New synthetic route to N-tocopherol derivatives: Synthesis of pyrrolopyridinol analogue of α-tocopherol from pyridoxine

Article abstract of DOI:10.1039/c0ob00991a

A new synthetic route to pyrrolopyridinol antioxidants from easily accessible pyridoxine was developed which includes phase-transfer catalytic alkylation and intramolecular Cu(i)-catalyzed amination as key steps.

Full text of DOI:10.1039/c0ob00991a

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PAPER
New synthetic route to N-tocopherol derivatives: synthesis of pyrrolopyridinol
analogue of a-tocopherol from pyridoxine†
Tae-gyu Nam,‡a,b Jin-Mo Ku,‡b,c Hyeung-geun Park,c Ned A. Porter*a and Byeong-Seon Jeong*d
Received 8th November 2010, Accepted 2nd December 2010
DOI: 10.1039/c0ob00991a
A new synthetic route to pyrrolopyridinol antioxidants from easily accessible pyridoxine was developed
which includes phase-transfer catalytic alkylation and intramolecular Cu(I)-catalyzed amination as key
steps.
Introduction
Since the seminal report by Pratt et al. in 2001 that the incor-
poration of nitrogen atom at a meta-position to the –OH in the
phenol ring significantly increases the IP (ionization potential)
but increases the O–H BDE (bond dissociation enthalpy) to a
smaller extent,1,2 a series of 6-aminopyridin-3-ols (1–5), electron-
rich phenolic antioxidants with air-stability, have been rationally
designed as lipid peroxyl radical-trapping chain-breaking antiox-
idants by Porter and coworkers.3–7 The pyridinols indeed showed
higher antioxidant activity than a-tocopherol (a-TOH), a nature’s
best lipophilic antioxidant.3,6,7
.
Among the series, tetrahydronaphthyridinol 3 showed ~30-fold
better antioxidant activity, expressed as rate constant (kinh) to
inhibit propagation of radical chain reaction, than a-TOH in
benzene.3 Certain lipophilic derivatives of 3 (e.g. N–C16H33) further
added beneficial properties such that they inhibit the oxidation of
cholesteryl linoleate in human LDL and spared consumption of
endogenous a-TOH in vitro.6 N-TOH (5), an a-TOH isostere, has
strongly suggested that it can act as an excellent antioxidant both
in membranes and in lipoproteins in vivo. Its lateral diffusional
movement in model membranes was about 1.5-fold faster than
a-TOH. Its binding affinity to the human a-tocopherol transfer
protein (hTTP)8 was exceptionally high compared to a-TOH.7
On the other hand, the pyrrolidine-fused aminopyridinol 2
showed 3-fold higher radical-trapping ability than that of the
piperidine-fused aminopyridinol 3, which is equivalent to ~90-
fold higher antioxidant activity than a-TOH.3,4 This information
prompted us to design a five-membered analogue 6, expecting
enhanced antioxidant activity over N-TOH (5) with similar
advantageous behaviors that 5 showed in lipid membranes and
LDLs retained.
Results and discussion
aDepartment of Chemistry, Vanderbilt University, Nashville, Tennessee
37235, USA. E-mail: n.porter@vanderbilt.edu; Fax: +1-615-343-5478;
Tel: +1-615-343-2693
I. Investigation of electrophilic aromatic hydroxylation
Electrophilic aromatic hydroxylation of 3-bromopyridines with
n-butyllithium and 2-nitro-m-xylene was the key step in the
preparation of the aminopyridinols 1–4.3–6 Albeit successful as
the earliest strategy for the discovery of novel antioxidants, this
approach has been challenged by the low yields and delicate
reaction conditions.
We isolated and identified by-products (8a and 8b) of this
electrophilic aromatic hydroxylation, and confirmed that the
formation of 8a and 8b was the cause of the troublesome low
bGyeonggi Bio-Center, Suwon, Gyeonggi-do 443-270, Republic of Korea
cResearch Institute of Pharmaceutical Science and College of Pharmacy,
Seoul National University, Seoul 151-742, Republic of Korea
dCollege of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic
of Korea. E-mail: jeongb@ynu.ac.kr; Fax: +82-53-810-4654; Tel: +82-53-
810-2814
† Electronic supplementary information (ESI) available: 1H, 13C NMR
spectra of all new compounds. See DOI: 10.1039/c0ob00991a
‡ These authors contributed equally to this work and should be considered
co-first authors.
