1594, 1242, 1188, 1095, 1026; (m, 2H), 3.75 (s, 3H), 3.86–3.89 (d, J = 12.3 Hz, 1H), 3.98 (d, J =
HRMS (ESI): Calcd for C19H20ClNO2 (MH+) 330.1261; Found : 12.9 Hz, 1H), 5.04 (s, 1H), 6.10 (t, J = 3.0 Hz, 1H), 6.77 (d, J = 9.1
25
330.1263. [α]D = – 143.2 (c 0.7, CH2Cl2). HPLC analysis: 86:14 Hz, 2H), 6.84 (d, J = 9.2 Hz, 2H), 6.92–6.96 (m, 1H), 6.98–7.02
er [Daicel Chiralpak-IA, n-hexane/2-propanol = 90/10), flow (m, 1H), 7.32–7.34 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 24.56,
rate (0.5 mL/min), t (minor) = 20.054 min, t (major) = 23.154 42.35, 55.40, 61.31, 64.64, 114.16 (2C), 121.18 (2C), 124.50,
min].
(S)-(2-(2-Bromophenyl)-1-(4-methoxyphenyl)-1,2,5,6-
tetrahydropyridin-3-yl)methanol (5j).
Reddish viscous liquid, (65 mg, 58% yield), H NMR (400 MHz, (MH+) 392.0661; Found: 392.0667. [α]D = – 95.4 (c 1.2,
CDCl3) δ 2.30–2.35 (m, 2H), 3.14–3.19 (m, 1H), 3.23–3.30 (m, CH2Cl2). HPLC analysis: 87:13 er [Daicel Chiralpak-IA, n-
2H), 3.52 (d, J = 13.9 Hz, 1H), 3.60 (d, J = 14.0 Hz, 1H), 3.76 (s, hexane/2-propanol = 90/10), flow rate (0.5 mL/min), t (minor)
3H), 5.55 (s, 1H), 5.91 (bs, 1H), 6.82 (d, J = 9.2 Hz, 2H), 6.90 (d, = 17.880 min, t (major) = 20.715 min].
J = 9.1 Hz, 2H), 7.14–7.18 (m, 1H), 7.33–7.39 (m, 1H), 7.53–
129.45, 129.52, 133.41, 136.46, 137.22, 143.84, 154.21,
156.91, 159.36; IR (KBr)/cm-1 3279, 3047, 2914, 2847, 1558,
1504, 1242, 1180, 1034; HRMS (ESI): Calcd for C19H19BrFNO2
1
25
6 | J. Name., 2012, 00, 1-3
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ARTICLE
(R)-3-(3-(Hydroxymethyl)-1-(4-methoxyphenyl)-1,2,5,6-
(KBr)/cm-1 3394, 2924, 2854, 1736, 1512, 1458, 1381, 1242,
tetrahydropyridin-2-yl)benzonitrile (5n).
1180, 1034, 875; HRMS (ESI): Calcd for C19H21NO2 (MH+)
Yellow viscous liquid, (71 mg, 74% yield), 1H NMR (400 MHz, 296.1650; Found: 296.1658. [α]D = – 140.5 (c 0.5, CH2Cl2).
CDCl3) δ 2.29–2.38 (m, 1H), 2.40–2.45 (m, 1H), 3.07–3.21 (m, HPLC analysis: 85:15 er [Daicel Chiralpak-IA, n-hexane/2-
2H), 3.74 (s, 3H), 3.82–3.85 (m, 1H), 3.98 (d, J = 13.0 Hz, 1H), propanol = 88/12), flow rate (0.5 mL/min), t (minor) = 13.505
5.11 (s, 1H), 6.13 (t, J = 3.1 Hz, 1H), 6.75 (d, J = 9.1 Hz, 2H), min, t (major) = 15.262 min].
25
6.83 (d, J = 9.1 Hz, 2H), 7.28–7.32 (m, 1H), 7.34–7.37 (m, 1H),
(S)-(1-(4-Methoxyphenyl)-2-phenyl-1,2,5,6-
7.47–7.50 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 24.55, 42.70, tetrahydropyridin-3-yl)methanol (ent-5q).
