Hydroxyarylketones via Ring-Opening of lactones with aryllithium reagents: An expedient synthesis of ( )-anabasamine

Article abstract of DOI:10.1055/s-0029-1217047

The regioselective ring-opening of lactones (δ-valerolactone and γ-butyrolactone) with aryllithium reagents is reported for the construction of a series of δ-hydroxy aryl ketones and γ-hydroxy aryl ketones. Application of this method for the expeditious syntheses of ( )-anabasamine and its nicotine-related analogue are also described.

Full text of DOI:10.1055/s-0029-1217047

PAPER
91
Hydroxyarylketones via Ring-Opening of Lactones with Aryllithium
Reagents: An Expedient Synthesis of ( )-Anabasamine
Synthesis of
(
)
e
-Anabasam
i
ine Miao, Stassi C. DiMaggio,1 Mark L. Trudell*
Department of Chemistry, University of New Orleans, New Orleans, LA 70148, USA
Fax +1(504)2806860; E-mail: mtrudell@uno.edu
Received 1 July 2009; revised 18 August 2009
mide [Table 1, entry 5 (NO2) and entry 6 (CN)].
Presumably, the sensitivity of these groups to the strongly
basic and nucleophilic organolithium reagents led to the
formation of intractable mixtures. Furthermore, no diol
Abstract: The regioselective ring-opening of lactones (d-valerolac-
tone and g-butyrolactone) with aryllithium reagents is reported for
the construction of a series of d-hydroxy aryl ketones and g-hydroxy
aryl ketones. Application of this method for the expeditious synthe-
ses of ( )-anabasamine and its nicotine-related analogue are also products, which could be formed from the subsequent ad-
described.
Key words: ketones, lactones, nucleophilic addition, ring-opening,
natural products
Table 1 Ring-Opening of d-Valerolactone (1)
O
OH
Ar
O
ArBr (2)
BuLi, Et2O
–78 °C
O
O
Ar
OH
d-Hydroxy ketones have been reported to be useful build-
ing blocks for the construction of both natural and non-
natural compounds.2,3 Synthesis of these versatile inter-
mediates has been achieved via a variety of methods that
include the photooxidation of aryldihydropyrans,4 oxida-
tion of b-hydroxy sulfones,5 and nucleophilic ring-open-
ing of d-valerolactone (1).2,3,6–8 Of these methods, the
latter has been the most widely used. However, an inves-
tigation of the scope and limitations of organolithium nu-
cleophiles has not been previously reported.
3
4
1
Entry Compd
2
BuLi
Yield of 3
(1.2 equiv) (%)a
Br
1
2
a
t-BuLi
t-BuLi
79
87
Br
Br
b
Cl
Previous work in our laboratories led to the development
of a synthetic process for the construction of d-hydroxy
pyridinyl ketone derivatives via the addition of pryridinyl-
lithium reagents with d-valerolactone.6 The success of this
reaction has prompted a broader study of its scope and
limitations. Herein, we report the reactivity of a series of
aryllithium and heteroaryllithium reagents with d-valero-
lactone and g-butyrolactone for the preparation of d-hy-
droxy aryl ketone and g-hydroxy aryl ketone derivatives.
3
4
5
c
d
e
t-BuLi
t-BuLi
t-BuLi
72
90
Cl
Br
MeO
O2N
NC
Br
b
–
As summarized Table 1, a series of d-hydroxy ketones 3
were readily prepared from the reaction of 1 with a variety
of aryllithium and heteroaryllithium reagents (General
Method A). The organolithium reagents were initially
generated in situ by treatment of the corresponding bro-
mide with either n-butyllithium or tert-butyllithium in di-
ethyl ether at –78 °C. The lactone 1 was then added to the
organolithium solution and the reaction was quenched
with brine to furnish the d-hydroxy ketones 3 in high
yields (Table 1). The d-hydroxy ketones generally existed
as a mixture of chain–ring tautomers (3:4, >90:10), with
the equilibrium favoring the open-chain form 3.9
Br
b
6
7
8
f
t-BuLi
n-BuLi
n-BuLi
–
Br
Br
g
h
81
63
N
N
Br
9
i
n-BuLi
n-BuLi
98c
79
MeO
S
N
It is noteworthy that the reaction conditions did not toler-
ate strong electron-withdrawing groups on the aryl bro-
10
j
Br
SYNTHESIS 2010, No. 1, pp 0091–0097
Advanced online publication: 19.10.2009
DOI: 10.1055/s-0029-1217047; Art ID: M03509SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
9
a General Method A; isolated yield.
b Intractable mixture.
c Using 1 (1.33 equiv); see Miao et al.6

92
L. Miao et al.
PAPER
dition of the organolithium to the hydroxy ketones, were tributions of lactones 1 and 5 can be explained by the re-
observed. These results suggest that, under the low tem- activity of the different ring systems toward
perature conditions, nucleophilic attack on the lactone 1 nucleophiles.11 Previous studies have shown 1 to be much
was significantly more favorable than reaction with the more susceptible toward ring-opening than 5. As such, in
newly formed ketones 3. As such, it is possible to obtain the reaction of 1 with the aryllithium reagents, the newly
the d-hydroxy aryl ketones in high yield by simple control formed hydroxy ketone 3 does not readily compete with
of the reaction stoichiometry.
the reactive lactone 1, thus, none of the corresponding diol
was formed. Alternatively, in the five-membered-ring
system, the lower relative reactivity of 5 allows the hy-
droxy ketone 7 to compete for the aryllithium reagent and
thus leads to the formation of the diol 6.