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yields (Scheme 1). As judged from the comparable yields of 3
and 8a, 2-nitroso-m-xylene appears to be at least as reactive as
2-nitro-m-xylene, so it is able to react with the aryllithium as
soon as it is generated during the reaction. The nitroso adduct
was assigned as 8a, a hydroxyamination product, formed through
N-attack by alkyllithium. Presumably, oxophilic lithium species,
enriched in the reaction mixture, coordinate the oxygen atom
of 2-nitroso-m-xylene to make nitrogen atom electrophilic. In
this circumstance, 2-nitroso-m-xylene dimer (azodioxide) can be
formed and also serve as an electrophile in such a manner that
the partially negative charged oxygen atom(s) in azodioxide is
preferentially coordinated with lithium species and promotes N-
attack. Significant improvement in the hydroxylation step was
reported by us through a CuI-mediated benzyloxylation-catalytic
hydrogenolysis sequence,7 but it is still not ideal for large scale
synthesis.
in the end, which is not readily available at this point. We needed
a new synthetic route for the preparation of pyrrolopyridinol 6.
II. Synthesis of pyrrolopyridinol analogue of a-tocopherol
We have recently demonstrated that pyridoxine (11, HCl salt), one
of the constituents of vitamin B6, is an excellent starting material
for the efficient synthesis of several bicyclic aminopyridinols such
as 12 (Scheme 3).9
Scheme 3 Pyridoxine, a highly effective natural resource for aminopy-
ridinols (R, R1, R2 = H or alkyl group).
Furthermore, a novel class of monocyclic aminopyridinols 13
with additional methyl group at C(5)-position compared to 1
can be also synthesized from pyridoxine.9 This new class of
aminopyridinols is also equipped with good antioxidant prop-
erties, including an excellent co-antioxidant activity and potential
toxicological benefits.9,10
A new synthetic route to the pyrrolopyridinol 6, a five membered
ring version of N-TOH (5) also starts from pyridoxine·HCl (11).
We designed a convergent synthetic strategy depicted in Scheme 4
in which two main parts (i.e., pyrrolopyridine carbaldehyde 14 and
chiral C16-isoprenoidal phosphonium salt 15) are coupled together
under Wittig reaction conditions as in the previous report for
5.7 As we have already established the efficient synthetic method
for 15 from the natural product phytol,7 this report will mainly
focus on our exploration for a new and efficient way toward 14.
The key intermediate 14 was expected to be synthesized by a
transition metal-mediated intramolecular amination of 3-alkoxy-
5-aminoalkyl-6-halopyridine 16. Manipulation of pyridoxine·HCl
(11) can afford a halide 17, which in turn is able to give an
alanine moiety-incorporated 16 under the phase-transfer catalytic
alkylation conditions.
Scheme 1 By-products from the electrophilic aromatic hydroxylation
with 2-nitro-m-xylene.
In our previous report,7 the preparation of N-TOH (5), as a
C(7)-racemate, featured chelation-controlled regioselective MeLi
addition to C(7)-position of 6 over C(2)-position (path A in
Scheme 2). Unlike a 1,8-naphthyridine 9, a pyrrolopyridine 10
is not a suitable electrophile toward MeLi addition to generate a
quaternary center at C(2)-position (path B in Scheme 2). In addi-
tion, this approach requires a highly efficient hydroxylation step
Scheme 4 Retrosynthesis of the pyrrolopyridinol 6 (P = protective group;
R = alkyl group; X, X’ = halogen).
Scheme 5 shows the synthesis of 6 from pyridoxine·HCl (11)
starting with the treatment of 11 with zinc dust in refluxing acetic
acid. This condition provided selective cleavage of the C(4¢)–
O bond over the C(5¢)–O bond, which was accompanied by
Scheme 2
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of 2-naphthalene aldimine of alanine tert-butyl ester (23) with
22 under phase-transfer conditions (KOH base and n-Bu4NBr in
CH2Cl2) and the subsequent hydrolysis of the imine under acidic
condition gave 25. Intramolecular Cu(I)-catalyzed amination was
accomplished in 90% yield using Buchwald’s protocol,13 and then
the NH in 26 was reductively methylated in 96% yield. Finally,
the tert-butyl ester was partially reduced with DIBAL-H to afford
aldehyde 28 in 93% yield. Assembly of the aldehyde 28 and the
chiral C16-isoprenoid side chain 15 was achieved by the Wittig
coupling (88% yield). The phosphonium iodide 15 was prepared
from phytol, a natural acyclic diterpene alcohol, by the six-step
sequence we have developed.7 Both benzyl protection group and
the isolated olefin of 29 were removed at the same time by catalytic
hydrogenation condition to afford 6 in almost quantitative yield.
III. Preliminary trial for asymmetric synthesis
We then turned our attention toward asymmetric synthesis of 6.
Since the streochemistry of the two chiral centers in the C16 side
chain is already established in the optically active C16-isoprenoid
starting material,7 we mainly focused on the enantioselective
synthesis of 25. For the identical stereochemistry to that of
a-TOH, the absolute configuration of the chiral center in the
aldehyde 28 should be S. It can be accomplished during the
formation of 25 from 22 by enantioselective alkylation using a
chiral phase-transfer catalyst (PTC). Preliminary results of our
efforts to synthesize optically pure 25 are summarized in Table 1.
