Improved synthesis of 2,4,6-trialkylpyridines from 1,5-diketoalkanes: The total synthesis of Anibamine

Article abstract of DOI:10.1039/c8ob02723d

Many pyridine syntheses have been developed to date. In this study, we focused on pyridine synthesis with 1,5-diketone derivatives and hydroxylamine. Treatment of simple 1,5-diketoalkanes and hydroxylamine in basic or acidic conditions gave aldol adducts without any pyridine compounds. However, by screening the reaction conditions, we found that acidic conditions produced via the formation of oxime intermediates derived from 1,5-diketoalkanes allowed the formation of the corresponding pyridine derivatives. This is the first example of 2,4,6-trialkylpyridine synthesis from quite simple 1,5-diketoalkanes. In order to demonstrate the utility of the reaction, we demonstrated the synthesis of pyridine derivatives and the total synthesis of a 6-substituted pyridyl-natural product, anibamine. This was achieved by following the above methodology using a reported compound as the starting material to give the product in 12% yield.

Full text of DOI:10.1039/c8ob02723d

Organic &
Biomolecular Chemistry
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Improved synthesis of 2,4,6-trialkylpyridines from
,5-diketoalkanes: the total synthesis of
Anibamine†
1
Cite this: Org. Biomol. Chem., 2019,
7, 2896
1
Takeru Miyakoshi and Hiroyuki Konno
*
Many pyridine syntheses have been developed to date. In this study, we focused on pyridine synthesis
with 1,5-diketone derivatives and hydroxylamine. Treatment of simple 1,5-diketoalkanes and hydroxyl-
amine in basic or acidic conditions gave aldol adducts without any pyridine compounds. However, by
screening the reaction conditions, we found that acidic conditions produced via the formation of oxime
intermediates derived from 1,5-diketoalkanes allowed the formation of the corresponding pyridine deriva-
tives. This is the first example of 2,4,6-trialkylpyridine synthesis from quite simple 1,5-diketoalkanes. In
order to demonstrate the utility of the reaction, we demonstrated the synthesis of pyridine derivatives and
the total synthesis of a 6-substituted pyridyl-natural product, anibamine. This was achieved by following
the above methodology using a reported compound as the starting material to give the product in 12%
yield.
Received 2nd November 2018,
Accepted 27th November 2018
DOI: 10.1039/c8ob02723d
rsc.li/obc
hydration reaction between in situ-formed enamino ester and
Introduction
alkylidene malonate intermediates. Subsequent oxidation
1
,5a
Pyridine is a crucial heterocyclic framework that features in affords the corresponding aromatized products.
In 1906,
natural products and has been incorporated into organic Chichibabin developed a pseudo-four-component pyridine
1
–3
materials and pharmaceuticals. It is obvious that this struc- synthesis based on three equivalents of an enolizable aldehyde
1
,5b
ture is a useful scaffold that can be used to create attractive and one equivalent of ammonia.
In 1957, the Bohlmann–
molecules. Hence, the development of methods for pyridine Rahtz reaction was discovered, based on the conjugate
synthesis has been an important and attractive target in addition of an enaminoester to an alkynone followed by
1
,5c
organic chemistry. Plenty of methods for pyridine synthesis thermal cyclodehydration leading to a pyridine core.
have been reported to date, for example, metal-catalyzed pyri- Recently, in 2016, Deng et al. developed a metal-free protocol
4
a–f
dine syntheses using Fe, Cu, Rh, etc.
Guan et al. reported pyridine synthesis based on a combi- imes and α,β-unsaturated aldehydes.
nation of the N–O bond reductive cleavage of ketoxime acetates reported a synthesis combining 1,4-addition, ozonolysis and
For instance, in 2017, for the synthesis of substituted pyridines from O-acetyl ketox-
6
a
Rychnovsky et al.
3
6b
with the C(sp )–N bond oxidative cleavage of N,N-dimethyl- condensation processes. Maulide et al. reported the metal-
aniline via a Fe(II)/Fe(III) catalytic cycle. In the same year, free formal [2 + 2 + 2] intermolecular cycloaddition of hetero-
Yoshikai et al. developed a copper-catalyzed condensation reac- alkynes and nitriles. Many substituted pyridine synthesis
4
a
6
c
4
b
tion of oxime acetates and α,β-unsaturated ketimines. In methods have been developed to date, however, even in these
015, Wan et al. reported pyridine synthesis via the cationic recent reports, it was found that almost all of the synthesized
rhodium(I)/MeOBiphep complex-catalyzed [2 + 2 + 2] cyclo- pyridine derivatives have rigid and bulky functionalities includ-
addition of oximes with diynes using ethanol. In contrast, ing phenyl, naphthyl, furanyl, pyrroyl, pyridyl, thiophenyl and
metal-free reactions have also been achieved. One of the most other such groups, or no functionalities, with nothing at the 2,6-
popular methods is the Hantzsch approach. The corres- positions to prevent side reactions. That is, pyridine derivative
ponding symmetrical heterocycles are obtained via a cyclode- synthesis with, for example, alkyl substitution at the 2,6-posi-
tions derived from 1,5-diketoalkanes, has not yet been reported.
2
4
c
Herein, we demonstrate the synthesis of 2,4,6-trialkylpyridine
derivatives from 1,5-diketoalkanes under acidic conditions and
apply this methodology to synthesize anibamine (1) (Fig. 1).
Department of Biochemical Engineering, Graduate School of Science and
Engineering, Yamagata University, Yonezawa, Yamagata 992-8510, Japan.
E-mail: konno@yz.yamagata-u.ac.jp
Anibamine (1), isolated from Aniba sp. by Jayasuriya et al. in
2004, is a novel pyridine quaternary alkaloid that effectively
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8ob02723d
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functionalities rarely transform the corresponding pyridines
1
0a–k
via the previously reported methods (Schemes 1 and 2).
In order to prevent side reactions, the screening of acidic
conditions was conducted and acidic conditions were found
that gave smooth cyclization after the formation of oxime
intermediates. The optimizations of the acidic conditions for
pyridine synthesis are shown in Table 1. The 1,5-diketone
derivatives 2a–b reacted with hydroxylamine to produce oxime
intermediates, which were exposed to acidic reagents. Several
sets of acidic conditions were attempted. The reaction pro-
ceeded in HCl and EtOH at reflux, albeit with low yields
Fig. 1 An overview of the preparation of 2,4,6-trialkylpyridine deriva-
tives and 1.
1
1
(
Table 1, entries 1 and 2). The alkene isomerized product 3a
was synthesized from 2a in yields of up to 20%. These con-
ditions were used by Shibuya et al. to synthesize 2,6-diphe-
1
25
competes with I-gp120 to bind with the human CCR5 recep-
11
7
tor with an IC50 value of 1 µM. Li et al. reported that 1, the
first and only pyridyl natural product CCR5 antagonist, shares
many common binding features with the other known CCR5
ligands in each model of a docking study. Therefore, 1 is an
attractive target for novel drug discovery. Previously, the total
nylpyridines for their research on photochemical reactions.
Consequently, we found that the use of acetic acid resulted in
conditions that yielded 3a in 28% yield (Table 1, entry 3), even
though the alkene portion was also isomerized when using
HCl, which made us consider that thermodynamic stability is
relevant. In addition, 3b was synthesized from 2b in 38% yield.
These conditions were used in the following pyridine synthesis
8
9
synthesis of 1 was reported by Zhang’s group. The key reac-
tion is the base-mediated pyridine formation involving acetyl-
acetone and cyanoacetamide. However, CuCN, a very toxic
reagent, was used and this did not seem to be a suitable strat-
egy for a structure–activity relationship (SAR) study.
(
Table 1).
Results and discussion
Metal-free pyridine synthesis tends to require substrates that
have bulky and rigid functionalities at the 2,6-positions, as
6
a–h
detailed in previous reports.
