Hetero Diels-Alder synthesis of 3-hydroxypyridines: Access to the nosiheptide core

Article abstract of DOI:10.1021/jo0703505

The 1-azadiene hetero Diels-Alder reaction of silylated enol oximes with alkynes was investigated and was optimized to furnish 2,5,6-trisubstituted 3-hydroxypyridines in high yields in one simple operation. Importantly, monosubstituted alkynyl ketones were found to lead to the formation of the 6-isomer with exceptional regioselectivity (>95:5). This methodology was applied to a scaleable synthesis of the core structure of the potent antibiotic nosiheptide. Protecting groups were optimized, which led to a racemization-free seven-step synthesis of the key building block.

Full text of DOI:10.1021/jo0703505

Hetero Diels-Alder Synthesis of 3-Hydroxypyridines: Access to the
Nosiheptide Core
Jin-Yong Lu† and Hans-Dieter Arndt*,†,‡
MPI fu¨r molekulare Physiologie, Otto-Hahn-Strasse 11, D-44227 Dortmund, Germany, and UniVersita¨t
Dortmund, Fachbereich Chemie, Otto-Hahn-Strasse 6, D-44221 Dortmund, Germany
hans-dieter.arndt@mpi-dortmund.mpg.de
ReceiVed February 20, 2007
The 1-azadiene hetero Diels-Alder reaction of silylated enol oximes with alkynes was investigated and
was optimized to furnish 2,5,6-trisubstituted 3-hydroxypyridines in high yields in one simple operation.
Importantly, monosubstituted alkynyl ketones were found to lead to the formation of the 6-isomer with
exceptional regioselectivity (>95:5). This methodology was applied to a scaleable synthesis of the core
structure of the potent antibiotic nosiheptide. Protecting groups were optimized, which led to a
racemization-free seven-step synthesis of the key building block.
Introduction
3-Hydroxypyridines1 are important scaffolds in very diverse
bioactive substances (Figure 1). Pyridoxin (1, vitamin B6) is a
vital cofactor for the enzymes of amino acid metabolism.2 Both
the natural 3-hydroxypyridines, such as caerulomycin B3 (2),
as well the as non-natural congeners, such as persynthamide4
(3), are endowed with distinctive modes of action. Remarkably,
a 3-hydroxypyridine core is characteristic for the thiopeptide
antibiotics nosiheptide5 (4) and nocathiacin,6 which are arguably
the most potent within the thiopeptide antibiotic class.7 In terms
of their molecular properties, 3-hydroxypyridines cannot form
an energetically favored keto tautomer, like the closely related
2- and 4-hydroxypyridines can, which leads to a much more
phenolic character of the parent heterocycle. On the other hand,
† MPI fu¨r molekulare Physiologie.
‡ Universita¨t Dortmund.
(1) Schmidt, A. Curr. Org. Chem. 2004, 8, 653.
(2) Eliot, A. C.; Kirsch, J. F. Annu. ReV. Biochem. 2004, 73, 383.
(3) McInnes, A. G.; Smith, D. G.; Wright, J. L. C.; Vining, L. C. Can.
J. Chem. 1977, 55, 4159.
FIGURE 1. Bioactive 3-Hydroxypyridines
(4) Stern, H. M.; Murphy, R. D.; Shepard, J. L.; Amatruda, J. F.; Straub,
C. T.; Pfaff, K. L.; Weber, G.; Tallarico J. A.; King, R. W.; Zon, L. I. Nat.
Chem. Biol. 2005, 1, 366.
(5) Pascard, C.; Ducruix, A.; Lunel, J.; Prange´, T. J. Am. Chem. Soc.
1977, 99, 6418.
(6) Constantine, K. L.; Mueller, L.; Huang, S.; Abid, S.; Lam, K. S.; Li,
W.; Leet, J. E. J. Am. Chem. Soc. 2002, 124, 7284.
(7) Bagley, M. C.; Dale, J. W.; Merritt, E. A.; Xiong, X. Chem. ReV.
2005, 105, 685.
3-hydroxypyridines easily adopt a zwitterionic (“betainic”) state
by an O f N proton transfer from the phenolic hydroxyl
function,1 which confers a considerably polar character.
