A practical procedure for the selective N-alkylation of 4-alkoxy-2-pyridones and its use in a sulfone-mediated synthesis of N-methyl-4-methoxy-2-pyridone

Article abstract of DOI:10.1016/j.tetlet.2005.09.095

It has been found that selective N-alkylation of 4-alkoxy-2-pyridones can be achieved under anhydrous, mild conditions with tetrabutylammonium iodide and potassium tert-butoxide being employed as the catalyst and the base, respectively. The procedure was applied to the preparation of 4-methoxy-1-methyl-2-pyridone, a valuable building block for heterocycle synthesis.

Full text of DOI:10.1016/j.tetlet.2005.09.095

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7917–7920
A practical procedure for the selective N-alkylation of
4-alkoxy-2-pyridones and its use in a sulfone-mediated
synthesis of N-methyl-4-methoxy-2-pyridone
David Conreaux,a Emmanuel Bossharth,a Nuno Monteiro,a,*
b
a,
*
`
Philippe Desbordes and Genevieve Balme
aLaboratoire de Chimie Organique 1, CNRS UMR 5181, Universite´ Claude Bernard—Lyon I, ESCPE. 43,
Bd du 11 Novembre 1918, 69622 Villeurbanne, France
bBayer CropScience, 14 /20 rue Baizet, BP9163, 69623 Lyon Cedex 09, France
Received 17 June 2005; revised 14 September 2005; accepted 16 September 2005
Available online 4 October 2005
Abstract—It has been found that selective N-alkylation of 4-alkoxy-2-pyridones can be achieved under anhydrous, mild conditions
with tetrabutylammonium iodide and potassium tert-butoxide being employed as the catalyst and the base, respectively. The
procedure was applied to the preparation of 4-methoxy-1-methyl-2-pyridone, a valuable building block for heterocycle synthesis.
ꢀ 2005 Elsevier Ltd. All rights reserved.
OMe
N-Alkylated 2-pyridones are important intermediates
in the synthesis of polycyclic compounds of biological
significance as illustrated by the recent synthetic
approaches toward the camptothecin family of anti-
tumor agents.1 They are also structural subunits of
naturally occurring products such as the heterocycle-
annelated pyridone alkaloid cerpegin having analgesic,
anti-ulcer, and anti-inflammatory activities2 or the anti-
biotic 4-hydroxypyridones funiculosine, which possesses
fungicide properties3 and aurodox, an antimicrobial
agent.4 However, there is still a need for efficient meth-
ods allowing the selective N-alkylation of 2-pyridones,
as known procedures generally suffer from low yields
and/or competition between N- and O-alkylation.5 In
the course of a program aimed at evaluating the syn-
thetic potential of N-alkylated-4-alkoxy-2-pyridones as
precursors of new drug-like heterocycles,6 we needed
to prepare a series of such compounds and were parti-
cularly interested in 4-methoxy-N-methyl-2-pyridone 1,
a known building block in heterocycle synthesis,3,6,7
and its phenylsulfonyl derivative 28 as model substrates.
OH
OMe
E
CN
O
N
O
N
H
O
N
H
Me
1 E = H
2 E = SO2Ph
3 E = CN (ricinin)
4
5
To the best of our knowledge, no satisfactory procedure
was available from the literature in terms of practicity
and low cost for the large scale preparation of 1. Alkyl-
ation of commercially available, but rather expensive,
4-hydroxy-2-pyridone (4) is rather difficult owing to its
low solubility in common organic solvents. Direct
bismethylation of 4 has been reported to proceed under
phase transfer conditions (H2O/benzene; 70 ꢁC) using
dimethylsulfate in the presence of benzyl triethylammo-
nium bromide.3 However, the process is sluggish, low
yielding (50%), and isolation of the product rather
tedious.
In 1917, Winterstein et al.9 reported the isolation of
N,O-dimethylpyridone 1 obtained upon heating of the
alkaloid ricinin (3) in aq H2SO4. Ricinin was initially
obtained from castor seeds (Ricinus communis L.)10
but can now be prepared from malononitrile according
Keywords: 4-Alkoxy-2-pyridones; N-Alkylation; Tetrabutyl ammo-
nium iodide; Desulfonylation.