From a reference investi-
gation, we focused on metal-free pyridine cyclization with
hydroxylamine, as employed by Kaiser et al. and Piccialli et al.,
1
0a–k
and shown in Scheme 1.
classical Knoevenagel route first requires the construction of
,5-diketones followed by reaction with hydroxylamine and
cyclization. The driving force is the elimination of water with
The method resulting from the
1
1
0c,d,j
the generation of an aromatic system.
In these cases, the Scheme 2 The cyclization of simple substrates using hydroxylamine.
corresponding substrates have rigid and bulky functionalities
that prevent side reactions. For this reason, we firstly
attempted pyridine synthesis using a simple substrate under
the same conditions. However, as a result, an aldol type reaction
1
0a–k
Table 1 Attempted pyridine cyclization under acidic conditions
occurred to give the side adducts shown in Scheme 2.
This suggests that substrates with non-bulky and non-rigid
Yield (2
steps)
Entry 2a,b/R
1
Condition
3a,b/R
2
1
2 N HCl/EtOH, ref
lux
6%
2
3
4
0.5 N HCl/EtOH, ref
lux
AcOH, ref lux
20%
28%
38%
AcOH, ref lux
Scheme 1 Metal-free pyridine synthesis using hydroxylamine.
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It was also proposed that 1,5-diketone derivatives may be yields than unblocked substrates (Table 2, entries 1, 2, and 3).
converted to multiple intermediates using hydroxylamine in Mesylation of the oxime 4b led to a lower yield (entry 8). The
reduced chemical yields. Accordingly, one of the two ketones phenyl group was found to barely influence the pyridine syn-
in 1,5-diketone starting materials was protected as a ketal, fol- thesis (Table 2, entries 4 and 5), as reported for other metal-
6
,12
lowed by oxime formation, and pyridine formation proceeded free methods.
Even the very bulky substrates 4f–g gave the
under the acidic conditions shown in Table 2. Using this corresponding pyridines (Table 2, entries 6 and 7), albeit in a
methodology, we demonstrated the synthesis of 3-substituted low yield in the case of 4f. The reason for this is that Michael
pyridine derivatives with a variety of functionalities at the addition occurred due to the presence of an oxime hydroxyl
2
-position. A medium length alkyl chain (C3–C4) gave better group to give a five membered heterocyclic compound, that is,
an isoxazole product. To the best of our knowledge, to date,
there have been only a few reports on 2,6-dialkyl-pyridine syn-
thesis without rigid and bulky functionalities at the 2,6-posi-
6
,12
tions.
Therefore, it can be said that this method is useful
Table 2 Synthesis of substituted pyridines via oxime-pyridine
cyclization
and has a higher tolerance than previously reported metal-free
methods (Table 2). Further screening of acidic reagents to find
more suitable acidic conditions is currently underway.
To demonstrate the higher tolerance of this reaction than
that of previously reported metal-free pyridine syntheses, we
next decided to apply this method to synthesize 1, which is a
6
-substituted pyridyl-natural product with IC = 1 µM against
50
a,b
7
Entry
1
Starting material
Product
Yield (%) CCR5. A structural feature of 1 is that it is a multi-substituted
pyridine framework and features two characteristic ten-carbon
37
alkyl chains with cis double bonds. A pyridine quaternary ion
9
is embodied by a fused five-membered ring. It is a challen-
ging task to construct a multi-substituted pyridine framework,
c
2
3
4
61
86
88
a well-known target in organic chemistry. For our synthetic
approach, we planned to employ our new metal-free pyridine
synthesis using 1,5-diketone derivatives. The retrosynthetic
analysis is shown in Scheme 3. The pyridine framework of 1 is
made up of a pyridine precursor with a terminal hydroxyl
group that can be derived from acetylacetone. Bromination,
followed by cross coupling, enables the formation of 1
(
Scheme 3).
Acetylacetone was used as a starting material to synthesize
precursor 12 in the pyridine formation. Firstly, the Horner–
Wadsworth–Emmons reaction of ketone 5, derived from acetyl-
acetone, gave unsaturated ethylester 6 in 67% yield as an E/
5
6
78
35
1
3,14
Z-mixture.
After the hydrogenolysis of 6 to obtain saturated
ethyl ester 7, saponification, followed by amidation afforded
Weinreb amide 9 in 84% yield over 2 steps. Weinreb amide 9
was a reasonable substrate to produce 10. A tert-butyldiphenyl-
silyl (TBDPS)-protected propargyl alcohol was used to intro-
d
7
8
65
31
e, f
a
b
c
Isolated yield. 2 steps yield. Reaction was conducted at 110 °C.
d
e
f
Methoxyamine was used. Oxime’s hydroxy group was mesylated.
steps yield.
3
Scheme 3 Retrosynthetic analysis of 1.
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duce a terminal alcohol group, which was then eliminated to Table 3 Screening of conditions for the bromination of 13
1
5
close a fused five-membered ring. It is noteworthy that
toluene was preferred over tetrahydrofuran (THF) in this
nucleophilic substitutional reaction. The hydrogenolysis of 10
afforded a cyclization precursor. The pyridine cyclization
method was attempted here, but the desired product was not
observed, instead giving a complex mixture, since a nucleophi-
lic attack on oxime by a deprotected hydroxyl group was
thought to have occurred. In order to prevent the deprotection
of TBDPS in the cyclization step, TBDPS was converted into a
pivaloyl group in 74% yield over 2 steps from 10, followed by
the hydrogenolysis of 11. Finally, the pyridine synthesis of 12
produced the desired pyridine framework 13 in 83% yield.
Surprisingly, this cyclization reaction occurred within
a
Entry
Condition
Yield (%)
b
b
1
2
3
4
5
NBS, conc. H
NBS, conc. H
NBS, conc. H
NBS, conc. H
NBS, conc. H
2
2
2
2
2
SO
SO
SO
SO
SO
4
4
4
4
4
, 50 °C
, 60 °C
7.1
22
21
39
55
c
, 60 °C,MW
c
, 60 °C
c
2
/H O = 2 : 1, 60 °C
a
b
c
Isolated yield. NBS (12 eq.). NBS (100 eq.).
3
0 minutes (Scheme 4).
Next, the bromination conditions of 13 were investigated in
order to achieve cross coupling (Table 3). Firstly, we tried the
bromination of 13 with NBS/conc. H SO at 50 °C, as reported
2
4
1
6
by Rajesh et al. However, the desired compound 14 was pro-
duced in only 7% yield (Table 3, entry 1). This result indicated
that 13 was unreactive because of the existence of alkyl groups
at the 2,4,6-positions, that is, resulting in a steric effect. In
order to activate the pyridine framework 13, increased temp-
erature and microwave conditions were applied to produce
2
2% and 21% yields, respectively (Table 3 entries 2 and 3). The
amount of NBS was increased to 100 eq. to give 39% yield
Table 3, entry 4). As a result, bromination with NBS (100 eq.)
in conc. H SO /H O, (2 : 1) at 60 °C afforded 14 in 55% yield. It
is noteworthy that the bromination of pyridine with no active Scheme 5 The synthesis of 1.
functionalities was achieved by adding H O, since in the
(
2
4
2
2
reported conditions, a brominated product was produced in a
lower yield (Table 3).
At the beginning of the cross coupling, we attempted a
Sonogashira cross coupling with 1-decyne and 14, which did
not give any coupling products due to steric hindrance. Next,
Suzuki–Miyaura cross coupling was employed. Boron reagent
1
5 was prepared Z-selectively via conditions described by
1
7a–d
Brown et al. and Takagi et al.
By Suzuki coupling dibromo-
pyridine 14 and organo boron 15 in the presence of
PdCl (PPh ) , two alkenyl chains 15 were successfully intro-
2
3 2
1
8
duced to the pyridine framework 14 to give 16. Finally, elim-
ination of the hydroxyl group of 16 with MsCl allowed the for-
mation of the desired five-membered ring.