A deeper exploration and utilization of this interesting
heteroaromatic scaffold have been hampered by the lack of
flexible synthetic access. Common approaches often necessitate
10.1021/jo0703505 CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/21/2007
J. Org. Chem. 2007, 72, 4205-4212
4205

Lu and Arndt
TABLE 1. 3-Hydroxypyridines 9a-ca by HDA Fusion of
SCHEME 1. Mechanistic Rationale for the Direct
Formation of 3-Hydroxypyridines by HDA Cycloaddition
1-Azadienes 6 with Limiting Dimethyl Acetylenedicarboxylate (5a)
entry diene (eq)
conditions
toluene (0.3 M), 80 °C, 12 h 33% (9a) COOMe
THF (0.6 M), reflux, 20 h 48% (9a) COOMe
CH3CN (0.6 M), 80 °C, 20 h 48% (9a) COOMe
xylenes (0.4 M), 140°C, 3 h 85% (9a) COOMe
yield
R3
1
2
3
4
5
6
7
8
6a (1.2)
6a (1.2)
6a (1.2)
6a (1.2)
6a (3.0)
6b (3.0)
6c (3.0)
6d (1.0)
neat, 150 °C, 1 h
neat, 150 °C, 3 h
neat, 150 °C, 4 h
99% (9a) COOMe
58% (9b)
64% (9a) COOMe
H
xylenes (0.4 M), 150 °C, 5 h 57% (9c) Thiazolyl
the use of harsh aromatic (re)functionalization reactions of
simpler pyridines or of a step-by-step elaboration from
3-hydroxypyridine(s) itself.8 Within a program that is directed
toward a total synthesis of nosiheptide, we give here an account
on a general, flexible method to generate 3-hydroxypyridines
with diverse substitution patterns.9,10c
To address a de novo generation of the 3-hydroxypyridine
scaffold, a Diels-Alder (DA) type reaction was envisioned,
which is typically the most modular and flexible means for
furnishing a six-membered ring.11 Conceptually, a 3-hydroxy-
pyridine (9) could arise from an alkyne (5) and a 1-aza diene
(6) via a [4 + 2] hetero Diels-Alder (HDA) cycloaddition in
one operation, if a suitable leaving group X is present on the
N1-nitrogen atom to promote aromatization of the expected
intermediate dihydropyridine (7) (Scheme 1). A 1,4-elimination
would then deliver the pyridine (8), which would give the free
3-hydroxypyridine (9) upon deprotection (Scheme 1).
a R1 ) R2 ) COOMe.
atom.14 The latter lead into the inverse-electron demand regime
and react preferentially with electron-rich alkenes, whereas the
former have been applied frequently with electron-poor dieno-
philes, mostly in the form of N,N-dialkylhydrazones, which have
been pioneered by Ghosez et al.13
Consequently, we started to explore hydrazones (6, X )
NR′R′′) initially, but for alkynes, their transformations were
hampered by the formation of product mixtures and by
incomplete elimination of HX from the putative dihydropyridine
intermediate (7).15 We then turned our attention to silylated
oximes (6, X ) OSiR3), which are more easily accessible and
should allow the facile deprotection of the hydroxypyridine
products (8). Literature precedence was limited,10a,b but a few
six-π-transformations of unsaturated oximes had been docu-
mented before in intramolecular cases.16 The silylated oximes
were easily available from â-ketoesters or ketones by R-nitro-
sation and bis-silylation of the resulting oximes, which delivered
the distillable azadienes 6a (R ) TMS, R3 ) COOMe, Table
1) and 6b (R ) TMS, R3 ) H) or the chromatography-stable
azadienes 6c (R ) TES, R3 ) COOMe) and 6d (R ) TES, R3
) 4′-carboxyethyl-1′-thiazolyl), rather straightforwardly.17
Initially, dimethyl acetylenedicarboxylate (DMAD, 5a, R1 )
R2 ) COOMe) was found to react smoothly with the silylated
oxime enol ether 6a under neutral conditions. The cycloaddition
was only moderately solvent dependent (Table 1, entries 1-4),
but high temperatures and high concentrations were found to
be beneficial. Neat conditions (in a sealed tube) proved to be
optimal and gave the best results (entry 6). To reach full
conversion of the alkyne, an excess of trimethylsilyl (TMS)-
derivatized dienes 6a and 6b (Table 1) had to be applied to
account for their somewhat unstable nature (vide infra). A brief
screening of σ- or π-Lewis acids as potential promoters (LiNTf2,
MgI2, Me2AlCl, PdCl2, and PEt3AuCl)18 was not met with
success. Nevertheless, both the unsubstituted azadiene 6b as
well as the more complex, thiazole-bearing diene 6d transformed
HDA reactions that follow this general pattern have been
studied in some detail, mostly for reactive dienophiles.12
1-Azadienes are known to be intrinsically unreactive due to
unfavorable orbital coefficients and are prone to tautomerization,
but they can be activated and/or stabilized either with electron-
donating13 or electron-withdrawing substituents on the N1-
(8) Some examples: (a) Harris, S. A.; Folkers, K. J. Am. Chem. Soc.
