Efficient preparation of the 18-methoxycoronaridine side-chain precursor

Article abstract of DOI:10.1055/s-2006-942489

An efficient synthesis of the side-chain precursor crucial to the preparation of 18-methoxycoronaridine (18-MC) has been developed. This procedure represents an improvement upon the original synthesis, in which regioisomers were separated by chromatography to provide the requisite precursor. Incorporation of the protected primary alcohol moiety in the early stages of the synthesis provides the requisite regioisomer unambiguously and obviates the need for chromatography at any point. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942489

PAPER
2743
Efficient Preparation of the 18-Methoxycoronaridine Side-Chain Precursor
Efficient
Preparation
o
a
f
the 18-Me
t
thoxyc
t
oronar
h
idine Side Ch
e
ain
P
recurs
w
or
P. Rainka, Matthew S. Dowling, Chi-Hsin R. King, Harold Meckler, R. Jason Herr*
Medicinal Chemistry and Chemical Development Departments, Albany Molecular Research, Inc., P.O. Box 15098, Albany,
NY 12212-5098, USA
E-mail: rjason.herr@albmolecular.com
Received 23 March 2006
the side-chain precursor 1 as depicted in Scheme 2. This
Abstract: An efficient synthesis of the side-chain precursor crucial
preparation of side chain component 1 began with the a-
to the preparation of 18-methoxycoronaridine (18-MC) has been
alkylation of commercially available dimethyl allylma-
lonate (5) with 2-chloroethyl methyl ether to provide the
developed. This procedure represents an improvement upon the
original synthesis, in which regioisomers were separated by chro-
matography to provide the requisite precursor. Incorporation of the bissubstituted malonate 6. This diester 6 was monodecar-
protected primary alcohol moiety in the early stages of the synthesis
boxylated using the Krapcho protocol and the resulting
provides the requisite regioisomer unambiguously and obviates the
need for chromatography at any point.
monoester moiety was reduced with lithium aluminum
hydride to provide the racemic alcohol 7. Alcohol 7 was
then oxidized using the Swern procedure to provide the
Key words: 18-methoxycoronaridine, 18-MC, debenzylation
intermediate aldehyde, which was immediately protected
without purification to provide the more stable cyclic ace-
18-Methoxycoronaridine hydrochloride [18-MC·HCl (3), tal 8. The olefinic portion of 8 was then converted to the
Scheme 1] is a congener of ibogaine that has shown prom- alcohol 9 by hydroboration with 9-BBN dimer, followed
ise as an agent for the treatment of drug abuse.1 Syntheses by workup with alkaline hydrogen peroxide. A major
of racemic2,3 and enantiopure4 18-MC have been pub- drawback to this latter manipulation was the generation of
lished, as well as a communication from our group for the significant amounts of the 1,5-cylooctanediol byproduct
chemical resolution of enantiomers5 for evaluation in rat 11, which could only be separated from the desired alco-
models of addiction. In order to prepare kilogram amounts hol 9 by a tedious large-scale chromatographic purifica-
of racemic 3 for ongoing biological studies, however, we tion. Another liability was the formation of the
required some process modifications to the published syn- hydroboration regioisomer 10, which was always formed
theses to improve the overall chemical throughput. In this in small amounts and which also had to be removed from
communication, we describe our efforts to improve upon the crude product to enable the later chemistry. The isolat-
the large-scale preparation of the aldehyde side-chain pre- ed alcohol 9 was then oxidized using the Swern procedure
cursor 1, which was required for the convergent cycload- to provide the requisite side-chain precursor 1.
dition step to provide multi-gram amounts of the key
intermediate 4 (Scheme 1).