9,18
The crude product
was purified by preparative HPLC to afford 1 as a trifluoroacetic
acid salt in 45% yield over two steps and a mixture of its isomers
(
E,Z and Z,E) as trifluoroacetic acid salts in 29% yield over two
9
steps. We observed that the NMR spectrum of the synthesized 1
matched that of the natural compound (Scheme 5).
7
Experimental
General
All solvents used were reagent grade. CH Cl was distilled over
2
2
CaH
2
and THF over Na. All commercial reagents were of the
1
highest purity available. An oil bath was used for heating. H
(400, 500 or 600 MHz) and C NMR (100, 125 or 150 MHz)
1
3
Scheme 4 Synthesis of the pyridine framework 13.
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spectra were recorded on JNM-ECX400, JNM-ECX500 or 3.35 mmol) and t-BuOK (375 mg, 3.35 mmol) were added to a
JNM-ECA600 spectrometers. Chemical shifts are expressed in flask. The flask was flushed with nitrogen and then charged
1
ppm relative to CHCl
3
(7.26 ppm for H and 77.16 ppm for with toluene (15 mL) and 1-bromooctyne (488 mg, 2.23 mmol).
1
3
1
C) and CD
3
CN (1.94 ppm for H and 1.32 and 118.26 ppm The mixture was stirred at 50 °C for 9 h. The reaction mixture
for C). Analytical TLC was performed on Merck Silica gel was then added to H O and extracted with toluene. The
1
3
2
6
4
0F254. Crude products were purified by column chromato- organic layers were washed with brine, dried over MgSO , fil-
graphy on Silica Gel 60 N [Kanto, particle size, (spherical, tered and concentrated in vacuo. The residue was purified by
neutral) 63–210 μm or 100–200 μm]. Analytical HPLC was column chromatography (AcOEt–hexane 1 : 20 v/v) to give 15
17d
carried out using a COSMOSIL 5C18-AR-II column (4.6 ID × (364 mg, 61%, E : Z = 4 : 96) as a yellow oil.
1
50 mm) with a gradient of MeCN (0.1% TFA) in H
2
1
O (0.1%
(2E,Z)-Ethyl 3-methyl-5-(2,2-dimethyldioxolane)-hex-2-enoate
−
TFA) at a run time of 35 min (flow rate of 1 mL min ), with a (6). A stirring solution of 2,4-pentanedione (40.1 g, 400 mmol),
SHIMADZU SPD-10A used as a UV-Vis detector, HITACHI 1,2-ethanediol (24.8 g, 400 mmol) and p-TsOH (catalytic
L-6000 Pump and HITACHI L-6200 Intelligent Pump. amount) in toluene (130 mL) was refluxed for 24 h in Dean–
Preparative HPLC was performed using a COSMOSIL 5C18- Stark apparatus. The reaction mixture was cooled to room
AR-II column (10 ID × 250 mm) with a linear gradient of MeCN temperature and the solvent was carefully removed under
(
2
0.1% TFA) in H O (0.1% TFA) at a run time of 35 min (flow reduced pressure. To the residue was added a saturated
−1
rate of 2 mL min ), with a SHIMADZU SPD-10Ai used as a aqueous solution of NaHCO and AcOEt. The organic layer was
3
UV-Vis detector and HITACHI L-6200 Intelligent Pump. UV dried over MgSO4, filtered and removed under reduced
measurements were recorded at a wavelength of 254 nm. High- pressure. The resulting residue, 5, was used in the following
resolution mass spectra (HRMS) were obtained using a JEOL reaction without further purification (39.1 g, 68% crude yield).
AccuTOF JMS-T100LC (ESIMS).
Ethyl diethylphosphonoacetate (15.7 g, 70.0 mmol) in THF
t-Butyldiphenylsilyloxy-2-propyne. Imidazole (817 mg, (5 mL) was added to a solution of THF (20 mL) and NaH
1
2.0 mmol) and TBDPSCl (1.84 mL, 7.20 mmol) were added to (2.80 g, 70.0 mmol) at 0 °C. After the mixture was stirred for
a solution of propargyl alcohol (355 µL, 6.00 mmol) in DMF 30 min, residue 5 (2.90 g, 20.0 mmol) in THF (5 mL) was
20 mL) at 0 °C. The solution was allowed to warm to room added to the reaction mixture at 0 °C, and the solution was
temperature and was then stirred overnight. The reaction then allowed to gradually warm to room temperature with stir-
mixture was added to a saturated aqueous solution of NH Cl ring overnight. The reaction was quenched by the addition of a
and the aqueous layer was extracted using Et O. The combined saturated solution of aqueous NH Cl at 0 °C. After the separ-
(
4
2
4
organic layers were washed with brine, dried over MgSO , fil- ation of the organic layers, the aqueous layer was extracted
4
tered and concentrated in vacuo to give t-butyldiphenylsilyloxy- with AcOEt. The combined organic layers were washed with
2
4
-propyne (1.40 g, 79% yield). This product was used without brine, dried over MgSO , filtered and concentrated in vacuo.
1
5
further purification.
The residue was purified by column chromatography (AcOEt–
Bromodecyne. NBS (5.0 g, 3.40 mmol) and AgNO
.0 mmol) were added to a solution of 1-decyne (3.62 mL, 2 steps) as a pale yellow oil.
3
(1.0 g, hexane, 1 : 5 v/v) to give 6 (E/Z-mixture, 4.23 g, 67% yield over
1
3,14 1
6
2
3
H NMR (600 MHz, CDCl )
0 mmol) in acetone (500 mL) at room temperature and stirred δ 1.25 (t, J = 7.2 Hz, 0.9H), 1.26 (t, J = 7.2 Hz, 2.1H), 1.31 (s,
under a shading mask overnight. The reaction mixture was fil- 2.1H), 1.32 (s, 0.9H), 1.96 (s, 0.9H), 2.23 (s, 2.1H), 2.44 (s,
tered carefully and concentrated in vacuo. The residue was pur- 1.5H), 3.07 (s, 0.5H), 3.91–3.94 (m, 4H), 4.13 (q, J = 7.2 Hz,
1
3
ified by column chromatography (hexane) to give 1-bromo-1- 2H), 5.74 (s, 0.75H), 5.77 (s, 0.25H) as an E,Z-mixture.
decyne (3.95 g, 90%) as a colorless oil.
C
1
7a
3
NMR (CDCl , 150 MHz) δ 14.4, 20.2, 24.2, 24.4, 26.6, 41.2, 49.7,
[
Z]-1-Bomo-1-decene. 1-Bromodecyne (508 mg, 2.30 mmol) 59.68, 59.70, 64.6, 64.8, 109.5, 110.0, 119.4, 119.8, 154.5, 155.3,
−1
in THF (0.4 mL) was added to a solution of 9-BBN (1.0 M in 166.5, 166.7 as an E,Z-mixture. IR (film) ν max cm : 2983,
THF, 5.52 mL, 2.76 mmol) under a nitrogen atmosphere at 1714, 1645, 1446, 1379, 1149, 1042. HRMS (ESI) m/z: calcd for
+
0
°C. The reaction mixture was allowed to warm to room tem-
C
11
H
18
O
4
Na [M + Na] 237.1103, found 237.1114.
perature and was then stirred for 30 h. After the evaporation of
Ethyl 3-methyl-5-(2,2-dimethyldioxolane)-hexanoate (7). Pd/
the solvent in vacuo, the residue was added to hexane (2.3 mL) C (catalytic amount) was added to a solution of 6 (645 mg,
and AcOH (158 µL, 2.76 mmol). After stirring for 30 h, ethanol- 3.01 mmol) in AcOEt (12 mL) and the reaction mixture was
amine (333 µL, 5.52 mmol), H O and hexane were added to stirred for 2 h under a hydrogen atmosphere. The reaction
2
the reaction mixture. After the separation of the organic layers, mixture was filtered and the solvent was removed under
the combined organic layers were washed with brine, dried reduced pressure. The desired product 7 was obtained as a
1
over MgSO , filtered and concentrated in vacuo. The residue colorless oil (650 mg, 100% yield). H NMR (400 MHz, CDCl )
4
3
was purified by column chromatography (hexane) to give (Z)-1- δ 1.01 (d, J = 6.8 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H), 1.33 (s, 3H),
bromo-1-decene (259 mg, 51% over 2 steps, E : Z = 4 : 96) as a 1.57 (dd, J = 13.6, 5.2 Hz, 1H), 1.68 (dd, J = 14.4, 6.0 Hz, 1H),
1
7b,c
yellow oil.