1939, 61, 1245. (b) Umemura, K.; Noda, H.; Yoshimura, J.; Konn, A.;
Yonezawa, Y.; Shin, C.-g. Tetrahedron Lett. 1997, 38, 3539. (c) Mongin,
F.; Tre´court, F.; Gervais, B.; Mongin, O.; Que´guiner, G. J. Org. Chem.
2002, 67, 3272.
(9) This work was presented in part at the Glaxo/Dortmund symposium
on Chemical Biology, Stevenage, UK 2005.
(10) (a) Igarashi, J.-e.; Kawakami, Y.; Kinoshita, T.; Furukawa, S. Chem.
Pharm. Bull. 1990, 38, 1832. (b) Behforouz, M.; Gu, Z.; Stelzer, L. S.;
Ahmadian, M.; Haddad, J.; Scherschel, J. A. Tetrahedron Lett. 1997, 38,
2211. (c) Concurrent with this work, some related efforts have been
reported: Fletcher, M. D.; Hurst, T. E.; Miles, T. J.; Moody, C. J.
Tetrahedron 2006, 62, 5454.
(11) Selected overviews: (a) Oppolzer, W. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I. Eds.; Permagon Press: Oxford, 1991;
Vol 5, pp 315-401. (b) Tietze, L. F.; Kettschau, G. Top. Curr. Chem. 1997,
189, 1. (c) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogian-
nakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668.
(12) Reviews: (a) Behfourouz, M.; Ahmadian, M. Tetrahedron 2000,
56, 5259. (b) Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P. Tetrahedron
2002, 58, 379.
(14) (a) Boger, D. L.; Kasper, A. M. J. Am. Chem. Soc. 1989, 111, 1517.
(b) Boger, D. L.; Corbett, W. L.; Curran, T. T.; Kasper, A. M. J. Am. Chem.
Soc. 1991, 113, 1713. (c) For an organocatalytic variant see He, M.; Struble,
J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418.
(15) Tautomer formation. Data not shown.
(16) (a) Bu¨chi, G.; Galindo, J. J. Org. Chem. 1991, 56, 2605. (b) Franc¸ois,
D.; Maden, A.; Murray, W. V. Org. Lett. 2004, 6, 1931.
(17) See supporting information for details.
(13) (a) Serck-Poncin, B.; Hesbain-Frisque, A. M.; Ghosez, L. Tetra-
hedron Lett. 1982, 23, 3261. (b) Tamura, Y.; Tsugoshi, T.; Nakajima, Y.;
Kita, Y. Synthesis 1984, 930. (c) Ghosez, L.; Serck-Poncin, B.; Rivera.
M.; Bayard, P.; Sainte, F.; Demoulin, A.; Hesbain-Frisque, A. M.; Mockel,
A.; Munoz, L.; Bernard-Henriet, C. Lect. Heterocycl. Chem. 1985, 8, 69.
(d) Potts, K. T.; Walsh, E. B.; Bhattarcharjee, D. J. Org. Chem. 1987, 52,
2285. (e) Pautet, F.; Nebois, P.; Bouaziz, Z.; Fillion, H. Heterocycles 2001,
54, 1095.