The ring-opening reaction was also explored with g-buty-
rolactone (5; Table 2). Using the reaction conditions es-
tablished for 1 (General Method A), the reactivity of 5
differed significantly from that of the homologous lactone
1. In general, the major products from the reaction of 5 It was interesting to discover that the pyridinyllithium re-
with the various aryllithium reagents were the 1,1-diaryl- agents 2g, 2h and 2i did not readily undergo the secondary
butane-1,4-diols 6,10 while the corresponding g-hydroxy addition reaction. Only the corresponding g-hydroxy ke-
ketones 7 were the minor products.
tones 7 were obtained in good yield, with only trace
amounts (<10%) of the diols 6 present. Presumably, the
pyridinyl moiety of ketones 7g, 7h and 7i deactivates the
carbonyl towards addition of a second equivalent the or-
ganolithium reagent by formation of stabilized aggregate
intermediate species.12 As a result, the more reactive lac-
tone 5 is consumed prior to the competing second addi-
tion. Even employing an excess of the pyridinyllithium
reagents (2.0 equiv) did not lead to increased production
of the corresponding diols 6.
Table 2 Ring-Opening of g-Butyrolactone (5)
O
ArBr (2)
BuLi, Et2O
–78 °C
OH
Ar
O
OH
OH
+
Ar
Ar
O
6
7
5
Entry Compd
2
BuLi
6/7a
6/7b
Br
1
2
3
a
b
c
t-BuLi
65:16
72:18
68:13
9:71
10:67
11:63
With these results in hand, it was envisaged that the order
of addition of the lactone 5 may affect the product 6/7 dis-
tribution. To this end, the order of addition was reversed
by addition of a pre-cooled (–78 °C) solution of the aryl-
lithium reagent in diethyl ether to a solution of 5 in the
same solvent at –78 °C (General Procedure B). For the
aryl bromides 2a–d and 2j that were tested, all gave im-
proved yields of the g-hydroxy aryl ketone 7 over the cor-
responding diols 6 (Table 2). The g-hydroxy aryl ketones
7 existed nearly exclusively in the open-chain tautomer
form. Only trace amounts of the ring tautomers could be
observed by NMR for 7g and 7h.
Br
t-BuLi
t-BuLi
Br
Cl
Br
4
5
6
d
g
h
t-BuLi
n-BuLi
n-BuLi
77:15
–:70c
–:66c
14:68
MeO
Br
Br
In order to demonstrate the utility of this method for the
construction of more complex molecular scaffolds we
have completed the syntheses of the piperidine alkaloid
anabasamine 1213 and its unnatural nicotine analogue 13.
Anabasamine was of interest due to its structural similar-
ity to the tobacco alkaloids and its novel pharmacological
profile of cholinergic and anti-inflammatory activity.14
N
N
Br
7
8
i
n-BuLi
n-BuLi
–:89c
MeO
S
N
As illustrated in Scheme 1, the nucleophilic ring-opening
of lactones 1 and 5 by 2i gave the prerequisite hydroxy py-
ridinyl ketones 3i and 7i, respectively, in good yields
(Table 1 and Table 2). Generation of the piperidine (8)
and the pyrrolidine (9) ring systems were then readily
achieved by oxidation of the alcohols with Dess–Martin
reagent to furnish the corresponding aldehydes, followed
by reductive amination with methylamine hydrochloride/
sodium cyanoborohydride in methanol.15 The anabasine
derivative 8 (58%) and nicotine derivative 9 (54%) were
obtained in good overall yields for the two-step processes.
The 6-methoxypyridinyl moieties were then converted in
77% and 55% yield, respectively, into the 6-chloropyridi-
j
70:20
23:75
Br
a General Method A; isolated yield.
b General Method B; isolated yield.
c Trace amounts of 6 (<10%) observed by NMR.
The formation of diols 6a–d and 6j resulted from a second
addition of the organolithium reagent to the correspond-
ing ketone that was formed initially. These results are con-
sistent with the fact that the g-hydroxy ketones 7a–d and
6j are more reactive toward nucleophilic addition than the
lactone 5. Furthermore, the difference in the product dis-
Synthesis 2010, No. 1, 91–97 © Thieme Stuttgart · New York

PAPER
Synthesis of ( )-Anabasamine
93
rified by flash column chromatography (SiO2; hexanes–EtOAc) to
afford hydroxy aryl ketone 3 or 7.
O
O
2i, BuLi
Et2O
–78 °C
OH
n
O
5-Hydroxy-1-phenylpentan-1-one (3a)3
Prepared by Method A.
MeO
N
n
3i n = 2 (98%)
7i n = 1 (89%)
1 n = 2
5 n = 1
Yield: 565 mg (79%); light-yellow oil.
1H NMR (400 MHz, CDCl3): d = 1.61–1.68 (m, 2 H), 1.79–1.87 (m,
2 H), 1.99 (s, 1 H), 3.02 (t, J = 7.1 Hz, 2 H), 3.66 (t, J = 6.3 Hz,
2 H), 7.45 (t, J = 7.9 Hz, 2 H), 7.55 (t, J = 7.4 Hz, 1 H), 7.95 (m,
2 H).
13C NMR (101 MHz, CDCl3): d = 20.4, 32.4, 38.3, 62.6, 128.3,
128.8, 133.3, 137.1, 200.7.
1) Dess–Martin
CH2Cl2, r.t.
POCl3
115 °C
24 h
n
2) NH2Me⋅HCl
N
NaCNBH3
Me
MeO
N
8 n = 2 (58%)
9 n = 1 (54%)
Anal. Calcd for C11H14O2: C, 74.13; H, 7.92. Found: C, 73.63; H,
7.98.
