Stereoselective functionalisation of pinopyridine with anisidines and o-phenylenediamine

Article abstract of DOI:10.1016/j.mencom.2011.09.007

Benzylic oxidation of pinopyridine with SeO₂ affords the corresponding keto derivative (71% yield) whose reductive amination with o- and p-anisidines proceeds stereoselectively to give 8R-amino derivatives; the reaction with o-phenylenediamine

Full text of DOI:10.1016/j.mencom.2011.09.007

Mendeleev
Communications
Mendeleev Commun., 2011, 21, 253–255
Stereoselective functionalisation of pinopyridine
with anisidines and o-phenylenediamine
Eugene S. Vasilyev,a Alexander M. Agafontsev,a Vasilij D. Kolesnik,a
Yurii V. Gatilova and Alexey V. Tkachev*a,b
a N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian
Academy of Sciences, 630090 Novosibirsk, Russian Federation. Fax: +7 383 330 9752;
e-mail: atkachev@nioch.nsc.ru
b Department of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russian Federation
DOI: 10.1016/j.mencom.2011.09.007
Benzylic oxidation of pinopyridine with SeO2 affords the corresponding keto derivative (71% yield) whose reductive amination with
o- and p-anisidines proceeds stereoselectively to give 8R-amino derivatives; the reaction with o-phenylenediamine results in achiral
pyridophenazine derivative possessing intense blue fluorescence at 441 nm. Structures of o-anisidine derivative and substituted pyrido-
phenazine have been characterized by X-ray crystallography.
Me
Me
Me
Me
Chiral pyridines are of special interest as ligands for synthesis
of coordination compounds1 used as chiral catalysts in many organic
reactions,2 e.g., preparation of cyclopropanes via diaza com-
pounds,3 allylic oxidation or substitution,4 the Heck reaction5 and
dialkylzinc addition.6 Chiral pyridines are studied in supramole-
cular chemistry,7 molecular recognition processes8 and chemistry
of three-dimensional structures prepared by bidirectional asso-
ciation;9 and they are explored as components of self-assembled
systems,10 building blocks for chiral polymers,11 as well as bio-
logically active compounds.12
Pinopyridine 1 is available in optically active form as pro-
duct of simple transformation of natural a-pinene.13 Herein, we
report on additional stereoselective functionalisation of the pinane
moiety of pinopyridine and formation of unusual pyridophenazine
derivative.
Me
COOEt
Me
Ref. 13
N
(–)-α-pinene
1
SeO2, H2O,
1,4-dioxane, 71%
60 °C, 8 h
O
Me11
13
4
5
10
Me
15
16
14
Me
3
12
i, o-MeOC6H4NH2 or
p-MeOC6H4NH2, C6H6,
BF3·Et2O, reflux, 12 h
ii, NaBH4, MeOH,
O
6
9
2
1
7
17
N
Me
8
O
room temperature, 1 h
2
o-C6H4(NH2)2, C6H6,
BF3·Et2O, reflux, 6 h
Me
Pinopyridine 1 was prepared from (–)-a-pinene according to
published procedure.13 Benzylic oxidation of compound 1 with
SeO2 afforded keto derivative 2.† Reductive amination of ketone
2 with o- and p-anisidines proceeds smoothly‡ to form stereo-
selectively secondary amines 3§ and 4¶ (Scheme 1) as a result
COOEt
Me
Me
Me 10CH2
11
8
N
19
9
5
18
NH
20
21
COOEt
Me
6
15
23
24
7
8
OMe
†
22
16
N
N
Ethyl (5R,7S)-8-oxo-2,6,6-trimethyl-5,6,7,8-tetrahydro-5,7-methano-
18
quinoline-3-carboxylate 2. Selenium dioxide (1.03 g, 9.31 mmol) and water
(0.33 g) were added to 1,4-dioxane (55 ml) and the mixture was stirred
for 30 min at 60°C, then pinopyridine 1 (2.0 g, 7.7 mmol) was added
and the mixture was refluxed for 5 h. A new portion of SeO2 (0.309 g,
2.78 mmol) was added and the mixture was refluxed for additional 3 h.
The solvent was distilled off in vacuo, the residue was treated with EtOAc
(50 ml), the resulting solution was washed subsequently with saturated
aqueous NaHCO3 (50 ml) and brine (90 ml). The combined aqueous
washings were back-extracted with EtOAc (3´25 ml), the combined
organic extract was dried over Na2SO4, filtered and concentrated at reduced
pressure to leave the crude product which was then purified by column
chromatography (SiO2, hexane–EtOAc, 9:1®4:1) to afford ketone 2 as a
pale pink solid (1.5 g, 71%), mp 149–151°C, [a]D23 –166 (c 2.1, CHCl3).
