Reagent for synthesis of secondary amines by two consecutive N-alkylations and its application to orthogonally protected spermidine

Article abstract of DOI:10.1021/jo020205l

A novel reagent, tert-butyl 2-naphthalenesulfonylcarbamate, has been designed to allow the stepwise synthesis of secondary aliphatic amines by two consecutive N-alkylations with intermediate Boc-cleavage and final desulfonylation under mild and experiment

Full text of DOI:10.1021/jo020205l

SCHEME 1. Syn th esis of 2-Ns-NH-Boc (2)
Rea gen t for Syn th esis of Secon d a r y Am in es
by Tw o Con secu tive N-Alk yla tion s a n d Its
Ap p lica tion to Or th ogon a lly P r otected
Sp er m id in e†
Leif Grehn and Ulf Ragnarsson*
Department of Biochemistry, University of Uppsala,
Biomedical Center, P.O. Box 576,
SE-751 23 Uppsala, Sweden
urbki@bmc.uu.se
harsh conditions for the final deprotection. This paper
therefore addresses these issues.
Received March 25, 2002
A major procedure to accomplish nitrogen alkylation
by a primary or, especially, secondary alcohol is based
on the Mitsunobu reaction,6 which requires a relatively
acidic nitrogen donor. Reagents of the imidodicarbonate
type have been shown to be too weakly acidic, whereas
sulfonylcarbamates proved to be more satisfactory in this
context.7,8 Ideally, sulfonamides may allow a second
Mitsunobu reaction,8-10 but as mentioned above, to be
really useful they should allow deprotection under rea-
sonably mild conditions afterward, which so far seems
to be best fulfilled by the nitrobenzenesulfonyl group.10
Recently, after systematic studies which included mea-
suring the reduction potential of a large number of
compounds by cyclic voltammetry, we came up with the
2-naphthalenesulfonyl group as a candidate for examina-
tion in this context.11 2-Naphthalenesulfonamides do not
require sodium in liquid ammonia for reductive cleavage,
which can be more conveniently accomplished by mag-
nesium powder in methanol.12 As a first step toward the
exploration of this sulfonyl group for the synthesis of
secondary amines by a double-alkylation approach, we
have now prepared the reagent tert-butyl 2-naphtha-
lenesulfonylcarbamate, 2-Ns-NH-Boc (2), the synthesis
of which is outlined in Scheme 1.
Abstr a ct: A novel reagent, tert-butyl 2-naphthalenesulfon-
ylcarbamate, has been designed to allow the stepwise
synthesis of secondary aliphatic amines by two consecutive
N-alkylations with intermediate Boc-cleavage and final
desulfonylation under mild and experimentally convenient
conditions. Its application was demonstrated to make an
orthogonally protected spermidine derivative, suitable for
further selective modification. Each individual step, includ-
ing the final cleavage of 2-naphthalenesulfonyl to provide
the secondary amine nitrogen, took place in high yield.
A very large number of procedures are now available
for the synthesis of secondary aliphatic amines. Whereas
in the majority of these cases free primary amines have
been used as starting materials, protected derivatives of
carbox- and sulfonamides, dialkylphosphoramidates, and
carbamates, as well as others obtained by benzyl-, trityl-
and silylation, have also been applied in this context.1,2
Contrary to phthalimide,3 the classical precursor for the
synthesis of primary amines with a divalent protecting
group on nitrogen, many other more recently developed
reagents for this purpose with two monovalent orthogonal
such groups4 should in principle allow two subsequent
alkylation steps to be performed, i.e., also synthesis of
secondary amines. Among these reagents are imidodi-
carbonates and various acylcarbamates including phos-
phoramidates and sulfonylcarbamates,5 many of which
undergo facile alkylation and selective monodeprotection
to give carbamates or the corresponding amides. Never-
theless, they have found limited application for direct
double alkylation due to restrictions imposed in the
second alkylation step or, alternatively, the need for
The synthesis of 2 was performed in two steps.
Initially, 2-Ns-Cl was reacted with the potassium salt of
easily available di-tert-butyl imidodicarbonate.13 Com-
pounds such as 1, a sulfonylimidodicarbonate, have to
the best of our knowledge previously only been described
in two patents.14 By analogy with NBoc3, 1 underwent
facile aminolysis with cleavage of one Boc-group to give
(6) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Hughes, D. L. Org. React.