B(OH)2
N
5-Hydroxy-1-p-tolylpentan-1-one (3b)2c
Prepared by Method A.
n
n
N
N
IPrPd(η3-C3H6)Cl
t-BuONa, dioxane
85 °C, 8 h
Me
Me
N
Cl
N
Yield: 837 mg (87%); white solid; mp 36–38 °C.
10 n = 2 (77%)
11 n = 1 (55%)
12 n = 2 (80%)
13 n = 1 (81%)
N
1H NMR (400 MHz, CDCl3): d = 1.56–1.75 (m, 3 H), 1.84 (m, 2 H),
2.38 (s, 3 H), 3.00 (t, J = 7.1 Hz, 2 H), 3.67 (dd, J = 11.6, 6 Hz,
2 H), 7.26 (d, J = 7.3 Hz, 2 H), 7.87 (d, J = 8.2 Hz, 2 H).
13C NMR (101 MHz, CDCl3): d = 20.5, 21.9, 32.5, 38.2, 62.5, 128.4,
129.5, 134.6, 144.1, 200.5.
Scheme 1 Synthesis of ( )-anabasamine (12) and nicotine analogue
13
nyl derivatives 10 and 11, with phosphorous oxychloride
in a sealed pressure tube at 115 °C for 24 hours.
Anal. Calcd for C12H16O2: C, 74.97; H, 8.39. Found: C, 74.75; H,
8.49.
Finally, Suzuki–Miyaura coupling of the chloro deriva-
tives 10 and 11 with 3-pyridineboronic acid using a vari-
1-(4-Chlorophenyl)-5-hydroxypentan-1-one (3c)
ety of palladium/ligand systems and conditions, afforded Prepared by Method A.
the target natural product ( )-anabasamine (12) and the
corresponding nicotine derivative 13 in modest yields
(40–50%).16 However, the catalytic system reported by
Nolan and co-workers was found to be superior for this
system, providing 12 in 80% yield and 13 in 81% yield.17
Overall, this first total synthesis of the alkaloid ( )-ana-
basamine (12) was achieved in 35% yield via the five-step
sequence from 1. The nicotine derivative 13 was obtained
in 21% overall yield from 5.
Yield: 0.77 g (72%); white solid; mp 59–61 °C.
1H NMR (400 MHz, CDCl3): d = 1.61–1.69 (m, 3 H), 1.80–1.88 (m,
2 H), 3.00 (t, J = 7.1 Hz, 2 H), 3.68 (dd, J = 11.6, 5.8 Hz, 2 H), 7.43
(d, J = 8.4 Hz, 1 H), 7.90 (d, J = 8.5 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 20.4, 32.4, 38.3, 62.6, 129.1,
129.7, 135.4, 139.7, 199.3.
Anal. Calcd for C11H13ClO2: C, 62.12; H, 6.16. Found: C, 62.17; H,
6.10.
5-Hydroxy-1-(4-methoxyphenyl)pentan-1-one (3d)4
Prepared by Method A.
All chemicals were purchased from Aldrich Chemical Company
and used as received unless otherwise noted. Proton and carbon
NMR were recorded on a Varian 400 MHz spectrometer at ambient
temperature in CDCl3 from Cambridge Isotope Laboratories, Inc.
1H NMR chemical shifts are reported as d values (ppm) relative to
tetramethylsilane. 13C NMR chemical shifts are reported as d values
(ppm) relative to CDCl3 (77.0 ppm). Melting points (mp) were mea-
sured with an Electrothermal R Mel-Temp apparatus and are uncor-
rected. Atlantic Microlab, Inc., Norcross, GA performed all CHN
microanalyses.
Yield: 933 mg (90%); colorless oil.
1H NMR (400 MHz, CDCl3): d = 1.60–1.68 (m, 2 H), 1.77–1.85 (m,
2 H), 2.01 (s, 1 H), 2.96 (t, J = 7.1 Hz, 2 H), 3.65 (dd, J = 10.7, 5.9
Hz, 2 H), 3.85 (s, 3 H), 6.89–6.93 (m, 2 H), 7.91–7.95 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 20.6, 32.5, 38.0, 55.7, 62.5, 113.9,
127.5, 130.5, 163.7, 199.3.
Anal. Calcd for C12H16O3: C, 69.21; H, 7.74. Found: C, 69.63; H,
7.74.
5-Hydroxy-1-(pyridin-2-yl)pentan-1-one (3g)18
Nucleophilic Ring-Opening of 1 or 5; General Method A
Under an atmosphere of nitrogen, to a stirred solution of aryl bro-
mide 2 (5 mmol, 1 equiv) in anhydrous Et2O (80 mL), was added a
solution of BuLi (1.6 M in hexanes, 6 mmol, 1.2 equiv) dropwise
over 15 min at –78 °C. The solution was stirred for an additional 15
min at –78 °C and then a solution of lactone (1 or 5; 5 mmol, 1
equiv) in Et2O (20 mL) was added dropwise. The reaction was al-
lowed to warm to r.t. and stirred for 2 h. Brine (75 mL) was added
to quench the reaction and the organic layer was taken. The aqueous
layer was extracted with EtOAc (2 × 50 mL) and CH2Cl2 (2 × 50
mL). The combined organic portions were dried over MgSO4, fil-
tered and concentrated under reduced pressure. The residue was pu-
Prepared by Method A.
Yield: 730 mg (81%); yellow oil.