(18) Reviews: (a) Pindur, U.; Lutz, G.; Otto, C. Chem. ReV. 1993, 93,
741. (b) Kumar, A. Chem. ReV. 2001, 101, 1.
4206 J. Org. Chem., Vol. 72, No. 11, 2007

Hetero Diels-Alder Synthesis of 3-Hydroxypyridines
TABLE 2. 3-Hydroxypyridines from Unsymmetrical Alkynes
SCHEME 2. Mechanistic Pathways for Homodimer
Formation from Diene 6aa
entry
R1, R2
timea
total yield
ratio 9:10
d
e
f
g
h
i
k
l
m
n
o
p
q
Ph, COOMe
Ph, C(O)Me
Thz, C(O)Me
Thz, C(O)Me
Br, Ph
Ph, Cl
H, Ph
H, C(O)Me
H, C(O)Me
H, C(O)Ph
Ph, Ph
12 h
12 h
12 h
4 hb
4 h
93%
42%
62%
81%
48%
49%
90%
38%
54%
75%
0%
70:23
1:1
6:5
2:1
2:1
2 h
2:1
12 h
18 hc
12 h
12 h
12 h
12 h
12 h
66:24
>95:5d
>95:5d
98:2
TMS, H
C9H19, H
0%
0%
a At 150 °C neat, with 3 equiv of 6a. b At 180 °C in xylenes. c At 100
°C neat. d The minor isomer was not isolated. Thz ) 4-carboxymethylthi-
azolyl (17).
well. Increasing the size of the silyl group (TMS f triethylsilyl
(TES)) was found to lead to lower reactivity, but the azadienes
thus obtained were more stable and easier to handle. Interest-
ingly, when applying TMS- or TES-derivatized 1-azadienes (6)
to the cycloaddition reaction, no 3-O-silyl groups were retained
in the isolated products (9). This fact reflects the properties of
the pronounced leaving group of the betainic 3-hydroxypyridine
heterocycle.1 A close inspection of the crude reaction mixtures
by NMR and GC/MS revealed that a considerable portion of
the presumed initial product (8) suffered a loss of the SiR3-
group under the conditions of the cycloaddition, likely by the
attack of nucleophilic components of the reaction mixture
(eliminated silanol HX, decomposed 1-azadiene) or by the attack
of adventitious water. The remaining TMS/TES groups are lost
during workup,19 which saves a deprotection step.10c
a R ) TMS.
infra). We were not able to identify any intermediates or side
products apart from the apparent decomposition of diene 6a by
two consecutive desilylations (GC-MS) and the small amounts
(generally <5%) of the homodimer 11 of the diene 6a (Scheme
2).
Under forcing conditions, the homodimer 11 was reproducibly
formed (Scheme 2) always as a single 6-substituted regioisomer,
as was confirmed by extensive 2D-NMR analysis (COSY,
HSQC, and HMBC). The regiochemistry and high selectivity
is surprising, as presumably the 5-substituted isomer 12 could
be formed via a typical DA reaction (Scheme 2, bottom).
However, with 2-azadiene homodimers, similar end-to-end
fusion DA products have been reported.21 Interestingly, the TES-
activated diene 6c was found to be completely stable and
unreactive to itself under prolonged heat treatment up to 270
°C, which indicated that the bis-silylated 1-azadienes 6 are
unlikely to homodimerize under thermal conditions. Given the
fact that the TMS-activated diene 6a is slowly losing TMS
groups upon thermal stress (as monitored by TLC and GC-MS),
the clean formation of dimer 11 likely involves a desilylated
oxime (13 or 14), which could directly react further with 6a.
Another possibility would be an intramolecular â-elimination
of the enol ether 14 to a terminal alkyne 15, which might occur
under these forced conditions.22 Alkyne 15 would quickly be
captured by the excess of azadiene 6a present in the mixture to
form the apparent homodimer 11 with the same high regiose-
DMAD is one of the most reactive alkynes. Therefore, we
then turned our attention to more diverse and synthetically more
useful alkyne dienophiles (5, Table 2). It was pleasing to find
out that any alkyne bearing an electron-withdrawing group
would participate in good to excellent yields (entries d-n). The
reaction was limited only by volatility (entries l and m).