2.11 (dd, J = 14.8, 8.4 Hz, 1H), 2.15–2.24 (m, 1H), 2.51 (dd, J =
(
Z)-2-(Dec-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (15). 15.2, 5.6 Hz, 1H), 3.92–3.94 (m, 4H), 4.12 (q, J = 7.2 Hz, 2H).
1
3
PdCl
2
(PPh
3
) (47 mg, 0.067 mmol), Ph
3
P (35 mg, 0.134 mmol),
3
C NMR (100 MHz, CDCl ) δ 14.3, 21.2, 24.1, 26.5, 42.2, 44.9,
bis(pinacolato)diboron (623 mg, 2.45 mmol), PhOH (315 mg, 60.1, 64.4 (C2), 110.1, 173.2. IR (film) ν max cm− : 2982, 1734,
1
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374, 1189, 1074, 1035. HRMS (ESI) m/z: calcd for C11
Paper
1
H
21
O
4
(dd, J = 17.6, 1.2 Hz, 1H), 5.17 (dd, J = 10.8, 1.6 Hz, 1H),
5.86–5.97 (m, 1H). C NMR (100 MHz, CDCl ) δ 21.7, 24.2,
+
13
[M + H] 217.1440, found 217.1477.
3
N-Methyl-N,3-dimethyl-5-(2,2-dimethyldioxolane)-hexamide
25.2, 45.2, 48.4, 50.2, 64.4, 64.5, 110.2, 118.8, 130.9, 208.6. IR
9). To a solution of 7 (650 mg, 6.24 mmol) in EtOH (10 mL), (film) ν max cm− : 3080, 2981, 2956, 2880, 1714, 1638, 1377.
1
(
2
+
N NaOH (3.0 mL, 12.5 mmol) was added at 0 °C and the HRMS (ESI) m/z: calcd for C H O Na [M + Na] 235.1310,
1
2
20 3
resulting mixture was stirred at room temperature overnight. found 235.1302.
The organic solvent was carefully removed under reduced
3-Methyl-5-(2,2-dimethyldioxolane)-1-phenylhexanone (4d).
1
pressure. A saturated aqueous solution of NH Cl, 1 M HCl 60.2 mg, 53% yield, colorless oil. H NMR (500 MHz, CDCl )
4
3
2
(6 mL) and Et O was added to the mixture to achieve separ- δ 1.03 (d, J = 6.6 Hz, 3H), 1.35 (s, 3H), 1.65 (dd, J = 14.4, 6.6 Hz,
ation. The combined organic layers were dried over MgSO4, fil- 1H), 1.76 (dd, J = 14.4, 7.2 Hz, 1H), 2.40–2.45 (m, 1H), 2.77 (dd,
tered and concentrated in vacuo to give 8 (524 mg, 93% crude J = 16.2, 8.4 Hz, 1H), 3.21 (dd, J = 16.8, 4.8 Hz, 1H), 3.89–3.93
yield) as a colorless oil. To a solution of crude 8 in dry CH
2
Cl
2
(m, 4H), 7.45 (t, J = 7.2 Hz, 2H), 7.55 (tt, J = 7.2, 1.2 Hz, 1H),
1
3
(
10 mL), Et (1.55 mL, 11.1 mmol), N,O-dimethyl- 7.96 (dt, J = 7.8, 1.2 Hz, 2H). C NMR (150 MHz, CDCl )
3
N
3
hydroxylamine hydrochloride (0.543 g, 5.56 mmol), and BOP δ 21.8, 24.3, 25.9, 45.5, 46.5, 64.46, 64.51, 110.3, 128.2, 128.7,
reagent (2.46 g, 5.56 mmol) were added at 0 °C, and the reac- 132.9, 137.6, 200.4. IR (film) ν max cm− : 3060, 2957, 2879,
1
+
20 3
tion mixture was then stirred at room temperature overnight. 1685, 1598. HRMS (ESI) m/z: calcd for C15H O Na [M + Na]
After stirring, the mixture was added to H O and the aqueous 271.1310, found 271.1324.
2
layer was extracted with CH
2
Cl
2
. The combined organic layers
p-Methylphenyl-3-methyl-5-(2,2-dimethyldioxolane)-hexa-
1
were washed with brine, dried over MgSO4, filtered and con- none (4e). 32.6 mg, 79% yield, colorless oil. H NMR
centrated in vacuo. The residue was purified by column chrom- (400 MHz, CDCl ) δ 1.02 (d, J = 7.2 Hz, 3H), 1.35 (s, 3H), 1.64
3
atography (MeOH–CHCl
3
, 3 : 97 v/v) to give 9 (0.582 g, 84% (dd, J = 14.8, 6.4 Hz, 1H), 1.76 (dd, J = 14.8, 6.8 Hz, 1H), 2.41
1
yield over 2 steps) as a colorless oil. H NMR (CDCl3, (s, 3H), 2.45–2.37 (m, 1H), 2.73 (dd, J = 16.0, 8.4 Hz, 1H), 3.18
4
1
2
3
3
00 MHz,) δ 1.00 (d, J = 6.4 Hz, 3H), 1.33 (s, 3H), 1.57 (dd, J = (dd, J = 16.0, 4.8 Hz, 1H), 3.89–3.94 (m, 4H), 7.25 (d, J = 9.2 Hz,
1
3
4.8, 6.4 Hz, 1H), 1.70 (dd, J = 13.6, 5.2 Hz, 1H), 2.23–2.30 (m, 2H), 7.86 (d, J = 8.4 Hz, 2H). C NMR (100 MHz, CDCl
3
) δ 6.6,
H), 2.58 (dd, J = 18.4, 8.0 Hz, 1H), 3.17 (s, 3H), 3.66 (s, 3H), 21.8, 24.3, 26.0, 45.5, 46.4, 64.48, 64.50, 110.3, 128.4, 129.3,
1
3
−1
.92 (s, 4H). C NMR (CDCl , 100 MHz) δ 21.6, 24.2, 26.1, 135.2, 143.7, 200.1. IR (film) ν max cm : 2956, 2878, 1681,
3
+
2.2, 39.7, 45.3, 61.3, 64.46, 64.49, 110.3, 174.2. IR (film) ν max 1606, 1455. HRMS (ESI) m/z: calcd for C16
H
22
O
3
Na [M + Na]
−
1
cm : 2960, 1713, 1660, 1379, 1166, 1067, 1004. HRMS (ESI) 285.1467, found 285.1466.
m/z: calcd for C H NO Na [M + Na] 254.1368, found 254.1389.
+
4-Methyl-2-(2,2-dimethyldioxolane)-7-hexadecyn-6-one (4f).
