Molar-scale synthesis of 1,2:5,6-Di-0-isopropylidene-α-D- allofuranose: DMSO oxidation of 1,2:5,6-Di-0-isopropylidene-α-D- glucofuranose and subsequent sodium borohydride reduction

Article abstract of DOI:10.1021/op049903t

Two variants of oxidation with DMSO followed by sodium borohydride reduction have been investigated to make the synthesis of 1,2:5,6-di-0- isopropylidene-α-D-allofuranose (4) suitable for large-scale manufacturing.

Full text of DOI:10.1021/op049903t

Organic Process Research & Development 2004, 8, 777−780
Molar-Scale Synthesis of 1,2:5,6-Di-O-isopropylidene-r-D-allofuranose: DMSO
Oxidation of 1,2:5,6-Di-O-isopropylidene-r-D-glucofuranose and Subsequent
Sodium Borohydride Reduction
Signe M. Christensen,* Henrik F. Hansen, and Troels Koch
Santaris Pharma A/S, Boege Alle 3, DK-2970 Hoersholm, Denmark
Abstract:
Two variants of oxidation with DMSO followed by sodium
borohydride reduction have been investigated to make the
synthesis of 1,2:5,6-di-O-isopropylidene-r-D-allofuranose (4)
suitable for large-scale manufacturing.
Figure 1. LNA-nucleoside.
isopropylidene-R-D-ribofuranosid-3-ulose (3) to afford 4
(Scheme 1).
Introduction
The synthesis of 1,2:5,6-di-O-isopropylidene-R-D-allo-
furanose has received renewed interest due to its role as the
starting material for LNA (1) (locked nucleic acid, see Figure
1 below).1 The synthesis of the LNA monomers employing
1,2:5,6-di-O-isopropylidene-R-D-allofuranose (4) was first
reported by Wengel et al.1-7 LNA has been shown to be the
single nucleic acid modification that contributes to the highest
affinity ever obtained by regular Watson-Crick hydrogen
bonding to nucleic acids.4 The increasing demand on supply
of LNA for antisense,8-15 prompted us to look for cost-
efficient synthesis of 4 by a method that was suitable for
scale-up.
Results and Discussion
A variety of oxidation procedures exist for the oxidation
of 2; however, in addition to expensive reagents, most have
scale-up issues including waste concerns and tedious isolation
procedures (pyridinium chlorochromate (PCC) or pyridinium
dichromate (PDC);16-18 RuO2 or RuCl3, NaIO4).19,20 Oxida-
tion procedures using activated DMSO or other oxidized
forms of dimethyl sulfide21,22 all suffer the same problem of
emission of the malodorous volatile dimethyl sulfide. A
solution to this was addressed by Crinch and Neelamkavil
who, on a millimolar scale, oxidized 2 to 3 in 83% yield
using fluorous sulfoxide, which was readily recovered and
recycled.23 Another ingenious solution reported in the
literature is to substitute DMSO for dodecyl-methyl sulfoxide
to avoid the emission of dimethyl sulfide during Corey-
Kim and Swern oxidations.24,25 On a larger scale the emission
of dimethyl sulfide from the reaction can be trapped
efficiently in a scrubber containing a 15% aqueous solution
of sodium hypochlorite.
The present work describes the investigation of two
different methods for the oxidation of 1,2:5,6-di-O-isopro-
pylidene-R-D-glucofuranose (2) and subsequent stereospecific
borohydride reduction of the intermediate 1,2:5,6-di-O-
* To whom correspondence should be addressed. E-mail: smc@santaris.com.
Telephone: +45 45 17 98 00. Fax: +45 45 17 98 98.
(1) Singh, S. K.; Nielsen, P.; Koshkin, A.; Wengel, J. Chem. Commun. 1998,
455-456.
(2) Wengel, J.; Koshkin, A.; Singh, S. K.; Nielsen, P.; Meldgaard, M.;
Rajwanshi, V. K.; Kumar, R.; Skouv, J.; Nielsen, C. B.; Jakobsen, N.; Olsen,
C. E. Nucleosides Nucleotides 1999, 18, 1365-1370.
We first turned our attention to the known DMSO-acetic
anhydride oxidation followed by sodium borohydride reduc-
tion.26,27 The oxidation is likely to be initiated by formation
(3) Wengel, J. Acc.Chem. Res. 1999, 32, 301-310.