Monosubstituted aromatic alkynes were also found to react
smoothly (entry k), but diphenylacetylene and electron-rich
alkynes were inert under these conditions (entries o-q).
In all of the cases examined, the 3-hydroxypridine isomer
(9) with the more electronegative substituent in the 6-position
was favored (Table 2).20 The 5-isomers (10) were formed in
minor amounts for the disubstituted alkynes, but they were easily
separable by column chromatography in all cases. Higher
temperatures and elevated pressure slightly enhanced the
regioselectivity (compare entries f and g). To our delight, the
transformation was found to be completely regioselective with
two monosubstituted alkynyl ketones (entries l-n, also vide
(21) (a) Wulff, G.; Bo¨hnke, H. Angew. Chem., Int. Ed. Engl. 1986, 25,
90. (b) Nicolaou, K. C.; Nevalainen, M.; Safina, B. S.; Zak, M.; Bulat, S.
Angew. Chem., Int. Ed. 2002, 41, 1941. (c) Moody, C. J.; Hughes, R. A.;
Thompson, S. P.; Alcaraz, L. Chem. Commun. 2002, 1760.
(22) We have not succeeded in securing proof for the intermediacy of
alkyne 15, but â-eliminations of enol ethers have considerable precedence;
see for example (a) Hargrove, R. J.; Stang, P. J. J. Org. Chem. 1974, 39,
581. (b) Kuwajima, I.; Takeda, R. Tetrahedron Lett. 1981, 22, 2381. (c)
Seyferth, D.; Langer, P.; Do¨ring, M. Organometallics 1995, 14, 4457. (d)
Langer, P.; Do¨ring, M.; Seyferth, D.; Go¨rls, H. Chem.sEur. J. 2001, 7,
573.
(19) In our hands, both 3-O-TMS- and TES-protected 3-hydroxypyridines
were unstable to standard aqueous workup conditions as well as standard
SiO2-based purification (TLC and flash column chromatography).
(20) All regioisomers have been unequivocally assigned by means of
2-D NMR data (DQF-COSY, HSQC, HMBC).
J. Org. Chem, Vol. 72, No. 11, 2007 4207

Lu and Arndt
SCHEME 3. Synthesis of the Nosiheptide Core Structures
23 and 25a
with IBX to deliver the acetylenic ketone 17 in 90% yield
(Scheme 3). The 1-azadiene-HDA pyridine forming reaction was
most efficiently carried out, in this case, in an overheated toluene
solution (180 °C) to provide ketone 18 (55%) along with its
regioisomer 18a (28%), which was readily separated, also on a
multigram scale.
A regioselective thiazole annulation to 3-hydroxypyridine 18
was addressed next via a Hantzsch condensation. To realize a
selective R-bromination of the methyl ketone 18, it was found
to be necessary to deactivate the phenolic hydroxyl as a triflate
and to activate the ketone as a silylenol ether at the same time
(Scheme 3). With a phenolic TIPS protecting group present,
the partial bromination of the hydroxypyridine core was difficult
to suppress. The resulting silylenol ether 19 (79%) could be
cleanly and regioselectively transformed into the bromide 20
(97%), which set the stage for a mild Hantzsch reaction.26
Toward this end, the essential thioamide 22 was obtained from
the suitably protected cysteine derivative 21 in two standard
transformations (74%). After careful experimentation it was
found that the somewhat sensitive bromide 20 had to be
immediately reacted with thioamide 22. Dehydration with TFAA
then proceeded cleanly, and the differentiated nosiheptide core
23 could be obtained in a 69% yield (2 steps). However, after
scrutinizing the enantiomeric purity of the product 23 from
several runs, it became evident that, in the case of the cysteine
derivative 22, varying degrees of optical purity resulted,
especially upon attempted scale up activities. Enantiomeric
excess values were determined by trityl-group cleavage and
derivatization with (R)- and (S)-phenylethyl isocyanate, and they
revealed an enantiomeric excess (ee) of 60-85%.17 A solution
was found with the ketal-protected thioamide building block
24.27 Reaction of 24 with the bromide 22 resulted in the thiazole
25 in excellent yield (60%) over the sequence, and thiazole 25
was found to be of sufficient optical purity after derivatization
(>96% ee).17 Furthermore, conducting the reaction on a larger
scale (10 mmol) did not compromise the outcome. The
beneficial robustness of the cysteine building block 24 can be
tentatively explained by the 5-exo character of the developing
C2-enol(ate)28 as well as A1,3-strain arguments,29 which syner-
gistically disfavor a planarized intermediate and help to suppress
racemization.
