A New Synthesis of Lysergic Acid

James B. Hendrickson and Jian Wang

Org. Lett. 6, 3-5 (2004)

Abstract
()-Lysergic acid (1) has been synthesized via an economical 8-step route from
4-bromoindole and isocinchomeronic acid without the need to protect the
indole during the synthesis. Initial efforts to form the simpler 3-acylindole
derivatives first and then cyclize these were unsuccessful in the cyclization
step.
The ergot alkaloids pose an unusual opportunity for synthesis. The central
alkaloids are all amides of lysergic acid (1) and all possess a broad range of
pharmacological activity1-3. Only one of these, the diethylamide (LSD), however,
is strongly and notoriously psychoactive. As such it is listed as a class I
controlled substance. Since both the natural and synthetic derivatives are
easily convertible to lysergic acid and so to its diethylamide, all of these are
also controlled substances. As a result this potential pharmacological treasure
is essentially unavailable for practical clinical testing.
Figure 1

Bondset of lysergic acid synthesis.

We considered that a derivative of lysergic acid bearing an unremoveable
substituent, like an added C-alkyl group, could not be converted to lysergic acid
itself or its amide. Such derivatives would probably retain the broad
pharmacological activity of the ergot family but might easily avoid the unique
hallucinogenic property of LSD. This idea encouraged us to seek a short,

practical synthesis route to lysergic acid suitable for incorporation of C-alkyl

starting materials to create these derivatives.
Lysergic acid has already been synthesized about eight times 4. The shortest
path has 11 steps and none are serious candidates for practical manufacture.
Every synthesis to date contains redundant protection/deprotection sequences,
often as indole starting materials reduced and acylated, only at the end
reconstituted to the indole form. To eliminate this redundancy we decided that
the indole should be carried through intact.
Scheme 1

Attempt via Bondset ba Approachaa

Reagents: (i) EMgBr/ZnCl2/Et2O.

The simplest convergent bondset for assembling the lysergic skeleton should
be the boldface bonds in ring C, which just arise from indole and nicotinic acid
starting materials. No previous syntheses had utilized this approach except the
Julia route, which did not carry the indole moiety through unchanged.
Of the two initial constructions necessary for the bondset in Figure 1 we
began with the simplest (bond b) via an acylation of indole or 4haloindoles5 2 with the acid chloride 3 from the commercially available 6carboxynicotinic acid (isocinchomeronic acid), as outlined in Scheme 1. The
acid was esterified, selectively hydrolyzed only at the 6-position 6 with aqueous
Cu(NO3)2, and converted (SOCl2) to 3. The Grignard reagents from 2 were
acylated with 3 to form 4. However, a number of attempts at palladiumcatalyzed cyclizations of 4 (X = Br or I) or reduced pyridine derivatives of 4 and
their N-methyl salts were all unsuccessful.

We also considered that a thermal pericyclic cyclization of the

anion 5 of 4 might be accessible with subsequent loss of HX to form 6, but
several trials of this at elevated temperatures, with or without added base, led
only to intractable tars.
The alternative path to close ring C, making bond a first, was ultimately
successful, as summarized in Scheme 2. For this approach we needed a
nicotinic acid derivative with a halogen marking the 5-position.
Scheme 2

Synthesis of Lysergic Acid via Bondset ab Approachaa

Reagents: (i) Pd(PPh3)4/Na2CO3(aq)/EtOH; (ii) NaBH4,
CaCl2, EtOH; (iii) MnO2, CHCl3; (iv) NaOH, MeOH;
(v) NaBH4, TFA, CH2Cl2; (vi) MeI, CH2Cl2; (vii) NaBH4,
MeOH; (viii) NaOH, EtOH.
The common introduction of halogen on pyridines, via SOCl 2 on the N-oxide7,
provides only the ortho/para halides. However, sulfonyl halides can give rise to
meta substitution8 and the reaction of the N-oxide of 6-carboxynicotinic acid
with thionyl chloride affords9 the m-chloro derivative 7 on workup with
methanol. We believe this results from first forming the normal, nonplanar pchloro intermediate in Figure 2, which can then collapse via the pericyclic
rearrangement shown and subsequent loss of the p-chloride to afford 7.