(4) Koshkin, A.; Singh, S. K.; Nielsen, P.; Rajwanshi, V. K.; Kumar, R.;
Meldgaard, M.; Olsen, C. E.; Wengel, J. Tetrahedron 1998, 54, 3607-
3630.
(5) Koshkin, A.; Rajwanshi, V. K.; Wengel, J. Tetrahedron lett. 1998, 39, 4381-
(16) Austin, G. N.; Baird, P. D.; Fleet, G. W. J.; Peach, J. M.; Smith, P. W.;
Watkin, D. J. Tetrahedron 1987, 43, 3095-3108.
(17) Shing, T. K. M.; Wong, C.-H.; Yip, T. Tetrahedron: Asymmetry 1996, 7,
1323-1340.
(18) Tadano, K.; Idogaki, Y.; Yamada, H.; Suami, T. J. Org. Chem. 1987, 52,
1201-1210.
4384.
(6) Koshkin, A.; Nielsen, P.; Meldgaard, M.; Rajwanshi, V. K.; Singh, S. K.;
Wengel, J. J. Am. Chem. Soc. 1998, 120, 13252-13253.
(7) Singh, S. K.; Wengel, J. Chem. Commun. 1998, 1247-1248.
(8) Braasch, D. A.; Corey, R. Chem. Biol. 2000, 55, 1-7.
(9) Oerum, H.; Wengel, J. Curr. Opin. Mol. Therapeutics 2001, 3, 239-243.
(10) Kurreck, J.; Wyszko, E.; Gillen, C.; Erdmann, V. A. Nucleic Acids Res.
2002, 30, 1911-1918.
(11) Braasch, D. A.; Liu, Y.; Corey, D. R. Nucleic Acids Res. 2002, 30, 5160-
5167.
(12) Braasch, D. A.; Jensen, S.; Liu, Y.; Kaur, K.; Arar, K.; White, M. A.; Corey,
D. R. Biochemistry 2003, 42, 7967-7975.
(19) Wood, W. W.; Watson, G. M. J. Chem. Soc., Perkin Trans. I 1987, 2681-
2688.
(20) Baker, D. C.; Horton, D.; Tindall, C. G. Carbohydr. Res. 1972, 24, 192-
197.
(21) Butterworth, R. F.; Hanessian, S. Synthesis 1971, 70-88.
(22) Epstein, W. W.; Sweat, F. W. Chem. ReV. 1967, 67, 247-260.
(23) Crich, D.; Neelamkavil, S. J. Am. Chem. Soc. 2001, 123, 7449-7450.
(24) Ohsugi, S.; Nishide, K.; Oono, K.; Okuyama, K.; Fudesaka, M.; Kodama,
S.; Node, M. Tetrahedron 2003, 59, 8393-8398.
(25) Nishide, K.; Ohsugi, S.; Fudesaka, M.; Kodama, S.; Node, M. Tetrahedron
Lett. 2002, 43, 5177-5179.
(26) Whistler, R. L.; Anisuzzaman, A. K. M.; Kim, J. C. Carbohydr. Res. 1973,
31, 237-243.
(27) Sowa, W.; Thomas, G. H. S. Can. J. Chem. 1966, 44, 836-838.
(13) Grunweller, A.; Wyszko, E.; Bieber, B.; Jahnel, R.; Erdmann, V. A.;
Kurreck, J. Nucleic Acids Res. 2003, 31, 3185-3193.
(14) Wahlestedt, C.; Salmi, P.; Good, L.; Kela, J.; Johnsson, T.; Ho¨kfelt, T.;
Broberger, C.; Porreca, F.; Lai, J.; Ren, K.; Ossipov, M.; Koshkin, A.;
Jakobsen, N.; Skouv, J.; Oerum, H.; Jacobsen, M. H.; Wengel, J. Proc.
Natl. Acad. Sci. U.S.A. 2000, 97, 5633-5638.
(15) Elayadi, A.; Corey, D. R. Curr. Opin. InVest. Drugs 2001, 2, 558-561.