a (a) 3-butyn-2-ol, 1% PdCl2, 2% CuI, 2% PPh3, NEt3, DMF, 80 °C; (b)
IBX, THF/DMSO, 0 f 20 °C; (c) 6a (3 eq.), toluene, 180 °C; (d) Tf2O,
NEt3, CH2Cl2, 0 °C; (e) TIPSOTf, NEt3, CH2Cl2, 0 °C; (f) NBS, THF/
H2O; (g) HOSu, DCC, 0 °C, then NH4OH; (h) Lawesson’s reagent, CH2Cl2,
r.t.; (i) 22, KHCO3, THF, -40 °C; (k) TFAA, 2,6-lutidine, -20 °C; (l) 24,
KHCO3, THF, -40 °C.
To explore a more convergent synthetic strategy, 1-azadiene
6d was also combined with alkyne 17, which furnished the
functionalized bis-thiazolo-hydroxypyridine 26 (Scheme 4).
However, under a variety of conditions, only minor amounts
of the sought cycloaddition product 26 could be isolated, along
with a larger number of intractable side products that where
extremely difficult to remove. Therefore this route was not
investigated further.
lectivity observed for the alkynyl ketones. Further experimenta-
tion will be necessary to clarify this issue.
All of the data for the alkyne dienophiles above are in line
with the notion that a normal-electron demand HDA reaction
pathway is operative for these azadiene-alkyne HDA reactions.
The regioselectivity would result in each case from a matching
HOMO/LUMO pairing of the polarized dienes and dieno-
philes,23 with the diene being a 1-aza analogue of Danishefsky’s
diene.23b However, other mechanistic pathways such as a
stepwise-polar transformation cannot be unequivocally ruled out
at this stage,24 especially not in case of the side product 11.
In going further toward a synthesis of nosiheptide (4), it was
necessary to integrate a thiazole into the alkyne substrate. Along
this line bromothiazole 1625 was coupled to 3-butyn-2-ol under
modified Sonogashira conditions and was subsequently oxidized
(26) Aguilar, E.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 2473.
(27) Okumura, K.; Nakamura, Y.; Shin, C.-G. Bull. Chem. Soc. Jpn. 1999,
72, 1561.
(28) When compared with other R-amino acids, pseudo-prolines (ketal-
protected serine, threonine and cysteine derivatives) have, such as proline
itself, a much lower tendency to racemize at the R-carbon; for example see
Wo¨hr, T.; Wahl, T.; Nefzi, A.; Rohwedder, B.; Sato, T.; Sun, X. C.; Mutter,
M. J. Am. Chem. Soc. 1996, 118, 9218.
(29) (a) Johnson, F. Chem. ReV. 1968, 68, 375. (b) Seebach, D.;
Lamatsch, B.; Amstutz, R.; Beck, A. K.; Dobler, M.; Egli, M.; Fitzi, R.;
Gautschi, M.; Herrado´n, B.; Hidber, P. C.; Irwin, J. J.; Locher, R.; Maestro,
M.; Maetzke, T.; Mourin˜o, A.; Pfammatter, E.; Plattner, D. A.; Schickli,
C.; Schweizer, W. B.; Seiler, P.; Stucky, G.; Petter, W.; Escalante, J.; Juaristi,
E.; Quintana, D.; Miravitlles, C.; Molins, E. HelV. Chim. Acta 1992, 75,
913.
(23) (a) Houk, K. N. Acc. Chem. Res. 1975, 8, 361. (b) Danishefsky, S.
Acc. Chem. Res. 1981, 14, 400.
(24) (a) Tietze, L. F.; Fennen, J.; Geibler, H.; Schulz, G.; Anders, E.