The representative cinchonidine-derived quaternary ammonium
salts, 3012,14 and 31,15 developed by some of us were used as chiral
PTCs in this asymmetric transformation, and tuning of reaction
conditions including the change of electrophile from 21 to 32 were
performed. In summary, the best result (91% chemical yield and
87% ee) was obtained with the chiral PTC 31 and the electrophile
32 at -20 ◦C under the given conditions (entry 6) from this initial
screening. Full investigations on enantioselective alkylation with
various chiral PTCs as well as fine tuning of reaction conditions
are currently underway.
Scheme 5 Reagents and conditions: (a) Zn, AcOH, reflux, 6 h, 95%; (b)
DBDMH, CH2Cl2, rt, 30 min, 98%; (c) NaH, PhCH2Br, THF, reflux, 2 h;
(d) NaOMe, MeOH, rt, 30 min, 92% (for 2 steps); (e) SOCl2, CH2Cl2, rt,
10 min, 99%; (f) KOH, n-Bu4NBr, CH2Cl2, rt, 2 h; (g) 1 M HCl, THF,
rt, 1 h, 81% (for 2 steps); (h) CuOAc, K3PO4, diethylsalicylamide, DMF,
80 ◦C, 10 h, 90%; (i) HCHO, NaBH3CN, AcOH, MeOH, rt, 6 h, 96%; (j)
DIBAL-H, CH2Cl2, -78 ◦C, 30 min, 93%; (k) n-BuLi, THF, 0 ◦C, 1 h, then
rt, 1 h, 90%; (l) H2, Pd/C, EtOH, rt, 30 h, 99%.
Conclusions
We elucidated the detailed mechanism of the electrophilic aromatic
hydroxylation and suggested that 2-nitroso-m-xylene generated
during the reaction is the main cause of low yield. A new synthetic
route from pyridoxine·HCl to the pyrrolopyridinol 6 which cannot
be prepared by the known strategy for N-TOH (5) was developed
in which phase-transfer catalytic alkylation and Cu(I)-catalyzed
intramolecular amination were used as the key steps. A preliminary
screening on the conditions of the enantioselective phase-transfer
catalytic alkylation was carried out with the cinchona PTCs.
O-acetylation to afford 18 in 95% yield. Electrophilic aromatic
bromination at the C(6)-position of 18 was accomplished with DB-
DMH (1,3-dibromo-5,5-dimethylhydantoin) in almost quantita-
tive yield. It should be noted that C(6)-bromination must precede
the protection of C(3)-OH. Once the C(3)-OH is protected with
benzyl group, no useful synthetic conditions for ring halogenation
were found (data not shown).11 After the ring bromination, benzyl-
protection of the C(3)-OH and the following deacetylation gave
21 in 92% yield for two steps. C(5¢)-O-acetyl group in 19 turned
out to be a prerequisite for the successful benzylation; a pyridinol
that has free OH at C(5¢)-position resulted in unwanted extra
benzylation either at the C(5¢)-OH or at the ring nitrogen along
with the wanted C(3)-O-benzylation. Chlorination of the C(5¢)-
OH in 21 with thionyl chloride quantitatively afforded 22 as HCl
salt. Alanine moiety was then introduced to 22 in 92% yield by the
two-step sequence developed by some of us.12 Briefly, an alkylation
Experimental details
General. Unless noted otherwise, materials were purchased
from commercial suppliers and used without further purification.
Air- or moisture-sensitive reactions were carried out under an
inert gas atmosphere. THF and CH2Cl2 were dried using a
Solvent Purification System from Solvtek. Progress of reaction
was monitored by thin-layer chromatography (TLC) using silica
gel F254 plates. Purification of the products was performed by
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Table 1 Preliminary results for enantioselective formation of (S)-25 under phase-transfer conditions in the presence of chiral catalyst (30 or 31)a
Entry
PTC
T/◦C
Time (h)b
Yield (%)c
ee (%)d
1
2
3
4
30
30
30
31
31
30
31
0
2
1
3
1
1
2
1
72
85
70
81
86
91
86
67
74
65
74
79
87
81
-20
-40
0
-20
-20
-20
5
6e
7e
a Reaction was carried out with 22 (1.0 equiv), 23 (1.0 equiv), and CsOH·H2O (7.0 equiv) in the presence of either 30 (10 mol%) or 31 (5 mol%) in toluene
at the given conditions to afford the alkylated aldimine which was then subjected to hydrolysis in acidic conditions to give the optically enriched (S)-25.