10.1021/op049903t CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/20/2004
Vol. 8, No. 5, 2004 / Organic Process Research & Development
•
777

Figure 3. Formation of major by-product during oxidation
with DMSO/Ac2O.
anhydride could be reduced to 1:5 without any reduction in
the yield. When the complete oxidation of 2 was confirmed
by TLC, portionwise addition of sodium borohydride was
effected, with stirring and cooling to keep the slightly
exothermic reaction below 25 °C. The minimum amount of
sodium borohydride that was needed to reduce 3 was
determined to 0.42 equiv. We carefully followed the oxida-
tion and reduction by TLC and noticed formation of by-
products during the one-pot reaction. The major by-product
(formed in 20% yield) was isolated and identified by NMR
as the 1,2:5,6-di-O-isopropylidene-3-O-(methylthio)methyl-
R-D-glucofuranose (5).30,31 Formation of this by-product can
be explained by a Pummerer rearrangement (Figure 3), and
the formation is known from the Swern oxidation (DMSO/
TFAA) to be temperature dependent, i.e. formation increases
with increasing temperature. We have seen, however, that
increasing the reaction temperature on a 20-g scale resulted
in a faster oxidation without increasing formation of by-
product 5.
Figure 2. Mechanism of oxidation with DMSO/Ac2O followed
by reduction.
Scheme 1. Synthesis of
1,2:5,6-di-O-isopropylidene-r-D-allofuranose (4)
This finding was noted by Pojer et al.,30 who also found
that only a small quantity of acetic acid was required in the
reaction mixture for the efficient production of the meth-
ylthiomethyl ether at room temperature. We assumed that
the other by-products were acetylated carbohydrates. This
was indirectly confirmed by TLC analysis. Samples of 2 and
4 were acetylated and proved to comigrate with the by-
products. The by-products were hydrolysed by concentrated
NH4OH to afford products, which comigrated with 2 and 4.
To remove the acetylated by-products, the subsequent
extraction procedure was improved to afford pure 4. The
extraction procedure takes advantage of the fact that 4 is
soluble in water in addition to being soluble in many organic
solvents. Extraction of 4 from the concentrated MTBE layer
into an aqueous layer and then extracting the aqueous layer
with dichloromethane affords pure 4, leaving all impurities
in the MTBE layer. Omitting this extraction procedure results
in an impure product which will not crystallize from
cyclohexane. In our hands this procedure has proven to be
robust, affording yields ranging from 50 to 60%. Despite
the fact that the DMSO/Ac2O oxidation is slow, the
of an oxysulfonium salt intermediate via the nucleophilic
attack of the electronegative oxygen of DMSO on the
electrophilic carbon in acetic anhydride.28 (Figure 2) The
secondary alcohol reacts by nucleophilic attack on the
positively charged sulphur of the oxysulfonium salt with
subsequent backside displacement of the acetate ion to give
the alkoxysulfonium salt. The ketone group is formed by
elimination of dimethyl sulfide. The nucleophilic attack of
-
the hydride ion (or BH4 ion) can for steric reasons only
happen from the exo face of the tricyclic 1,2:5,6-di-O-
isopropylidene-R-D-ribofuranosid-3-ulose (3), yielding the
stereoselectivity during the reduction.29
We explored the possibility of combining the oxidation
and the reduction in one pot. As observed by J. D. Albright
and L. Goldman28 the molar ratio of alcohol to acetic
(28) Albright, J. D.; Goldman, L. J. Am. Chem. Soc. 1967, 89, 2416-2423.
(29) Theander, O. Acta Chem. Scand. 1964, 18, 2209-2216.
(30) Pojer, P. M.; Angyal, S. J. Aust. J. Chem. 1978, 31, 1031-1040.
(31) Jewell, J. S.; Szarek, W. A. Tetrahedron Lett. 1969, 43-46.
778
•
Vol. 8, No. 5, 2004 / Organic Process Research & Development

separation of the layers, and work-up as described above
affords crystalline and analytically pure 4 in total yield from
2 between 65 and 75%. As reported by Onodera, we observed
that higher reaction temperature during oxidation (60-65
°C) decreases the isolated yield of 4 (to ∼45%), but the purity
and ease of isolation of product was not affected. We
recommend that the reaction temperature does not exceed
55 °C. Attempts to combine the oxidation and reduction steps
in a one-pot fashion resulted in a decrease of isolated yield
of 4 to approximately 58%. In summary, this procedure is
fast, good yielding, and uses cheap chemicals; however it is
dependent on good temperature control during addition of
phosphorus pentoxide and during oxidation of 2. It is our
experience that the addition of the phosphorus pentoxide to
the dimethyl sulfoxide was best executed while the temper-
ature of the solution was kept below 20 °C.
Figure 4. Proposed oxidative species during oxidation with
DMSO/P2O5.
combination with the fast reduction process turns this one-
pot reaction into a robust, good yielding, cheap, and easy
process.