The focus of our second-generation synthesis effort cen-
tered on the development of an alternative route to 1 by a
Our initial large-scale preparation of 18-MC (3) adhered method, which would eliminate the isolation of alcohol 9
closely to the literature procedures,3,4 requiring an eigh- by chromatography. It seemed that the simplest approach
teen-step synthesis, including the seven-step synthesis of would be to prepare the side-chain precursor by a route
Bn
N
O
Bn
O
N
O
O
O
OCH3
H3CO
N
H
N
CO2CH3
H
H
CO2CH3
4
2
1
⋅HCl
OCH3
N
⋅HCl
H3CO
N
CH3
N
N
H
H
CO2CH3
CO2CH3
18-MC⋅HCl
(3)
(–)-ibogaine⋅HCl
Scheme 1 Convergent synthesis of 18-MC·HCl (3)
SYNTHESIS 2006, No. 16, pp 2743–2747
x
x.
x
x
.
2
0
0
6
Advanced online publication: 12.07.2006
DOI: 10.1055/s-2006-942489; Art ID: M01606SS
© Georg Thieme Verlag Stuttgart · New York

2744
M. P. Rainka et al.
PAPER
H3CO2C
H3CO
CO2CH3
NaH, DMA–toluene, ∆
1. LiCl, DMSO–H2O
2. LiAlH4, Et2O
H3CO2C
CO2CH3
ClCH2CH2OCH3
6
5
1. (ClCO)2, DMSO
CH2Cl2; Et3N
O
O
1. 9-BBN, CH2Cl2
2. aq H2O2–NaOH
OH
H3CO
2. HOCH2CH2OH
p-TsOH, benzene,
reflux
H3CO
7
8
O
O
HO
O
O
+
+
H3CO
CH3
OH
H3CO
OH
OH
10
11
9
O
1. chromatography
O
O
2. (ClCO)2, DMSO
CH2Cl2; Et3N
H3CO
H
1
Scheme 2 Reported synthesis of side-chain precursor 1
that incorporated the required alcohol functionality in the repeatedly run on 100-g scale to provide the monoalkylat-
early stages of the synthesis. Thus, our first approach was ed malonate in 50–72% yields and in > 95% purity (deter-
to sequentially bisalkylate dimethyl malonate (12), first mined by 1H NMR analyses).
with 1-chloro-2-methoxyethane followed by the benzyl
ether of 3-chloropropanol to provide the key unsymmetri-
cal malonate 14 (Scheme 3).
These same reaction conditions were then used to effect
the second alkylation, in which 13 was reacted with 1-
(benzyloxy)-2-chloropropane to produce the bisalkylated
malonate diester 14 (Scheme 3).6 Upon workup of the
ClCH2CH2OCH3
H3CO2C
CO2CH3
OCH3
alkylation reaction, 14 was isolated as a clean amber oil,
contaminated only by residual N,N-dimethylformamide
solvent (as determined by NMR analyses). No attempt
was made to purify this key intermediate further, as the
solvent impurity was removed in the next synthetic step.
This reaction was repeatedly run on 100–200-g scales to
produce the bissubstituted malonate 14 in near-quantita-
tive yields (always with some residual N,N-dimethyl-
formamide solvent, as determined by 1H NMR), and was
used to stockpile more than a kilogram of the key interme-
diate 14 for further use. It is also worth noting that the use
of the 3-chloropropyl electrophile with potassium iodide
is much less expensive than use of the commercially
available 3-bromopropyl benzyl ether, which provided
virtually no difference in isolated yield.
The chemistry route developed3,4 for the initial side chain
synthesis was applied to carry the bisalkylated malonate
14 forward to the requisite benzyl-protected acetal 18
(Scheme 4). During this phase of the research effort, only
a few process modifications were necessary to apply the
procedures to large-scale manipulation.
H3CO2C
CO2CH3
NaH, KI, THF–DMF (1:1)
0 °C to r.t. to reflux
12
13
50–72%
H3CO2C
BnO
CO2CH3
OCH3
ClCH2CH2CH2OBn
NaH, KI, THF–DMF (1:1)
0 °C to r.t. to reflux
14
95–99%
Scheme 3 Bis-alkylation strategy to prepare unsymmetrical malo-
nate 14
The first alkylation of malonate 12 with 2-haloethyl meth-
yl ethers was explored using a variety of leaving groups
(chlorine, bromine and tosylate) and reaction conditions,
including the use of different bases, phase-transfer cata-
lysts, varying temperature ranges and changes in the ratio
of the co-solvents. Ultimately it was found that the opti-
mal reaction conditions required the deprotonation of 12
with sodium hydride at 0 °C in a 1:1 co-solvent mixture of
tetrahydrofuran–N,N-dimethylformamide, followed by
warming the mixture to room temperature (Scheme 3).