N. Y. 1992, 42, 335.
* To whom correspondence should be addressed. Phone: +46 18 471
45 55. Fax: +46 18 55 21 39.
(7) Koppel, I.; Koppel, J .; Degerbeck, F.; Grehn, L.; Ragnarsson, U.
J . Org. Chem. 1991, 56, 7172.
(8) Henry, J . R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.; Harris,
G. D., J r.; Weinreb, S. M. Tetrahedron Lett. 1989, 30, 5709.
(9) Edwards, M. L.; Stemerick, D. M.; McCarthy, J . R. Tetrahedron
Lett. 1990, 31, 3417.
(10) Fukuyama, T.; J ow, C. K.; Cheung, M. Tetrahedron Lett. 1995,
36, 6373.
(11) Nyasse, B.; Grehn, L.; Maia, H. L. S.; Monteiro, L. S.; Rag-
narsson, U. J . Org. Chem. 1999, 64, 7135 and references therein.
(12) Nyasse, B.; Grehn, L.; Ragnarsson, U. Chem. Commun. 1997,
1017.
† This paper is dedicated in friendship to Hernani L. S. Maia on
the occasion of his 65th birthday.
(1) For
a recent review of synthesis of secondary amines, see:
Salvatore, R. N.; Yoon, C. H.; J ung, K. W. Tetrahedron 2001, 57, 7785.
(2) For reviews of protecting groups for the amino function, see: (a)
Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis,
3rd ed.; Wiley-Interscience: New York, 1999; Chapter 7. (b) Kocien´ski,
P. J . Protecting Groups; Thieme: Stuttgart, 1994; Chapter 6.
(3) Gibson, M. S.; Bradshaw, R. W. Angew. Chem. 1968, 80, 986;
Angew. Chem., Int. Ed. Engl. 1968, 7, 919.
(4) (a) Hendrickson, J . B.; Bergeron, R.; Sternbach, D. D. Tetrahe-
dron 1975, 31, 2517. (b) Smith, M. B.; March, J . March’s Advanced
Organic Chemistry. Reactions, Mechanisms, and Structure, 5th ed.;
Wiley-Interscience: New York, 2001; p 514.
(5) Ragnarsson, U.; Grehn, L. Acc. Chem. Res. 1991, 24, 285 and
references therein.
(13) (a) Carpino, L. A. J . Org. Chem. 1964, 29, 2820. (b) Clarke, C.
T.; Elliott, J . D.; J ones, J . H. J . Chem. Soc., Perkin Trans. 1 1978,
1088. (c) Grehn, L.; Ragnarsson, U. Synthesis 1987, 275. (d) Degerbeck,
F.; Grehn, L.; Ragnarsson, U. Acta Chem. Scand. 1993, 47, 896. (e)
Allan, R. D.; J ohnston, G. A. R.; Kazlauskas, R.; Tran, H. W. J . Chem.
Soc., Perkin Trans. 1 1983, 2983 (potassium salt).
10.1021/jo020205l CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/03/2002
J . Org. Chem. 2002, 67, 6557-6559
6557

SCHEME 2. Syn th esis of P r otected Sp er m id in es 5
a n d 6
The physical and spectral data of 6 were in complete
agreement with those of an authentic sample,17 previ-
ously prepared by derivatization of commercial spermi-
dine. The novel compound 5, with its two additional
classical protecting groups that can be manipulated at
will and independently of the aromatic sulfonyl residue,
should be useful for conjugation at N-1 and N-3 and, thus,
useful together with 6 in future synthetic work.
From a synthetic and principle point of view, sulfonyl-
carbamates8,19 and sulfonylimidodicarbonates are both
interesting and useful. Therefore, when other sulfonyl
protecting groups are required and suitable precursors
become available, as long as bases and nucleophiles do
not interfere with them, the sequence used to make 2
should be applicable. Also, as the corresponding N-15-
labeled imidodicarbonate is readily available,13d a facile
procedure for N-15 labeling is now also available.
2.13d This could also be prepared conveniently via the
sulfonamide,15 but in this experiment a small amount of
N-tert-butylation was detected. Experimentally, both
procedures are simple and go to completion. From
compound 2 a stable, nonhygroscopic potassium salt can
readily be prepared.