*
Corresponding authors. Tel.: +33 (0)4 72 43 14 16; fax: +33 (0)4 72
43 12 14; e-mail addresses: Monteiro@univ-lyon1.fr; Balme@
univ-lyon1.fr
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.095

7918
D. Conreaux et al. / Tetrahedron Letters 46 (2005) 7917–7920
to a four-step procedure as reported by Junek and co-
workers.11 The most significant drawback of the method
was again the low yield obtained for the N-methylation
of the 3-cyanopyridone precursor 5 (Me2SO4, aq NaOH,
rt, 53% yield). As it was predicted that sulfonylpyridone
2 would be available from phenylsulfonylacetonitrile (6)
according to the same reaction sequence, and that pyri-
done 1 would then be accessible from desulfonylation of
2, avoiding the N-methylation in the last step, we
planned to exploit this approach as a common route
to both compounds (Scheme 1).
and by carrying out the reaction at 90 ꢁC in aqueous
toluene.
Having succeeded in developing a practical, alternative
synthesis of pyridone 1,21 we then focused our attention
on the general applicability of the N-alkylation of pyri-
dones by mean of the t-BuOK/n-Bu4NI system. Quite
interestingly, methylation of cyanopyridone 5 under
the same conditions used previously for 9 was shown
to proceed smoothly to yield ricinin (3) in an improved
90% isolated yield compared to that reported by Junek
(53%). The alkylation protocol applied also to other
alkylating reagents as demonstrated by reaction of
4-alkoxypyridones 10a,b (Table 1)22 with methyl iodide,23
benzyl bromide, allyl bromide, propargyl bromide, as
well as the less activated n-butyl iodide. Even the sec-
ondary benzhydryl bromide24 participated in the process
but required higher temperature (50 ꢁC) and prolonged
reaction times.25
Thus, preparation of the cyclic precursor 9 was accom-
plished in three high yielding steps by using slight mod-
ifications of JunekÕs procedure. Notably, in our modified
method, cyclization of the enamine precursor was con-
ducted in 80% aq acetic acid12 instead of concd sulfuric
acid. With pyridone 9 in hand, the next issue to address
was the alkylation step. As expected, the aforemen-
tioned procedures involving aqueous systems proved
unsatisfactory in terms of yields (<50%) and ease of
product purification. We then decided to seek new con-
ditions and were pleased to find that selective N-methyl-
ation of 9 could be accomplished under mild condi-
tions by using the anhydrous system MeI/t-BuOK/cat.
n-Bu4NI13 in THF at room temperature. The desired
sulfonyl derivative 2 was obtained in nearly quantitative
yield. It is of interest that the reaction sequence has been
successfully scaled up to produce 45 g of 2 in a single
batch.
Table 1. Selective N-alkylation of 4-alkoxy-2-pyridones
OR
OR
R'X
t-BuOK, cat. n-Bu4NI
O
N
N
O
THF, RT
H
R'
10a R = Bn
10b R = Me
Entry
Pyridone
Alkyl halide
Yield (%)a
Removal of the phenylsulfonyl group in 2 was then
investigated. A screening of desulfonylation conditions
suggested from the literature were tried (Na/Hg,
MeOH;14 Mg/HgCl2, EtOH;15 H2, Raney Ni, EtOH;16
Bu3SnH, AIBN, toluene;17 i-PrMgBr, Ni(acac)2,
THF;18 NaBH4, DMF19) all of which failed to give the
desired product in satisfactory yield, if any. Finally,
the procedure developed by Julia for the desulfonylation
of acyclic vinyl sulfones by sodium dithionite (Na2S2O4)
proved to be quite effective. In the original report,20 the
reductant was used in combination with NaHCO3 and
AdogenTM under phase transfer conditions (benzene–
water, 80 ꢁC). However, optimization studies established
that desulfonylation of 2 proceeds faster and gives better
yields (up to 93%) by substituting AdogenTM for n-Bu4NI
1
2
3
10a
10a
10a
MeI
BnBr
91% (11a)
93% (11b)
90% (11c)
Br
Br
4
10a
83% (11d)
Br
5
10a
62%b (11e)
Ph
Ph
6
7
8
10b
10b
10b
MeI
BnBr
n-BuI
91% (1)
95% (11f)
94%c (11g)
a Yields refer to single runs. Reactions conducted overnight on a
half-millimolar scale. Ratio 10–R0X–t-BuOK–n-Bu4NI = 1:1.5:1.1:
0.05.
b 3 equiv of benzhydryl bromide were used (50 ꢁC, 3 days).
c 3 equiv of butyl iodide were used.
