The reduction of aryl diethyl phosphate esters with lithium di-tert-butylbiphenylide radical anion: Aromatic hydrocarbons via the deoxygenation of phenols

Article abstract of DOI:10.1055/s-2005-861790

The reduction of aryl diethyl phosphate esters by lithium 4,4′-di-tert-butylbiphenylide (LiDTBB) in THF at 0 °C is described. The reactions can be carried out either stoichiometrically (3.0 equiv LiDTBB) or with only a catalytic amount of DTBB (0.25 equiv) in the presence of lithium (2.1-3.0 equiv) and the phosphate. Products are separated from DTBB by solubility differences, by acid/base vs. neutral extraction, or by flash chromatography.

Full text of DOI:10.1055/s-2005-861790

PAPER
551
The Reduction of Aryl Diethyl Phosphate Esters with Lithium Di-tert-butylbi-
phenylide Radical Anion: Aromatic Hydrocarbons via the Deoxygenation of
Phenols
L
iDTBB Reduction of
i
A
ryl
D
c
iethyl Phos
h
phates to A
r
a
H
el J. Lusch,* Kevin R. Woller, Anthony M. Keller, Michael C. Turk
Department of Chemistry and Geology, Minnesota State University, Mankato, 242TN Trafton Science Center North, Mankato, MN 56001,
USA
Fax +1(507)3895625; E-mail: michael.lusch@mnsu.edu
Received 5 September 2004; revised 25 October 2004
Most known methods for deoxygenating phenols2 are not
Abstract: The reduction of aryl diethyl phosphate esters by lithium
carried out on the free hydroxy compound but rather in-
volve conversion into a suitable derivative, followed by
4,4¢-di-tert-butylbiphenylide (LiDTBB) in THF at 0 °C is de-
scribed. The reactions can be carried out either stoichiometrically
reduction via one of three types of reaction: (1) heteroge-
(3.0 equiv LiDTBB) or with only a catalytic amount of DTBB (0.25
equiv) in the presence of lithium (2.1–3.0 equiv) and the phosphate. neous catalytic hydrogenation,3 (2) homogeneous Pd(0)-
catalyzed reduction,4 or (3) alkali dissolving metals or
Products are separated from DTBB by solubility differences, by
other zero-valent metal reduction.5 Dissolving metal re-
acid/base vs. neutral extraction, or by flash chromatography.
Key words: reduction, phosphates, deoxygenation, phenols, arenes
duction, particularly of phosphate esters of phenols, with
lithium, sodium, or potassium metal in liquid ammonia
solution at –33 °C or colder has been reported as a useful
method for this transformation.5d–h We have recently been
investigating a modification of this reduction of aryl
phosphates6 in which the reducing agent is lithium di-tert-
butylbiphenylide (LiDTBB), an aromatic radical-anion
reagent that can be conveniently generated7 and used in
the organic solvent THF at ice temperature (0–5 °C)
(Scheme 1), rather than in corrosive and toxic NH3 at the