Figure 2

Proposed mechanism for formation of 7.

When the 4-haloindoles 2 were converted to the boronic acid 8 (via KH + BuLi
and B(n-BuO)3), the Suzuki coupling was successful in forming 9a in 91% yield.
While this work was in progress, a closely related reaction appeared in a note
by Doll10 coupling 8 with 5-bromonicotinic ester, but the subsequent addition of
the missing carbon 4 for lysergic acid failed.
We presumed that an appropriate base would easily initiate the cyclization of
the diester 9a to the tetracyclic ketone corresponding to 10. However,
treatment of the diester with NaH, even in glycol at 197C, yielded only starting
material. A number of attempts to cyclize the corresponding, very insoluble
diacid with thionyl chloride or variants of PPA led only to recovery of diacid or
intractable mixtures with no evidence of cyclization.
Following a similar but intermolecular version from Potier 11 we reduced the
ester selectively12 with NaBH4 and CaCl2to 9b and then oxidized it to the
aldehyde 9c with MnO2. The aldehyde cyclized at room temperature easily and
quantitatively with only 2 mol% of NaOH to yield 10. Various efforts to cyclize
the alcohol 9b or its tosylate to 11 all recovered only starting materials. The
difference in the ease of cyclization of 9c over its precursors surprised us but
we became convinced from models that there was severe steric resistance to
the stereoelectronic demands for cyclization except for the aldehyde case.
Typical reduction13 of the indole-alcohol 10 with NaBH4/TFA afforded 11, which
proved to be unstable, decomposing in a matter of hours. Accordingly, the
remaining steps were carried through without isolation. Freshly
prepared 11 was methylated directly with methyl iodide and the crude
salt 12 reduced with excess NaBH4 in methanol to a mixture of methyl
lysergate and its cis-isomer isolysergate in a 6:1 ratio, as a pale yellow solid.
These diastereomers are reported to be somewhat unstable 14 and so were
immediately hydrolyzed to lysergic acid with NaOH, which also equilibrated
them to the more stable lysergic acid, which was then finally recrystallized to
mp 241-242C (lit. 242-243C).
The 1H NMR spectra of the mixed esters were identical with spectra kindly
provided by Prof. Ichiya Ninomiya, and the NMR spectra ( 1H and 13C) of the

lysergic acid agreed with that of a natural sample kindly provided by Dr. David
Nichols.
The last three operations (10 to 1) are carried out easily in good yield without
isolation and purification; this result lends value to the initial conception
in Figure 1 that the most economical synthesis of lysergic acid is one that
originates in the two main starting materials, a simple indole and a nicotinic
acid derivative, both retaining their aromaticity to the very end. This synthesis
comprises eight steps from isocinchomeronic acid and 4-bromoindole and
proceeds in an unoptimized overall yield of 10.6%. Chirality is only introduced
in the final reduction step, and enantioselective measures for this reduction
have not yet been examined, nor has the parallel synthesis of C-alkyl
derivatives.
Experimental
1