Looking for a similar procedure with less formation of
by-products, we then turned our attention to the use of
phosphorus pentoxide in DMSO as the oxidant. Phosphorus
pentoxide was used in preference to chromium trioxide,
oxalyl chloride, chromic acid, and PCC in a few examples.32-34
Onodera et al. reported a thorough investigation of the
reaction conditions.35-38 They recommended that with the
use of dimethyl sulfoxide as solvent, oxidations are best
performed at room temperature, since decomposition of the
sugar is observed at higher temperatures. They also observed
that the use of too large an excess of phosphorus pentoxide
decreases the yield of the product and that a catalytic amount
of phophorus pentoxide is also ineffective. On the basis of
these results, they suggest that one equivalent of phosphorus
pentoxide participate in the oxidation per alcohol moiety.
The oxidation mechanism is believed to proceed by a
mechanism similar to that described for the Ac2O/DMSO
oxidation, by which the oxidative species is the sulfoxonium
derivative 6 (Figure 4).
Oxidation of 2 with one equivalent of phosphorus
pentoxide in dimethyl sulfoxide for 3 h at 50 °C afforded 3
(>65%). The oxidation proceeds with less formation of by-
product as compared to that from the DMSO/Ac2O proce-
dure, but the work-up was difficult since aqueous washes of
the DMSO/P2O5 mixture affords H3PO4 (aqueous layer
becomes pH 1), which catalyses the hydrolysis of the
isopropylidene protection. In small scale this is not a
problem, but in large scale, where the separation of layers
is more time-demanding, this causes a decreased yield of
isolated product. Taking advantage of the fact the MTBE
and DMSO are not mixable enabled us to extract the
intermediate ulose 3 from the DMSO/P2O5 mixture, leaving
the polar by-products in the DMSO layer (i.e. loss of
isopropylidene protection). The MTBE layer was added
slowly to a cold, stirred, aqueous solution of sodium
borohydride, thereby neutralising the formed H3PO4 in situ.
The presence of MTBE during reduction diminishes the
excessive foaming. Subsequent addition of dichloromethane,
Conclusions
We have developed two procedures for the large-scale
synthesis of 1,2:5,6-di-O-isopropylidene-R-D-allofuranose
(4). Both reactions afford crystalline and analytically pure
product without employing chromatography. To our knowl-
edge, this is the largest-scale synthesis of 4 reported to date.
Experimental Section
1,2:5,6-Di-O-isopropylidene-R-D-glucofuranose (98+%)
was purchased from Pliva Pharmaceutical Industry Inc. and
used without further purification. P2O5 (min 99%) was
purchased from ACROS, and NaBH4 powder (98+%) was
purchased from Aldrich. Solvents were HPLC grade, of
which DMSO was dried over molecular sieves (4 Å). If the
water content by KF is >0.2%, the yield of the two-pot,
two-step procedure will decrease, and sometimes the reaction
does not go to completion. TLC analysis was performed on
Merck silica 60 F254 aluminum sheets and developed with 2
M aqueous sulphuric acid followed by charring. The
intermediate 3 can be developed with a solution of 2,4-
dinitrophenylhydrazine (100 mg) in ethanol (90 mL) and
1
concentrated hydrochloric acid (10 mL). H and 13C NMR
spectra were recorded respectively at 400 and 100 MHz with
the solvent as internal standard (δH: CDCl3 7.26 ppm; δC:
CDCl3 77.0 ppm). J values are given in Hz. Elemental
analyses were obtained from the University of Copenhagen,
Microanalytical Department. Measurements of optical rota-
tion were obtained from The Technical University of
Denmark.
One Pot, Two-Step Procedure Using DMSO/Ac2O/
NaBH4. 1,2:5,6-Di-O-isopropylidene-R-D-glucofuranose (2)
(260 g, 1.0 mol) was dissolved in a mixture of anhydrous
DMSO (2 L) and Ac2O (500 mL, 5.0 mol) and stirred at
20-25 °C for 24 h in a 5-L glass flask under a nitrogen
blanket. By this time TLC (eluent: DCM/MeOH, 95:5)
indicated complete conversion of 2. The solution was cooled
on an ice-water bath, and sodium borohydride (16 g, 0.42
mol) was added portionwise during 15 min to keep reaction
temperature in the range of 20-25 °C. After complete
addition of sodium borohydride, the reaction mixture was
stirred for 1 h at 20-25 °C. By then TLC (eluent: DCM/
(32) Taber, D. F.; Amedio, J. C.; Jung, K.-Y. J. Org. Chem. 1987, 52, 5621-
5622.