1H NMR (400 MHz, CDCl3): d = 1.63–1.71 (m, 2 H), 1.77–1.87 (m,
2 H), 1.92 (s, 1 H), 3.25 (t, J = 7.3 Hz, 2 H), 3.69 (t, J = 6.1 Hz,
2 H), 7.46 (ddd, J = 7.5, 4.8, 1.0 Hz, 1 H), 7.83 (td, J = 7.7, 1.7 Hz,
1 H), 8.03 (d, J = 7.9 Hz, 1 H), 8.66 (d, J = 4.7 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 19.5, 20.3, 25.5, 32.4, 35.8, 37.4,
62.5, 62.6, 95.1, 120.2, 122.1, 123.6, 127.3, 137.2, 137.6, 147.7,
149.1, 153.5, 161.1, 202.1.
Anal. Calcd for C10H13NO2: C, 67.02; H, 7.31; N, 7.82. Found: C,
66.96; H, 7.46; N, 7.73.
Synthesis 2010, No. 1, 91–97 © Thieme Stuttgart · New York

94
L. Miao et al.
PAPER
5-Hydroxy-1-(pyridin-3-yl)pentan-1-one (3h)2d
Yield: 529 mg (68%); white solid; mp 125–127 °C.
Prepared by Method A.
1H NMR (400 MHz, CDCl3): d = 1.50–1.60 (m, 2 H), 2.11 (s, 1 H),
2.37 (t, J = 7.1 Hz, 2 H), 3.64 (t, J = 5.6 Hz, 2 H), 3.83 (s, 1 H),
7.24–7.28 (m, 4 H), 7.30–7.34 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 27.0, 39.3, 63.2, 76.5, 127.7, 128.6,
133.0, 145.6.
Yield: 350 mg (63%); yellow oil.
1H NMR (400 MHz, CDCl3): d = 1.64–1.72 (m, 2 H), 1.83–1.99 (m,
3 H), 3.06 (t, J = 7.1 Hz, 2 H), 3.70 (t, J = 6.1 Hz, 2 H), 7.43 (dd,
J = 8.0, 4.8 Hz, 1 H), 8.25 (m, 1 H), 8.77 (dd, J = 4.8, 0.8 Hz, 1 H),
9.17 (d, J = 2.1 Hz, 1 H).
13C NMR (101 MHz, CDCl3): d = 20.3, 32.2, 38.7, 62.3, 124.0,
132.4, 135.8, 149.6, 153.4, 199.4.
Anal. Calcd for C16H16Cl2O2: C, 61.75; H, 5.18. Found: C, 61.76; H,
5.36.
1,1-Di(4-methoxyphenyl)butane-1,4-diol (6d)
Prepared by Method A.
Anal. Calcd for C10H13NO2: C, 67.02; H, 7.31; N, 7.82. Found: C,
65.74; H, 7.39; N, 7.67.
Yield: 584 mg (77%); colorless oil.
4-Hydroxy-1-(6-methoxypyridin-3-yl)butan-1-one (3i)6
Prepared by General Method A.
1H NMR (400 MHz, CDCl3): d = 1.54–1.61 (m, 2 H), 1.73 (s, 1 H),
2.36 (t, J = 7.6 Hz, 2 H), 2.83 (s, 1 H), 3.66 (m, 2 H), 3.78 (d,
J = 6.0 Hz, 6 H), 6.80–6.85 (m, 4 H), 7.29–7.33 (m, 4 H).
Yield: 1.0 g (98%); pale-yellow solid; mp 42–44 °C.
1H NMR (400 MHz, CDCl3): d = 8.80 (d, J = 2.4 Hz, 1 H), 8.14 (dd,
J = 8.7, 2.4 Hz, 1 H), 6.79 (d, J = 8.7 Hz, 1 H), 4.01 (s, 3 H), 3.68
(t, J = 6.3 Hz, 2 H), 2.97 (t, J = 7.1 Hz, 2 H), 1.92 (br s, 1 H), 1.81–
1.87 (m, 2 H), 1.64–1.70 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 198.3, 166.9, 149.2, 138.4, 126.8,
111.4, 62.5, 54.3, 38.2, 32.4, 20.4.
13C NMR (75 MHz, CDCl3): d = 27.5, 39.4, 55.5, 63.4, 100.2, 113.6,
127.5, 139.8, 158.5.
Anal. Calcd for C18H22O4: C, 71.50; H, 7.33. Found: C, 70.69; H,
7.26.
1,1-Di(thiophen-2-yl)butane-1,4-diol (6j)
Prepared by Method A.
Anal. Calcd for C10H15NO3: C, 63.14; H, 7.23; N, 6.69. Found: C,
62.97; H, 7.19; N, 6.64.
Yield: 445 mg (70%); white solid; mp 94–96 °C.
1H NMR (400 MHz, CDCl3): d = 1.67–1.74 (m, 2 H), 1.92 (t,
J = 4.9 Hz, 1 H), 2.48 (t, J = 7.0 Hz, 2 H), 3.70 (dd, J = 10.8, 5.7
Hz, 2 H), 4.33 (s, 1 H), 6.93–6.97 (m, 4 H), 7.22 (dd, J = 4.9, 1.4
Hz, 2 H).
5-Hydroxy-1-(thiophen-2-yl)pentan-1-one (3j)
Prepared by Method A.
Yield: 726 mg (79%); yellow oil.
1H NMR (400 MHz, CDCl3): d = 1.62–1.71 (m, 3 H), 1.82–1.90 (m,
2 H), 2.97 (t, J = 7.2 Hz, 2 H), 3.67 (dd, J = 10.4, 6 Hz, 2 H), 7.13
(dd, J = 4.9, 3.8 Hz, 1 H), 7.63 (dd, J = 4.9, 1.1 Hz, 1 H), 7.73 (dd,
J = 3.8, 1.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 20.9, 32.3, 39.1, 62.4, 128.4,
132.2, 133.9, 144.4, 193.8.