11
21
4
1
Synthetic procedure for the pyridine precursor (see the ESI† 125 mg, 93% yield, colorless oil. H NMR (400 MHz, CDCl
for the other procedures): δ 0.88 (t, J = 7.0 Hz, 3H), 0.99 (d, J = 6.4 Hz, 3H), 1.20–1.31 (brs,
-Methyl-2-(2,2-dimethyldioxolane)-decan-6-one (4b). n-BuLi 10H), 1.33 (s, 3H), 1.37–1.40 (m, 2H), 1.65 (dd, J = 14.8, 6.4 Hz,
2.5 M in hexane, 0.5 mL, 0.938 mmol) was added in a drop- 1H), 1.57 (dd, J = 14.4, 6.0 Hz, 1H), 2.35 (t, J = 7.2 Hz, 2H),
wise manner to a solution of 9 (107 mg, 0.469 mmol) in Et 2.30–2.40 (m, 2H), 2.78 (dd, J = 19.6, 8.4 Hz, 1H), 3.89–3.96 (m,
10 mL) at −78 °C under a nitrogen atmosphere and the reac- 4H). C NMR (100 MHz, CDCl ) δ 14.2, 19.1, 21.4, 22.8, 24.2,
3
)
4
(
2
O
1
3
(
3
tion was stirred for 3 h, maintaining the temperature at 26.0, 27.9, 29.0, 29.1, 29.2, 31.9, 45.1, 53.4, 64.48, 64.52, 81.3,
1
−
78 °C. The reaction mixture was quenched by adding a satu- 94.2, 110.1, 188.3. IR (film) ν max cm− : 2928, 2857, 2211,
+
rated aqueous solution of NH Cl at −78 °C and the aqueous 1672. HRMS (ESI) m/z: calcd for C H O Na [M + Na]
4
19 32 3
phase was extracted with AcOEt. The combined organic layers 331.2249, found 331.2259.
were washed with brine, dried over MgSO
4
, filtered and con-
6-Methyl-8-(2,2-dimethyldioxolane)-nonan-4-one (4c). Pd/C
centrated in vacuo. The residue was purified by column chrom- (catalytic amount) was added to a solution of 4a (159 mg,
atography (AcOEt–hexane, 1 : 4 v/v) to give 4b (84.7 mg, 80% 0.749 mmol) in AcOEt (1.4 mL) and the reaction mixture was
1
yield) as a colorless oil. H NMR (400 MHz, CDCl
3
) δ 0.86 (t, J = stirred overnight under a hydrogen atmosphere. The reaction
7
2
1
1
.6 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H), 1.26 (qt, J = 7.6, 7.5 Hz, mixture was then filtered and the solvent was removed under
H), 1.28 (s, 3H), 1.46–1.53 (m, 3H), 1.57 (dd, J = 14.0, 6.4 Hz, reduced pressure. The desired product 4c (161 mg, 101%) was
1
H), 2.17–2.26 (m, 2H), 2.33 (t, J = 7.2 Hz, 2H), 2.56 (dd, J = obtained as a colorless oil. H NMR (400 MHz, CDCl
3
) δ 0.90
9.2, 7.6 Hz, 1H), 3.91–3.84 (m, 4H). C NMR (100 MHz, (t, J = 8.0 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H), 1.32 (s, 3H),
) δ 14.0, 21.6, 22.4, 24.1, 25.3, 26.0, 43.1, 45.2, 50.6, 1.54–1.64 (m, 2H), 1.54 (dd, J = 16.0, 7.2 Hz, 1H), 1.62 (dd, J =
1
3
CDCl
3
−1
6
1
2
4.37, 64.41, 110.2, 211.2. IR (film) ν max cm : 2957, 2875, 14.4, 6.4 Hz, 1H), 2.19–2.30 (m, 2H), 2.35 (dt, J = 7.2, 0.8 Hz,
+
13
713, 1373. HRMS (ESI) m/z: calcd for C H O Na [M + Na]
2H), 2.54–2.63 (m, 1H), 3.87–3.95 (m, 4H). C NMR (100 MHz,
CDCl ) δ 13.9, 17.3, 21.7, 24.2, 25.4, 45.3, 45.4, 50.7, 64.44,
-Methyl-8-(2,2-dimethyldioxolane)-nonen-4-one (4a). 237 mg, 64.48, 110.3, 211.1. IR (film) ν max cm : 2960, 2876, 1711,
1
3
24 3
51.1623, found 251.1603.
3
−
1
6
1
+
8
5% yield, colorless oil. H NMR (400 MHz, CDCl ) δ 0.95 (d, 1376. HRMS (ESI) m/z: calcd for C H O Na [M + Na]
3 12 22 3
J = 6.4 Hz, 3H), 1.31 (s, 3H), 1.56 (dd, J = 14.4, 5.6 Hz, 1H), 1.63 237.1467, found 237.1444.
dd, J = 14.0, 6.8 Hz, 1H), 2.22–2.31 (m, 2H), 2.64 (dd, J = 19.6, 4-Methyl-2-(2,2-dimethyldioxolane)-7-hexadecan-6-one (4g).
.4 Hz, 1H), 3.15 (d, J = 6.8 Hz, 2H), 3.87–3.95 (m, 4H), 5.12 Pd/C (catalytic amount) was added to a solution of 4f (125 mg,
(
8
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.405 mmol) in AcOEt (1.4 mL) and the reaction mixture was 121.5, 147.5, 157.5, 161.6. IR (film) ν max cm− : 2955, 2925,
1
0
stirred overnight under a hydrogen atmosphere. The reaction 2863, 1716, 1608, 1456, 1381, 1265. HRMS (EI) m/z: calcd for
+
mixture was then filtered and the solvent was removed under
C
10
H
15N [M] 149.1205, found 149.1197.
reduced pressure to give the desired product 4g (123 mg, 97%
4,6-Dimethyl-2-phenylpyridine (3d). 8.0 mg, 88% yield over 2
1
1
yield) as a colorless oil. H NMR (500 MHz, CDCl ) δ 0.88 (t, J = steps, pale orange oil. H NMR (500 MHz, CDCl ) δ 2.37 (s,
3
3
7
3
.0 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H), 1.25 (brs, 14H), 1.32 (s, 3H), 2.59 (s, 3H), 6.94 (s, 1H), 7.34 (s, 1H), 7.39 (tt, J = 7.3,
H), 1.50–1.65 (m, 2H), 1.55 (dd, J = 14.5, 5.5 Hz, 1H), 1.62 (dd, 1.5 Hz, 1H), 7.46 (t, J = 7.3 Hz, 2H), 7.97 (dt, J = 6.5, 2.0 Hz,
1
3
J = 15.0, 6.5 Hz, 1H), 2.20–2.29 (m, 2H), 2.36 (dt, J = 7.0, 2H). C NMR (125 MHz, CDCl ) δ 21.2, 24.7, 118.9, 122.7,
3
13
2
.0 Hz, 2H), 2.59 (m, 1H), 3.88–3.94 (m, 4H). C NMR 127.2, 128.67, 128.73, 140.1, 147.9, 157.1, 158.2. IR (film) ν
) δ 14.3, 21.7, 22.8, 24.0, 24.2, 25.4, 29.43, max cm− : 3060, 3029, 2955, 2925, 2854, 2359, 2338, 1741,
1
(125 MHz, CDCl
3
2
1
1
3
9.46, 29.59, 29.64, 29.7, 32.0, 43.5, 45.3, 50.7, 64.45, 64.49, 1607, 1456, 1230, 1029. HRMS (ESI) m/z: calcd for C H N
1
3
14
−1
+
10.3, 211.3. IR (film) ν max cm : 2925, 2854, 1713, 1465, [M + H] 184.1126, found 184.1100.
+
375. HRMS (ESI) m/z: calcd for C19
35.2562, found 335.2580.