(33) Jordaan, J. H.; Smedley, S. Carbohydr. Res. 1971, 16, 177-183.
(34) Stevens, C. L.; Glinski, R. P.; Taylor, K. G. J. Org. Chem. 1968, 33, 1586-
1592.
(35) Onodera, K.; Hirano, S.; Kashimura, N. J. Am. Chem. Soc. 1965, 87, 4651-
4652.
(36) Onodera, K.; Kashimura, N.; Miyazaki, N. Carbohydr. Res. 1972, 21, 159-
165.
(37) Onodera, K.; Hirano, S.; Kashimura, N. Carbohydr. Res. 1968, 6, 276-
285.
(38) Onodera, K.; Kashimura, N. In Methods in Carbohydrate Chemistry;
Academic Press: New York, 1972; pp 331-336.
Vol. 8, No. 5, 2004 / Organic Process Research & Development
•
779

MeOH, 95:5) indicated complete formation of target com-
pound (4), and water (2.5 L) was added. The resulting
mixture was extracted with DCM (3 × 1 L). The combined
organic layer was washed with water (2 × 1 L) and brine (1
L), dried (MgSO4) to diminish residual salts (which interfere
with the subsequent extraction method), filtered, and con-
centrated in vacuo to afford an oil. The oil was dissolved in
MTBE (300 mL) and extracted with water (2 × 750 mL).
The combined aqueous layer was extracted with DCM (2 ×
400 mL). The combined DCM layer was dried (MgSO4),
filtered and concentrated in vacuo to give an oil. Two
crystallizations from cyclohexane (500 mL and 300 mL,
respectively) afforded analytically pure 1,2:5,6-di-O-isopro-
pylidene-R-D-allofuranose (4) (151 g, 58%). 1H NMR
(CDCl3, 400 MHz): δ 5.80 (1H, d, J1,2 ) 3.8 Hz, H-1), 4.59
(1H, dd, J2,1 ) 4.0 Hz, J2,3 ) 5.1 Hz, H-2), 4.29 (1H, ddd,
J5,6b ) 4.9 Hz, J5,6a ) 6.6 Hz, J5,4 ) 6.6 Hz, H-5), 4.08-
3.97 (3H, m, H-3, H-4, H-6a), 3.80 (1H, dd, J6b,5 ) 4.8 Hz,
J6b,6a ) 8.5 Hz, H-6b), 2.55 (1H, d, JOH,3 ) 8.4 Hz, 3-OH),
1.56, 1.45, 1.36, 1.35 (4 × 3H, 4 × s, 2 × isopropylidene).
13C NMR (CDCl3, 100 MHz): δ 112.6, 109.6, 103.7, 79.6,
78.8, 75.5, 72.4, 65.7, 26.5, 26.4, 26.2, 25.2.
darkens, and the product will be of inferior quality. The
mixture was cooled to 18-20 °C between each addition.
After addition of P2O5 was completed, the mixture was stirred
at 18-25 °C for 10-15 min. 1,2:5,6-Di-O-isopropylidene-
R-D-glucofuranose (2) (260 g, 1.0 mol) was dissolved in
anhydrous DMSO (1.3 L) and added during 30 min (to keep
temperature between 18 and 25 °C) to the stirred solution
of P2O5 in DMSO under N2 atmosphere. The resulting
solution was heated to 50-55 °C for 3 h. TLC (eluent:
DCM/MeOH, 95:5) shows complete conversion of 2 (Rf )
0.68) to ulose (3) (Rf ) 0.81). The reaction mixture was
allowed to reach 25-30 °C and was extracted twice with
MTBE (1.5 and 1 L) in a 6-L separation funnel. The
combined MTBE layer (∼4 L) was concentrated in vacuo
(water-bath temperature set to 40 °C) to approximately 2 L
and allowed to reach 25-30 °C. NaBH4 (24 g, 0.63 mol)
was dissolved in water (1 L, 55.6 mol) at 0-10 °C, and the
concentrated MTBE layer was added to the aqueous layer
during 30 min to keep the temperature between 0 and 10
°C. TLC (eluent: EtOAc/heptane, 6:4) after 30 min shows
full conversion of 3 (Rf ) 0.53) to 1,2:5,6-di-O-isopropyl-
idene-R-D-allofuranose (4) (Rf ) 0.39). The reaction mixture
was allowed to reach 25-30 °C. DCM (1 L) and water (500
mL) were added, and the layers were separated. The aqueous
layer was extracted once more with DCM (500 mL). The
combined organic layers were concentrated in vacuo to an
oil which was subsequently dissolved in MTBE (300 mL)
and extracted with water (3 × 500 mL). The combined
aqueous layer was extracted with DCM (3 × 500 mL). The
combined DCM layer was dried (Na2SO4, 100 g), filtered,
and concentrated in vacuo to an oil. Crystallization from
cyclohexane (500 mL), washing of crystals with cold
n-pentane, and drying hereof in vacuo afforded analytically
pure 1,2:5,6-di-O-isopropylidene-R-D-allofuranose (4) 191
g (73% yield). NMR data were in accordance with the above.