13C NMR (75 MHz, CDCl3): d = 27.5, 42.9, 63.2, 76.1, 123.9, 124.8,
126.9, 152.4.
Anal. Calcd for C12H14O2S2: C, 56.66; H, 5.55. Found: C, 56.91; H,
5.83.
General Method B
Under an atmosphere of nitrogen, to a stirred solution of aryl bro-
mide 2 (5 mmol, 1 equiv) in anhydrous Et2O (40 mL), was added a
solution of BuLi (1.6 M in hexanes, 6 mmol, 1.2 equiv) dropwise
over 15 min at –78 °C. The solution was stirred for an additional 15
min at –78 °C and then added slowly via cannula to a solution of
lactone 5 (5 mmol, 1 equiv) in Et2O (40 mL) at –78 °C. The reaction
was allowed to warm to r.t. and stirred for 2 h. Brine (75 mL) was
added to quench the reaction and the organic layer was taken. The
aqueous layer was extracted with EtOAc (2 × 50 mL) and CH2Cl2
(2 × 50 mL). The combined organic portions were dried over
MgSO4, filtered and concentrated under reduced pressure. The res-
idue was purified by flash column chromatography (SiO2; hexanes–
EtOAc) to afford the g-hydroxy aryl ketone 7.
Anal. Calcd for C9H12O2S: C, 58.67; H, 6.56. Found: C, 58.50; H,
6.70.
1,1-Diphenylbutane-1,4-diol (6a)2a
Prepared by Method A.
Yield: 393 mg (65%); white solid; mp 104–106 °C.
1H NMR (400 MHz, CDCl3): d = 1.54–1.61 (m, 2 H), 1.94 (s, 1 H),
2.41 (t, J = 7.2 Hz, 2 H), 3.24 (s, 1 H), 3.63 (t, J = 5.6 Hz, 2 H),
7.18–7.23 (m, 2 H), 7.27–7.32 (m, 4 H), 7.39–7.43 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 27.4, 39.2, 63.3, 78.1, 126.3, 127.0,
128.4, 147.3.
Anal. Calcd for C16H18O2: C, 79.31; H, 7.49. Found: C, 79.06; H,
7.55.
4-Hydroxy-1-phenylbutan-1-one (7a)7
Prepared by Method B.
1,1-Di-p-tolylbutane-1,4-diol (6b)
Prepared by Method A.
Yield: 582 mg (71%); colorless oil.
1H NMR (400 MHz, CDCl3): d = 1.84 (t, J = 5.3 Hz, 1 H), 1.99–
2.06 (m, 2 H), 3.14 (t, J = 6.9 Hz, 2 H), 3.75 (dd, J = 5.9, 11.3 Hz,
2 H), 7.43–7.48 (m, 2 H), 7.54–7.59 (m, 1 H), 7.96–7.99 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 27.1, 35.5, 62.6, 128.3, 128.8,
133.4, 137.1, 200.8.
Yield: 486 mg (72%); white solid; mp 106–108 °C.
1H NMR (400 MHz, CDCl3): d = 1.53–1.62 (m, 2 H), 1.83 (s, 1 H),
2.31 (s, 6 H), 2.38 (t, J = 7.2 Hz, 2 H), 2.94 (s, 1 H), 3.64 (s, 2 H),
7.10 (d, J = 8.0 Hz, 4 H), 7.29 (d, J = 8.2 Hz, 4 H).
13C NMR (75 MHz, CDCl3): d = 21.2, 27.5, 39.2, 63.4, 78.0, 126.2,
129.1, 136.5, 144.5.
Anal. Calcd for C10H12O2: C, 73.15; H, 7.37. Found: C, 72.88; H,
7.42.
Anal. Calcd for C18H22O2: C, 79.96; H, 8.20. Found: C, 79.66; H,
8.19.
4-Hydroxy-1-p-tolylbutan-1-one (7b)5b
Prepared by Method B.
1,1-Di(4-chlorophenyl)butane-1,4-diol (6c)10b
Prepared by Method A.
Yield: 593 mg (67%); white solid; mp 42–44 °C.
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Synthesis of ( )-Anabasamine
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1H NMR (400 MHz, CDCl3): d = 1.86 (s, 1 H), 1.98–2.05 (m, 2 H),
2.41 (s, 3 H), 3.11 (t, J = 6.9 Hz, 2 H), 3.75 (s, 2 H), 7.27 (d, J = 8.0
Hz, 2 H), 7.88 (d, J = 8.2 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 21.9, 27.2, 35.5, 62.6, 128.4, 129.5,
134.6, 144.2, 200.4.
(d, J = 4.4 Hz, 2 H), 3.08 (t, J = 6.9 Hz, 2 H), 2.14 (s, 1 H), 1.98–
2.05 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 198.5, 167.0, 149.3, 138.4, 126.8,
111.4, 62.3, 54.3, 35.3, 27.0.
Anal. Calcd for C10H13NO3: C, 61.53; H, 6.71; N, 7.18. Found: C,
61.70; H, 6.82; N, 7.03.
Anal. Calcd for C11H14O2: C, 74.13; H, 7.92. Found: C, 73.98; H,
7.98.
4-Hydroxy-1-(thiophen-2-yl)butan-1-one (7j)21
Prepared by Method B.
1-(4-Chlorophenyl)-4-hydroxybutan-1-one (7c)19
Prepared by Method B.
Yield: 641 mg (75%); colorless oil.
Yield: 628 mg (63%); colorless oil.