OMe
SO2Ph
CN
MeO
i
SO2Ph
ii
N
NC
SO2Ph
70%
90%
CN
8
6
7
(E/Z = 1)
OMe
OMe
OMe
SO2Ph
O
SO2Ph
O
v
iii
90%
iv
93%
99%
N
O
N
N
H
Me
1
Me
2
9
Scheme 1. Reagents and conditions: (i) neat MeC(OMe)3, D (–MeOH); (ii) neat Me2NCH(OMe)2, 140 ꢁC; (iii) 80% aq AcOH reflux; (iv) MeI
(1.5 equiv), t-BuOK, cat. n-Bu4NI, THF, 0 ꢁC to rt; (v) Na2S2O4, NaHCO3, n-Bu4NI, toluene–H2O, 90 ꢁC.

D. Conreaux et al. / Tetrahedron Letters 46 (2005) 7917–7920
7919
12. AcOH gives better results compared to H2SO4 used in the
original synthesis. See, Yano, S.; Ohno, T.; Ogawa, K.
Heterocycles 1993, 36, 145–148.
In conclusion, we have described an efficient protocol for
the selective N-alkylation of 4-alkoxy-2-pyridones,
which also holds promise for the alkylation of 2-pyri-
dones in general. We have also established an alternative,
practical procedure for the synthesis of 4-methoxy-1-
methyl-2-pyridone 1, a versatile building block in hetero-
cycle synthesis. The method is particularly well suited for
the preparation of 1 in multi-gram scale.
13. Addition of n-Bu4NI probably results in the formation of
a 2-pyridone anion loosely associated with a quaternary
ammonium counteranion through anion exchange, which
enhances its reactivity toward alkylation. See, Czernecki,
S.; Georgoulis, C.; Provelenghiou, C. Tetrahedron Lett.
1976, 17, 3535–3536. It is worth to note that alkylation of
4-hydroxy-2-pyridone (4) failed under identical conditions
due most probably to its low solubility in the reaction
solvent.
Acknowledgments
´
14. See: Najera, C.; Yus, M. Tetrahedron 1999, 55, 10547–
This research was assisted financially by a grant to D.C.
and E.B. from Bayer CropScience and the Centre
National de la Recherche Scientifique.
10658, and references cited therein.
15. Lee, G.; Choi, E.; Lee, E.; Pak, C. Tetrahedron Lett. 1993,
34, 4541–4542.
16. Sheehan, S.; Padwa, A. J. Org. Chem. 1997, 62, 438–439.
17. Caddick, S.; Khan, S. Tetrahedron Lett. 1993, 34, 7469–
7470.
18. Clayden, J.; Julia, M. J. Chem. Soc., Chem. Commun.
1993, 1682–1683.
19. Wrobel, Z. Tetrahedron 1998, 54, 2607–2618. When
applied to 2 the reaction afforded the corresponding
saturated dealkoxylactam:
References and notes
1. (a) Josein, H.; Ko, S.-B.; Bom, D.; Curran, D. P. Chem.
Eur. J. 1998, 4, 67–83; (b) Comins, D. L.; Saha, J. K.
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Nolan, J. M. Org. Lett. 2001, 3, 4255–4257.
2. (a) Villemin, D.; Liao, L. Tetrahedron Lett. 1996, 37,
8733–8734; (b) Lazaar, J.; Hoarau, C.; Mongin, F.;
SO2Ph
10 equiv. NaBH4
´
´
Trecourt, F.; Godard, A.; Queguiner, G.; Marsais, F.
2
Tetrahedron Lett. 2005, 46, 3811–3813.
DMF, RT
55%
N
O
3. Buck, J.; Madeley, J. P.; Pattenden, G. J. Chem. Soc.,
Perkin Trans. 1 1992, 1, 67–77.
Me
4. (a) Dolle, R. E.; Nicolaou, K. C. J. Am. Chem. Soc. 1985,
107, 1695–1698; (b) Vogeley, L.; Palm, G. J.; Mesters, J.
R.; Hilgenfeld, R. J. Biol. Chem. 2001, 276, 17149–17155.
5. For recent efforts made in this area, see: (a) Comins, D.;
Jianhua, G. Tetrahedron Lett. 1994, 35, 2819–2822; (b)
Rico, I.; Halvorsen, K.; Dubrule, C.; Lattes, A. J. Org.