Melting point: 74-75 °C (lit. 77-78 °C).27
Anal. Calcd for C12H20O6‚1/2H2O: C, 53.52; H, 7.86.
Found: C, 53.77; H, 7.72.
Melting point: 75-76 °C (lit. 77-78 °C).27
Optical rotation [R]25D +37.6° (c 1, chloroform); lit. [R]25
D
+38° (c 1, chloroform).39
1,2:5,6-Di-O-isopropylidene-3-O-(methylthio)methyl-R-
D-glucofuranose (5)26,31 was isolated by dry column vacuum
1
chromatography40 of the MTBE layer. Analytical data: H
NMR (CDCl3, 400 MHz): δ 5.87 (1H, d, J1,2 ) 3.6 Hz,
H-1), 4.78, 4.69 (2 × 1H, 2 × d, J ) 11.5 Hz, O-CH2-S),
4.55 (1H, d, J2,1 ) 3.8 Hz, H-2), 4.31 (1H, d, J3,4 ) 3.0 Hz,
H-3), 4.25 (1H, dt, J5,4 ) 8.0 Hz, J5,6 ) 5.9, H-5), 4.12 (1H,
dd, J4,5 ) 8.0 Hz, J4,3 ) 3.0 Hz, H-4), 4.09 (1H, dd, J6a,6b
)
8.5 Hz, J6a,5 ) 6.1 Hz, H-6a), 3.97 (1H, dd, J6b,6a ) 8.5 Hz,
J6b,5 ) 5.7 Hz, H-6b), 2.17 (3H, s, S-CH3), 1.49, 1.41, 1.32,
1.31 (4 × 3H, 4 × s, 2 × isopropylidene).
Anal. Calcd for C12H20O6: C, 55.37; H, 7.74. Found: C,
55.31; H, 7.71.
13C NMR (CDCl3, 100 MHz): 111.7, 108.9 (2 ×
isopropylidene), 105.1 (C-1), 82.7 (O-CH2-S), 81.0, 78.9,
74.6, 72.2, 67.4, 26.7, 26.7, 26.2, 25.3, 13.8.
Optical rotation[R]25D +37.8° (c 1, chloroform); lit. [R]25
D
+38° (c 1, chloroform).40
Anal. Calcd for C14H24O6S: C, 52.48; H, 7.55. Found:
C, 52.52; H, 7.51.
Acknowledgment
We thank Dr. Christoph Rosenbohm for helpful discus-
sions throughout the completion of this work, Ulla Maxmill-
ing (Department of Chemistry, The Technical University of
Denmark) for measurement of the optical rotation and
melting temperatures, and Kirsten Dayan (Department of
Chemistry, University of Copenhagen) for measurement of
NMR spectra.
Two-Pot, Two-Step Procedure Using DMSO/P2O5/
NaBH4. Anhydrous DMSO (650 mL) was cooled to 18-20
°C under nitrogen in a 3-L round-bottom glass flask. DMSO
will be solidified at 18 °C, so it is important to keep it just
above freezing point. To this cold solution was added P2O5
(142 g, 1.0 mol, 1 equiv) in three portions under N2
atmosphere. The addition of P2O5 to DMSO is exothermic,
and if the mass temperature exceeds 28 °C, the colour
Received for review May 14, 2004.
OP049903T
(39) Collins, P. M. Tetrahedron 1965, 21, 1809-1815.
(40) Pedersen, D. S.; Rosenbohm, C. Synthesis 2001, 16, 2431-2434.
780
•
Vol. 8, No. 5, 2004 / Organic Process Research & Development