H
36
O
3
Na [M + Na]
2-p-Methylphenyl-4,6-dimethylpyridine (3e). 16.4 mg, 78%
1
yield over 2 steps, pink oil. H NMR (600 MHz, CDCl ) δ 2.35
3
Synthetic procedure for the pyridine (see the ESI† for the (s, 3H), 2.40 (s, 3H), 2.57 (s, 3H), 6.91 (s, 1H), 7.25 (d, J =
1
3
other procedures):
7.8 Hz, 2H), 7.31(s, 1H), 7.86 (d, J = 8.4 Hz, 2H). C NMR
2
-Butyl-4,6-dimethylpyridine
(3b).
AcONa
(33
mg, (125 MHz, CDCl ) δ 21.3, 21.4, 24.5, 118.7, 122.6, 127.1 129.5,
3
−
1
0
0
0
.402 mmol) and hydroxylamine hydrochloride (18.6 mg, 137.0, 138.7, 148.1, 157.0, 158.0. IR (film) ν max cm : 3032,
.268 mmol) were added to a solution of 4b (30.9 mg, 2923, 2855, 1605, 1566, 1515, 1454, 1231, 1036. HRMS (ESI) m/
.134 mmol) in EtOH (0.5 mL) and H O (0.5 mL) and the reac- z: calcd for C H N [M + H] 198.1283, found 198.1266.
+
2
14 16
tion mixture was stirred for 5 h. After stirring, the reaction
mixture was added to H
2-Decynyl-4,6-dimethylpyridine (3f). 14.4 mg, 36% yield over
1
2
O and the aqueous layer was extracted 2 steps, yellow oil. H NMR (500 MHz, CDCl
3
) δ 0.872 (t, J =
with CHCl . The combined organic layers were dried over 6.9 Hz, 3H), 1.24–1.30 (brs, 10H), 1.41–1.44 (m, 2H), 1.61 (tt, J
3
MgSO
4
, filtered and concentrated in vacuo to give the oxime = 7.5, 7.2 Hz, 2H), 2.26 (s, 3H), 2.40 (t, J = 7.2 Hz, 2H), 2.48 (s,
1
3
intermediate. A stirring solution of the oxime intermediate in 3H), 6.87 (s, 1H), 7.03 (s, 1H). C NMR (150 MHz, CDCl
3
)
AcOH (1.68 mL) was refluxed for 12 h. The reaction mixture δ 14.2, 19.5, 20.8, 22.8, 24.5, 28.6, 29.16, 29.26, 29.31, 32.0,
was then cooled to room temperature and the solvent was care- 80.6, 90.4, 123.2, 125.0, 143.1, 147.4, 158.5. IR (film) ν
fully removed under reduced pressure. The residue was added max cm− : 2926, 2855, 2229, 1601. HRMS (ESI) m/z: calcd for
1
+
to a saturated aqueous solution of NaHCO and extracted with C H N [M + H] 244.2065 found, 244.2063.
3
17 26
CH
MgSO
2
Cl
2
. The organic layers were washed with brine, dried over
, filtered and concentrated in vacuo. The residue was 2 steps, yellow oil. H NMR (400 MHz, CDCl
2-Decanyl-4,6-dimethylpyridine (3g). 37.3 mg, 65% yield over
1
4
3
) δ 0.865 (t, J =
purified by column chromatography (AcOEt–hexane, 1 : 2 v/v) 6.8 Hz, 3H), 1.24 (brs, 14H), 1.66 (tt, J = 7.6, 7.6 Hz, 2H), 2.25
1
to give 3b (19.1 mg, 86% yield over 2 steps) as a yellow oil. H (s, 3H), 2.47 (s, 3H), 2.68 (t, J = 8.0 Hz, 2H), 6.76 (s, 1H), 6.77
1
3
NMR (400 MHz, CDCl
3 3
) δ 0.92 (t, J = 7.6 Hz, 3H), 1.37 (tq, J = (s, 1H). C NMR (100 MHz, CDCl ) δ 14.2, 21.0, 22.8, 24.4,
7
.6, 7.6 Hz, 2H), 1.65 (tt, J = 8.0, 7.6 Hz, 2H), 2.25 (s, 3H), 2.46 29.5, 29.68 (C2), 29.70, 29.73, 30.5, 32.0, 38.6, 120.6, 121.5,
1
3
−1
(s, 3H), 2.69 (t, J = 8.0 Hz, 2H), 6.75 (s, 1H), 6.76 (s, 1H).
C
147.5, 157.5, 161.9. IR (film) ν max cm : 2925, 2853, 1608,
NMR (100 MHz, CDCl
3
) δ = 14.1, 21.0, 22.8, 24.5, 32.5, 38.3, 1571, 1458, 1374, 1218, 1036. HRMS (ESI) m/z: calcd for
20.5, 121.5, 147.4, 157.5, 161.8. IR (film) ν max cm− : 2956, C H N [M + H] 248.2378, found 248.2397.
1
+
1
2
17 30
928, 2860, 1608, 1570, 1460, 1375, 1220, 1037. HRMS (EI) m/z:
5-Methylnonen-4,8-dione (2a). To a solution of 4a (28.7 mg,
0.135 mmol) in acetone (1.4 mL) and H O (1.4 mL), p-TsOH
,6-Dimethyl-2-(propen-1-ny)-pyridine (3a). 28.3 mg, 37% (catalytic amount) was added and the reaction mixture was
+
calcd for C11
H
17N [M] 163.1361, found 163.1384.
2
4
1
yield over 2 steps, yellow oil. H NMR (500 MHz, CDCl
3
) δ 1.91 stirred at 40 °C for 4 h. A saturated aqueous solution of
dd, J = 7.0, 2.0 Hz, 2.82H), 2.04 (dd, J = 7.5, 3.5 Hz, 0.18H), NaHCO was added to the mixture at room temperature and
.27 (s, 2.82H), 2.30 (s, 0.18H), 2.48 (s, 2.82H), 2.50 (s, 0.18H), the aqueous phase was extracted with AcOEt. The organic
.95 (dq, J = 15.0, 9.0 Hz, 0.06H), 6.45 (dq, J = 19.5, 2.0 Hz, layers were washed with brine, dried over MgSO , filtered and
(
3
2
5
1
0
9
1
2
4
H), 6.67 (dq, J = 19.5, 8.5 Hz, 0.94H), 6.79 (s, 0.94H), 6.81 (s, concentrated in vacuo. The residue was purified by column
.06H) 6.88 (s, 0.94H) 6.90 (s, 0.06H) as E,Z-mixture (E : Z = chromatography (AcOEt–hexane, 1 : 5 v/v) to give 2a (21.8 mg,
1
3
1
4 : 6). C NMR (100 MHz, CDCl
22.3, 130.2, 131.7, 147.6, 155.6, 157.8. IR (film) ν max cm−1
925, 1603, 1449, 968, 848, 665. HRMS (EI) m/z: calcd for 2.33 (dd, J = 16.5, 7.0 Hz, 1H), 2.42–2.53 (m, 3H), 3.14 (d, J =
3
) δ 18.5, 21.0, 24.5, 118.8, 96% yield) as a colorless oil. H NMR (400 MHz, CDCl
3
) δ 0.93
:
(d, J = 7.0 Hz, 3H), 2.11 (s, 3H), 2.30 (dd, J = 16.5, 6.5 Hz, 1H),
+
C
10
H
13N [M] 147.1048, found 147.1050.
7.5 Hz, 2H), 5.12 (ddt, J = 18.0, 2.0, 1.5 Hz, 1H), 5.17 (dd, J =
1
3
4
,6-Dimethyl-2-(propanyl)-pyridine (3c). 38.9 mg, 61% yield 10.0, 1.0 Hz, 1H), 5.84–5.92 (m, 1H). C NMR (100 MHz,
1
over 2 steps, yellow oil. H NMR (600 MHz, CDCl ) δ 0.953 (t, CDCl ) δ 19.9, 24.9, 30.0, 47.7, 48.3, 49.7, 118.5, 130.3, 207.6,
3
3
J = 7.8 Hz, 3H), 1.70 (dq, J = 7.8, 7.8 Hz, 2H), 2.26 (s, 3H), 2.47 207.8. IR (film) ν max cm− : 2960, 2879, 2360, 1714, 1638,
1
1
3
(s, 3H), 2.67 (t, J = 7.8 Hz, 2H), 6.76 (s, 1H), 6.78 (s, 1H).