Exp er im en ta l Section
After several successful experiments starting from 2
had been performed, we decided to concentrate our efforts
next on the polyamine spermidine, H2N-(CH2)3-NH-
(CH2)4-NH2, which is known to be both involved in a
variety of important biological functions and a component
of alkaloids and toxins.16 For the synthesis of substances
of these types, selectively protected derivatives of sper-
midine are required and used.16a,b Several years ago, we
converted spermidine to the N1-Z,N3-Boc-protected de-
rivative by a multistep approach.17 In Scheme 2, the
synthesis of this substance (6) from the novel reagent 2
is outlined.
In the first step, the reagent 2 was condensed with
4-Boc-aminobutanol under Mitsunobu conditions to give
the intermediate 3 in 97% yield. In the next step, by
analogy with tert-butyl imidodicarbonates,18 regiospecific
sulfonylcarbamate cleavage could be effected by catalytic
amounts of Mg(ClO4)2 without affecting the ordinary Boc-
group on the other nitrogen. The resulting product 4 was
obtained in 94% yield. This compound underwent alky-
lation under Mitsunobu conditions with 3-Z-aminopro-
panol in THF to give 5 in 60% yield. This figure is similar
to those obtained by Weinreb et al. in Mitsunobu reac-
tions with N-methyl-4-toluenesulfonamide,8 but it could
be raised to 94% or greater by alkylation with 3-Z-
aminopropyl bromide instead, either with NaH as a base
or under liquid-liquid phase-transfer catalysis condi-
tions. The latter procedure turned out to be particularly
attractive in this case. Finally, the 2-Ns-group of 5 was
cleaved by magnesium in methanol to furnish 6 in 95%
yield,12 demonstrating practical reductive cleavage of
2-naphthalenesulfonyl for protection of amino functions.11
Gen er a l Meth od s. Melting points are uncorrected. All
solvents used as reaction media were of analytical quality and
dried over molecular sieves (4 Å, activated at 320 °C overnight).
Light petroleum refers to a fraction with a bp of 40-65 °C. All
chemicals were of commercial grade and used as such, if not
otherwise stated. Dry THF for the Mitsunobu syntheses was
kept under argon. All glassware used were dried in a flame
immediately before use, and all reactions were executed under
dry argon. TLC analyses were performed on 0.25 mm thick
precoated silica plates eluting with (A) 2:1 toluene/MeCN, (B)
19:1 CH2Cl2/Et2O, (C) 19:1 CH2Cl2/MeOH, (D) 5:3:1:1 EtOAc/
acetone/HOAc/water, or (E) 40:10:1 CH2Cl2/acetone/HOAc; spots
were visualized by inspection under UV light and/or by Cl2/
dicarboxidine spray20 and, for free amino compounds, also by
ninhydrin spray. Preparative column chromatography was car-
ried out on silica (70-230 mesh). IR spectra were recorded in
1
KBr pellets. H and 13C specta were recorded at 400 and 100.4
MHz, respectively, in ∼5% solution in CDCl3 at 25 °C, when not
otherwise stated. All shifts are given in parts per million using
δH(TMS) ) 0 and δC(CDCl3) ) 77.02 as references.
Di-ter t-b u t yl 2-n a p h t h a len esu lfon ylim id od ica r b on a t e
(1). 2-Ns-Cl (2.82 g, 12.0 mmol) in CH2Cl2 (30 mL) was cooled
in ice, and dry KNBoc213e (2.55 g, 10.0 mmol) was added in small
portions with rapid stirring. The resulting slurry was treated
with 18-crown-6 (264 mg, 1.00 mmol) in CH2Cl2 (3 mL). Finally,
ground K2CO3 (276 mg, 2.00 mmol) was added in small portions,
whereupon the mixture was stirred overnight. The turbid
mixture was partitioned between Et2O (150 mL) and 0.2 M citric
acid (50 mL); ether was washed with 0.2 M citric acid, 1 M
NaHCO3, and brine (3 × each) and dried (MgSO4). Evaporation
furnished white solid 1 (2-NsNBoc2, 3.87 g, 95%); essentially
pure (TLC (A)), mp 119.5-120.5 °C (white needles from Et2O/
1
hexane). H NMR: δ 1.48 (s, 18H), 7.63 and 7.68 (2 × dt, J 1
≈
7.5 Hz, J 2 ≈ 1 Hz, 1H + 1H), 7.93 and 8.00 (2 × perturbed d, J
≈ 8 Hz, 1H + 1H), 7.98 (d, J ) 8.7 Hz, 1H), 8.07 (dd, J 1 ) 8.7
Hz, J 2 ) 1.9 Hz, 1H), 8.65 (pert d, J ) 1.8 Hz, 1H). 13C NMR
(100.4 MHz): δ 27.55, 85.94, 123.07, 127.61, 127.96, 129.05,
129.41, 129.57, 130.80, 131.78, 135.41, 135.68, 147.66. FT IR ν
(cm-1): 1135, 1305, 1360, 1740, 1774, 2983. Anal. Calcd for
(14) (a) Sowinski, F. A.; Vogt, B. R. Ger. Offen. 2451566, 1975; Chem.