IR (c 0.75% in KBr, nmax/cm–1): 1724, 1705, 1255. 1H NMR (500 MHz,
CCl4–CDCl3) d: 0.77 (s, 3H, H10), 1.40 (t, 3H, H14, J 7.2 Hz), 1.59 (s, 3H,
H11), 2.1 (m, 1H, H9pro-S), 2.87 (s, 3H, H17), 3.17 (m, 3H, H9pro-R, H5, H7), 4.31
(q, 2H, H13, J 7.2 Hz), 7.99 (s, 1H, H4). 13C NMR (125 MHz, CCl4–CDCl3)
d: 13.70 (C14), 22.10 (C10), 23.92 (C17), 26.10 (C11), 38.34 (C9), 46.16 (C5),
51.57 (C6), 57.47 (C7), 69.68 (C13), 127.02 (C3), 142.31 (C15), 148.40 (C2),
158.10 (C16), 164.80 (C12), 197.20 (C8). MS, m/z (%): 272.1280 (12, [M – H]+,
calc. for [C16H18O3N1]+: 272.1360), 258 (18), 246 (16), 245 (100), 244 (96),
230 (82), 228 (30), 217 (39), 216 (57), 204 (19), 202 (49), 83 (27).
3, 61%
N
19
20
23
or
22
Me
COOEt
Me
21
Me
5, 30%
8
N
19
22
18 NH
20
24
23
21
MeO
4, 65%
Scheme 1 (The numbering scheme is given for NMR interpretation only.)
of reduction of the primary Shiff bases. Analysis of high-field
2D H–1H and 13C–1H-correlation NMR spectra of products 3
1
and 4 showed both derivatives to belong to the same configura-
tion series as concerns that of the C(8) atom. The stereochemistry
of the compounds synthesized was determined by X-ray analysis
of o-anisidine derivative 3 (Figure 1).†† Secondary amines 3 and
4 are formed in highly stereoselective manner: no C(8)-epimers
© 2011 Mendeleev Communications. All rights reserved.
– 253 –

Mendeleev Commun., 2011, 21, 253–255
C(22)
O(3)
O(3)
C(20)
N(1)
C(13)
C(2)
C(18)
O(1)
C(17)
C(16)
C(14)
C(19)
C(10)
C(11)
C(3)
C(15)
N(12)
N(1)
C(10)
C(12B)
N(2)
C(2)
C(4)
C(20)
O(2)
C(21)
C(11A)
O(2)
C(9)
C(11)
C(12A)
C(6A)
C(8)
C(7A)
N(7)
C(8A)
C(4A)
C(16)
C(4A)
C(5)
C(3)
C(14)
C(6)
C(12)
C(8)
C(7)
C(19)
C(6)
C(4)
O(1)
C(17)
C(5)
C(13)
C(9)
C(18)
C(15)
Figure 1 Crystal structure of compound 3.
Figure 2 Crystal structure of compound 5.
were detected. (R)-Configuration of the C(8) atom corresponds
to attack of a reducing reagent from the less hindered side of the
C=N bond in the intermediate Shiff bases.
Our attempts to carry out the similar reductive amination of
ketone 2 with o-phenylenediamine brought about another result.‡‡
The primary Shiff base was unstable under the reaction con-
ditions and underwent further transformations affording fused
tetracyclic derivative 5 (Scheme 1).§§ This compound possessed
an intense blue fluorescence (lmax 441 nm in CHCl3). Chemical
structure of the unusual heterocycle was proved by X-ray crystal-
lography (Figure 2).¶¶
‡
A solution of BF3·Et2O (14 mg, 0.1 mmol) in benzene (5 ml) was added
to a solution of ketone 2 (300 mg, 1.1 mmol) and o- or p-anisidine (246 mg,
2 mmol) in benzene (50 ml), the reaction mixture was kept at reflux for
12 h. The mixture was concentrated at reduced pressure, the residue was
dissolved in MeOH (50 ml), NaBH4 (38 mg, 1 mmol) was added to the
methanolic solution and the mixture was left at room temperature for 1 h.
The solvent was distilled off, the residue was treated with EtOAc, the
organic solution was washed with saturated aqueous NH3 (10 ml) and
extracted with EtOAc (3´25 ml). The combined organic extract was dried
over Na2SO4, filtered and concentrated at reduced pressure. The crude
product was purified by column chromatography (SiO2, hexane–EtOAc,
20:1®5:1) to give anisidine derivatives 3 or 4.