Following the addition of the electrophile at room temper-
ature, the mixture was further heated to reflux and stirred
for 12 hours.6 Upon workup, the crude reaction mixture
was purified by a simple high vacuum distillation to pro-
vide the adduct 13 as a clear amber oil. This reaction was
Krapcho decarboalkoxylation7 of the malonate 14 provid-
ed the desired ester 15 in 67–86% yields (7 g to 200 g
scale). The extraction of the crude product into hexane
from a large volume of water also removed the excess
N,N-dimethylformamide from the previous step. Reduc-
tion of this ester moiety of 15 with lithium aluminum hy-
Synthesis 2006, No. 16, 2743–2747 © Thieme Stuttgart · New York

PAPER
Efficient Preparation of the 18-Methoxycoronaridine Side-Chain Precursor
2745
HOCH2CH2OH, PpTs
CO2CH3
H3CO2C
CO2CH3
OCH3
LiCl, 140 °C
benzene, reflux
– H2O
H3CO
aq DMSO
67–86%
BnO
OBn
O
15
14
O
conditions
OH
O
O
and/or
O
1. (ClCO)2–DMSO
CH2Cl2, –78 °C
H3CO
H3CO
OBn
H3CO
1. LiAlH4, THF, r.t.
OH
OH
18
H3CO
9
19
2. H2O
2. Et3N, –78 °C to r.t.
90–99%
OBn
O
16
74–89%
and/or
H
H3CO
OBn
O
O
CHO
HOCH2CH2OH, PpTs
20
H3CO
PhH, reflux
– H2O
H3CO
OBn
Scheme 5 Failed deprotections of benzyl ether 18
OBn
17
18
77–93%
Scheme 4 Elaboration of malonate 14 to debenzylation precursor
18
tion mixture to ethylene glycol and pyridinium p-toluene-
sulfonate in refluxing benzene converted the lactol 19 into
alcohol 9, but the resulting reaction product was not clean
enough to use as a process. The initial attempts to remove
the benzyl group of 18 by hydrogenolysis in the presence
of water-wet palladium on carbon catalyst failed to pro-
duce 9 when run in methanol or ethanol solvents, but pro-
vided the lactol 19 when acetic acid was used as a solvent.
Evidently, the water present in this wet catalyst was suffi-
cient to deprotect the acetal functionality in the acidic en-
vironment, thus allowing the deprotected primary alcohol
product to cyclize onto the in situ generated aldehyde 20
to form the lactol 19.
dride was accomplished easily on 5–112-g scales to
provide the alcohol 16 in 74–89% isolated yields. A water
quench of the reaction mixture and removal of the result-
ing salts by a simple vacuum filtration was all that was
necessary to provide crude 16 in a purity that was suffi-
cient for use without further purification (>95% purity by
1H NMR analyses). Oxidation of 16 using the Swern pro-
tocol afforded the crude aldehyde, which was suspended
in diethyl ether, filtered through a plug of Celite and con-
centrated under reduced pressure to provide the aldehyde
17 in 90–99% yields (4–100-g scales) and in good purity
(>95% by 1H NMR analyses). This aldehyde 17 was then
protected with ethylene glycol in refluxing benzene, using
pyridinium p-toluenesulfonate (PpTs) as the acid catalyst,
to provide the requisite acetal 18 in 77–93% yields (10–
121-g scales) and in good purity (>95% by 1H NMR anal-
yses). It is interesting to note that the use of p-toluene-
sulfonic acid in refluxing toluene (the conditions of the
original route) failed to provide the desired acetal product
18 cleanly, although the reasons for this failure are un-
clear. Although the synthetic sequence depicted in
Scheme 4 was carried out in successive pilot scale reac-
tions to demonstrate overall large-scale feasibility, a 200-
g campaign from diester 14 all the way through to acetal
18 successfully validated the route, to provide 109 g of
useful material for investigation of debenzylation condi-
tions. This constituted a 63% overall yield of 18 from 14
(in >95% purity by 1H NMR analyses).