H and 13C NMR spectra were recorded on a Varian Unity Inova 400 MHz
instrument at ambient temperature using TMS as internal standard and
CDCl3 as solvent. Mass spectrometry was recorded on the Micromass QUATTRO
II instrument. The solvents and reagents were purified by the following
methods: diethyl ether, glyme and THF were distilled from sodium with
benzophenone as an indicator. DMF, CH 2Cl2and xylene were distilled from
calcium hydride. Benzene and toluene were distilled from P 2O5. Methanol and
ethanol were dried over magnesium. Triglyme was distilled from LiAlH 4.
Trimethylamine was distilled from NaOH. Anhydrous CaCl 2 has been roasted in
a crucible and allowed to cool in a desiccator.
1. 4-Bromo-indole (2a)
To a solution of 3-methoxycarbonylindole (7.0g, 40.0mmol) in TFA was added
Thallium(III) trifluoroacetate (32.6g, 60.0 mmol) in TFA (140 ml), and the
mixture was stirred for 2 hours at r.t. After TFA was evaporated in vacuo, a dark
brown oil was obtained. This oil was dissolved in DMF (100 ml) and
CuBr2(35.8g, 160.0 mmol) was added. The reaction was stirred at 120C for 1
hour then was cooled and CH2Cl2:MeOH (95:5, v/v) (300 ml) was added.
Insoluble precipitates were filtered off through a plug of celite. The filtrate was
washed with brine (100 ml x 2), and the organic layer was dried over Na 2SO4. A
crystalline material (7.60g) was obtained in 63% yield after the removal of
solvent under reduced pressure. This material was directly subjected to
decarboxylation for the preparation of 4-bromo-indole in the next step. To a
solution of 4-bromo-indole-3-carboxylic acid methyl ester (5.06g, 20.0 mmol) in
200 ml methanol was added 200 ml of 40% aq. NaOH. The reaction was
refluxed for 1.5 h with stirring. After evaporation of the solvent, the residue was
poured into 200 ml water, and extracted with CH 2Cl2:MeOH (95:5, v/v; 200 ml x
3). The extract was washed with brine, dried over Na 2SO4, and evaporated in
vacuo to leave a brown oil. Purification by chromatography using hexane:ethyl
acetate (6:1) afforded a light colored oil (2.68 g) in 69.1% yield.
2. 4-Iodo-indole (2b)

To a solution of 3-methoxycarbonylindole (7.0g, 40.0mmol) in TFA was added

Thallium(III) trifluoroacetate (32.6g, 60.0 mmol) in TFA (140 ml), and the
mixture was stirred for 2 hours at r.t. After TFA was evaporated in vacuo, a dark
brown oil was obtained. This oil was suspended in 450 ml H 2O, and KI (19.9 g,
120.0 mmol) was added to this suspension. The reaction was stirred at r. t. for
2 hours. CH2Cl2:MeOH (95:5, v/v) (300 ml) was added to the reaction mixture
and insoluble precipitates were filtered off through a plug of celite. The organic
layer was separated and washed with aq. sodium thiosulfate then brine.
Removal of the solvent left a brownish solid. Quick purification by a short plug
of silica gel afforded a white solid (8.68g) as 4-iodo-indole-3-carboxylic acid
methyl ester in 72.1% yield. This material was used directly in the next step. To
a solution of 4-iodo-indole-3-carboxylic acid methyl ester (6.02g, 20.0 mmol) in
200 ml methanol was added 200 ml of 40% aq. NaOH. The reaction was
refluxed for 1.5 h with stirring. After evaporation of the solvent, the residue was
poured into 200 ml water, and extracted with CH 2Cl2:MeOH (95:5, v/v; 200 ml x
3). The extract was washed with brine, dried over Na 2SO4, and evaporated in
vacuo to leave an off-white solid. Purification by chromatography using
hexane : ethyl acetate (6:1) afforded a white crystalline solid (3.51g) in 72.3%
yield.
3. Pyridine-2,5-dicarboxylic acid 5-methyl ester (3)
To a solution of pyridine-2,5-dicarboxylic acid dimethyl ester (5.91g, 30 mmol)
in 100 ml methanol was added copper(II)nitrate trihydrate (14.5g, 60 mmol) in
a 500 ml round bottom flask equipped with a reflux condenser and a stirring
bar. The reaction was refluxed for 80 mins. A deep violet-blue precipitation was
observed after 20 mins and lasted throughout the course of the reaction. The
reaction was cooled to r.t., and the reaction mixture was reduced to 1/3 of its
original volume. The deep violet-blue solid was collected by filtration and
washed with cold methanol then cold water. This solid material was dissolved in
50 ml glyme, and H2S gas was bubbled into the solution. The black precipitate
was formed in 2 mins, and the deep violet-blue solid disappeared after 15 mins.
The black precipitate was filtered out through a plug of celite and the filtrate
was concentrated to 20 ml. Excess hexanes were added into this solution, and
a white solid was formed. The white solid was collected by filtration.
Recrystallization of this solid from acetone afforded 4.83g product in 88.9%
yield (mp 194.1-195.1C, Lit6).
4. 6-(4-Iodo-indole-3-carbonyl)-nicotinic acid methyl ester (4b)
To a solution of EtMgBr (10 ml, 1.575 M in ether, 15.75 mmol) was added a
solution of 4-iodo-1H-indole (3.65g, 15.0 mmol) in ether (anhydrous, 20 ml).
The resulting twophase system was allowed to stand for 15 min under stirring
whereupon ZnCl2 (15 ml, 1.0m in ether, 15.0 mmol) was added with stirring.
The two-phase system was allowed to stand for 30 min when 6-chlorocarbonylnicotinic acid methyl ester (3.14g, 15.75 mmol) in anhydrous ether (10 ml) was
added rapidly under vigorous stirring. The reaction mixture was allowed to
stand for 2 hours whereupon NH4Cl (aq. sat. 25 ml) was added. The organic