b Reaction time for consumption of the aldimine 23 to transform the corresponding alkylated aldimine. c Isolated yield of (S)-25 for the two steps from
22. d Enantiopurity was determined by HPLC analysis of (S)-25, using a chiral column [Chiralpak AD-H column, hexanes:2-propanol = 90 : 10, flow
rate = 1 mL min-1, detection = 280 nm], and absolute configuration was tentatively assigned as S according to the trend shown in the reports on the
enantioselective alkylation of 23.12 e 32 was used instead of 22.
flash column chromatography using silica gel 60 (230–400 mesh)
or a Biotage SP-1 system with indicated solvents. Infrared (IR)
spectra were recorded on a JASCO FT/IR-300E and Perkin-
Elmer 1710 FT spectrometer.NMR spectra were taken with a
300, 400, 500 MHz Bruker NMR spectrometer, or 300, 400 MHz
JEOL NMR spectrometer. Chemical shifts (d) were expressed in
ppm using solvent as an internal standard and coupling constant
(J) in hertz. Low-resolution mass spectra (MS) were recorded
on a VG Trio-2 GC-MS spectrometer, and high-resolution mass
spectra (HRMS) were measured on a JEOL JMS-AX 505wA,
JEOL JMS-HX/HX 110A spectrometer or performed at Ohio
State University. Melting points were measured on a Buchi B-540
melting point apparatus and were not corrected.
were filtered off through a Celite pad and the filter cake was washed
with CH3CN. After concentration of the filtrate, water (250 mL)
was added to the residue and the pH of the solution was adjusted to
5~6 with NaHCO3. CH2Cl2 was added to the mixture and the pH
was finally adjusted to about 7 in that time white solid precipitated.
The solid was filtered and the filtrate was concentrated. The residue
was purified by flash silica gel column chromatography (CHCl3–
1
MeOH = 20 : 1) to afford 18 (45.0 g, 95%) as a colorless oil. H-
NMR (300 MHz, DMSO-d6) d 8.72 (s, 1H), 7.89 (s, 1H), 5.04 (s,
2H), 2.35 (s, 3H), 2.15 (s, 3H), 2.03 (s, 3H); 13C-NMR (75 MHz,
DMSO-d6) d 170.5, 149.6, 146.9, 140.9, 132.5, 128.9, 62.3, 20.9,
20.2, 11.6 ppm; IR (KBr) n 3463, 3012, 1746, 1565, 1500, 1451,
1420, 1357, 1245, 1214, 1033, 895, 765 cm-1; MS (FAB+): m/z
196 [M+H]+; HRMS calculated for C10H14NO3: 196.074; Found:
196.0968 [M+H]+.
2,4-Dimethyl-5-acetoxymethylpyridin-3-ol (18). [Activation of
Zn:10~20 g of zinc dust was washed with 1 M HCl in a 1 : 11
ratio. This solution was stirred for 10 min at room temperature.
The solution was then filtered and the filter cake of zinc was
washed with H2O, MeOH, and Et2O. The zinc was then dried
under vacuum for approximately 2 h. Pyridoxine hydrochloride (1,
50.0 g, 0.243 mol) was dissolved in acetic acid (200 mL). Activated
zinc dust (63.6 g, 0.972 mol) was added to this solution in small
portions. The solution was refluxed for 2 h (if it seemed that the
reaction was not proceeding, a small amount of zinc dust was
added to make the reaction be completed). After completion of
the reaction,the excess zinc andthe inorganic salt of zinc formed
6-Bromo-2,4-dimethyl-5-acetoxymethyl-3-hydroxypyridine (19).
To a suspension of 18 (6.50 g, 33.3 mmol) in CH2Cl2 (180 mL) was
added 1,3-dibromo-5,5-dimethylhydantoin (4.76 g, 16.7 mmol)
and the resulting mixture was stirred for 30 min at room
temperature. Water (100 mL) was added to the mixture and then
extracted with dichloromethane (200 mL ¥ 3). The organic layer
was washed with brine and dried over MgSO4, concentrated to
◦
afford 19 (8.95 g, 98%) as a light yellow solid, m.p. 100–103 C;
1H-NMR (300 MHz, CHCl3-d) d 5.03 (s, 2H), 2.27 (s, 3H), 2.11 (s,
3H), 1.88 (s, 3H); 13C-NMR (75 MHz, CHCl3-d) d 171.3, 149.3,
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146.5, 137.1, 134.6, 129.2, 63.8, 21.1, 19.2, 13.1;IR (KBr) n 3366,
1739, 1590, 1412,,1378, 1241, 1109, 1029, 970, 917, 791 cm-1; MS
(FAB+): m/z 274 [M+H]+; HRMS calculated for C10H13BrNO3:
274.0079; Found: 274.0082 [M+H]+.
was stirred for 2 h at room temperature. The reaction mixture
was diluted with CH2Cl2 (30 mL) and water (5 mL) and the
aqueous layer was extracted with dichloromethane (10 mL ¥ 2).