Abstr. 1975, 83, 97399m. (b) Heitsch, H.; Wagner, A.; Kleemann, H.
W.; Gerhards, H.; Schoelkens, B. Eur. Pat. Appl. EP 533058; Chem.
Abstr. 1993, 119, 117248d.
C
20H25NO6S: C, 58.95; H, 6.18; N, 3.44. Found: C, 59.2; H, 6.2;
N, 3.4.
ter t-Bu tyl 2-n aph th alen esu lfon ylcar bam ate (2). (a) Fr om
(15) Neustadt, B. R. Tetrahedron Lett. 1994, 35, 379.
(16) (a) For recent reviews on various aspects of polyamines, see:
Karigiannis, G.; Papaioannou, D. Eur. J . Org. Chem. 2000, 1841. (b)
Kuksa, V.; Buchan, R.; Kong Thoo Lin, P. Synthesis 2000, 1189. (c)
Guggisberg, A.; Hesse, M. In The Alkaloids. Chemistry and Biology;
Cordell, G. A., Ed.; Academic: New York, 1998; Vol. 50, Chapter 6, p
219 (polyamine alkaloids). (d) Schultz, S. Angew. Chem. 1997, 109,
324; Angew. Chem., Int. Ed. Engl. 1997, 36, 314 (polyamine toxins).
(17) Almeida, M. L. S.; Grehn, L.; Ragnarsson, U. J . Chem. Soc.,
Perkin Trans. 1 1988, 1905.
1. Compound 1 (845 mg, 2.05 mmol) in MeCN (10 mL) was
treated with 2-diethylaminoethylamine (302 mg, 2.60 mmol) and
left overnight. Most of the solvent was evaporated and the oily
residue redissolved in CH2Cl2 (50 mL) and then partitioned
between EtOAc (200 mL) and 0.2 M citric acid (60 mL); EtOAc
(19) Maia, H. L. S.; Monteiro, L. S.; Degerbeck, F.; Grehn, L.;
Ragnarsson, U. J . Chem. Soc., Perkin Trans. 2 1993, 495.
(20) Svahn, C. M.; Gyllander, J . J . Chromatogr. 1979, 170, 292.
(18) Stafford, J . A.; Brackeen, M. F.; Karanewsky, D. S.; Valvano,
N. L. Tetrahedron Lett. 1993, 34, 7873.
6558 J . Org. Chem., Vol. 67, No. 18, 2002

was washed with citric acid and brine as above and dried (Na2-
SO4). Evaporation furnished white solid 2, which after careful
trituration with light petroleum, was collected, rinsed, and dried;
yield 612 mg (97%), pure by TLC (C,E), mp 170-173 °C dec
with light petroleum, filtered, rinsed, and dried in vacuo; yield
356 mg (94%), pure by TLC (A), mp 85.5-86.5 °C (white fluffy
needles from Et2O at -20 °C). 1H NMR: δ 1.41 (s, 9H), 1.43-
1.55 (2 overlap m, 4H), 2.99 and 3.05 (2 pert t, 2H + 2H), 4.53
and 5.01 (2 br sign, 1H + 1H), 7.61 and 7.65 (2 pert dt, J 1 ≈ 7
Hz, J 2 ≈ 1.5 Hz, 1H + 1H), 7.84 (dd, J 1 ) 8.8 Hz, J 2 ) 1.8 Hz,
1H), 7.91 (pert dd, J 1 ≈ 8 Hz, J 2 ≈ 1 Hz, 1H), ∼7.96 (2 overlap
d, J ≈ 8 Hz, 1H + 1H), 8.44 (pert d, J ) 1.8 Hz, 1H). 13C NMR:
δ 26.73, 27.25, 28.38, 39.84, 42.91, 79.29, 122.31, 127.54, 127.90,
128.39, 128.75, 129.22, 129.50, 132.16, 134.79, 136.73, 156.08.