layer was separated, and the aqueous layer was extracted with CH 2Cl2 (3x50
ml). The combined organic layer was washed with NaHCO 3 (aq. sat. 25 ml)
followed by brine (25 ml), and dried over Na 2SO4. Removal of the solvent in
vacuo afforded a yellowish solid. Recrystallization of this solid from acetone
afforded 4.25g of the desired crystalline product (mp. 245.7-246.8C) in 69.8%
yield.
5. 3-Chloro-pyridine-2,5-dicarboxylic acid dimethyl ester (7)
Pyridine-2,5-dicarboxylic acid (8.35g, 50.0 mmol) was suspended in 250ml
0.2% (w/w) aq. Na2WO4 (0.5g) in a 1 liter round bottom flask. To this solution
was added H2O2 in water (30% w/w, 8.5g, 75.0 mmol). The resulting mixture
was stirred and heated at 80- 85C for 10 hours. The resulting solid was
collected by filtration and washed with cold water. Drying the material under
vacuum overnight yielded 9.06 g product solid (mp. 253.2-254.1C, dec;
Lit.9 254C, dec.) as pyridine-2,5-dicarboxylic acid N-oxide in 99% yield. This
solid was used in the next step.
To a solution of thionyl chloride (9.52g, 5.84 ml, 80 mmol) in 200 ml CH 2Cl2 was
added DMF (2 ml) at 0C. Pyridine-2,5-dicarboxylic acid N-oxide (3.66g, 20.0
mmol) was added into this mixture portionwise. The resulting mixture was
heated at 65C for 2 hours. The reaction was cooled to r.t. then placed in an
ice-bath. The reaction was quenched with methanol (30 ml) slowly at 0C. The
solvent was removed in vacuo and the crude product was partitioned between
CH2Cl2 (100 ml) and aq. NaHCO3 (sat. 50 ml). The organic layer was separated
and the aqueous layer was extracted with additional CH 2Cl2 (100 ml x 2). The
combined organic layer was dried over Na2SO4 and the solvent was removed in
vacuo. Purification of the crude oil through a short plug of silica gel using
hexane : ethyl acetate (2:1) afforded a white solid (3.73g, mp. 126.0-127.0C)
in 81.2% yield.
6. Indole-4-boronic acid (8)
To a suspension of KH (4.57 g of a 30% suspension in mineral oil, 32.9 mmol)
was added a solution of 4-bromo-indole (5.88g, 30.0 mmol) in anhydrous ether
(25 ml). The reaction was stirred at r.t. for 30 min under N 2 and the reaction
was cooled in an acetone-dry ice bath (-78C) with stirring. Precooled t-BuLi
solution in hexane (33.0 ml, 66.0 mmol) was cannulated into the reaction and
the reaction was kept stirring for another 20 min. Neat B(n-BuO)3 (24.1 ml, 90.0
mmol) was added into the reaction by syringe under vigorous stirring. The
reaction mixture became thick when it was allowed to warm to r.t., and more
anhydrous ether (30 ml) was added under N 2. The reaction was allowed to
stand overnight at r.t. with vigorous stirring. The thick reaction mixture was
diluted with more anhydrous ether and then transferred slowly into 1 M
aqueous H3PO4 (300 ml) at 0C. The mixture was stirred at r.t. for 40 min, and
extracted with ether (100 ml x 30). The combined organic layer was extracted
with 1 N NaOH (50 ml x 3). Ether (100 ml) was added to this aqueous solution
and the mixture was acidified to pH = 2 using 1M H 3PO4. The organic layer was
separated and the aqueous layer was extracted with ether (100 ml x 2). The