less convenient temperatures below –33 °C required to
liquefy this gas. Although the use of sodium naphthalen-
ide in THF had been described in a study of the mecha-
nism of the reductive cleavage of aryl diethyl phosphates
with electron-donors reductive cleavages with LiDTBB
had not been reported5i prior to disclosure of our initial re-
sults.6 Subsequently, the generation of organolithium re-
agents from phosphates with catalytically-generated
LiDTBB, and their in situ reaction with various electro-
philes (Barbier conditions) was reported.8 The 4,4¢-di-
tert-butylbiphenyl (DTBB)9 precursor to the radical-anion
is in turn easily prepared by FeCl3-catalyzed Friedel–
Crafts bis-alkylation of biphenyl by tert-butyl chloride in
CH2Cl2.9b Usually the required diethyl phosphates can be
efficiently prepared from the corresponding phenols via
phosphorylation with diethyl chlorophosphate generated
in situ from the inexpensive diethyl phosphite and
CCl45d,10 (Scheme 2), or by other methods.2a,5e–h,11 In this
Synthetic organic chemists continually seek innovative
chemical transformations that are chemo- and regioselec-
tive. Because hydroxyl groups contribute unusual activity
and specific directive effects to substitutions in aromatic
compounds, their use in regioselective syntheses is attrac-
tive. However, their utility is greatly expanded when they
can be chemoselectively removed in a later synthetic step.
Several natural products or analogs have been synthesized
utilizing this type of transformation. The synthesis of 4-
demethoxydaunomycinone, the aglycone of the antitumor
and antileukemic agent idarubicin (4-demethoxydaunoru-
bicin), has been accomplished by reduction of the triflate
ester prepared from natural daunomycinone.1a A similar
transformation has been applied in the synthesis of the
Gelsemium alkaloid koumine1b and the isoflavonoid phy-
toalexin ( )-homopterocarpin.1c Furthermore, the useful-
ness of the benzannulation reaction of chromium carbene
complexes with alkynes (Dötz reaction) is enhanced by
the ability to remove the phenolic hydroxy group intro-
duced as a result of CO insertion during the formation of
the aromatic ring. Synthesis of the furanocoumarin angeli-
cin,1d,e and model studies for the synthesis of olivin and
chromomycinone,1d have demonstrated the value of this
procedure.
Li
CH3
C
CH3
CH3
C
CH3
Li Metal
CH3
C
CH3
CH3
C
CH3
THF, 0 °C
CH3
CH3
CH3
CH3
DTBB
LiDTBB
Scheme 1 Preparation of lithium 4,4¢-di-tert-butylbiphenylide (LiDTBB).
SYNTHESIS 2005, No. 4, pp 0551–0554
x
x
.
x
x
.2
0
0
5
Advanced online publication: 18.01.2005
DOI: 10.1055/s-2005-861790; Art ID: M06904SS
© Georg Thieme Verlag Stuttgart · New York