The organic solution was dried over MgSO4 and concentrated
to give the crude 24. Purification of 24 for analysis: The residue
was purified by silica gel column chromatography (hexanes :
EtOAc = 20 : 1) to give 24 as a colorless oil. 1H-NMR (300 MHz,
CHCl3-d) d 8.15 (s, 1H), 7.97–8.02 (m, 2H), 7.83–7.90 (m, 4H),
7.51–7.55 (m, 2H), 7.26–7.30 (m, 2H), 7.07–7.12 (m, 2H), 4.50
(d, 1H, J = 11.1 Hz), 4.28 (d, 1H, J = 11.1 Hz), 3.66 (dd, 2H,
J = 34.5, 16.5 Hz), 2.45 (s, 3H), 2.34 (s, 3H), 1.61 (s, 3H), 1.55 (s,
9H); 13C-NMR (75 MHz, CHCl3-d) d 173.3, 158.6, 152.2, 151.4,
145.2, 140.4, 136.8, 135.2, 134.4, 133.4, 132.4, 131.0, 128.9, 128.8,
128.5, 128.2, 127.8, 127.7, 127.5, 127.0, 124.0, 82.0, 74.8, 71.2,
40.8, 28.4, 22.8, 19.6, 15.7.
The crude 24 was dissolved in THF (4 mL) followed by
addition of 1 M HCl in water (1 mL). The resulting mixture
was stirred for 1 h at room temperature. After concentration of
the reaction mixture, the residue was diluted with water (10 mL)
and washed with ether (10 mL ¥ 3). The aqueous layer was then
basified with sat. Na2CO3 solution and extracted with EtOAc
(30 mL ¥ 2). The combined organic solution was dried over MgSO4
and concentrated. The residue was purified by silica gel column
chromatography (hexanes:EtOAc = 2 : 1) under 280 nm to give 25
(255 mg, 81%) as a colorless oil. 1H-NMR (300 MHz, DMSO-d6)
d 7.38–7.49 (m, 5H), 4.82 (s, 2H), 3.11 (s, 2H), 2.35 (s, 6H), 1.78 (s,
2H), 1.40 (s, 9H), 1.17 (s, 3H); 13C-NMR (75 MHz, DMSO-d6) d
176.3, 151.5, 150.4, 144.4, 139.8, 137.0, 132.3, 128.8, 128.6, 128.5,
80.4, 74.3, 59.8, 41.0, 27.8, 25.9, 19.1, 15.5; IR (KBr) n 2975, 1724,
1573, 1452, 1369, 1249, 1214, 1159, 1114, 848, 748, 700 cm-1; MS
(FAB+): m/z 449 [M+H]+; HRMS calculated for C22H30BrN2O3:
449.1440; Found: 449.1445 [M+H]+.
6-Bromo-2,4-dimethyl-5-acetoxymethyl-3-benzyloxypyridine-
(20), 6-Bromo-2,4-dimethyl-5-hydroxymethyl-3-benzyloxypyridine
(21). To a suspension of 60% sodium hydride (160 mg, 4.0 mmol)
in dry THF (1 mL) was slowly added a solution of 19 (910 mg,
3.32 mmol) in dry THF (10 mL). After addition of benzyl bromide
(0.42 mL, 3.5 mmol), the mixture was refluxed for 2 h. The mixture
containing 20 was cooled to room temperature. Purification of
20 for analysis: The mixture was concentrated and the residue
was diluted with chloroform and water. The aqueous layer was
extracted with chloroform. The combined organic solution was
dried over MgSO4 and concentrated. The residue was purified by
silica gel column chromatography (hexanes : EtOAc = 5 : 1) to give
◦
1
20 as a colorless oil, m.p. 97 C; H-NMR (300 MHz, CHCl3-
d) d 7.41–7.45 (m, 5H), 5.25 (s, 2H), 4.82 (s, 2H), 2.51 (s, 3H),
2.33 (s, 3H), 2.11 (s, 3H); 13C-NMR (75 MHz, CHCl3-d) d 171.1,
154.3, 152.1, 144.1, 139.1, 136.6, 129.5, 129.1, 128.9, 128.4, 75.5,
63.8, 21.1, 19.9, 13.5;IR (KBr) n 3788, 2924, 1727, 1591, 1355,
1208, 1104, 964, 841 cm-1; MS (FAB+): m/z 364 [M+H]+; HRMS
calculated for C17H19BrNO3: 364.0548; Found: 364.0554 [M+H]+.
Methanol was added until the mixture became a clear solution
and then 30% sodium methoxide solution in methanol (0.63 mL)
was added to this solution. After concentration of the mixture, the
residue was diluted with chloroform (50 mL) and water (10 mL).