FT IR ν (cm-1): 1162, 1331, 1527, 1686, 3227, 3370. Anal. Calcd
for C19H26N2O4S: C, 60.29; H, 6.92; N, 7.40. Found: C, 60.4; H,
6.9; N, 7.4.
N1-Ben zyloxyca r b on yl-N3-ter t-b u t yloxyca r b on yl-N2-2-
n a p h t h a len esu lfon yl-sp er m id in e (5). P h a se Tr a n sfer -
In d u ced Alk yla tion of Su lfon a m id e F u n ction . A mixture
of compound 4 (757 mg, 2.00 mmol), chromatographed Z-NH-
(CH2)3-Br22 (653 mg, 2.40 mmol), and TBAHS (136 mg, 0.40
mmol) in benzene (10 mL) was treated with 50% NaOH (4 mL)
with rapid stirring.23 Traces of starting material remained after
4 h, but after 6 h, the reaction was completed (TLC (C)). After
the mixture was diluted with CH2Cl2, the solution was parti-
tioned between Et2O and 1 M KHSO4. The Et2O extract was
washed with 1 M KHSO4, 1 M NaHCO3, and brine (three times
each), dried (MgSO4), and evaporated; the sticky residue was
triturated with light petroleum, filtered, repeatedly rinsed, and
dried in vacuo; yield 1.13 g (98%), pure by TLC (C). A recrystal-
lized specimen, mp 104-105 °C, was identical to an authentic
sample (Supporting Information).
1
(microcrystalline solid; from CH2Cl2/Et2O). H NMR: δ 1.36 (s,
9H), 7.34 (br s, 1H), 7.63 and 7.68 (2 × pert t, J 1 ≈ 7.5 Hz, J 2
≈
1.5 Hz, 1H + 1H), 7.94 (pert dd, J 1 ) 8.0 Hz, J 2 ≈ 0.7 Hz, 1H),
7.95-8.01 (sign overlap, ∼2H), 8.00 (pert dd, J 1 ) 8.9 Hz, J 2
≈
0.6 Hz, 1H), 8.61 (pert d, J ≈ 1 Hz, 1H). 13C NMR: δ 27.84,
84.23, 122.72, 127.65, 127.94, 129.21, 129.30, 129.48, 130.26,
131.86, 135.28, 135.67, 149.10. FT IR ν (cm-1): 1128, 1142, 1343,
1745, 3234. Anal. Calcd for C15H17NO4S: C, 58.62; H, 5.57; N,
4.56. Found: C, 58.8; H, 5.7; N, 4.6. (b) F r om 2-Na p h th a le-
n esu lfon a m id e. Crude 2-Ns-NH2 (12.85 g, 62.0 mmol) was
suspended in CH2Cl2 (90 mL), and DMAP (756 mg, 6.2 mmol)
and NEt3 (6.89 g, 68.2 mmol) were added. The resulting mixture
was treated dropwise with Boc2O (14.89 g, 68.2 mmol) in CH2-
Cl2 (125 mL) with vigorous agitation (30 min). Evolution of CO2
became brisk within a few min and gave a clear tan solution
after 1 h. The next day, all starting material had been consumed
(TLC (C,E)). Partitioning was performed with EtOAc and 0.2 M
citric acid. The organic phase was washed with 0.2 M citric acid
and brine (three times each) and dried (Na2SO4); the solid
residue was carefully triturated with light petroleum, rinsed (five
times), and dried under high vacuum; yield 18.31 g (96%), pure
by TLC and suitable for further work. A recrystallized sample
was identical in all respects to the product above. From the light
petroleum used for trituration and rinsing of the crude product,
a side product was isolated (See Supporting Information).