‡‡ A solution of BF3·Et2O (21 mg, 0.15 mmol) in benzene (5 ml) was added
to a solution of ketone 2 (300 mg, 1.1 mmol) and o-phenylenediamine
(238 mg, 2.2 mmol) in benzene (50 ml), and the reaction mixture was
refluxed for 6 h. The mixture was cooled to room temperature and poured
into saturated aqueous NH3 (10 ml), the reaction products were extracted
with EtOAc (3´25 ml). The combined organic extract was dried over
Na2SO4, filtered and concentrated at reduced pressure to leave the crude
product which was then purified by column chromatography (SiO2, hexane–
EtOAc, 40:1®10:1) and subsequent crystallization from MeOH to give
pyridophenazine 5 (117 mg, 30%).
§
Ethyl (5R,7S,8R)-8-(2-methoxyphenylamino)-2,6,6-trimethyl-5,6,7,8-
tetrahydro-5,7-methanoquinoline-3-carboxylate 3: yield 61%, yellowish
crystals, mp 124°C (MeOH), [a]D23 –4.5 (c 0.85, CHCl3). IR (c 0.75% in
KBr, nmax/cm–1): 3417, 1724, 1243. 1H NMR (500 MHz, CCl4–CDCl3) d:
0.78 (s, 1H, H10), 1.40 (t, 3H, H14, J 8 Hz), 1.42 (s, 3H, H11), 1.50 (m, 1H,
H9pro-S), 2.80 (s, 3H, H17), 2.76–2.82 (m, 3H, H5, H7, H9pro-R), 3.83 (s, 3H,
H24), 4.36 (q, 2H, H13), 4.71 (s, 1H, H8), 4.95 (br.s, 1H, H25), 6.64 (td,
1H, H21, J 8 and 2 Hz), 6.75 (d, 2H, H22, H19, J 8 Hz), 6.83 (td, 1H, H20,
J 8 and 2 Hz), 7.74 (s, 1H, H4). 13C NMR (125 MHz, CCl4–CDCl3) d:
14.24 (C14), 22.78 (C10), 24.46 (C17), 26.57 (C11), 33.46 (C9), 39.87 (C6),
44.16 (C7), 46.46 (C5), 55.38 (C24), 60.02 (C8), 60.67 (C13), 109.71 (C22),
109.94 (C19), 116.49 (C21), 121.13 (C20), 123.23 (C3), 134.61 (C4), 138.09
(C18), 138.19 (C15), 147.05 (C23), 157.79 (C2), 159.61 (C16), 166.33 (C12).
MS, m/z (%): 380.2093 (87, [M]+, calc. for [C23H28O3N2]+: 380.2094),
311 (100), 283 (33), 258 (43), 123 (88). UV [EtOH, lmax/nm (e)]: 207
(40100), 245 (13200), 286 (7400).
§§ Ethyl 2-methyl-5-(prop-1-en-2-yl)pyrido[2,3-a]phenazine-3-carboxylate
5: yield 30%, yellowish crystals, mp 183–185°C (MeOH). IR (c 0.75%
1
in KBr, nmax/cm–1): 1721, 1239. H NMR (500 MHz, CCl4–CDCl3) d:
1.46 (t, 3H, H14, J 7.5 Hz), 2.31 (s, 3H, H11), 3.20 (s, 3H, H17), 4.47 (q,
2H, H13, J 7.5 Hz), 5.27 (s, 1H, H1a0), 5.59 (t, 1H, H1b0, J 2 Hz), 7.87 (dd,
1H, H21, J 2 and 3 Hz), 7.88 (dd, 1H, H20, J 2 and 3 Hz), 7.90 (s, 1H, H6),
8.23–8.25 (m, 1H, H22), 8.56–8.58 (m, 1H, H19), 8.90 (s, 1H, H4). 13C NMR
(125 MHz, CCl4–CDCl3) d: 14.35 (C14), 24.60 (C11), 25.93 (C17), 60.48
(C13), 118.44 (C10), 125.34 (C3), 125.87 (C6), 126.06 (C15), 129.19 (C22),
130.07 (C21), 131.08 (C19), 131.18 (C20), 137.33 (C4), 140.87 (C23), 141.90
(C7), 142.69 (C18), 143.80 (C16), 144.71 (C9), 145.04 (C8), 147.56 (C5),
159.50 (C2), 166.13 (C12). MS, m/z (%): 357.1471 (29, [M]+, calc. for
[C22H19N3]+: 357.1472), 284 (76), 149 (28), 97 (41), 83 (54), 71 (60),
69 (82), 57 (100), 55 (74). UV [EtOH, lmax/nm (e)]: 192 (24800), 200
(44600), 229 (33700), 270 (35900), 308 (51600).