552
M. J. Lusch et al.
PAPER
1) 2 equiv LiDTBB
THF, 0 °C
O
O
(EtO)2POH
CCl4, Et3N
Ar OH
Ar
O
P
OEt
Ar
H
+
Li O
P
OEt
+
DTBB
2) EtOH
OEt
OEt
Scheme 2 Preparation and LiDTBB reduction of aryl diethyl phosphates
paper we describe our results with the LiDTBB reduction tion of only 0.25 equivalents of DTBB containing 3.0
of the diethyl phosphate esters of a variety of phenols equivalents of Li metal, to give an 80% yield of 3 after
(Scheme 2).
3.75 hours of stirring at 0 °C. Time required for the cata-
lytic reaction could be decreased to a more reasonable 2.5
hours by increasing the 0.10 M concentration of the phos-
phate to 0.50 M (entry 4), yielding 73% of 3. Other phos-
phates could be reduced similarly (Table 1).
Initially we attempted the stoichiometric reduction (theo-
retically 2.0 equiv of radical-anion) of the diethyl phos-
phate 2 of 4-acetamidophenol (1, acetaminophen) with
LiDTBB. Addition of 2 to a THF solution of 2.3 equiva-
lents of LiDTBB at 0 °C, however, gave only a 10% yield The product arenes could be isolated and the DTBB re-
of acetanilide (3) product (Table 1, entry 1), but increas- covered by a number of methods. In some cases there was
ing the amount of LiDTBB to 2.9 equivalents resulted in a sufficiently large difference in solubility between
a 74% yield of 3 (entry 2). We also discovered that the re- DTBB, which is very soluble in hexanes, and the reduc-
duction could be conducted catalytically with respect to tion product to permit facile separation. Thus in the reduc-
DTBB (entry 3) by adding the phosphate to a THF solu- tion of 2 and 5, addition of hexanes to the crude product
Table 1 Aryl Diethyl Phosphate Ester Preparation and LiDTBB Reduction
O
C
O
C
H
H3C
N
R
H3C
N
R
Et2N
R
H
1: R = OH
4: R = OH
7: R = OH
2: R = O2P(OEt)2
3: R = H
5: R = O2P(OEt)2
6: R = H
8: R = O2P(OEt)2
9: R = H
OCH3
R
CH3
H2
CH3
C
H2
C
H3C
C
R
H2C
C
H
C
N
H
R
CH3
CH3
10: R = OH
13: R = OH
16: R = OH
11: R = O2P(OEt)2
12: R = H
14: R = O2P(OEt)2
15: R = H
17: R = O2P(OEt)2
18: R = H
Entry ArOH Aryl diethyl Phosphate Moles
Lithium DTBB
Concentra- Conditions
Time
ArH
ArH
phosphate
yield (%) reduced (equiv) (equiv) tion
product yield (%)
1
2
1
1
2
2
85–96
85–96
85–96
85–96
ca 100
93
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
2.3
2.9
3.0
3.0
3.0
2.1
3.0
3.0
3.0
3.0
2.3
0.10 M
0.10 M
0.10 M
0.50 M
0.10 M
0.50 M
0.10 M
0.10 M
0.50 M
0.10 M
Stoichiometrica
Stoichiometrica
Catalyticb
5 min
5 min
3.75 h
2.5 h
3c
3c
3c
3c
10
74
80
73
2.5
3
1
2
0.25
0.25
3.0
4
1
2
Catalyticb
5
4
5
Stoichiometrica
Catalyticb
5 min
2.0 h
6 (3)c 83
6
7
8
0.25
3.0
9d
61
65
32
48
28
7
10
13
13
16
11
14
14
17
ca 100
76–90
76–90
92
Stoichiometrica
Stoichiometrica
Catalyticb
5 min
12e,12
8
3.0
20 min 15e
9
0.25
3.0
5.5 h
15e
10
Stoichiometrica
5 min
18e,2a
a Stoichiometric mode of reaction: Solution of phosphate in THF added rapidly to LiDTBB in THF at 0 °C.
b Catalytic mode of reaction: Solution of phosphate and DTBB in THF stirred with Li metal at 0 °C.
c Separated from DTBB by adding hexanes to the crude product and filtering.
d Separated from DTBB by treating the crude product with 5% aq HCl, extracting with CH2Cl2 to remove DTBB, making the aq layer basic
with NaOH, and extracting the reduction product with CH2Cl2.
e Separated from DTBB by flash chromatography on silica gel.13
Synthesis 2005, No. 4, 551–554 © Thieme Stuttgart · New York