25
55.33, 61.53, 64.50, 111.65, 114.15 (2C), 118.85 121.11 (2C), [α]D = + 42.3 (c 0.1, CH2Cl2). HPLC analysis: 18:82 er [Daicel
124.84, 128.62, 130.92, 132.02, 133.46, 136.75, 140.74, Chiralpak-IA, n-hexane/2-propanol = 88/12), flow rate (0.5
143.70, 154.20; IR (KBr)/cm-1 3418, 2924, 2947, 2230, 1605, mL/min), t (major) = 13.397 min, t (minor) = 15.273 min].
1512, 1458, 1242, 1188, 1034; HRMS (ESI): Calcd for
25
(S)-(1-(4-Methoxyphenyl)-2-(pyridin-2-yl)-1,2,5,6-
C20H20N2O2 (MH+) 321.1603; Found: 321.1609. [α]D = – 143.3 tetrahydropyridin-3-yl)methanol (5r).
1
1
(c 0.8, CH2Cl2). HPLC analysis: 88:12 er [Daicel Chiralpak-IA, n- Dark red viscous liquid, (56 mg, 63% yield), H NMR H NMR
hexane/2-propanol = 85/15), flow rate (0.5 mL/min), t (major) (400 MHz, CDCl3) δ 2.33–2.37 (bs, 2H), 3.19–3.25 (m, 1H),
= 16.913 min, t (minor) = 21.912 min].
3.34-3.40 (m, 1H), 3.74 (s, 3H), 4.08 (m, 2H), 5.27 (s, 1H), 5.99
(t, J = 3.9 Hz, 1H), 6.76-6.80 (m, 2H), 6.82-6.83 (m, 2H), 7.16–
7.19 (m, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H),
(R)-4-(3-(Hydroxymethyl)-1-(4-methoxyphenyl)-1,2,5,6-
tetrahydropyridin-2-yl)benzonitrile (5o).
Pale yellow viscous liquid, (74 mg, 78% yield), 1H NMR (400 8.50 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 23.81, 43.93, 55.49,
MHz, CDCl3) δ 2.28–2.34 (m, 1H), 2.38–2.47 (m, 1H), 3.08–3.17 63.71, 65.88, 114.48 (2C), 117.45 (2C), 120.86, 122.50, 124.11,
(m, 2H), 3.74 (s, 3H), 3.84 (d, J = 12.3 Hz, 1H), 3.97 (d, J = 12.9 124.93, 136.86, 137.42, 148.07, 159.26, 161.77; IR (KBr)/cm-1
Hz, 1H), 5.12 (s, 1H), 6.12 (t, J = 3.1 Hz, 1H), 6.75 (d, J = 9.1 Hz, 3294, 3055, 2924, 2839, 1466, 1242, 1034; HRMS (ESI): Calcd
25
2H), 6.82 (d, J = 9.1 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 7.50 (d, J = for C18H20N2O2 (MH+) 297.1603; Found: 297.1608. [α]D = –
8.4 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 24.62, 42.77, 55.28, 111.5 (c 0.8, CH2Cl2). HPLC analysis: 91:9 er [Daicel Chiralpak-
61.88, 64.42, 110.77, 114.09 (2C), 118.70, 121.02 (2C), 124.58, IB, n-hexane/2-propanol = 85/15), flow rate (0.5 mL/min), t
129.36 (2C), 131.55 (2C), 136.78, 143.73, 144.74, 154.13; IR (minor) = 22.747 min, t (major) = 28.847 min].
(KBr)/cm-1 3418, 2924, 2862, 2230, 1659, 1512, 1458, 1250,
(R)-(1-(4-Methoxyphenyl)-2-(pyridin-3-yl)-1,2,5,6-
1188, 1095, 1034; HRMS (ESI): Calcd for C20H20N2O2 (MH+) tetrahydropyridin-3-yl)methanol (5s).
25
321.1603; Found: 321.1605. [α]D = – 182.4 (c 1.5, CH2Cl2). Red viscous liquid, (64 mg, 72% yield), 1H NMR (400 MHz,
HPLC analysis: 90:10 er [Daicel Chiralpak-IA, n-hexane/2- CDCl3) δ 2.27–2.32 (m, 1H), 2.40–2.50 (m, 1H), 3.09–3.17 (m,
propanol = 80/20), flow rate (0.5 mL/min), t (minor) = 16.974 2H), 3.73 (s, 3H), 3.87 (d, J = 13.0 Hz, 1H), 3.99 (d, J = 12.9 Hz,
min, t (major) = 18.771 min].