¶
Ethyl (5R,7S,8R)-8-(4-methoxyphenylamino)-2,6,6-trimethyl-5,6,7,8-
tetrahydro-5,7-methanoquinoline-3-carboxylate 4: yield 66%, yellowish
oil, [a]D23 –1.9 (c 0.323, CHCl3). IR (c 0.75% in KBr, nmax/cm–1): 3370,
1721, 1242. 1H NMR (500 MHz, CCl4–CDCl3) d: 0.72 (s, 1H, H10), 1.40
(t, 3H, H14, J 8 Hz), 1.42 (s, 3H, H11), 1.48 (m, 1H, H9pro-S), 2.79 (s, 3H,
H17), 2.73–2.81 (m, 3H, H5, H7, H9pro-R), 3.74 (s, 3H, H4), 4.36 (q, 2H, H3),
4.59 (d, 1H, H8, J 2 Hz), 6.71 (d, 2H, H19, H23, J 8 Hz), 6.76 (dt, 2H, H22,
H20, J 8 and 3 Hz), 7.74 (s, 1H, H4). 13C NMR (125 MHz, CCl4–CDCl3)
d: 14.37 (C14), 22.90 (C10), 24.59 (C17), 26.73 (C11), 33.40 (C9), 40.07
(C6), 44.04 (C7), 46.57 (C5), 55.65 (C24), 60.86 (C13), 61.48 (C8), 114.80
(C19, C23), 155.31 (C20, C22), 123.36 (C3), 134.88 (C4), 138.18 (C15), 142.33
(C18), 152.70 (C21), 157.82 (C2), 159.65 (C16), 166.37 (C12). MS, m/z (%):
380.2093 (100, [M]+, calc. for [C23H28O3N2]+: 380.2094), 312 (21),
311 (82), 283 (34), 258 (22), 188 (23), 164 (18), 123 (75). UV [EtOH,
¶¶ Crystal data for compound 5: C22H19N3O2 +MeOH, M = 389.44, tri-
–
clinic, space group P1, at 150 K: a = 8.6823(4), b = 10.7126(5) and
c = 11.6696(6) Å, a = 99.017(2)°, b = 93.122(2)°, g = 112.283(2)°, V =
= 984.19(8) Å3, Z = 2, dcalc = 1.314 g cm–3, m(MoKa) = 0.88 cm–1,
F(000) = 412. The intensities of 16554 reflections were measured on a
Bruker APEX II CCD diffractometer [l(MoKa) = 0.71073 Å, j and
w-scans, 2q < 56°] and 4695 independent reflections (Rint = 0.0372)
were used in the further refinement. Final R values are R1 = 0.0426 for
3857 observed reflections with I > 2s(I), and R1 = 0.0530, wR2 = 0.1265,
GOF = 1.046 for all independent reflections.
The structures of 3 and 5 were solved by the direct method and refined
by the full-matrix least-squares technique against F2 in the anisotropic–
isotropic approximation. The hydrogen atoms of ethanol molecule for
compound 5 were located from the Fourier density synthesis and refined
isotropically, the positions of all the rest hydrogen atoms were calculated
geometrically and refined in riding model. All calculations were performed
using SHELXTL PLUS 6.14.
l
max/nm (e)]: 203 (22300), 242 (8900), 285 (3700).
†† Crystal data for compound 3: C23H28N2O3, M = 380.47, monoclinic, space
group P21, at 296 K: a = 7.5040(8), b = 8.1816(11) and c = 17.2951(19) Å,
b = 90.281(5)°, V = 1061.8(2) Å3, Z = 2, dcalc = 1.190 g cm–3, m(MoKa) =
= 0.79 cm–1, F(000) = 408. The intensities of 5462 reflections were measured
with a Bruker APEX II CCD diffractometer [l(MoKa) = 0.71073 Å, j and
w-scans, 2q < 56°] and 3514 independent reflections (Rint = 0.0693)
were used in the further refinement. Final R values are R1 = 0.0522 for
3011 observed reflections with I > 2s(I), and R1 = 0.0597, wR2 = 0.1493,
GOF = 1.026 for all independent reflections.
CCDC 813734 and 813735 contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2011.
– 254 –

Mendeleev Commun., 2011, 21, 253–255
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Scheme 2
Formation of unexpected pyridophenazine derivative 5 seems
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The work was supported in part by the Russian Foundation
for Basic Research (grant no. 10-03-00346-a).
Received: 2nd March 2011; Com. 11/3690
– 255 –