Chem. 1994, 59, 415–420; (c) Liu, H.; Ko, S. B.; Josien, H.;
Curran, D. P. Tetrahedron Lett. 1995, 36, 8917–8920; (d)
Almena, I.; Diaz-Ortiz, A.; Diez-Barra, E.; de la Hoz, A.;
Loupy, A. Chem. Lett. 1996, 5, 333–334; (e) Sato, T.;
Yoshimatsu, K.; Otera, J. Synlett 1995, 845–846; (f)
Bowman, W. R.; Bridge, C. F. Synth. Commun. 1999, 29,
4051–4059; (g) Nadin, A.; Harrison, T. Tetrahedron Lett.
1999, 40, 4073–4076; (h) Sugahara, M.; Moritani, Y.;
Kuroda, T.; Kondo, K.; Shimadzu, H.; Ukita, T. Chem.
Pharm. Bull. 2000, 48, 589–591; (i) Janin, Y. L.; Huel, C.;
Flad, G.; Thirot, S. Eur. J. Org. Chem. 2002, 1763–1769;
(j) Ruda, M. C.; Bergman, J.; Wu, J. J. Comb. Chem. 2002,
4, 530–535.
6. For an illustration, see: Bossharth, E.; Desbordes, P.;
Monteiro, N.; Balme, G. Org. Lett. 2003, 5, 2441–2444.
7. (a) Sugasawa, T.; Sasakura, K.; Toyoda, T. Chem. Pharm.
Bull. 1974, 22, 763–770; (b) Chiba, T.; Kato, T.; Yoshida,
A.; Moroi, R.; Shimomura, N.; Momose, Y.; Naito, T.;
Kaneko, C. Chem. Pharm. Bull. 1984, 32, 4707–4720; (c)
Fujiwara, T.; Tanaka, N.; Tanaka, K.; Toda, F. J. Chem.
Soc., Perkin Trans. 1 1989, 3, 663–664; See also (d)
Sieburth, S. McN.; Lin, C.-H.; Rucando, D. J. Org. Chem.
1999, 64, 950–953, and references cited therein.
20. Bremner, J.; Julia, M.; Launay, M.; Stacino, J. P.
Tetrahedron Lett. 1982, 23, 3265–3266.
21. Experimental part: Preparation of 1 from phenylsulfonyl-
acetonitrile 6:
3-Methoxy-2-(phenylsulfonyl)but-2-enenitrile (7): Phenyl-
sulfonylacetonitrile (1.9 g, 10.5 mmol) and 1,1,1-trimeth-
oxyethane (1.5 g, 12.5 mmol) were placed in a round-
bottomed flask fitted with a distillation apparatus. The
mixture was heated with stirring until a gentle distillation
of methanol started (oil bath heated to approx. 100 ꢁC).
Once distillation ceased, the mixture was allowed to reach
room temperature, at which point it solidified. The solid
residue was taken up in methanol (20 mL) and the
resulting suspension was cooled to ꢀ20 ꢁC and let to
stand for 2 h at that temperature. The precipitate was
collected by suction filtration, washed with cold methanol
(5 mL), and dried under vacuum to yield 2.2 g (90%) of 7
as a colorless solid (1:1 mixture of E and Z isomers).
NMR data were in agreement with that reported in the
literature.26
5-(Dimethylamino)-3-methoxy-2-(phenylsulfonyl)penta-
2,4-dienenitrile (8): A neat mixture of 7 (1.02 g, 3.5 mmol)
and N,N-dimethyl formamide dimethyl acetal (0.63 g,
5.3 mmol) was heated at 140 ꢁC for 3 h. The mixture was
then allowed to reach room temperature and concentrated
in vacuo to give a reddish oil, which was subjected to
column chromatography (silica gel; ethyl acetate–petro-
leum ether: 55:45) to afford 8 as a pale yellow solid
1
8. Related 3-sulfonyl-2-pyridones have been reported to
possess interesting biological properties: Dunbar, J. E.;
Harris, R. F.; McCarthy, J. R., Jr.; US Patent US
3,847,927, 1974.
9. Winterstein, E.; Keller, J.; Weinhagen, A. B. Arch. Pharm.
1917, 255, 513–539.
(720 mg, 70%). Mp 147 ꢁC. H NMR (300 MHz, CDCl3):
2.96 (s, 3H); 3.21 (s, 3H); 3.93 (s, 3H); 5.20 (br s, 1H);
7.49–7.51 (m, 4H); 7.96 (d, J = 6.7 Hz, 2H). 13C NMR
(75 MHz, CDCl3): 37.61; 46.01; 61.17; 85.19; 86.91; 117.5;
126.90; 128.83; 132.58; 143.67; 154.32; 178.56.