1H), 5.12 (s, 1H), 6.13 (s, 1H), 6.75 (d, J = 9.0 Hz, 2H), 6.84 (d, J
= 9.1 Hz, 2H), 7.13–7.15 (m, 1H), 7.42–7.44 (m, 1H), 8.32 (s,
1H), 8.41 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 24.70, 42.52,
(R)-(2-(3,4-Dichlorophenyl)-1-(4-methoxyphenyl)-1,2,5,6-
tetrahydropyridin-3-yl)methanol (5p).
1
Orange liquid, (76 mg, 70% yield), H NMR (400 MHz, CDCl3) δ 55.37, 60.18, 64.41, 141.18 (2C), 121.29 (2C), 123.07, 124.44,
2.25–2.30 (m, 1H), 2.36–2.44 (m, 1H), 3.08–3.17 (m, 2H), 3.73 135.00, 136.63, 136.92, 143.86, 148.23, 149.69, 154.24; IR
(s, 3H), 3.85 (d, J = 12.3 Hz, 1H), 3.97 (d, J = 12.9 Hz, 1H), 5.03 (KBr)/cm-1 3410, 2924, 2862, 1651, 1582, 1512, 1242, 1034;
(s, 1H), 6.09 (t, J = 3.1 Hz, 1H), 6.75 (d, J = 9.1 Hz, 2H), 6.83 (d, J HRMS (ESI): Calcd for C18H20N2O2 (MH+) 297.1603; Found:
= 9.1 Hz, 2H), 6.93 (dd, J = 8.2 Hz, J = 2.0 Hz, 1H), 7.23–7.25 (m, 297.1605. [α]D25 = – 103 (c 0.4, CH2Cl2). HPLC analysis: 81:19 er
2H); 13C NMR (75 MHz, CDCl3) δ 24.56, 42.53, 55.36, 61.33, [Daicel Chiralpak-IA, n-hexane/2-propanol = 80/20), flow rate
61.51, 114.19 (2C), 121.04 (2C), 124.49, 128.29, 129.70, (1.0 mL/min), t (minor) = 19.082 min, t (major) = 22.508 min].
130.39, 131.13, 131.86, 137.03, 139.51, 143.81, 154.18; IR
(R)-(1-(4-Methoxyphenyl)-2-(pyridin-4-yl)-1,2,5,6-
(KBr)/cm-1 3410, 3055, 2916, 2839, 1605, 1512, 1458, 1396, tetrahydropyridin-3-yl)methanol (5t).
1242, 1188, 1034; HRMS (ESI): Calcd for C19H19Cl2NO2 (MH+) Yellow viscous liquid, (67 mg, 76% yield), 1H NMR (400 MHz,
364.0871; Found: 364.0876. [α]D25 = – 193 (c 1.3, CH2Cl2). HPLC CDCl3) δ 2.26–2.31 (m, 1H), 2.39–2.47 (m, 1H), 3.08–3.22 (m,
analysis: 93:7 er [Daicel Chiralpak-IA, n-hexane/2-propanol = 2H), 3.73 (s, 3H), 3.87 (d, J = 12.7 Hz, 1H), 3.98 (d, J = 12.8 Hz,
90/10), flow rate (0.5 mL/min), t (minor) = 17.848 min, t 1H), 5.08 (s, 1H), 6.12 (t, J = 3.2 Hz, 1H), 6.74 (d, J = 9.1 Hz, 2H),
(major) = 21.804 min].
6.83 (d, J = 9.1 Hz, 2H), 7.05 (d, J = 6.0 Hz, 2H), 8.41 (d, J = 5.9
Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 24.60, 42.79, 55.38, 61.26,
64.38, 114.17 (2C), 115.35, 118.22, 120.82 (2C), 123.89,
(R)-(1-(4-Methoxyphenyl)-2-phenyl-1,2,5,6-
tetrahydropyridin-3-yl)methanol (5q).