1H NMR (400 MHz, CDCl3): d = 1.87 (t, J = 5.3 Hz, 1 H), 1.99–
2.06 (m, 2 H), 3.08 (t, J = 7.0 Hz, 2 H), 3.75 (q, J = 5.8 Hz, 2 H),
7.12–7.15 (m, 1 H), 7.64 (dd, J = 4.9, 1.0 Hz, 1 H), 7.75 (dd,
J = 3.8, 1.0 Hz, 1 H).
1H NMR (400 MHz, CDCl3): d = 1.77 (s, 1 H), 1.96–2.04 (m, 2 H),
3.10 (t, J = 6.9 Hz, 2 H), 3.74 (t, J = 6.0 Hz, 2 H), 7.44 (d, J = 8.5
Hz, 2 H), 7.92 (d, J = 8.5 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 27.0, 35.4, 62.4, 129.1, 129.7,
135.4, 139.8, 199.5.
13C NMR (75 MHz, CDCl3): d = 27.4, 36.2, 62.4, 128.4, 132.3,
133.9, 144.4, 193.7.
Anal. Calcd for C10H11ClO2: C, 60.46; H, 5.58. Found: C, 60.66; H,
5.81.
Anal. Calcd for C8H10O2S: C, 56.44; H, 5.92. Found: C, 56.05; H,
6.10.
4-Hydroxy-1-(4-methoxyphenyl)butan-1-one (7d)20
Prepared by Method B.
6¢-Methoxy-1-methylanabasine (8)
To a solution of the d-hydroxy aryl ketone 3i (1.25 g, 6 mmol) in
CH2Cl2 (60 mL) at r.t. under an atmosphere of nitrogen, was added
a solution of Dess–Martin reagent in CH2Cl2 (3.80 g, 9.0 mmol, 12
mL). The mixture was stirred for 1.5 h, then diluted with Et2O (50
mL) and poured into a solution of Na2S2O3 (8.5 g) in sat. NaHCO3
(60 mL) and stirred for 5 min until clear. The organic layer was tak-
en and the aqueous mixture was extracted with Et2O (3 × 50 mL).
The combined organic portions were washed with sat. NaHCO3 (50
mL), H2O (50 mL) and dried over Na2SO4. The solids were filtered
and the solvent was removed under reduced pressure to afford the
corresponding aldehyde in nearly quantitative yield. The aldehyde
was then used in the next step without further purification. The al-
dehyde (1.2 g, 6.0 mmol), MeNH2·HCl (400 mg, 6.0 mmol) and
NaCNBH3 (400 mg, 9.0 mmol) were dissolved in anhydrous MeOH
(25 mL) and stirred under nitrogen at r.t. for 48 h. The solvent was
removed under reduced pressure followed by addition of sat.
Na2CO3 (100 mL) to the residue. The mixture was exacted with
CH2Cl2 (3 × 100 mL) and the combined extracts were dried over
Na2SO4. The solids were filtered, the solvent removed under re-
duced pressure and the residue purified by column chromatography
(SiO2; MeOH–CH2Cl2, 1:9) to afford 8.
Yield: 660 mg (68%); white solid; mp 46–48 °C.
1H NMR (400 MHz, CDCl3): d = 1.93 (t, J = 5.2 Hz, 1 H), 1.97–
2.04 (m, 2 H), 3.08 (t, J = 6.9 Hz, 2 H), 3.74 (q, J = 5.7 Hz, 2 H),
3.87 (s, 3 H), 6.93 (d, J = 9.0 Hz, 2 H), 7.96 (d, J = 9.0 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 27.3, 35.2, 55.7, 62.6, 114.0, 127.5,
130.6, 163.7, 199.4.
Anal. Calcd for C11H14O3: C, 68.02; H, 7.27. Found: C, 67.97; H,
7.37.
4-Hydroxy-1-(pyridin-2-yl)butan-1-one (7g)8
Prepared by Method A.
Yield: 577 mg (70%); yellow oil.
1H NMR (400 MHz, CDCl3): d = 1.98–2.05 (m, 2 H), 2.57 (t,
J = 5.7 Hz, 1 H), 3.31 (t, J = 7.0 Hz, 2 H), 3.70 (q, J = 6.0 Hz, 2 H),
7.48 (ddd, J = 7.6, 4.8, 1.2 Hz, 1 H), 7.84 (td, J = 7.7, 1.7 Hz, 1 H),
8.03 (d, J = 7.9 Hz, 1 H), 8.66 (d, J = 4.7 Hz, 1 H).
13C NMR (101 MHz, CDCl3): d = 27.8, 34.5, 62.2, 122.1, 127.5,
137.3, 149.1, 153.6, 202.7.
Yield: 720 mg (58%); oil.
Anal. Calcd for C9H11NO2: C, 65.44; H, 6.71; N, 8.48. Found: C,
64.76; H, 7.04; N, 8.29.
1H NMR (400 MHz, CDCl3): d = 8.02 (d, J = 2.0 Hz, 1 H), 7.61 (dd,
J = 8.6, 2.4 Hz, 1 H), 6.71 (d, J = 8.4 Hz, 1 H), 3.93 (s, 3 H), 3.02
(d, J = 11.6 Hz, 1 H), 2.75 (dd, J = 11.0, 2.4 Hz, 1 H), 2.14 (m, 1 H),
1.99 (s, 3 H), 1.81 (d, J = 12.8 Hz, 1 H), 1.73–1.52 (m, 4 H), 1.42–
1.30 (m, 1 H).
l3C NMR (100 MHz, CDCl3): d = 163.6, 145.8, 137.7, 111.0, 67.5,
57.5, 53.4, 44.4, 35.7, 26.0, 24.9.