combined ether layer was dried over Na 2SO4 and evaporation of solvent in
vacuo left a beige solid (4.24g, 88.0%).
7. 3-(4-indolyl)-pyridine-2,5-dicarboxylic acid diethyl ester (9a)
Into 500 ml anhydrous toluene in a 1 liter round bottom flask equipped with
stirring bar was bubbled in a stream of argon via a needle for 30 min.
Pd(PPh3)4 (0.878g, 0.75 mmol) and 3-chloro-pyridine-2,5-dicarboxylic acid
dimethyl ester (3.44g, 15.0 mmol) were added into this solvent and the
resulting mixture was stirred at r.t. under argon for 1 hour. A solution of indole4-boronic acid (1.86g, 11.5 mmol) in 50 ml EtOH and a solution of 2M aqueous
Na2CO3 (11.5 ml) was added into the reaction mixture at r.t. under argon. The
mixture was heated under argon with vigorous stirring at 105C for 8 hours.
The reaction mixture was cooled and brine (200 ml) was added. The organic
layer was separated and aqueous layer extracted with additional CH 2Cl2 (2x100
ml). The combined organic layer was dried over Na 2SO4 and evaporation of the
solvent left a yellowish solid. Purification of the crude material through a short
plug of silica gel (hexane:ethyl acetate, 1:2) afforded a yellow solid. The TLC of
this material showed it to be a mixture of three different compounds due to
ester exchange. This solid was dissolved in 500 ml EtOH and the solution was
stirred overnight at r.t. in the presence of catalytic HCl in diethyl ether. A single
compound (3.54g) was obtained (mp. 212.3-213.0C) in 91.0% yield.
8. 6-Hydroxymethyl-5-(4-indolyl)-nicotinic acid ethyl ester (9b)
To a solution of 3-(4-indolyl)-pyridine-2,5-dicarboxylic acid diethyl ester (0.34g,
1.0 mmol) in anhydrous EtOH (10 ml) was added Ba(BH 4)2 (24.6mg, 0.65 mmol)
followed by CaCl2 (44.3mg, 0.4 mmol) at 0C. The reaction was warmed to r.t.
and stirred for 2 hours. 1 M H2SO4 (1 ml) was added to the reaction, and the
resulting white precipitation (CaSO4) was filtered out through a plug of celite.
The filtrate was concentrated and partitioned between ethyl acetate (20 ml)
and NaHCO3 (aq. 15 ml). The organic layer was separated and the aqueous
layer was extracted with additional ethyl acetate (2x20 ml). The combined
organic layer was dried over Na2SO4, and the solvent was removed. The crude
material was purified by silica gel chromatography using hexane-ethyl acetate
(3:1 to 1:1). A colorless solid (mp. 198.1-199.0C) was obtained (231 mg) in
78% yield.
Alternatively, the product could also be made using Ca(BH 4)2 as the reducing
reagent in the same solvent and temperature for same period of time. The
NMR, mass spectrum, elemental analysis and mp. of this product were identical
to that of the product obtained by the previous method. The yield of this
reaction was 85%.
9. 6-formyl-5-(4-indolyl)-nicotinic acid ethyl ester (9c)
To a solution of 6-hydroxymethyl-5-(4-indolyl)-nicotinic acid ethyl ester (296
mg, 1.0 mmol) in 5 ml CH2Cl2was added freshly made MnO2 (870 mg, 10.0
mmol). The reaction was stirred at r.t. for 2 hours then filtered from the solution
through a plug of celite, and the solvent was removed in vacuo. Purification of