4-Methoxy-3-(phenylsulfonyl)pyridin-2(1H)-one (9):
A
10. Yuldashev, P. Kh. Chem. Nat. Compd. 2001, 37, 274–275.
11. Mittelbach, M.; Katsner, G.; Junek, H. Monatsh. Chem.
1984, 115, 1467–1470; Mittelbach, M.; Katsner, G.; Junek,
H. Arch. Pharm. 1985, 318, 481–486.
solution of 8 (5.04 g, 19.0 mmol) in 80% aq acetic acid
(25 mL) was refluxed for 4 h. The reaction mixture, which
solidified upon cooling to room temperature, was diluted
with ethyl acetate (10 mL) and cooled in ice water. The

7920
D. Conreaux et al. / Tetrahedron Letters 46 (2005) 7917–7920
solid product was collected by suction filtration and
112–114 ꢁC (lit.27 113–114 ꢁC). NMR data were in agree-
ment with that reported in the literature.3
22. Compound 10a is commercially available; 10b was
obtained by desulfonylation of 9 (51% yield) according
to the same procedure as used for 2.
23. Lower yields have been reported for N-methylation of 10
using Me2SO4 in aq NaOH: (a) Katagiri, N.; Sato, M.;
Yoneda, N.; Saikawa, S.; Sakamoto, T.; Muto, M.;
Kaneko, C. J. Chem. Soc., Perkin Trans. 1 1986, 1289–
1296; (b) Gwaltney, S. L., II; Imade, H. M.; Barr, K. J.;
Li, Q.; Gehrke, L.; Credo, R. B.; Warner, R. B.; Lee, J. Y.;
Kovar, P.; Wang, J.; Nukkala, M. A.; Zielinski, N. A.;
Frost, D.; Ng, S.-C.; Sham, H. L. Bioorg. Med. Chem.
Lett. 2001, 11, 871–874.
washed with cold ethyl acetate (5 mL). Recrystallization
from methanol gave 9 as a pale yellow solid (4.5 g, 90%).
Mp 220 ꢁC (dec). 1H NMR (300 MHz, DMSO-d6): 3.90 (s,
3H); 6.26 (d, J = 7.5 Hz, 1H); 7.50–7.60 (m, 3H); 7.69 (d,
J = 7.5 Hz, 1H); 7.88 (dd, J = 8.7–1.7 Hz, 2H). 13C NMR
(75 MHz, DMSO-d6): 58.30; 94.64; 112.01; 127.87; 129.27;
133.38; 143.24; 144.25; 159.52; 170.68.
4-Methoxy-1-methyl-3-(phenylsulfonyl)pyridin-2(1H)-one
(2): To a stirred, cooled solution (0 ꢁC) of pyridone 9
(1.78 g, 6.7 mmol) in THF (20 mL) were successively
added t-BuOK (0.82 g, 7.3 mmol) and n-Bu4NI (0.125 g,
0.34 mmol) under nitrogen and the resulting reaction
mixture was held at 0 ꢁC for 15 min. Methyl iodide (1.4 g,
9.9 mmol) was then added and the mixture was allowed to
reach room temperature and stirred overnight. The
reaction mixture was then quenched with water (20 mL)
and THF was removed in vacuo to leave a white
suspension in water, which was collected by suction
filtration, washed with water, and dried over P2O5 to give
2 as an off-white solid (1.8 g, 99%). Mp 207–208 ꢁC. 1H
NMR (200 MHz, CDCl3): 3.44 (s, 3H, NMe); 4.01 (s, 3H,
OMe); 6.07 (d, J = 7.7 Hz, 1H); 7.45–7.60 (m, 4H); 8.11
(d, J = 6.8 Hz 2H). 13C NMR (75 MHz, CDCl3): 37.95;
57.92; 94.21; 113.20; 128.50; 128.99; 133.30; 144.11;
144.98; 159.46; 169.82. Anal. Calcd for C13H13NO4S: C,
55.90; H, 4.69; N, 5.01. Found C, 55.80; H, 4.79; N, 4.95.
24. Benzhydryl has been recently introduced as a nitrogen
protecting group for uracils: Wu, F.; Buhendwa, M. G.;
Weaver, D. F. J. Org. Chem. 2004, 69, 9307–9309.