The aqueous layer was extracted with chloroform (10 mL ¥
2) and the combined organic solution was dried over MgSO4
and concentrated. The residue was purified by silica gel column
chromatography (hexanes : EtOAc = 2 : 1) to yield 21 (984 mg,
92%) as a white solid, m.p. 109 ◦C; 1H-NMR (300 MHz, CHCl3-
d) d 7.39–7.44 (m, 5H), 4.79–4.81 (m, 4H), 2.59 (t, 1H), 2.47 (s,
3H), 2.41 (s, 3H); 13C-NMR (75 MHz, CHCl3-d) d 153.6, 152.3,
143.7, 138.1, 136.6, 133.8, 129.1, 128.9, 128.4, 75.4, 62.3, 19.7,
13.4; IR (KBr) n 3369, 2919, 1575, 1407, 1365, 1216, 1097, 1010,
746, 700 cm-1; MS (FAB+): m/z 322 [M+H]+; HRMS calculated
for C15H17BrNO2: 322.0443; Found: 322.0448 [M+H]+.
tert-Butyl
5-benzyloxy-2,4,6-trimethyl-2,3-dihydro-1H-
mixture of
pyrrolo[2,3-b]pyridine-2-carboxylate (26). To
a
copper(I) acetate (3 mg, 0.022 mmol), N,N-diethylsalicylamide
(17 mg, 0.089 mmol) and potassium phosphate tribasic (189 mg,
0.89 mmol) was added a solution of 25 (200 mg, 0.445 mmol)
in dry DMF (1 mL). After the reaction mixture was stirred for
10 h at 80 ◦C, 1 M NaOH (2 mL) was added to the mixture. The
mixture was diluted with EtOAc (100 mL) and water (10 mL)
and the organic layer was washed with water (10 mL ¥ 4).
After drying the organic layer with MgSO4 and filtration, the
filtrate was concentrated. The residue was purified by silica gel
column chromatography (hexanes : EtOAc = 2 : 1) to afford 26
(148 mg, 90%) as a white solid, m.p. 127 ◦C; 1H-NMR (400 MHz,
CHCl3-d) d 7.35–7.47 (m, 5H), 4.94 (s, 1H), 4.73 (s, 2H), 3.50 (d,
1H, J = 16.4 Hz), 2.79 (d, 1H, J = 16.4 Hz), 2.39 (s, 3H), 2.12 (s,
3H), 1.57 (s, 3H), 1.47 (s, 9H); 13C-NMR (75 MHz, CHCl3-d) d
174.0, 157.1, 146.9, 144.9, 136.7, 136.5, 127.9, 127.4, 127.3, 116.9,
81.2, 74.4, 64.7, 37.2, 26.4, 18.4, 12.3; IR (KBr) n 3856, 3218,
2975, 2925, 1727, 1606, 1452, 1369, 1257, 1157, 846, 750 cm-1; MS
(FAB+): m/z 369 [M+H]+; HRMS calculated for C22H28N2O3:
369.2178; Found: 369.2173 [M+H]+.
3-Benzyloxy-6-bromo-5-chloromethyl-2,4-dimethylpyridine hy-
drochloride (22). To a solution of 21 (5.25 g, 16.29 mmol)
in CH2Cl2 (30 mL) was added thionyl chloride (1.25 mL,
17.10 mmol). The mixture was stirred for 10 min at room
temperature and concentrated to afford 22 (6.08 g, 99%) as a white
solid, m.p. 131.8 ◦C; 1H-NMR (300 MHz, CHCl3-d) d 7.31–7.37
(m, 5H), 4.80 (s, 2H), 4.66 (s, 2H), 2.57 (s, 3H), 2.36 (s, 3H); 13C-
NMR (75 MHz, CHCl3-d) d 153.7, 152.8, 146.7, 135.8, 135.3,
133.1, 129.3, 129.2, 128.6, 76.2, 42.6, 18.2, 13.8; IR (KBr) n 2923,
1571, 1405, 1365, 1216, 1155, 1091, 919, 740 cm-1; MS (FAB+):
m/z 342 [M+H]+.
