Synthesis of the Bestmann-Ohira reagent

Article abstract of DOI:10.1055/s-2006-950307

The conversion of an aldehyde to a terminal alkyne by means of a one-carbon chain extension is a key reaction in organic synthesis. By using dimethyl 1-diazo-2-oxopropylphosphonate, the Bestmann-Ohira reagent, the transformation can be achieved in one pot. A reliable, convenient sequence for the preparation of the Bestmann-Ohira reagent is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950307

4266
PRACTICAL SYNTHETIC PROCEDURES
Synthesis of the Bestmann–Ohira Reagent
Synthesis
ö
of the
B
estm
r
ann–Oh
g
Institut für Bioorganische Chemie der Heinrich-Heine-Universität Düsseldorf im
Forschungszentrum Jülich, Im Stetternicher Forst Geb. 15.8, 52426 Jülich, Germany
Fax +49(2461)616196; E-mail: j.pietruszka@fz-juelich.de
PSP
Received 19 June 2006; revised 24 July 2006
No73
Abstract: The conversion of an aldehyde to a terminal alkyne by means of a one-carbon chain extension is a key reaction in organic syn-
thesis. By using dimethyl 1-diazo-2-oxopropylphosphonate, the Bestmann–Ohira reagent, the transformation can be achieved in one pot. A
reliable, convenient sequence for the preparation of the Bestmann–Ohira reagent is described.
Key words: alkynes, diazo compounds, carbenoids, phosphorus
1, K2CO3, MeOH
RCHO
O
R
C
CH
O
O
O
P
OMe
OMe
O
NBoc
Me
Me
Me
Me
Me
N2
1
2
3
Scheme 1 One-pot procedure for the conversion of an aldehyde to an alkyne using reagent 1
Alkenylidenes are versatile reactive intermediates in or- to be unreliable (the yields varying between 24–80%) and
ganic synthesis that have been utilized in the synthesis of in addition the workup (a time-consuming filtration) was
natural products numerous times. One outstanding appli- problematic. Direct Michaelis–Arbuzov reaction9 be-
cation is the transformation of an aldehyde to a chain- tween trimethyl phosphite and chloroacetone (6) is not
extended alkyne via a Fritsch–Buttenberg–Wiechell- possible, since isopropenyl dimethyl phosphate is the ma-
type rearrangement.1 While two-step processes, e.g. the jor (Perkow) product.10 On the other hand, iodoacetone is
Corey–Fuchs procedure,2 are highly popular, one-pot con- not commercially available, but would lead to the desired
versions, e.g. using the Colvin3 or Gilbert–Seyferth re- product. Noyori et al. developed a practical variant that al-
agent,4 have been less regularly applied. The convenient lowed the in situ formation of iodoacetone from starting
Bestmann–Ohira reagent (1) is an alternative that allows material 6; subsequent treatment with trimethyl phosphite
the addition of the reagent to the aldehyde under mild re- furnished the product 4.11 The oxophosphonate 4 was
action conditions thus avoiding the use of a strong base ready to use after filtration and distillation. Small amounts
under low-temperature conditions (Scheme 1).5 A variety of impurities sometimes remained after the first distilla-
of different aldehydes have been successfully subjected to tion leading to a slow discolorization. Repeating the
the transformation. Versatile building blocks such as the workup procedure yielded the pure product (62–71%; up
2,3-O-isopropylidene-D-glyceraldehyde6 or the Garner al- to 100-g scale).
dehyde derived7 alkynes 2 or 3, respectively, have been
Sulfonyl azides are well-established reagents for diazo
synthesized using this procedure. No racemization of al-
transfer,12 with tosyl azide being the most frequently used.
dehydes (and hence alkynes) was observed in these and
similar cases. Herein we describe a reliable, scalable syn-
(a) t-BuLi, THF, –78 °C
(b) CuI, –6 °C to –30 °C
(c) AcCl, –40 °C
O
thesis of the reagent 1 that has been successfully tested in
our laboratories numerous times.
O
O
P
P
OMe
OMe
OMe
OMe
Me
Me
(24–80%)
First, a synthesis of the b-oxophosphonate 4 was essential
(Scheme 2). Acylation of the a-lithiated phosphonate 5
was the first option.8 Nevertheless, the procedure proved
5
4
O
(a) KI, acetone–MeCN, r.t.
(b) P(OMe)3, r.t. to 50 °C
Cl
Me
SYNTHESIS 2006, No. 24, pp 4266–4268
Advanced online publication: 09.10.2006
x
x.
x
x
.
2
0
0
6
(62–71%)
6
DOI: 10.1055/s-2006-950307; Art ID: T09006SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Syntheses of b-oxophosphonate 4