the crude material by silica gel chromatography using hexane-ethyl acetate

(2:1) afforded a yellow solid (271mg, 92%) with mp. 198.4-199.2C.
10. 6-Hydroxy-4,6-dihydro-indolo[4,3-fg]quinoline-9-carboxylic acid
methyl ester (10)
To a solution of 6-formyl-5-(4-indolyl)-nicotinic acid ethyl ester (117.8 mg, 0.4
mmol) in anhydrous methanol (1.0 ml) in a 2 ml conical vial was added 0.5 M
NaOMe/MeOH ( 16.0 l, 0.008 mmol). The reaction was stirred at r.t. for 2
hours. Solid precipitated out of the solution during the course of the reaction,
and the starting material disappeared completely after 2 hours as indicated by
TLC. The solution was cooled to 0C and the liquid was removed with a pipette.
The remaining solid was recrystallized from MeOH to afford 102.0 mg yellow
crystalline solid (mp. 234.6-235.8C) in 91% yield.
11. 4,6-Dihydro-indolo[4,3-fg]quinoline-9-carboxylic acid methyl ester
(11)
To a solution of 6-hydroxy-4,6-dihydro-indolo[4,3-fg]quinoline-9-carboxylic
methyl ester (90 mg, 0.32mmol) in 10 ml anhydrous THF was added BH 3 in THF
(1.0 M, 0.64 ml, 0.64mol) under argon. The resulting mixture was stirred at r.t.
for 2 hours. The TLC showed the disappearance of the starting material and a
new fluorescent spot under UV on TLC. The solvent was removed in vacuo and
the crude material was partitioned between CH 2Cl2 (3 ml) and aq. NaHCO3 (sat.,
2 ml). The organic layer was separated and the aqueous was extracted with
additional CH2Cl2 (2x3 ml). The combined organic layers were dried over
Na2SO4 and concentrated. The crude material was purified by silica gel PTLC
using CH2Cl2:MeOH (98:2). A white solid was obtained (mp. 212.9-213.9C, 35.2
mg) in 41% yield.
12. ()-Lysergic acid (1)
To a solution of 4,6-dihydro-indolo[4,3-fg]quinoline-9-carboxylic acid methyl
ester (29.2 mg, 0.116 mmol) in CH2Cl2 (1ml) was added MeI (33.0 mg, 14.6 l,
0.24 mmol) at 0C. The reaction was stirred at 0C for 2 hours and the starting
material disappeared after 2 hours as indicated by TLC. The solvent was
removed in vacuo and the crude product was dissolved in methanol (1 ml). To
that mixture was added NaBH4 (15.2 mg, 0.4 mmol) and the reaction was
stirred at r.t. for 5 min. The organic solvent was removed in vacuo and the
remaining solution was partitioned between CH 2Cl2 (2 ml) and water (2 ml). The
organic layer was separated and the aqueous layer was extracted with
additional CH2Cl2 (3 ml x 2). The organic layers were combined and dried over
Na2SO4. The solvent was removed and the crude material was purified by PTLC
(CH2Cl2:MeOH, 98:2). A white solid was obtained (21.4 mg, 65%). 1H NMR
showed it to be a mixture of methyl lysergate and methyl isolysergate in 6:1
ratio using N-methyl as the integration indicator.
To a solution of methyl lysergate & methyl isolysergate (6:1 mixture above,
15.6 mg, 0.028 mmol) in ethanol (0.5 ml) was added 1 N NaOH (0.5 ml). The
reaction was heated at 35C for two hours. 0.1 N HCl solution was used to

carefully adjust the pH to 6 and the solid material was collected by removing
the liquid. The solid was recrystallized from ethanol to afford 12.2 mg, (95%) of
lysergic acid.