PAPER
LiDTBB Reduction of Aryl Diethyl Phosphates to ArH
553
Entry 7: The crude mixture of 12 and DTBB was separated by flash
chromatography on a 50 mm × 16.5 cm column of silica gel, eluting
with hexanes, to give liquid 12 (1.24 g, 65%).
dissolved the DTBB, leaving behind nearly pure acetanil-
ide (3/6). In cases where the reduction product was suffi-
ciently acidic or basic (e.g., 9), it could be separated from
the neutral DTBB by aqueous base or acid extraction.
Whenever these two techniques could not be applied, the
DTBB was separated from the reduction product by flash
chromatography13 (e.g., 12, 15, 18), effecting the separa-
tion of DTBB from even very similar aromatic hydrocar-
bons such as 12. In most cases the recovery of DTBB was
80–100%, allowing it to be reused after simple recrystal-
lization.
Entry 8: The crude mixture of 15 and DTBB was separated by flash
chromatography on a 50 mm × 16.5 cm column of silica gel, eluting
with hexanes–EtOAc (95:5) to give 15 (0.54 g, 32%); Rf 0.21; mp
52–52.8 °C. In addition DTBB was recovered (6.71 g, 84%); Rf
0.55; mp 124.5–127 °C.
Entry 9: In similar fashion the crude mixture of 15 and DTBB was
separated by flash chromatography on a 50 mm × 15 cm column of
silica gel, eluting with hexanes–EtOAc (95:5), to give 15 (0.82 g,
48%).
Entry 10: The crude mixture of 18 and DTTB was separated by
flash chromatography on a 50 mm × 15 cm. column of silica gel,
eluting with hexanes–CH2Cl2 (60:40), to give liquid 18 (0.41 g,
28%); Rf 0.32. DTBB was recovered (7.21 g, 90%) as well; Rf 0.59;
mp 124–26 °C.
General Procedures
Stoichiometric Reduction
A deep green solution of LiDTBB (3.0 equiv) in anhyd THF (100
mL) was prepared7 by stirring a solution of DTBB (7.99 g, 0.03
mol) and Li metal (cut in small pieces) (0.21 g, 0.03 mol) at 0 °C
under an Ar atmosphere14 for 3–4 h. Rapidly adding to this a solu-
tion of the diethyl phosphate (0.01 mol) in THF (5 mL) via syringe
discharged the color of the radical-anion by the end of the addition
to give a red to brown solution. After stirring for a further 5 min, the
reaction was quenched by rapidly adding EtOH (1–5 mL) via sy-
ringe and stirring until any remaining small pieces of metallic lithi-
um dissolved. The reaction mixture was then poured into water (100
mL) and extracted with CH2Cl2 (3 × 100 mL). The combined organ-
ic solutions were dried over anhyd MgSO4 and the solvents re-
moved in vacuo to leave a mixture of the crude reduction product
and DTBB.
Acknowledgment
Support of this research by Minnesota State University, Mankato is
gratefully acknowledged.
References
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To a solution of DTBB (0.64 g, 2.5 mmol, 0.25 equiv) in anhyd THF
(20 mL) at 0 °C under Ar14 was added Li metal (cut in small pieces)
(0.21 g, 0.03 mol, 3.0 equiv). This mixture was stirred until the
green color of the LiDTBB filled the solution and then the phos-
phate (0.01 mol) in THF (5 mL) was added rapidly via syringe,
completely discharging the green color. This reaction mixture was
stirred at 0 °C for 2–5.5 h until the green color returned. The reac-
tion was then quenched with EtOH (1–5 mL) and worked up as
above.
(2) For summaries of deoxygenation methods see the following
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Product Isolation Procedures and Recovery of DTBB
Based on Solubility Differences (Entry 3)
Addition of hexanes to the crude mixture of acetanilide (3) and
DTBB resulted in the dissolution of the DTBB. Filtration and wash-
ing of the insoluble residue gave 3 (1.15 g, 80%); mp 106–108 °C.
Evaporation of the hexanes solution gave recovered DTBB.
Based on Acid/Base/Neutral Character (Entry 6)
The EtOH-quenched reaction mixture containing amine 9 and
DTBB was stirred with water (25 mL) and 5% aq HCl solution (25
mL), and the mixture was then extracted with CH2Cl2 (3 × 25 mL).
The organic extracts were dried over anhyd MgSO4 and evaporated
in vacuo to leave recovered DTBB. The aqueous acid solution was
then made strongly basic with 6 N aq NaOH (25 mL) and extracted
with CH2Cl2 (3 × 25 mL). Drying of the organic extracts over anhyd
MgSO4 and evaporation in vacuo gave liquid amine 9 (0.90 g, 61%).
(h) Catalytic transfer hydrogenation with H2NNH2·H2O or
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Pd/C: Weaver, J. D.; Eisenbraun, E. J.; Harris, L. E.
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With Pd/CaCO3 or Pd/C: Vowinkel, E.; Wolff, C. Chem.
Ber. 1974, 107, 907. (k) Nonaflates and other
Separation by Flash Chromatography
Flash silica gel (40 mm, 60 Å) was purchased from Scientific Absor-
bants, Inc.
fluorosulfonates. With Pd/C: Subramanian, L. R.; Martinez,
A. G.; Fernandez, A. H.; Alvarez, R. M. Synthesis 1984, 481.
Synthesis 2005, No. 4, 551–554 © Thieme Stuttgart · New York

554
M. J. Lusch et al.
PAPER
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–
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–
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–
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–
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Synthesis 2005, No. 4, 551–554 © Thieme Stuttgart · New York