C
1406, 1368, 1168, 1043, 994, 922. HRMS (EI) m/z: calcd for
+
NMR (150 MHz, CDCl ) δ 14.1, 21.0, 23.6, 24.5, 40.5, 120.7, C H O [M] 168.1150, found 168.1150.
3
10 16 2
2902 | Org. Biomol. Chem., 2019, 17, 2896–2905
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4
-Methyldecan-2,6-dione (2b). From 4b (29.1 mg, δ 21.5, 24.3, 25.7, 27.2, 38.9, 45.1, 51.7, 53.1, 64.5, 64.6, 85.2,
.175 mmol), the same conditions as 2a were used to afford 2b 110.1, 177.6, 187.1. IR (film) ν max cm− : 2978, 2877, 1740,
1
0
(
1
+
35.1 mg, quant.) as a colorless oil. H NMR (600 MHz, CDCl
δ 0.89 (t, J = 7.2 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H), 1.29 (qt, J = 333.1678, found 333.1653.
.6, 7.2 Hz, 2H), 1.53 (tt, J = 7.8, 7.8 Hz, 2H), 2.12 (s, 3H), 2.28 6-Methyl-8-(2,2-dimethyldioxolane)-1-pivaloyloxy-2-nonan-4-
dd, J = 7.8, 3.0 Hz, 1H), 2.31 (dd, J = 7.2, 3.0 Hz, 1H), one (12). Pd/C (catalytic amount) was added to a solution of 11
3
)
26 5
1679, 1137. HRMS (ESI) m/z: calcd for C17H O Na [M + Na]
7
(
2
1
3
.36–2.47 (m, 4H), 2.50 (m, 1H). C NMR (150 MHz, CDCl
3
)
(74.1 mg, 0.239 mmol) in AcOEt (10 mL), which was then
δ 14.0, 20.3, 22.5, 25.5, 26.0, 30.4, 43.1, 49.3, 50.4, 208.5, 210.7. stirred overnight under a hydrogen atmosphere. The reaction
IR (film) ν max cm− : 2959, 2933, 2874, 1714. HRMS (EI) m/z: mixture was then filtered and the solvent was removed under
1
+
calcd for C11
H
20
O
2
[M] 184.1463, found 184.1442.
reduced pressure to give the desired product 12 (76.1 mg,
1
t-Butyldiphenylsiloxy-6-methyl-8-(2,2-dimethyldioxolane)-2- 101% yield) as a colorless oil. H NMR (400 MHz, CDCl3)
nonyn-4-one (10). n-BuLi (2.5 in hexane, 1.73 mL, δ 0.93 (d, J = 6.4 Hz, 3H), 1.17 (s, 9H), 1.30 (s, 3H), 1.55 (dd, J =
.32 mmol) was added to a solution of t-butyldiphenylsilyloxy- 14.8, 5.2 Hz, 1H), 1.60 (dd, J = 14.8, 6.4 Hz, 1H), 1.89 (quintet,
-propyne (1.27 g, 4.32 mmol) in toluene (5 mL) at −78 °C J = 6.8 Hz, 2H), 2.23 (dd, J = 14.8, 5.6 Hz, 1H), 2.27–2.23 (m,
M
4
2
under a nitrogen atmosphere. After 30 min at 0 °C, 9 (500 mg, 1H), 2.41 (dt, J = 18.0, 6.8 Hz, 1H), 2.47 (dt, J = 17.6, 7.2 Hz,
2
.16 mmol) in toluene (5 mL) was added at −78 °C and the 1H), 2.60 (dd, J = 19.6, 8.4 Hz, 1H), 3.88–3.92 (m, 4H), 4.03 (t,
1
3
reaction mixture was allowed to warm to room temperature. J = 6.8 Hz, 2H). C NMR (100 MHz, CDCl ) δ 21.7, 22.8, 24.1,
3
After stirring for 12 h, the reaction was quenched with a satu- 25.4, 27.3, 38.9, 39.5, 45.2, 50.7, 63.7, 64.4, 64.5, 110.2, 178.6,
1
rated aqueous solution of NH
4
Cl at 0 °C. The aqueous layer 209.7. IR (film) ν max cm− : 2960, 2876, 1727, 1285, 1158.
+
was extracted with AcOEt and the combined organic layers HRMS (ESI) m/z: calcd for C H O Na [M + Na] 337.1991,
1
7
30 5
were washed with brine, dried over MgSO
centrated in vacuo. The residue was purified by column chrom-
atography (AcOEt–hexane, 1 : 6 v/v) to give 10 (0.972 g, 96% (563 mg, 6.86 mmol) and hydroxylamine hydrochloride
4
, filtered and con- found 337.2003.
4,6-Dimethyl-2-(3-pivaloyloxy)-propylpyridine (13). AcONa
1
yield) as a yellow oil. H NMR (400 MHz, CDCl
3
,) δ 0.98 (d, J = (191 mg, 2.74 mmol) were added to a solution of 12 (216 mg,
.4 Hz, 3H), 1.06 (s, 9H), 1.32 (s, 3H), 1.58 (dd, J = 14.8, 6.0 Hz, 0.686 mmol) in EtOH (0.3 mL) and H O (0.3 mL) and the reac-
H), 1.64 (dd, J = 14.0, 6.4 Hz, 1H), 2.29 (dd, J = 15.6, 8.0 Hz, tion mixture was stirred for 4 h. After completion of the reac-
H), 2.31–2.36 (m, 1H), 2.76 (dd, J = 15.2, 4.0 Hz, 1H), 3.91 (m, tion, H O was added to the mixture and the aqueous layer was
then extracted with CHCl . The combined organic layers were
6
1
1
4
2
2
1
3
H), 4.45 (s, 2H), 7.38–7.47 (m, 6H), 7.68–7.71 (m, 4H).
C
3
NMR (100 MHz, CDCl ) δ 19.3, 21.5, 24.2, 25.7, 26.7, 45.0, 52.6, dried over MgSO , filtered and concentrated in vacuo to give
3
4
5
1
2
3.0, 64.46, 64.53, 84.5, 89.7, 110.1, 128.0, 130.2, 132.6, 135.7, the oxime intermediate. A stirring solution of the oxime inter-
87.5. IR (film) ν max cm : 3071, 3049, 2957, 2932, 2858, mediate in AcOH (8.6 mL) was heated to 110 °C for 30 min.
−
1
213, 1676, 1428, 1112. HRMS (ESI) m/z: calcd for The reaction mixture was then cooled to room temperature
+
C
28
H
36
O
4
SiNa [M + Na] 487.2281, found 487.2253.
and the solvent was carefully removed under reduced pressure.