Yellow viscous oil, (51 mg, 58% yield), 1H NMR (400 MHz, 124.57, 136.73, 143.87, 148.52, 149.08, 154.08; IR (KBr)/cm-1
CDCl3) δ 2.23–2.28 (m, 1H), 2.40–2.45 (m, 1H), 3.17–3.21 (m, 3711, 3040, 2916, 2847, 1512, 1458, 1260, 1188; HRMS (ESI):
25
2H), 3.73 (s, 3H), 3.93 (m, 2H), 5.09 (s, 1H), 6.07 (bs, 1H), 6.75 Calcd for C18H20N2O2 (MH+) 297.1603; Found: 297.1611. [α]D
(d, J = 9.1 Hz, 2H), 6.86 (d, J = 9.1 Hz, 2H), 7.12–7.15 (m, 2H), = – 105.9 (c 0.7, CH2Cl2). HPLC analysis: 96:4 er [Daicel
7.20–7.22 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 24.54, 42.22, Chiralpak-IA, n-hexane/2-propanol = 80/20), flow rate (1.0
55.39, 62.31, 64.94, 114.03 (2C), 120.73 (2C), 123.79, 127.27, mL/min), t (minor) = 20.044 min, t (major) = 24.477 min].
127.88 (2C), 128.87 (2C), 137.95, 139.10, 144.41, 153.73; IR
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25
(S)-(1-(4-Methoxyphenyl)-2-(thiophen-2-yl)-1,2,5,6-
(MH+) 296.1650; Found: 296.1655. [α]D
CH2Cl2).
(4aR,10bS)-1,3,4,4a,5,10b-Hexahydro-2H-chromeno[4,3-
=
– 31.7 (c 0.4,
tetrahydropyridin-3-yl)methanol (5u).
Reddish viscous oil, (48 mg, 53% yield), 1H NMR (400 MHz,
CDCl3) δ 2.24–2.29 (m, 1H), 2.43–2.52 (m, 1H), 3.21–3.24 (m, b]pyridine (7).
2H), 3.75 (s, 3H), 4.02–4.09 (m, 2H), 5.41 (s, 1H), 6.03–6.05 (m, To a stirred solution of ceric ammonium nitrate (CAN) (441 mg,
1H), 6.66–6.68 (m, 1H), 6.78 (d, J = 9.2 Hz, 2H), 6.83–6.84 (m, 0.8 mmol) in distilled H2O (2.0 mL) at 0 °C was added
1H), 6.87 (d, J = 9.2 Hz, 2H), 7.12–7.13 (m, 1H); 13C NMR (75 compound
6 (95 mg, 0.32 mmol) in CH3CN (3.0 mL) dropwise
MHz, CDCl3) δ 24.98, 41.06, 55.41, 57.89, 64.97, 114.13 (2C), for 10 minutes. This reaction mixture was further stirred at rt
120.69 (2C), 123.85, 124.81, 126.12, 126.64, 138.29, 141.57, for 1 hr and monitored by TLC. Once, compound 6 was
144.02, 153.97; IR (KBr)/cm-1 3493, 2924, 2854, 1651, 1512, consumed completely, reaction was quenched with saturated
1242, 1034; HRMS (ESI): Calcd for C17H19NO2S (MH+) 302.1214; NaHCO3 (5.0 mL) and extracted with EtOAc (3 × 5 mL). The
25
Found: 302.1219. [α]D = – 123 (c 0.2, CH2Cl2). HPLC analysis: combined organic layer was dried over Na2SO4 and
86:14 er [Daicel Chiralpak-IA, n-hexane/2-propanol = 90/10), concentrated under reduced pressure after filtration. The
flow rate (0.5 mL/min), t (minor) = 30.484 min, t (major) = crude mas was purified through a small pad of silica gel
36.166 min].