tert-Butyl
pyridin-5-yl)-2-methyl-2-(naphthalen-2-ylmethyleneamino)propa-
noate (24), tert-Butyl 2-amino-3-(6-bromo-2,4-dimethyl-
3-benzyloxypyridin-5-yl)-2-methylpropanoate (25). To
2-amino-3-(6-bromo-2,4-dimethyl-3-benzyloxy-
a
tert-Butyl
5-benzyloxy-1,2,4,6-tetramethyl-2,3-dihydro-1H-
suspension of potassium hydroxide (240 mg, 3.52 mmol) in
CH2Cl2 (4 mL) were added 23 (200 mg, 0.70 mmol) and n-
tetrabutylammonium bromide (23 mg, 0.07 mmol). 22 (265 mg,
0.70 mmol) was added to the mixture and the resulting suspension
pyrrolo[2,3-b]pyridine-2-carboxylate (27). To a solution of 26
(80 mg, 0.217 mmol) in methanol (3 mL) were added 37%
formaldehyde (0.9 mL, 10.85 mmol) and acetic acid (0.6 mL,
10.85 mmol). After addition of sodium cyanoborohydride
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(136 mg, 2.17 mmol), the reaction mixture was stirred for
6 h at room temperature. Methanol was evaporated and the
residue was basified with sat. Na2CO3 solution. Extraction of the
mixture with EtOAc (50 mL ¥ 2) was performed. The combined
organic solution was washed with brine and dried over MgSO4,
concentrated. The residue was purified by silica gel column
chromatography (hexanes : EtOAc = 6 : 1) to give 27 (80 mg, 96%)
as a colorless oil. 1H-NMR (300 MHz, CHCl3-d) d 7.28–7.48 (m,
5H), 4.71 (s, 2H), 3.24 (d, 1H, J = 16.2 Hz), 2,93 (s, 3H), 2.76 (d,
1H, J = 16.2 Hz), 2.40 (s, 3H), 2.09 (s, 3H), 1.50 (s, 3H), 1.45 (s,
9H); 13C-NMR (75 MHz, CHCl3-d) d 173.4, 158.3, 147.2, 144.6,
137.9, 136.1, 128.9, 128.4, 128.3, 117.7, 81.8, 75.4, 69.3, 38.4,
28.3, 28.2, 22.1, 19.5, 13.0; IR (KBr) n 2976, 1726, 1585, 1455,
1397, 1367, 1213, 1155, 1112, 1016, 846, 733 cm-1; MS (FAB+):
m/z 383 [M+H]+; HRMS calculated for C23H31N2O3: 383.2335;
Found: 383.2339 [M+H]+.
MS (FAB+): m/z 505 [M+H]+; HRMS calculated for C34H53N2O:
505.4158; Found: 505.4156 [M+H]+.
1,2,4,6-Tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)-2,3-
dihydro-1H-pyrrolo[2,3-b]pyridin-5-ol (6). To a solution of 29
(27 mg, 0.0535 mmol) in ethanol (1 mL) was added palladium
(10% on activated carbon, 5 mg). The mixture was stirred with
hydrogen balloon at room temperature for 30 h. The solid in the
reaction mixture was filterd through Celite pad and the filtrated
R
was filtered again with syringe filter (Advantecꢀ JP050AN). The
filtrate was concentrated to give 6 (22 mg, 99%) as a pale yellow
oil. 1H-NMR (300 MHz, DMSO-d) d 7.33 (bs, 1H), 2.71 (d, 1H,
J = 16.1 Hz), 2.60 (s, 3H), 2.50 (d, 1H, J = 15.57 Hz), 2.16 (s,
3H), 1.97 (s, 3H), 1.56–1.45(m, 3H), 1.34–1.06 (m, 21H), 0.85–
0.79 (m, 12H); 13C-NMR (75 MHz, DMSO-d) d 155.4, 140.7,
139.9, 131.8, 117.6, 64.9, 64.2, 38.7, 38.2, 36.9, 36.8, 36.8, 36.7,
36.5, 32.0, 31.9, 27.3, 25.9, 24.1, 23.7, 23.5, 22.5, 22.4, 21.2, 21.1,
19.6, 19.2, 15.1, 12.6; IR (KBr) n 3608, 2927, 1461, 1396, 1218,
1093 cm-1; MS (FAB+): m/z 417 [M+H]+; HRMS calculated for
C27H49N2O: 417.3845; Found: 417.3856 [M+H]+.
5-Benzyloxy-1,2,4,6-tetramethyl-2,3-dihydro-1H-pyrrolo[2,3-
b]pyridine-2-carbaldehyde (28)
To a cooled (-78 ◦C) solution of 27 (70 mg, 0.18 mmol) in
anhydrous CH2Cl2 (1 mL) was added 1 M DIBAL-H in CH2Cl2
(0.18 mL, 0.18 mmol). After the mixture was stirred for 30 min at
-78 ◦C, the mixture was quenched with a few drops of methanol
and warmed up to room temperature. sat. Sodium potassium
tartrate solution (2 mL) was added and the mixture was stirred
for 1 h at room temperature. Extraction with CH2Cl2 (20 mL ¥ 2)
was carried out and the combined extracts were dried over MgSO4
and concentrated. The residue was purified by silica gel column
chromatography (hexanes : EtOAc = 2 : 1) to yield 28 (52 mg, 93%)
3-Benzyloxy-6-bromo-5-bromomethyl-2,4-dimethylpyridine (32).
To a cooled (-78 ◦C) solution of 21 (210 mg, 0.652 mmol)
in anhydrous CH2Cl2 (3.2 mL) was added 1 M phosphorus
tribromide (652 mL, 0.652 mmol). After stirring for 10 min at
-78 ◦C, the mixture was allowed to warm up to room temperature.