References
1. Hofmann, A. Ergot Alkaloids, Pharmacology; Spano, P. F., Trabucchi,
M., Eds.; Karger: Basel, Switzerland, 1978; Vol. 16, Supp. 1, p 1.
2. Lemberger, L. Fed. Proc. 1978, 37, 2176.
3. Berde, D.; Schild, O. Handbook of Experimental Pharmacology;
Springer Verlag: Berlin, Germany, 1978; Vol. 49, p 1.
4.
a. Kornfeld, E. A.; Fornefeld, E. J.; Kline, G. B.; Mann, M. J.; Morrison,
D. E.; Jones, R. G.; Woodward, R. B. J. Am. Chem. Soc. 78, 3087
(1956)
b. Julia, M.; LeGoffic, F.; Igolen, J.; Baillarge, M. Tetrahedron Lett.
20, 1569 (1969)
c. Armstrong, V. W.; Coulton, S.; Ramage, R. Tetrahedron Lett. 47,
4311 (1976)
Ramage, R.; Armstrong, V. W.; Coulton, S. Tetrahedron 9
(Suppl.), 157 (1981)
d. Oppolzer, W.; Francotte, E.; Baettig, K. Helv. Chim. Acta 64(2),
478 (1981)
e. Rebek, J., Jr.; Tai, D. F. Tetrahedron Lett. 24(9), 859 (1983)
Rebek, J., Jr.; Tai, D. F.; Shue,Y. K. J. Am. Chem. Soc. 106, 1813
(1984)
f. Kurihara, T; Terada, T.; Yoneda, R. Chem. Pharm. Bull. 34, 442
(1986).
Kurihara, T.; Terada, T.; Harusawa, S.; Yoneda, R. Chem. Pharm.
Bull. 35, 4793 (1987)
g. Kiguchi, T.; Hashimoto, C.; Naito, T.; Ninomyia, I. Heterocycles
19(12), 2279 (1982)
Ninomyia, I.; Hashimoto, C.; Kiguchi, T; Naito, T. J. Chem. Soc.,
Perkin Trans. 1, 941 (1985)
h. Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett.
29(25), 3117 (1988)
5. Somei, M.; Kizu, K. Chem. Pharm. Bull. 33, 3696 (1985)
6. Ooi, G. K. S.; Magee, R. J. J. Inorg. Nucl. Chem. 32, 3315 (1970)

7. Joule, J. A.; Miller, K. Heterocyclic Chemistry, 4th ed.; Blackwell

Science: Oxford, UK, 2000; p 100
8. AR Katritzky; JM Lagowski, The Chemistry of the Pyridine N-Oxides;
Academic Press: N.Y., 1971; p 288.
9. Quarroz, D. Swiss Patent CH 657,124, 1986; Chem. Abstr. 106,
32852 (1987)
10.

Doll, M. K.-H. J. Org. Chem. 64, 1372 (1999)

11.

Potier, P.; Langlois, Y. Tetrahedron 31, 419 (1975)

12.
Matsumoto, I.; Yoshizawa, J. Japanese Patent JP
48029783 (1973)
13.
Gribble, G. W.; Nutaitis, C. F. Org. Prep. Proced. Int. 17, 317
(1985)
14.
a. Glenn, A. L. Quart. Rev. 8, 192 (1954)
b. Stoll, A.; Petrzilka, T. Helv. Chim. Acta 36, 1125 (1953)