Ultimately, however, a transfer hydrogenation reaction
using cyclohexene and catalytic amounts of triethylamine
in the presence of Pearlman’s catalyst (50% wet) in etha-
nol at 50 °C provided the desired alcohol 9 in near-quan-
titative yields in both pilot (500 mg) and larger-scale (40
g) runs (Scheme 6).8 Interestingly, we observed that the
reaction fails when conducted either without triethyl-
amine or at an internal reaction temperature of 60 °C or
higher.
O
O
Pd(OH)2, cat. Et3N
O
O
cyclohexene
EtOH, 50 °C
H3CO
H3CO
OBn
OH
9
18
98%
O
1. (ClCO)2–DMSO
CH2Cl2, –78 °C
O
O
2. Et3N, –78 °C to r.t.
(refs 3,4)
H3CO
We then turned our attention to the surprisingly non-triv-
ial task of removing the benzyl protecting group from 18,
the final step in our synthesis of the known primary alco-
hol 92,3 (Scheme 5).
H
1
Scheme 6 Elaboration of benzyl ether 18 to aldehyde 1
A variety of reductive conditions for the debenzylation re-
action were examined, with varying degrees of success
observed. The use of boron trichloride in dichloromethane
at low temperature returned only the starting material 18.
When lithium metal in a solvent mixture of ammonia and
tetrahydrofuran at –78 °C was used, most of the starting
material was converted to a mixture of the product 9 and
the lactol 19. Interestingly, subjection of the crude reac-
In summary, a new route was developed for the synthesis
of the 18-MC side-chain precursor 1. After some synthetic
process research, this route was able to provide large
quantities (>100 g) of the debenzylation precursor 18
from dimethyl malonate in six steps, with a good yield
overall (66%) and with a high degree of purity (>95% by
1H NMR analyses).
Synthesis 2006, No. 16, 2743–2747 © Thieme Stuttgart · New York

2746
M. P. Rainka et al.
PAPER
All non-aqueous reactions were performed under an atmosphere of
dry nitrogen unless otherwise specified. Commercial grade reagents
and anhydrous solvents were used as received from vendors and no
attempts were made to purify or dry these components further. Re-
moval of solvents under reduced pressure was accomplished with a
Buchi rotary evaporator using a Teflon-linked KNF vacuum pump.
Data for 1H NMR spectra were obtained on a Bruker AC 300 MHz
NMR spectrometer and are reported in ppm (d) values, using tet-
ramethylsilane as an internal reference. Mass spectroscopic analy-
ses were performed on a PESciex API 150EX mass spectrometer,
using atmospheric pressure chemical ionization (APCI).
1H NMR (300 MHz, CDCl3): d = 1.49–1.78 (m, 4 H), 1.78–1.92 (m,
2 H), 2.47 (s, 1 H), 3.22 (s, 3 H), 3.28–3.36 (m, 2 H), 3.36–3.43 (m,
2 H), 3.61 (s, 3 H), 4.44 (s, 2 H), 7.27–7.38 (m, 5 H).
MS (APCI): m/z = 281 [C16H24O4 + H]+.
5-Benzyloxy-2-(2-methoxyethyl)pentan-1-ol (16)
A solution of methyl 5-benzyloxy-2-(2-methoxyethyl)pentanoate
(15; 112.0 g, 400 mmol) in Et2O (500 mL) was added dropwise over
2 h to a suspension of LiAlH4 (15.2 g, 400 mmol) in Et2O (1.6 L) at
r.t. under nitrogen. The mixture was stirred for 15 h, after which
EtOAc (240 mL) was added dropwise, followed by H2O (160 mL)
and 1 N NaOH solution (240 mL). The organic layer was collected,
dried over Na2SO4, filtered and the solvents were removed under re-
duced pressure to afford 5-benzyloxy-2-(2-methoxyethyl)pentan-1-
ol (16) as a clear colorless oil (100.0 g, 89% yield).