N1,N2-Bis-ter t-b u t yloxyca r b on yl-N1-2-n a p h t h a len esu l-
fon yl-1,4-d ia m in obu ta n e (3). A solution of 2 (738 mg, 2.40
mmol) and Boc-NH-(CH2)4-OH21 (526 mg, ∼95%, 2.64 mmol) in
THF (7 mL) was cooled in ice. Solid TPP (756 mg, 2.88 mmol)
was added with thorough mixing followed by DEAD (0.511 mL,
∼3.12 mmol) at 0 °C over 20 min. After 1 h at 0 °C and 6 h at
rt, reaction was complete (TLC (A,B)) and the solvent was
stripped off. The oily residue was dissolved in CH2Cl2 (10 mL)
and chromatographed on silica with 40:1 CH2Cl2/Et2O as an
eluent; yield of crude and chromatographically pure product 1.12
g (97%), mp 130.5-131.5 °C (white microcrystalline solid from
Et2O at -20 °C). 1H NMR: δ 1.28 (s, 9H), 1.46 (s, 9H), 1.59 (pert
m, J ≈ 7.3 Hz, 2H), 1.85 (pert m, J ≈ 7.5 Hz, 2H), 3.21 (br q, J
≈ 6 Hz, 2H), 3.91 (t, J ) 7.5 Hz, 2H), 4.65 (br sign, 1H), 7.62
and 7.67 (2 pert dt, J 1 ≈ 7 Hz, J 2 ≈ 1.4 Hz, 1H + 1H), 7.80 (dd,
J 1 ) 8.7 Hz, J 2 ) 1.9 Hz, 1H), 7.92 (pert d, J ≈ 8 Hz, 1H), 7.95
(d, J ) 8.5 Hz, 1H), 7.97 (pert d, partly obscured, 1H), 8.50 (d,
J ) 1.8 Hz, 1H). 13C NMR: δ 27.19, 27.50, 27.81, 28.41, 40.05,
46.83, 79.09, 84.31, 122.31, 127.65, 127.93, 128.99, 129.08,
129.24, 129.71, 131.74, 134.95, 137.08, 150.88, 155.95. FT IR ν
(cm-1): 1130, 1143, 1157, 1170, 1348, 1682, 1729, 3355. Anal.
Calcd for C24H34N2O6S: C, 60.23; H, 7.16; N, 5.85. Found: C,
60.4; H, 7.2; N, 5.9.
N1-Ben zyloxyca r b on yl-N3-ter t-b u t yloxyca r b on yl-sp er -
m id in e (6). To a suspension of 5 (1.14 g, 2.00 mmol) in dry
MeOH (30 mL) was added Mg powder (0.15 g, 6.0 mmol) and
the resulting slurry sonicated for 30 min,11 when TLC (C,D)
confirmed that most of the starting material had been consumed.
The solvent was stripped off at reduced pressure; the residual
sludge was partitioned between CH2Cl2 (150 mL) and 1:1 2 M
NaOH/brine (300 mL) containing Na2-EDTA (∼3.0 g, ∼8 mmol)
and the aqueous layer further extracted with CH2Cl2 (2 × 75
mL). The combined extracts were washed with brine, dried (Na2-
SO4), and evaporated. The residual colorless viscous oil soon
solidified upon trituration with light petroleum; the powder was
collected by filtration, rinsed, and dried in vacuo, yield 723 mg
1
(95%), essentially pure by TLC (D). H NMR indicated that the
product consisted of very pure title compound. The recrystallized
product was identical to an authentic sample.17
Ack n ow led gm en t . Grants from TFR and Helge
Ax:son J ohnson’s stiftelse and a scholarship from O.E.
och E. J ohansson’s stiftelse (to L.G.) and from NFR and
Magn. Bergvall’s stiftelse (to U.R.) are gratefully ac-
knowledged.
N2-ter t-Bu tyloxyca r bon yl-N1-2-n a p h th a len esu lfon yl-1,4-
d ia m in obu ta n e (4). Recrystallized 3 (478 mg, 1.00 mmol) in
MeCN (4 mL) was heated to 60 °C under N2 and the solution
treated with Mg(ClO4)2 (90 mg, 0.40 mmol) in portions and left
under stirring. After 3 h, TLC (A,B) indicated that the reaction
was about halfway complete and, after 15 h, virtually complete.
The solvent was stripped off at reduced pressure, and the
semisolid residue was dissolved in CH2Cl2 and partitioned
between Et2O and 1 M KHSO4. The extract was washed in turn
with 1 M KHSO4, 1 M NaHCO3, and brine (three times each),
dried (MgSO4) and evaporated; the solid residue was triturated
Su p p or tin g In for m a tion Ava ila ble: Isolation of a side
product and synthetic procedures for reference substances 4
and 5 and the potassium salt of 2, as well as alternative
procedures for synthesis of 5. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O020205L
(22) Wei, W.-H.; Tomohiro, T.; Kodaka, M.; Okuno, H. J . Org. Chem.
2000, 65, 8979.
(23) Ma¨eorg, U.; Pehk, T.; Ragnarsson, U. Acta Chem. Scand. 1999,
53, 1127.
(21) Mattingly, P. G. Synthesis 1990, 366.
J . Org. Chem, Vol. 67, No. 18, 2002 6559