(S)-(1-(4-Methoxyphenyl)-2-(5-nitrofuran-2-yl)-1,2,5,6-
tetrahydropyridin-3-yl)methanol (5v).
column using hexane:acetone as eluting solvent, afforded 7
(46 mg, 75% yield) as colorless viscous liquid. 1H NMR (400
MHz, CDCl3) δ 1.41–1.52 (m, 2H), 2.02–2.07 (m, 2H), 2.62 (s,
1
Dark red viscous liquid, (62 mg, 63% yield), H NMR (400 MHz, 1H), 2.76–2.83 (m, 1H), 3.16–3.20 (m, 1H), 3.27–3.38 (m, 2H),
CDCl3) δ 2.28–2.35 (m, 2H), 3.22–3.25 (m, 2H), 3.64 (s, 2H), 3.58–3.65 (m, 1H), 4.07 (d, J = 3.8 Hz, 1H), 7.18–7.22 (m, 1H),
3.77 (s, 3H), 4.11 (s, 1H), 5.86 (bs, 1H), 6.85 (d, J = 9.0 Hz, 2H), 7.28–7.30 (m, 1H), 7.35 (dd, J = 7.9 Hz, J = 1.3 Hz, 1H), 7.61 (dd,
6.98 (m, 2H), 7.27–7.30 (m, 2H); 13C NMR (75 MHz, CDCl3) δ J = 7.7 Hz, J = 1.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 26.31,
25.03, 41.22, 55.48, 57.96, 65.05, 114.22 (2C), 120.89 (2C), 28.04, 48.15, 58.59, 64.95, 70.16, 125.23, 128.05, 128.56,
123.91, 124.84, 126.16, 126.63, 138.40, 141.83, 144.13, 130.85, 132.36, 156.15; IR (KBr)/cm-1 3433, 2932, 1597, 1350,
154.04; IR (KBr)/cm-1 3420, 2924, 2848, 1512, 1458, 1404, 1103; HRMS (ESI): Calcd for C12H15NO (MH+) 190.1232; Found:
1250, 1188; HRMS (ESI): Calcd for C17H18N2O5 (MH+) 331.1294; 190.1235 [α]D25 = – 29.2 (c 0.1, CH2Cl2).
25
Found: 331.1298. [α]D = – 146 (c 0.4, CH2Cl2). HPLC analysis:
((1S,2R,6S)-3-(4-Methoxyphenyl)-2-(4-nitrophenyl)-7-oxa-
86:14 er [Daicel Chiralpak-IA, n-hexane/2-propanol = 85/15), 3-azabicyclo[4.1.0] heptan-1-yl)methanol (10).
flow rate (0.5 mL/min), t (minor) = 25.996 min, t (major) = To a stirred solution of compound 5c (64 mg, 0.19 mmol) in
30.493 min].
(4aR,10bS)-1-(4-Methoxyphenyl)-1,3,4,4a,5,10b-
hexahydro-2H-chromeno[4,3-b]pyridine (6).
CH2Cl2 (2.0 mL) at 0 °C was added m-CPBA (56 mg, 0.38 mmol)
predissolved in CH2Cl2 (1.0 mL) through syringe. This reaction
mixture was further stirred for 3 hr at the same temperature
To a stirred solution of compound 5j (160 mg, 0.43 mmol) in and monitored by TLC. Once, compound 5c was consumed,
dry EtOH (4 mL) was added 10% Pd/C (10 wt %) and purged reaction was stirred with NaHCO3 solution (3.0 mL, 10 mol %
with H2 and stirred under H2 at room temperature for 4 hrs. sol.) for 10 minutes. This reaction mixture was extracted with
Reaction mixture was filtered through celite and washed with CH2Cl2 (5.0 mL) and combined organic layer was washed with
ethanol. Solvent was evaporated under vacuo and crude brine solution and dried over Na2SO4. The crude mass after
material was used for further oxidation without purification at concentrated under vacuo was purified through column
this stage. This crude material was taken in DMF (3.0 mL) and chromatography by unsing hexane/EtOAc as eluting solvents,
added Pd(OAc)2 (18 mg, 20 mol%) and KOtBu (94 mg, 0.42 which afford compound 10 (50 mg, 75% yield) as a colorless
1
mmol) and PPh3 (44 mg, 0.4 equivalents) and degassed the viscous liquid. H NMR (400 MHz, CDCl3) δ 2.44 (d, J = 4.2 Hz,