Dimethyl 2-(2-Methoxyethyl)malonate (13)
Dimethyl malonate (12; 100.0 g, 757 mmol) was added dropwise
over 40 min to a solution of NaH (33.3 g, 832 mmol, 60% dispersion
in mineral oil) in THF (500 mL) and DMF (500 mL) at 0 °C under
nitrogen, after which the mixture was warmed to r.t. over 30 min.
The mixture was treated with 1-chloro-2-methoxyethane (76 mL,
832 mmol) followed by KI (138 g, 832 mmol) and the resulting
mixture was heated at 60 °C for 15 h. The cooled mixture was dilut-
ed with H2O (1 L) and extracted with EtOAc (2 × 1 L). The com-
bined organic extracts were washed with brine (500 mL), dried over
Na2SO4 and the solvents were removed under reduced pressure. The
resulting clear yellow oil was distilled under reduced pressure (89–
105 °C/0.10 mm Hg) to afford dimethyl 2-(2-methoxyethyl)mal-
onate (13) as a clear amber oil (101.8 g, 70% yield).
1H NMR (300 MHz, CDCl3): d = 1.27–1.55 (m, 2 H), 1.55–1.79 (m,
5 H), 3.02 (t, J = 7.0 Hz, 2 H), 3.40 (s, 3 H), 3.40–3.67 (m, 4 H),
4.51 (s, 2 H), 7.27–7.38 (m, 5 H).
MS (APCI): m/z = 252 [C15H24O3]+.
5-Benzyloxy-2-(2-methoxyethyl)pentanal (17)
A solution of DMSO (65.9 mL, 928 mmol) in CH2Cl2 (36 mL) was
added dropwise to a solution of oxalyl chloride (40.5 mL, 464
mmol) in CH2Cl2 (1.5 mL) at –70 °C under nitrogen, at a rate which
maintained the internal reaction temperature below –60 °C. The
mixture was then treated with a solution of 5-benzyloxy-2-(2-meth-
oxyethyl)pentan-1-ol (16; 100.0 g, 357 mmol) in CH2Cl2 (300 mL)
at a rate which maintained the internal reaction temperature below
–60 °C. The mixture was stirred at –70 °C for 1 h, after which Et3N
(200 mL, 1.43 mol) was added at a rate which maintained the inter-
nal reaction temperature below –60 °C. The mixture was slowly
warmed to r.t. and washed with H2O (1 L). The aqueous layer was
back-extracted with Et2O (1 × 1 L) and the combined organic ex-
tracts were washed with H2O (800 mL) and brine (800 mL), dried
over Na2SO4, filtered and the solvents were removed under reduced
pressure to produce a yellow oil. The residue was diluted with Et2O
(500 mL), filtered and the filtrate solvents were removed under re-
duced pressure to afford 5-benzyloxy-2-(2-methoxyethyl)pentanal
(17) as a colorless oil (131.0 g, > 99% yield).
1H NMR (300 MHz, CDCl3): d = 2.13–2.27 (m, 2 H), 3.31 (s, 3 H),
3.42 (t, J = 7.0 Hz, 2 H), 3.55 (t, J = 7.0 Hz, 1 H), 3.75 (s, 6 H).
MS (APCI): m/z = 191 [C8H14O5 + H]+.
Dimethyl 2-(3-Benzyloxypropyl)-2-(2-methoxyethyl)malonate
(14)
Dimethyl 2-(2-methoxyethyl)malonate (13; 107.5 g, 640 mmol)
was added dropwise over 30 min to a solution of NaH (23.3 g, 585
mmol, 60% dispersion in mineral oil) in THF (500 mL) and DMF
(500 mL) at 0 °C under nitrogen, after which the mixture was
warmed to r.t. over 30 min. The mixture was treated with 1-(benzyl-
oxy)-2-chloropropane (107.5 g, 640 mmol) followed by KI (96.6 g,
640 mmol) and the resulting mixture was heated at 60 °C for 15 h.