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of the Bestmann–Ohira Reagent
4267
phosphonate 4 as a colorless liquid; yield: 101.3 g (62%) (Lit.11b
71%). The spectroscopic data were in full agreement with those pre-
viously reported;16 bp 69–70 °C/0.47 mbar (Lit.11b 85–88 °C/0.67
mbar).
NaN3, TBAC,
CH2Cl2, H2O
AcNH
SO2Cl
AcNH
SO2N3
(91%)
7
4
8
IR (film): 3002, 2959, 2923, 2854, 1710 (C=O), 1463, 1361, 1260
(P=O), 1080, 825 cm–1.
O
O
P
O
O
P
(a) NaH, toluene
(b) 8, THF
1H NMR (500 MHz, CDCl3): d = 2.29 (s, 3 H, H3), 3.07 (d,
OMe
OMe
OMe
OMe
Me
Me
2JH,P = 22.8 Hz, 2 H, H1), 3.78 (d, 3JH,P = 11.0 Hz, 6 H, OCH3).
(77%)
13C NMR (125 MHz, CDCl3): d = 31.8 (s, C3), 42.6 (d, 1Jc,p = 127.4
N2
2
2
1
Hz, C1), 53.4 (d, Jc,p = 6.4 Hz, OCH3), 197.7 (d, Jc,p = 3.1 Hz,
C=O).
Scheme 3 Diazo-transfer reagent 8 and its use for the synthesis of 1
p-Acetamidobenzenesulfonyl Azide (8)
To a stirred suspension of chloride 7 (100 g, 430 mmol) in CH2Cl2
To simplify the workup procedure, Baum et al. reported (800 mL) was added TBAC (300 mg), followed by a solution of
an alternative (Scheme 3);13 commercially available sul-
fonyl chloride 7 was easily transformed to the correspond-
NaN3 (42 g, 660 mmol) in H2O (200 mL) (CAUTION: AZIDES CAN
CAUSE EXPLOSIONS!17). Stirring was continued at r.t.; two clear
phases formed overnight. The organic layer was washed with H2O
ing azide 8 under phase-transfer conditions (73–91%). A
(2 × 150 mL), dried (MgSO4), and the solvent removed under re-
modified procedure from Vandewalle et al.14 was used for
duced pressure. A colorless solid was obtained that was directly
used without any further purification; yield: 93.4 g (91%) (Lit.13
73%).
the diazo transfer. Deprotonation of the oxophosphonate
4 with sodium hydride in toluene was followed by treat-
ment with reagent 8 (in THF) instead of using tosyl azide
and benzene. The reaction led to the desired Bestmann–
Ohira reagent (1) in 77% yield (40–50 g scale). For com-
plete purification column chromatography was essential;
however, for most applications a simple filtration through
Celite is sufficient.
IR (film): 3304, 3266, 3187, 3112, 2130 (N=N=N), 1680, 1586,
1528, 1405, 1370, 1317, 1266, 1170, 1087, 840, 752 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.25 (s, 3 H, CH3), 7.78 (d,
3J = 8.9 Hz, 2 H, arom CH), 7.90 (d, 3J = 8.9 Hz, 2 H, arom CH),
8.00 (br, 1 H, NH).
13C NMR (126 MHz, CDCl3): d = 24.8 (CH3), 119.7 (arom Cipso),
128.9, 132.4 (arom CH), 144.1 (arom Cpara), 169.4 (C=O).
Summing up, a short, reliable procedure for the versatile
Bestmann–Ohira reagent (1) is reported. The required
starting materials are commercially available and have
been conveniently transformed in up to 50-g scale to the
final product.15
Dimethyl 1-Diazo-2-oxopropylphosphonate (1)
A 1-L, three-necked flask was equipped with an overhead stirrer
and an addition funnel. The flask was charged with phosphonate 4
(54.0 g, 325 mmol) in toluene (300 mL) and the soln cooled to 0 °C.
NaH (13.1 g of 55% in paraffin; 300 mmol) was added in portions.
After the gas evolution had ceased, a soln of azide 8 (71.8 g, 300
mmol) in THF (100 mL) was added dropwise; the highly viscous