6
-Methyl-8-(2,2-dimethyldioxolane)-1-pivaloyloxy-2-nonyn-4- The residue was added to a saturated aqueous solution of
one (11). To a solution of AcOH (11.5 µL, 0.165 mmol) and NaHCO and then extracted with CH Cl . The organic layers
3
2
2
TBAF (0.2 mL, 0.165 mmol) in THF (0.4 mL), a solution of 10 were washed with brine, dried over MgSO
56.3 mg, 0.11 mmol) in THF (0.4 mL) was added at room centrated in vacuo. The residue was purified by column chrom-
temperature. After stirring for 5 min, the reaction mixture was atography (AcOEt–hexane, 1 : 4 v/v) to give 13 (142 mg, 83%
4
, filtered and con-
(
1
3 3
added to a saturated aqueous solution of NaHCO and the yield over 2 steps) as a yellow oil. H NMR (600 MHz, CDCl )
aqueous layer was extracted with AcOEt. The combined δ 1.19 (s, 9H), 2.08–2.02 (m, 2H), 2.26 (s, 3H), 2.47 (s, 3H), 2.77
organic layers were washed with brine, dried over MgSO , fil- (t, J = 7.8 Hz, 2H), 4.08 (t, J = 6.6 Hz, 2H), 6.76 (s, 1H), 6.80 (s,
4
1
3
3
tered and concentrated in vacuo to give the alcohol product. To 1H). C NMR (150 MHz, CDCl ) δ 21.0, 24.4, 27.3, 28.9, 34.7,
a solution of the obtained alcoholic product in THF (0.4 mL), 38.9, 64.1, 120.8, 121.9, 147.7, 157.8, 160.3, 178.7. IR (film) ν
DIPEA (371 µL, 2.2 mmol), DMAP (catalytic amount) and PivCl max cm− : 2961, 2872, 1727, 1609, 1284, 1157, 1038. HRMS
1
+
(
54.3 mL, 0.44 mmol) were added at 0 °C and the mixture was (ESI) m/z: calcd for C15
stirred overnight. The reaction mixture was added to a satu- 250.1808.
rated aqueous solution of NH Cl at 0 °C and the aqueous layer 3,5-Dibromo-4,6-dimethyl-2-propanolpyridine (14). NBS
was extracted with AcOEt. The combined organic layers were (2.3 g, 13 mmol) was added to a solution of 13 (32.3 mg,
washed with brine, dried over MgSO , filtered and concen- 0.130 mmol) in conc. H SO (2 mL) and H O (1 mL) at 60 °C
trated in vacuo. Purification by column chromatography and the reaction mixture was stirred for 4 d at 60 °C. The
AcOEt–hexane, 1 : 5 v/v) gave 11 (27.9 mg, 74% yield over mixture was then poured into crushed ice and 4 M NaOH and
H
24NO
2
[M + H] 250.1807, found
4
4
2
4
2
(
2
1
steps) as a colorless oil. H NMR (500 MHz, CDCl
3
) δ 1.00 (d, the aqueous layer was extracted with AcOEt. The combined
J = 6.0 Hz, 3H), 1.23 (s, 9H), 1.32 (s, 3H), 1.60 (dd, J = 14.5, organic layers were washed with brine, dried over MgSO4, fil-
5
2
3
.5 Hz, 1H), 1.65 (dd, J = 14.0, 6.5 Hz, 1H), 2.32–2.37 (m, 1H), tered and concentrated in vacuo. The residue was purified by
.34 (dd, J = 17.5, 8.5 Hz, 1H), 2.84 (dd, J = 15.5, 4.0 Hz, 1H), column chromatography (AcOEt–hexane, 1 : 1 v/v) to give 14
.91–3.94 (m, 4H), 4.81 (s, 2H). C NMR (100 MHz, CDCl3) (23.0 mg, 55%) as a white solid. Mp 64–66 °C. H NMR
1
3
1
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(
3
600 MHz, CDCl ) δ 2.00 (quintet, J = 6.0 Hz, 2H), 2.62 (s, 6H),
Conflicts of interest
3
.10 (t, J = 7.2 Hz, 2H), 3.26 (brs, 1H), 3.69 (t, J = 6.0 Hz, 2H).
1
3
3
C NMR (CDCl , 100 MHz) δ 25.0, 25.7, 30.3, 35.0, 62.4, 121.2, There are no conflicts to declare.
−1
1
2
C
21.7, 147.4, 155.1, 157.5. IR (film) ν max cm : 3347, 2927,
870, 1548, 1439, 1388, 1042, 756. HRMS (ESI) m/z: calcd for
+
10
H
14NOBr
2
[M + H] 321.9442, found 321.9467.
Anibamine (1) . PdCl
1.2 mg, 4.40 µmol), and 3,5-dibromo-4,6-dimethyl-2-propanol-
pyridine (17.8 mg, 55.1 µmol) were stirred in toluene (0.36 mL)
and Na CO aq. (2 M, 0.2 mL) under nitrogen for 0.5 h. A solu-
2 3 2 3
(PPh ) (1.6 mg, 2.20 µmol), PPh
Notes and references
(
1 C. Allais, J. M. Grassot, J. Rodriguez and T. Constantieux,
Chem. Rev., 2014, 114, 10829–10868.
2
3
tion of diisopropyl (Z)-1-decenylboronate (59 mg, 220 µmol) in
EtOH (0.2 mL) was added to the mixture, which was then
refluxed for 10 h before being diluted with AcOEt. The organic
2 H. Nishiyama, H. Sakaguchi, T. Nakamura, M. Horihata,
M. Kondo and K. Itoh, Organometallics, 1989, 8, 846–
848.
layer was dried over MgSO , filtered and concentrated in vacuo.
3 (a) R. Sakai, T. Higa, C. W. Jefford and G. Bernardinelli,
4
The residue was purified by column chromatography (AcOEt–
hexane, 1 : 1 v/v) to give the coupling product. This compound
was reacted on without further purification. To a solution of
the product in CH Cl (0.15 mL), Et N (60 µL, 496 µmol) and
2 2 3
MsCl (30 µL, 331 µmol) were added at 0 °C and then the reac-
tion mixture was allowed to warm to room temperature. After
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stirring overnight, the reaction mixture was then added to H
2
O
and extracted with CH Cl . The organic layer was dried over
2
2
MgSO , filtered and concentrated in vacuo. The residue was
4
purified by RP-HPLC to give anibamine (1) (13.4 mg, 45% over
9
,18 1
2
steps) as a yellow oil.
H NMR (600 MHz, CD
3
CN) δ 0.87
(t, J = 7.2 Hz, 6H), 1.20 (m, 7H), 1.23 (m, 7H), 1.27 (m, 6H),
1
2
.35 (m, 4H), 1.80 (m, 4H), 2.27 (s, 3H), 2.38 (tt, J = 8.1, 7.8 Hz,
H), 2.54 (s, 3H), 3.23 (m, 2H), 4.61 (t, J = 7.5 Hz, 2H), 6.04 (dt,
J = 10.8, 7.5 Hz, 1H), 6.07 (dt, J = 12.0, 7.2 Hz, 1H), 6.27 (d, J =
1
3
1
1.4 Hz, 1H), 6.28 (d, J = 11.4 Hz, 1H). C NMR (150 MHz,
CD CN) δ 14.4, 18.3, 19.1, 21.2, 23.4, 29.3, 29.4, 29.5, 29.7,
9.97, 30.00, 30.04, 30.07, 32.6, 33.0, 58.6, 122.1, 123.1, 132.2,
3
2
1
2
35.9, 139.4, 139.5, 148.8, 155.2, 155.6. IR (film) ν max cm−
926, 2855, 1739, 1690, 1198. HRMS (ESI) m/z: calcd for
1
:
+
C H N [M] 424.3943, found 424.3972.
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In summary, we have developed a method for the acid-pro-
moted synthesis of pyridines via oxime intermediates avoiding
any aldol-type reactions. To the best of our knowledge, this is
the first reported method that uses simple non-bulky, non-
rigid, 1,5-diketone substrates to synthesize the corresponding
pyridine derivatives. Therefore, we think this method has a
higher tolerance than previously reported metal-free methods.
In this study, we applied the methodology to construct the
pyridine framework of 1 as a demonstration and achieved the
total synthesis of 1 in 12% yield from reported compound 6,
which was about twice the yield of the previous total syn-
thesis. We assume that the alkyl functionalities of 1 can be
easily changed while using this method, for the purposes of a
SAR study. The further optimization of the reaction con-
ditions for the preparation of a variety of pyridine derivatives
and their application to analogue syntheses are currently
underway.
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