The cooled mixture was washed with brine (1 L) and the aqueous
layer was back-extracted with EtOAc (2 × 500 mL). The combined
organic extracts were washed with brine (500 mL), dried over
Na2SO4, filtered and the solvents were removed under reduced pres-
sure to afford dimethyl 2-(3-benzyloxypropyl)-2-(2-methoxyeth-
yl)malonate (14) as a reddish-orange oil that contained residual
amounts of DMF solvent, but was otherwise suitable for use without
further purification (200.0 g, >99% yield).
1H NMR (300 MHz, CDCl3): d = 1.53–1.70 (m, 4 H), 1.70–1.79 (m,
2 H), 2.37–2.44 (m, 1 H), 3.28 (s, 3 H), 3.39 (t, J = 7.0 Hz, 2 H),
3.48 (t, J = 7.0 Hz, 2 H), 4.48 (s, 2 H), 7.27–7.38 (m, 5 H), 9.58 (s,
1 H).
MS (APCI): m/z = 250 [C15H22O3]+.
2-[4-Benzyloxy-1-(2-methoxyethyl)butyl]-[1,3]dioxolane (18)
A solution of 5-benzyloxy-2-(2-methoxyethyl)pentanal (17; 121.0
g, 484 mmol), ethylene glycol (40.5 mL, 726 mmol) and pyridinium
p-toluenesulfonate (12.0 g, 48 mmol) in benzene (970 mL) was
heated to reflux under nitrogen for 20 h. The cooled mixture was
poured into sat. NaHCO3 solution (1.5 L) and extracted with Et2O
(2 × 1 L). The combined organic extracts were dried over Na2SO4,
filtered and the solvents were removed under reduced pressure to
afford 2-[4-benzyloxy-1-(2-methoxyethyl)butyl]-[1,3]dioxolane
(18) as a yellow oil (109.4 g, 77% yield).
1H NMR (300 MHz, CDCl3): d = 1.43–1.58 (m, 2 H), 1.97–2.06 (m,
2 H), 2.21 (t, J = 7.0 Hz, 2 H), 3.26 (s, 3 H), 3.39 (t, J = 7.0 Hz, 2
H), 3.47 (t, J = 7.0 Hz, 2 H), 3.71 (s, 6 H), 4.48 (s, 2 H), 7.27–7.38
(m, 5 H).
MS (APCI): m/z = 339 [C18H26O6 + H]+.
Methyl 5-Benzyloxy-2-(2-methoxyethyl)pentanoate (15)
A solution of dimethyl 2-(3-benzyloxypropyl)-2-(2-methoxyeth-
yl)malonate (14; 200.0 g, 590 mmol), LiCl (50.0 g, 1.18 mol) and
H2O (100 mL) in DMSO (600 mL) was heated at reflux under nitro-
gen for 22 h. The cooled mixture was diluted with H2O (400 mL)
and extracted with hexanes (3 × 500 mL). The combined organic ex-
tracts were washed with brine (500 mL), dried over Na2SO4, filtered
and the solvents were removed under reduced pressure to afford
dimethyl 5-benzyloxy-2-(2-methoxyethyl)pentanoate (15) as a
clear yellow oil (112.0 g, 67% yield over two steps).
1H NMR (300 MHz, CDCl3): d = 1.53–1.85 (m, 7 H), 3.32 (s, 3 H),
3.38–3.48 (m, 4 H), 3.80–3.91 (m, 2 H), 3.90–3.96 (m, 2 H), 4.45
(s, 2 H), 4.79 (s, 1 H), 7.27–7.38 (m, 5 H).
MS (APCI): m/z = 295 [C17H26O4 + H]+.