4-Hydroxy-1-(pyridin-3-yl)butan-1-one (7h)2d
Prepared by Method A.
Yield: 545 mg (66%); light-yellow solid; mp 36–38 °C.
1H NMR (400 MHz, CDCl3): d = 1.98–2.05 (m, 2 H), 2.40 (t,
J = 5.1 Hz, 1 H), 3.13 (t, J = 7.0 Hz, 2 H), 3.74 (dd, J = 11.3, 5.8
Hz, 2 H), 7.40 (dd, J = 8.0, 4.8 Hz, 1 H), 8.23 (dt, J = 8.0, 2.0 Hz,
1 H), 8.74 (dd, J = 4.8, 1.7 Hz, 1 H), 9.16 (d, J = 2.2 Hz, 1 H).
Anal. Calcd for C12H18N2O: C, 69.87; H, 8.80; N, 13.58. Found: C,
69.90; H, 8.71; N, 13.42.
13C NMR (100 MHz, CDCl3): d = 26.8, 35.6, 61.7, 124.0, 132.4,
6¢-Methoxynicotine (9)22
The nicotine derivative was prepared from 7i (1.2 g, 6.0 mmol) in
similar fashion to that of 8, to furnish 9.
135.8, 149.6, 153.4, 199.4.
Anal. Calcd for C9H11NO2: C, 65.44; H, 6.71; N, 8.48. Found: C,
65.85; H, 6.82; N, 8.45.
Yield: 670 mg (54%); yellow oil.
1H NMR (400 MHz, CDCl3): d = 8.03 (d, J = 2.4 Hz, 1 H), 7.62 (dd,
J = 8.6, 2.4 Hz, 1 H), 6.74 (d, J = 8.8 Hz, 1 H), 3.93 (s, 3 H), 3.24
(t, J = 8.0 Hz, 1 H), 3.01 (t, J = 8.4 Hz, 1 H), 2.28 (m, 1 H), 2.15 (s,
3 H), 2.01–1.68 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 163.8, 146.1, 137.8, 131.0, 111.1,
68.4, 57.0, 53.4, 40.2, 34.7, 22.4.
4-Hydroxy-1-(6-methoxypyridin-3-yl)butan-1-one (7i)
Prepared by Method A.
Yield: 870 mg (89%); pale-yellow solid; mp 35–37 °C.
1H NMR (400 MHz, CDCl3): d = 8.82 (d, J = 2.4 Hz, 1 H), 8.15 (dd,
J = 8.7, 2.5 Hz, 1 H), 6.79 (d, J = 8.7 Hz, 1 H), 4.01 (s, 3 H), 3.75
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L. Miao et al.
PAPER
Anal. Calcd for C11H16N2O: C, 68.72; H, 8.39; N, 14.57. Found: C,
68.57; H, 8.70; N, 14.40.
6¢-(3-Pyridinyl)nicotine (13)23
Prepared from 11 (118 mg, 0.60 mmol) in a similar fashion to that
of 12, to furnish 13.
6¢-Chloro-1-methylanabasine (10)
Yield: 116 mg (81%); pale-yellow oil.
The methoxy derivative 8 (500 mg, 2.4 mmol) was dissolved in
POCl3 (10 mL) and sealed in a glass pressure tube. The reaction was
stirred at 115 °C for 24 h. The reaction mixture was cooled to 0 °C
then the excess POCl3 was removed under reduced pressure. The
viscous residue was added to ice-water (50 mL), then the aqueous
solution was slowly added to sat. Na2CO3 (50 mL) at 0 °C. The mix-
ture was extracted with CH2Cl2 (5 × 50 mL), dried over Na2SO4,
and concentrated under reduced pressure. The residue was purified
by gravity column chromatography (SiO2; MeOH–CH2Cl2, 1:9) to
afford 10.
1H NMR (400 MHz, CDC13): d = 9.19 (s, 1 H), 8.64 (s, 2 H), 8.32
(d, J = 8.4 Hz, 1 H), 7.84 (dd, J = 8.0, 1.6 Hz, 1 H), 7.74 (d, J = 8.4
Hz, 1 H), 7.41 (m, 1 H), 3.29 (t, J = 8.0 Hz, 1 H), 3.18 (t, J = 8.4 Hz,
1 H), 2.39–2.33 (m, 2 H), 2.22 (s, 3 H), 2.07–1.74 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 154.1, 150.1, 150.0, 148.4, 139.5,
136.2, 135.5, 134.5, 123.8, 120.8, 68.8, 57.2, 40.6, 35.4, 22.8.
Anal. Calcd for C15H17N3: C, 75.28; H, 7.16; N, 17.56. Found: C,
75.01; H, 7.47; N, 17.31.
Yield: 404 mg (77%); yellow oil.
Acknowledgment
lH NMR (400 MHz, CDCl3): d = 8.29 (d, J = 2.0 Hz, 1 H), 7.67 (dd,
J = 8.0, 2.4 Hz, 1 H), 7.29 (d, J = 8.4 Hz, 1 H), 3.02 (d, J = 11.6 Hz,
1 H), 2.82 (dd, J = 12.0, 3.2 Hz, 1 H), 2.14–2.08 (m, 1 H), 1.98 (s,
3 H), 1.82 (d, J = 12.0 Hz, 1 H), 1.73–1.66 (m, 3 H), 1.55–1.33 (m,
2 H).
This research was funded by the National Institute on Drug Abuse
(DA11528), the Louisiana Board of Regents and the University of
New Orleans.