reaction mixture with nitrogen for 20 minutes. This reaction 1H), 3.23 (d, J = 11.6 Hz, 1H), 3.44 (d, J = 11.7 Hz, 1H), 3.69–
o
mixture was heated at 110 C for 4 hrs and monitored by TLC. 3.78 (m, 6H), 4.63–4.70 (m, 1H), 5.02 (s, 1H), 5.40 (s, 1H), 6.68
The reaction was quenched with saturated NaHCO3 solution (d, J = 9.4 Hz, 2H), 7.03 (d, J = 8.9 Hz, 1H), 7.46 (d, J = 8.4 Hz,
(5.0 mL) and extracted with EtOAc (2 × 8 mL). The combined 2H), 7.84–7.95 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 25.17,
organic layer was washed with brine and dried over Na2SO4 32.70, 43.34, 55.70, 58.15, 69.66, 72.58, 114.92 (2C), 121.97
and concentrated under reduced pressure to give crude mass (2C), 123.75 (2C), 130.25 (2C), 137.58, 144.45, 147.76, 155.05;
which was purified by silica gel column chromatography by IR (KBr)/cm-1 3433, 2916, 2854, 1713, 1574, 1381, 1257, 1080,
using hexane:EtOAc, gave
1
6
(62 mg, 61% yield) as colorless 756; HRMS (ESI): Calcd for C19H20N2O5 (MH+) 357.1450; Found:
viscous liquid. H NMR (400 MHz, CDCl3) δ 1.47–1.59 (m, 1H), 357.1455. [α]D25 = + 43.8 (c 0.2, CH2Cl2).
1.84–1.87 (m, 2H), 2.03–2.07 (m, 1H), 2.77 (m, 1H), 3.29–3.40
(2R,3S,4S)-3-(Hydroxymethyl)-1-(4-methoxyphenyl)-2-(4-
(m, 3H), 3.66 (s, 3H), 4.31 (d, J = 3.9 Hz, 1H), 6.63 (d, J = 9.1 Hz, nitrophenyl) piperidine-3,4-diol (11).
2H), 6.94–7.00 (m, 3H), 7.08 (m, 1H), 7.13–7.16 (m, 1H), 7.52– To a stirred solution of compound 5c (60 mg, 0.18 mmol) in
7.54 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 25.85, 27.62, 47.45, acetone (2.5 mL) and H2O (0.5 mL) was added 4-
55.15, 58.37, 61.89, 64.56, 113.65 (2C), 125.39 (2C), 127.11, Methylmorpholine N-oxide (NMO) (32 mg, 0.27 mmol) and
127.80, 128.61 (2C), 129.95 (2C), 133.70 (2C); IR (KBr)/cm-1 OsO4 (20 mol %, 1.76 mL, 0.02 M solution in tert-BuOH). This
2932, 1597, 1298, 1180, 1034; HRMS (ESI): Calcd for C19H21NO2 reaction mixture was stirred at room temperature for 12 hrs
and monitored by TLC. The reaction mixture was evaporated
8 | J. Name., 2012, 00, 1-3
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under reduced pressure, once 5c was completely consumed. 13C NMR (75 MHz, CDCl3) δ 22.68, 27.19, 29.68, 42.65, 55.24,
The resulting mass was stirred with EtOAc (10 ml) and 64.90, 113.85 (2C), 124.83, 127.32, 127.90 (2C), 128.28,
saturated NaHCO3 (8.0 mL) for 10 minutes. Organic layer was 128.73, 131.23, 132.44, 135.92, 141.29, 170.16; IR (KBr)/cm-1
separated and the aqueous layer was again extracted with 3433–3063 (br), 2939, 1690, 1589, 1173, 1034; HRMS (ESI):
25
EtOAc (2 × 10 mL). The combined organic layer was dried over Calcd for C19H21NO3 (MH+) 312.1599; Found: 312.1592 [α]D
=
Na2SO4 and evaporated under reduced pressure after + 49.4 (c 0.1, CH2Cl2).
filtration. The resulting mass was purified through column
((2S,3R)-1-(4-Methoxyphenyl)-2-phenylpiperidin-3-
chromatography using hexane/EtOAc as eluting solvents, yl)methanol (16).