The reaction mixture was concentrated to give solid. Benzene
(20 mL) was added to this crude solid, and the suspension was
stirred for 1 h followed by decantation. EtOAc (100 mL) was added
to the residual solid and the resulting solution was washed with
sat NaHCO3 solution. The organic layer was washed with brine
and dried over Na2SO4 and concentrated. The residue was purified
with flash silica gel column chromatography (hexanes : EtOAc =
6 : 1) to afford 32 (234 mg, 93%) as a white solid, m.p. 83.5 ◦C;
1H-NMR (300 MHz, CHCl3-d) d 7.39 (s, 5H), 4.79 (s, 2H), 4.58
(s, 2H), 2.47 (s, 3H), 2.33 (s, 3H); 13C-NMR (125 MHz, CHCl3-d)
153.6, 151.7, 142.6, 137.6, 136.0, 131.2, 128.7, 128.5, 128.0, 75.1,
30.2, 19.4, 12.9; IR (KBr) n 2923, 1574, 1497, 1434, 1401, 1366,
1227, 1207, 1132, 958, 905, 776, 751, 696 cm-1; MS (FAB+): m/z
384 [M+]+; HRMS calculated for C15H16Br2NO: 383.9599; Found:
383.9606 [M+H]+.
1
as a colorless oil. H-NMR (300 MHz, CHCl3-d) d 9.64 (s, 1H),
7.36–7.49 (m, 5H), 4.73 (s, 2H), 3.11 (d, 1H, J = 16.5 Hz), 2.90 (s,
3H), 2.73 (d, 1H, J = 16.5 Hz), 2.42 (s, 3H), 2.11 (s, 3H), 1.39 (s,
3H); 13C-NMR (75 MHz, CHCl3-d) d 201.0, 158.2, 148.1, 145.2,
137.7, 137.1, 128.9, 128.5, 128.3, 117.2, 75.4, 71.7, 34.9, 28.1, 19.6,
17.4, 13.2; IR (KBr) n 3363, 2925, 2859, 2705, 1731, 1585, 1477,
1400, 1213, 1089, 1016, 738 cm-1; MS (FAB+): m/z 311 [M+H]+.
5 - Benzyloxy - 1,2,4,6 - tetramethyl - 2 - ((4R,8R) - 4,8,12 - trime -
thyltridec-1-enyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (29). To
acooled (0 ◦C) solution of 15 (217 mg, 0.362 mmol) in anhydrous
THF (1.5 mL) was added 1.6 M n-butyllithium in hexane solution
(226 mL, 0.362 mmol), and the mixture was stirred at 0 ◦C for 1 h.
A solution of 28 (45 mg, 0.145 mmol) in anydrous THF (2.9 mL)
was added to the mixture using cannular at 0 ◦C and then the
resulting mixture was stirred at room temperature for 1 h. The
reaction mixture was quenched with sat NH4Cl solution (2 mL)
and was diluted with EtOAc and water. Extraction with EtOAc
(20 mL ¥ 2) was carried out and the combined extracts were dried
over Na2SO4 and concentrated. The residue was purified by silica
gel column chromatography (hexanes : EtOAc = 20 : 1) to afford
29 (66 mg, 90%) as a colorless oil. 1H-NMR (300 MHz, CHCl3-d)
d 7.46–7.29 (m, 5H), 5.55 (d, 1H, J = 11.7 Hz), 5.50–5.41 (m,
1H), 4.69 (s, 3H), 2.97–2.77 (m, 2H), 2.81 (s, 3H), 2.38 (s, 3H),
2.06 (s, 3H), 2.17–2.03 (m, 1H), 1.95–1.84 (m, 1H), 1.56–0.99 (m,
18H), 0.85–0.79 (m. 12H); 13C-NMR (75 MHz, CHCl3-d) d 157.1,
143.8, 137.6, 136.2, 134.5, 132.3, 132.2, 128., 128.0, 127.8, 118.5,
77.2, 75.0, 65.5, 65.4, 41.2, 39.3, 37.3, 37.1, 37.0, 35.3, 33.6, 32.7,
28.0, 26.8, 25.5, 25.4, 24.8, 24.6, 24.5, 22.7, 22.6, 19.7, 18.9, 12.7;
IR (KBr) n 2925, 1586, 1465, 1394, 1216, 1095, 1016, 734 cm-1;
Acknowledgements
This work was supported by the National Science Foundation,
and by a Research Foundation Grant funded by the Korean Gov-
ernment (MOEHRD, Basic Research Promotion Fund) (KRF-
2008-331-E00460).
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1754 | Org. Biomol. Chem., 2011, 9, 1749–1755
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This journal is
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Org. Biomol. Chem., 2011, 9, 1749–1755 | 1755
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