25. In a typical experiment, t-BuOK (0.55 mmol) and n-Bu4NI
(0.025 mmol) were added to a cooled solution (0 ꢁC) of
pyridone 10 (0.5 mmol) in THF (5 mL) and the resulting
reaction mixture was held at 0 ꢁC for 15 min. The alkyl
halide (0.75 mmol) was added and the resulting mixture
was left to stir overnight. The mixture was then concen-
trated in vacuo, and after usual workup with 1 N aq
NaOH and dichloromethane, the crude product was
purified by flash chromatography on silica gel eluting
with an appropriate combination of ethyl acetate and
dichloromethane. Selected data for N-alkylated pyridones
11: 1H NMR (CDCl3, 300 MHz). 11b: d 7.42–7.27 (m,
10H); 7.13 (d, J = 7.5 Hz, 1H); 6.05 (d, J = 2.6 Hz, 1H);
5.95 (dd, J = 2.6 and 7.5 Hz, 1H); 5.09 (s, 2H); 4.99 (s,
2H). 11c: d 7.30–7.25 (m, 5H); 7.03 (d, J = 7.35 Hz, 1H);
5.90–5.75 (m, 3H); 5.16 (dd, J = 1.3 and 10.2 Hz, 1H);
5.10 (d, J = 1.3 and 17.1 Hz, 1H); 4.89 (s, 2H); 4.41 (dt,
J = 1.3 and 5.65 Hz, 2H). 11d: d 7.48 (d, J = 7.5 Hz, 1H);
7.40–7.35 (m, 5H); 6.03 (dd, J = 2.6 and 7.5 Hz, 1H); 5.98
(d, J = 2.6 Hz, 1H); 4.98 (s, 2H); 4.68 (d, J = 2.6 Hz, 2H);
2.47 (t, J = 2.6 Hz, 2H). 11e: d 7.45 (s, 1H); 7.40–7.30 (m,
11H); 7.14 (m, 4H); 7.02 (d, J = 7.9 Hz, 1H); 6.08 (d,
J = 2.6 Hz, 1H); 5.93 (dd, J = 2.6 and 7.9 Hz, 1H); 4.99 (s,
2H). 11f: d 7.35–7.25 (m, 5H); 7.11 (d, J = 7.5 Hz, 1H);
5.97 (d, J = 2.8 Hz, 1H); 5.89 (dd, J = 2.8 and 7.5 Hz,
1H); 5.09 (s, 2H); 3.76 (s, 3H). 11g: d 7.05 (d, J = 8.3 Hz,
1H); 5.81 (m, 2H); 3.79 (t, J = 7.4 Hz, 3H); 3.68 (s, 3H);
1.62 (m, 2H); 1.28 (m, 2H); 0.87 (t, J = 7.4 Hz, 3H).
4-Methoxy-1-methylpyridin-2(1H)-one
(1):
Na2S2O4
decomposes rapidly in aqueous solution to chiefly thio-
sulfate and sulfite, and should therefore be added in
portions as follows: To a mixture of pyridone 2 (2.0 g,
7.2 mmol), NaHCO3 (6.0 g, 71.4 mmol), and n-Bu4NI
(0.53 g, 1.44 mmol) in toluene (80 mL) and water (80 mL)
was added a first portion of Na2S2O4 (2.5 g, 14.3 mmol)
and the well-stirred mixture was warmed to 90 ꢁC in the
dark under an atmosphere of nitrogen. After 2 h an
additional portion of Na2S2O4 (2.5 g) was cautiously
added and stirring was continued for an additional 2 h.
This addition procedure was repeated until complete
desulfonylation had occurred as judged from TLC anal-
ysis (silica gel, acetone). In general, 8–14 equiv of Na2S2O4
were necessary to achieve complete conversion. The
reaction mixture was then cooled to room temperature.
The organic layer was collected and the aqueous phase
was extracted with ethyl acetate and dichloromethane
(5 · 20 mL each). The organic extracts were combined,
dried over MgSO4, and concentrated in vacuo. The residue
was subjected to column chromatography (silica gel;
acetone) to afford 1 as a white solid (0.93 g, 93%). Mp
´
26. Perez, M. A.; Soto, J. L.; Guzman, F.; Diaz, A. Synthesis
1984, 1045–1047.
27. den Hertog, H. J.; Buurman, J. D. Recl. Trav. Chim. Pays-
Bas 1956, 75, 257.