4-[1,3]Dioxolan-2-yl-6-methoxyhexan-1-ol (9)2,3
Solid palladium hydroxide on activated carbon (Pearlman’s cata-
lyst, 20% palladium hydroxide on carbon, ~50% wet, 38 g) was
added to a solution of 2-[4-benzyloxy-1-(2-methoxyethyl)butyl]-
[1,3]dioxolane (18; 40.0 g, 136 mmol), cyclohexene (141 mL, 1.36
Synthesis 2006, No. 16, 2743–2747 © Thieme Stuttgart · New York

PAPER
Efficient Preparation of the 18-Methoxycoronaridine Side-Chain Precursor
2747
mol) and Et3N (1.0 mL) in EtOH (500 mL) at r.t. under nitrogen, af-
ter which the mixture was heated at 50 °C for 22 h. The cooled mix-
ture was filtered through a plug of Celite, eluting with EtOH (200
mL), and the filtrate solvents were removed under reduced pressure
to afford 4-[1,3]dioxolan-2-yl-6-methoxyhexan-1-ol (9) as a clear
colorless oil (27.2 g, 98% yield).
(2) (a) Bandarage, U. K.; Kuehne, M. E.; Glick, S. D. Curr.
Med. Chem.: CNS Agents 2001, 1, 113. (b) Kuehne, M. E.;
He, L.; Jokiel, P. A.; Pace, C. J.; Fleck, M. W.;
Maisonneuve, I. M.; Glick, S. D.; Bidlack, J. M. J. Med.
Chem. 2003, 46, 2716.
(3) Bandarage, U. K.; Kuehne, M. E.; Glick, S. D. Tetrahedron
1999, 55, 9405.
1H NMR (300 MHz, CDCl3): d = 1.32–1.72 (m, 5 H), 1.72–1.85 (m,
2 H), 3.32 (s, 3 H), 3.48 (t, J = 7.0 Hz, 2 H), 3.65 (t, J = 7.0 Hz, 2
H), 3.80–3.91 (m, 2 H), 3.90–3.96 (m, 2 H), 4.79 (d, J = 3.7 Hz, 1
H).
(4) Kuehne, M. E.; Wilson, T. E.; Bandarage, U. K.; Dai, W.;
Yu, Q. Tetrahedron 2001, 57, 2085.
(5) King, C.-H.; Meckler, H.; Herr, R. J.; Trova, M. P.; Glick, S.
D.; Maisonneuve, I. M. Bioorg. Med. Chem. Lett. 2000, 10,
473.
MS (APCI): m/z = 204 [C10H20O4]+.
(6) We found that heating sodium hydride-containing mixtures
in THF–DMF (1:1) co-solvent mixtures at reflux does not
result in the autocatalytic decomposition pathway exhibited
by sodium hydride–DMF mixtures above 70 °C. For
literature discussion on this topic see: (a) Buckley, J.;
Webb, R. L.; Laird, T.; Ward, R. J. Chem. Eng. News 1982,
60 (July 12), 5. (b) DeWall, G. Chem. Eng. News 1982, 60
(Sept. 13), 5. (c) Krishnan, V. S. H.; Chowdary, K. S.;
Dubey, P. K.; Vijaya, S. Indian J. Heterocycl. Chem. 1999,
9, 147. (d) Yu, R. H.; Schultze, L. M.; Rohloff, J. C.;
Dudzinski, P. W.; Kelly, D. E. Org. Process Res. Dev. 1999,
3, 53.
Acknowledgment
The authors wish to acknowledge and thank Mr. Chester J. Opalka,
formerly of Albany Molecular Research, Inc., for many helpful dis-
cussions during the early stages of this research effort, and Mr. Ro-
nald G. Powles and Dr. Zinovy Itov, formerly of Albany Molecular
Research, Inc., for previous research efforts that contributed to the
advancement of this work.
References
(7) (a) Krapcho, A. P. Synthesis 1982, 805. (b) Krapcho, A. P.
Synthesis 1982, 893.
(8) For a similar transformation, see: Böerjesson, L.; Csöeregh,
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Synthesis 2006, No. 16, 2743–2747 © Thieme Stuttgart · New York