which afforded 11 (42 mg, 65 % yield). 1H NMR (400 MHz, Compound 5q (140 mg, 0.32 mmol), was reduced by following
CDCl3) δ 1.94–1.98 (m, 1H), 2.27–2.35 (m, 1H),3.11–3.21 (m, previous procedure and purified through column
2H), 3.56 (d, J = 11.6 Hz, 1H), 3.67 (s, 3H), 3.73 (bs, 1H), 3.75– chromatography to afford 16 as colorless viscous liquid with
1
3.79 (m, 1H), 4.19 (t, J = 3.7 Hz, 1H), 4.65 (s, 1H), 6.65 (d, J = 90% yield (126 mg). H NMR (400 MHz, CDCl3) δ 1.62–1.69 (m,
9.0 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 7.99 2H), 1.83 (d, J = 6.4 Hz, 2H), 2.61–2.70 (m, 2H), 3.00–3.09 (m,
(d, J = 8.8 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 29.44, 51.47, 2H), 3.50–3.55 (m, 2H), 3.75 (s, 3H), 3.76–3.83 (m, 1H), 6.56 (d,
55.22, 63.94, 67.55, 69.20, 73.56, 114.14 (2C), 122.67 (2C), J = 9.0 Hz, 2H), 6.78 (d, J = 8.9 Hz, 2H), 7.16–7.22 (m, 3H), 7.29
125.11 (2C), 130.69 (2C), 144.11, 145.21, 146.74, 156.02; IR (t, J = 6.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 25.51, 27.42,
(KBr)/cm-1 3441, 2939, 1597, 1520, 1350, 1250, 1103; HRMS 45.96, 55.18, 56.60, 65.27, 67.46, 113.66 (2C), 125.11, 126.72
(ESI): Calcd for C19H22N2O6 (MH+) 375.1556; Found: 375.1560. ,128.02 (2C) ,128.47 (2C), 139.24 , 142.13, 146.05, 155.21;
[α]D25 = – 61.5 (c 0.15, CH2Cl2).
HRMS (ESI): Calcd for C19H23NO2 (MH+) 298.1808, Found:
298.1813. [α]D25 = – 56.3 (c 0.1, CH2Cl2).
(R)-1-(4-Methoxyphenyl)-2-phenyl-1,2,5,6-
tetrahydropyridine-3-carboxylic acid (12).
2-Methoxy-N-(((2S,3S)-1-(4-methoxyphenyl)-2-
To a stirred solution of compound 5q (81 mg, 0.2 mmol) in phenylpiperidin-3-yl)methyl) aniline (19).
acetonitrile (1.5 mL) and H2O (0.5 mL) at 0 °C, was added To a stirred solution of 16 (90 mg, 0.3 mmol) in dry CH2Cl2 (2.0
slowly a freshly prepared solution (1.5 mL) of oxidizing agents mL) at rt was added Et3N (168 μL, 1.2 mmol) and TsCl (69 mg,
[prepared through reported procedure,25 (2.3 mg of CrO3 and 0.36 mmol) in dry CH2Cl2 (1.5 mL) by syringe. The resulting
1.14 grams of H5IO6), in H2O (12.0 mL)] over a period of 30 mixture was further stirred for 6 hrs at the same temperature
minutes. The combined mixture was further stirred for and monitored by TLC. The reaction was quenched with
additional 1 hr at rt and monitored by the TLC. The reaction saturated NaHCO3 (3.0 mL) and extracted with CH2Cl2 (2 × 5
was extracted with CH2Cl2 (2 × 10 mL), once 5q was over. The mL). The combined organic layer was dried over Na2SO4 and
combined organic fractions are passed through a small pad of concentrated in reduced pressure to give the crude product,
Na2SO4 and concentrated under reduced pressure. The crude which was used further without isolation. The crude mass was
mass was purified through preparative TLC technique by taken in dry EtOH (3 mL) and added o-anisidine 18 (74 mg, 0.6
1
eluting with CH2Cl2, to afford 12 (57 mg, 68%). H NMR (400 mmol) and further refluxed for additional 4 hrs. Once the
MHz, CDCl3) δ 2.38 (m, 1H), 2.60–2.73 (m, 1H), 3.20–3.28 (m, reaction is over by TLC, EtOH was evaporated under reduced