suspension slowly discolored to yellow-brown and stirring became
easier. After 16 h the mixture was diluted with petroleum ether, fil-
tered through a pad of Celite, rinsed thoroughly with Et2O, and the
solvents removed under reduced pressure. For many applications
the remaining slightly impure yellow oil can be directly used. Flash
column chromatography (silica gel, PE–EtOAc, 1:1) furnished the
product 1; yield: 44.5 g (77%) (Lit.14 80%).
The reactions were carried out by using standard Schlenk tech-
niques under dry N2 with magnetic stirring. Glassware was oven
dried at 120 °C overnight. Solvents were dried and purified by con-
ventional methods prior to use; THF was freshly distilled from Na/
benzophenone. Common solvents for chromatography (PE, EtOAc)
were distilled prior to use; PE refers to petroleum ether (bp 40–
60 °C). Flash column chromatography was performed on silica gel
60, 0.040–0.063 mm (230–400 mesh). TLC (monitoring the course
of the reactions) was performed on pre-coated plastic sheets (Poly-
gram SIL G/UV254, Macherey–Nagel) with detection by UV
(254 nm) or by coloration with cerium molybdenum soln [phosph-
omolybdic acid (25 g), Ce(SO4)2·H2O (10 g), concd H2SO4
(60 mL), H2O (940 mL)]. 1H and 13C NMR spectra were recorded at
r.t. in CDCl3 with a Bruker ARX 300/500. Chemical shifts are given
in ppm relative to TMS as internal standard (1H) or relative to the
resonance of the solvent (13C: CDCl3 d = 77.0). Higher order d and
J values are not corrected. 13C signals were assigned by means of
H–H and C–H COSY spectroscopy. Microanalyses were performed
at the Institut für Organische Chemie, Stuttgart. IR spectra were ob-
tained on a Perkin-Elmer 283.
IR (film): 2959, 2855, 2222, 2123 (C=N2), 1736, 1658, 1461, 1366,
1273, 1182, 1023, 836, 804 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.24 (s, 3 H, H3), 3.81 (d,
3JH,P = 11.9 Hz, 6 H, OCH3).
13C NMR (125 MHz, CDCl3): d = 27.5 (C3), 54.0 (d, 3JC,P = 5.8 Hz,
OCH3), 60.8 (br, C1), 190.3 (d, 3JC,P = 3.2 Hz, C2).
Anal. Calcd for C5H9N2O4P (192.11): C, 31.26; H, 4.72; N, 14.58.
Found: C, 31.40; H, 4.83; N, 14.01.
Acknowledgment
Dimethyl 2-Oxopropylphosphonate (4)
We gratefully acknowledge the Deutsche Forschungsgemeinschaft,
the Fonds der Chemischen Industrie, the Otto-Röhm-Gedächtnis-
stiftung and the Landesgraduiertenförderung Baden Württemberg
for the generous support of our projects. Donations from Boehrin-
ger Ingelheim KG, Degussa AG, Bayer AG, BASF AG, Wacker
AG, and Novartis AG were greatly appreciated.
To a stirred suspension of KI (164 g, 980 mmol) in acetone (200
mL) and MeCN (250 mL) was added chloroacetone (6; 78 mL, 980
mmol). Stirring was continued for 1 h at r.t. Trimethyl phosphite
(116 mL, 980 mmol) was slowly added. After 12 h at r.t., the mix-
ture was heated to 50 °C to ensure complete conversion. Filtration
through a pad of Celite and evaporation of the solvents under re-
duced pressure yielded the crude product. Distillation furnished the
Synthesis 2006, No. 24, 4266–4268 © Thieme Stuttgart · New York

4268
J. Pietruszka, A. Witt
PRACTICAL SYNTHETIC PROCEDURES
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Synthesis 2006, No. 24, 4266–4268 © Thieme Stuttgart · New York