13C NMR (100 MHz, CDC13): d = 150.1, 149.1, 139.5, 137.9,
124.4, 65.5, 57.3, 44.6, 36.2, 26.0, 24.8.
References
(1) New address: S. C. DiMaggio, Department of Chemistry,
Xavier University of Louisiana, New Orleans, LA 70118,
USA
Anal. Calcd for C11H15N2Cl: C, 62.70; H, 7.18; N, 13.30. Found: C,
62.57; H, 7.30; N, 13.40.
(2) (a) Descotes, G.; Soula, J.-C. Bull. Soc. Chim. Fr. 1964,
2636. (b) Crich, D.; Huang, X.; Newcomb, M. Org. Lett.
1999, 1, 225. (c) Bailey, W. F.; Khanolkar, A. D.
Tetrahedron 1991, 47, 7727. (d) Ohkawa, S.; Terao, S.;
Terashita, Z.; Shibouta, Y.; Nishikawa, K. J. Med. Chem.
1991, 34, 267.
6¢-Chloronicotine (11)
Prepared from 9 (460 mg, 2.4 mmol) in a similar fashion to that of
10, to furnish 11.
Yield: 280 mg (55%); yellow oil.
1H NMR (400 MHz, CDCl3): d = 8.30 (d, J = 2.0 Hz, 1 H), 7.68 (dd,
J = 8.4, 2.2 Hz, 1 H), 7.29 (d, J = 8.4 Hz, 1 H), 3.23 (m, 1 H), 3.09
(t, J = 8.0 Hz, 1 H), 2.31 (m, 2 H), 2.16 (s, 3 H), 2.01–1.91 (m, 1 H),
1.90–1.78 (m, 1 H), 1.72–1.64 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 150.2, 149.3, 138.0, 137.5, 124.4,
68.2, 57.1, 40.5, 35.5, 22.7.
(3) Rosenblum, S. B.; Bihovsky, R. J. Am. Chem. Soc. 1990,
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(4) (a) Atkinson, R. S. Chem. Commun. 1970, 177.
(b) Atkinson, R. S. J. Chem. Soc. 1971, 784.
(5) (a) Fuji, K.; Node, M.; Usami, Y.; Kiryu, Y. J. Chem. Soc.,
Chem. Commun. 1987, 449. (b) Fuji, K.; Usami, Y.; Kiryu,
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(6) Miao, L.; DiMaggio, S. C.; Shu, H.; Trudell, M. L. Org. Lett.
2009, 11, 1579.
(7) Yang, S.-B.; Gan, F.-F.; Chen, G.-J.; Xu, P.-F. Synlett 2008,
2532.
(8) Gómez, I.; Alonso, E.; Ramón, D. J.; Yus, M. Tetrahedron
Anal. Calcd for C10H13N2Cl: C, 61.07; H, 6.66; N, 14.24. Found: C,
60.87; H, 6.86; N, 14.10.
( )-Anabasamine (12)13
Under an atmosphere of argon, 10 (125 mg, 0.60 mmol, 1.0 equiv),
pyridine-3-boronic acid (110 mg, 0.90 mmol, 1.5 equiv), h3-al-
lyl[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]palladium(II)
chloride (35 mg, 0.060 mmol, 0.1 equiv) and sodium tert-butoxide
(118 mg, 1.2 mmol, 2.0 equiv) were added to anhydrous dioxane
(10 mL). The reaction mixture was stirred vigorously at 85 °C for 8
h. The cooled reaction mixture was filtered through Celite 545 (2 g)
and rinsed with EtOAc (5 mL) and CH2Cl2 (5 mL). The filtrate was
concentrated under reduced pressure. The residue was purified by
column chromatography (SiO2; hexanes–EtOAc, 30:70) to afford
12.
2000, 56, 4043.
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Ueda, I.; Nojima, H. J. Med. Chem. 1972, 15, 855.
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(13) Mukhamedzhanova, S. Z.; Aslanov, Kh. A.; Sadykov, A. S.;
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Yield: 120 mg (80%); yellow oil.
lH NMR (400 MHz, CDCl3): d = 9.20 (d, J = 1.6 Hz, 1 H), 8.65 (d,
J = 1.6 Hz, 1 H), 8.63 (s, 1 H), 8.33 (dd, J = 8.0, 1.2 Hz, 1 H), 7.81
(dd, J = 8.0, 2.0 Hz, 1 H), 7.73 (d, J = 8.0 Hz, 1 H), 7.40 (m, 1 H),
3.06 (d, J = 11.6 Hz, 1 H), 2.89 (dd, J = 11.2, 2.4 Hz, 1 H), 2.18–
2.12 (m, 1 H), 2.04 (s, 3 H), 1.86–1.54 (m, 6 H). 1H NMR data were
consistent with previously reported values.13
13C NMR (100 MHz, CDCl3): d = 153.9, 149.9, 149.8, 148.3, 139.8,
136.1, 135.0, 134.4, 123.8, 120.7, 68.1, 57.5, 44.8, 36.1, 26.1, 24.9.
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S.; Huang, J.; Zhang, C.; Trudell, M. L.; Nolan, S. P.
Organometallics 2002, 21, 2866.
Anal. Calcd for C16H19N3: C, 75.85; H, 7.56; N, 16.59. Found: C,
75.77; H, 7.86; N, 16.20.
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Synthesis of ( )-Anabasamine
97
(17) Viciu, M. S.; Germaneau, R. F.; Navarro-Fernandez, O.;
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(23) Schmidt, B.; Neitemeier, V. Synthesis 1998, 42.
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Synthesis 2010, No. 1, 91–97 © Thieme Stuttgart · New York