1H), 3.30–3.35 (m, 1H), 3.76 (s, 3H), 5.23 (s, 1H), 6.12 (s, 1H), pressure and resulting residue was purified by column
6.76 (d, J = 9.1 Hz, 2H), 6.89 (d, J = 9.1 Hz, 2H), 7.01 (dd, J = 8.0, chromatography to afforded 19 (83 mg, 68% yield) as a
1
1.4 Hz, 2H), 7.18–7.26 (m, 3H); 13C NMR (75 MHz, CDCl3) δ colorless viscous liquid. H NMR (400 MHz, CDCl3) δ 1.58–1.75
29.65, 44.12, 55.54, 63.54, 114.61 (2C), 123.49 (2C), 127.98, (m, 4H), 2.10–2.13 (m, 1H), 2.93–3.00 (m, 1H), 3.12–3.16 (m,
128.67, 129.16, 130.46, 131.40, 131.74, 133.31, 134.18, 1H), 3.49–3.57 (m, 2H), 3.78 (s, 3H), 3.86 (s, 3H), 5.04 (d, J =
141.74, 160.01, 171.00; IR (KBr)/cm-1 3441-3061 (br), 2939, 3.6, 1H), 6.47–6.49 (m, 1H), 6.56–6.60 (m, 1H), 6.72–6.76 (m,
1690, 1582, 1512, 1126; HRMS (ESI): Calcd for C19H19NO3 (MH+) 2H), 6.78–6.81 (m, 2H), 6.84 (d, J = 9.2, 2H), 6.91(d, J = 9.2 Hz,
310.1443; Found: 310.1439. [α]D25 = – 127.4 (c 0.25, CH2Cl2).
(2R,3S)-1-(4-Methoxyphenyl)-2-phenylpiperidine-3-
carboxylic acid (14).
2H), 6.99–7.03 (m, 1H), 7.14 (d, J = 7.6 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 24.28, 24.51, 31.47, 42.12, 46.55, 55.39, 55.75,
56.69, 110.37, 113.62, 114.80 (2C), 115.00, 115.94, 117.00,
To a stirred solution of compound ent-5q (96 mg, 0.32 mmol) 118.46, 120.11, 121.03, 127.61 (2C), 128.07, 136.08, 144.81,
in dry EtOH (4 mL) was added 10% Pd/C (10 wt %) and purged 145.62, 147.28, 151.61; IR (KBr)/cm-1 3393, 2932, 2831, 1598,
with H2 and stirred under H2 at room temperature for 4 hrs. 1512, 1366, 1180, 1034; Calcd for C26H30N2O2 (MH+) 403.2385;
Reaction mixture was filtered through celite and washed with Found: 403.2389. [α]D25 = – 54.6 (c 0.15, CH2Cl2).
ethanol. Solvent was evaporated under vacuo and crude
material was used for further oxidation without purification at
Acknowledgements
this stage. The oxidation of crude saturated syn-alcohol to
corresponding acid was carried out by following the previous
procedure, similar to compound 12, to afford 14 (66 mg, 66%
This work was financially supported by BITS Pilani. P. Ramaraju
thanks, UGC-New Delhi for Senior Research Fellowship. We
also thank DST-FIST for the financial support to Department of
Chemistry.
1
yield) after two steps. H NMR (400 MHz, CDCl3) δ 1.86–1.94
(m, 1H), 2.01–2.08 (m, 2H), 3.25–3.30 (m, 2H), 3.43–3.46 (m,
2H), 3.66 (s, 3H), 3.92 (d, J = 3.9 Hz, 1H), 6.63 (d, J = 9.1 Hz,
2H), 7.04 (d, J = 8.5 Hz, 2H), 7.15 (m, 3H), 7.38–7.42 (m, 2H);
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Abstract: An enantioselective multi-component synthesis of 1,2,5,6-tetrahydropyridines (THPs)
has been developed through a one-pot domino-process. This transformation proceeds through
proline-catalyzed direct Mannich reaction-cyclization of glutaraldehyde with in situ generated
imines, followed by site-selective oxidation-reduction sequence under mild conditions. Chiral
1,2,5,6-THPs are obtained in good to high yields (up to 80%) and with the excellent
enantioselectivity (up to 98:2 er). The usefulness of this operationally simple method is also
shown to synthesize other medicinally important nitrogen-heterocycles.