Liebigs Ann. 1995, 1681. (b) Domingo, L. R. Tetrahedron 2002, 58, 3765.
(25) Kelly, T. R.; Lang, F. J. Org. Chem. 1996, 61, 4623.
4208 J. Org. Chem., Vol. 72, No. 11, 2007

Hetero Diels-Alder Synthesis of 3-Hydroxypyridines
SCHEME 4. Attempted Convergent Synthesis of a
Bis-thiazolo-pyridinea
-OH), 8.32 (1H, d, J ) 2.5, CH). 13C NMR (100.6 MHz, CDCl3)
δ ) 52.93 (COOCH3), 53.06 (COOCH3), 122.89 (CAr), 130.87
(CAr), 138.16 (CAr), 139.39 (CAr), 155.74 (C-OH), 165.48
(COOCH3), 166.83 (COOCH3). IR (KBr): ν ) 3100 m, 2954 s,
1644 s, 1605 s, 1504 s, 962 s cm-1. HRMS (FAB), [M + H+],
calcd: 212.0553, found: 212.0516. Anal. calcd for C9H9NO5: C,
51.19; H, 4.30; N, 6.63; found: C, 51.0; H, 4.4; N, 6.4.
Dimethyl 2-(4-(Ethoxycarbonyl)thiazol-2-yl)-3-hydroxypyri-
dine-5,6-dicarboxylate (9c). Alkyne 5a (0.12 mL, 1 mmol) and
1-aza diene 6d (0.30 g, 0.64 mmol) in xylenes (1.5 mL) yielded
0.132 g (0.36 mmol, 57%) of 9c as a yellow, fluorescent solid. mp
) 136-138 °C. TLC: Rf ) 0.11 (EtOAc/cyclohexane ) 1:2). GC-
MS (method B): TR ) 9.88 min, m/z ) 366. 1H NMR (400 MHz,
CDCl3) δ ) 1.41-1.45 (3H, t, J ) 7.2, CH2CH3), 3.95 (3H, s,
COOCH3), 3.99 (3H, s, COOCH3), 4.41-4.47 (2H, q, J ) 7.0,
CH2CH3), 7.81 (1H, s, CH), 8.30 (1H, s, CH), 11.94 (1H, s, OH).
13C NMR (100.6 MHz, CDCl3) δ ) 14.29 (CH2CH3), 53.01
(COOCH3), 53.08 (COOCH3), 61.79 (CH2CH3), 126.36 (CAr),
129.12 (CAr), 129.51 (CAr), 135.55 (CAr), 141.35 (CAr), 146.74 (CAr),
153.75 (C-OH), 160.18 (CAr), 165.23 (COOCH3), 165.86
(COOCH3), 168.69(COOEt). IR (KBr): ν ) 3402 b, 2960 s, 2922
s, 1741 s, 1726 s, 1568 m, 1221 s, 798 s cm-1. HRMS (FAB), [M
+ H+], calcd: 367.0594, found: 367.0629.
a Trichlorobenzene, microwave irradiation, 200 °C, 15 min.
In conclusion, we have shown that, in one simple operation
from alkynes and silylated enol-oximes, 1-azadiene HDA
reactions do provide diverse 3-hydroxypyridines in good yields
and selectivities. The choice of diene and dienophile is flexible
as long as electronically activated alkynes are employed, and
the diene must not be further deactivated by steric bulk. Good
to excellent selectivities are obtained from these conditions.
Alkynyl ketones were found to deliver the 6-isomer with almost
perfect regioselectivity.
This transformation was then utilized to elaborate the fully
functionalized core building block 25 for nosiheptide in seven
steps from commercial materials, which convincingly demon-
strates the power of the 1-azadiene HDA reaction for accessing
3-hydroxypyridines with complex substitution patterns.30 Im-
portantly, racemization of a cysteine thioamide during the course
of a Hantzsch condensation could be suppressed by a judicious
choice of protecting groups, and this process could lead to a
scaleable synthesis of the important building block 25. These
results will allow for further work toward a total synthesis
procedure of nosiheptide (4) in the future.
Dimethyl 3-Hydroxy-5-phenylpyridine-2,6-dicarboxylate (9d).
Alkyne 5d (0.16 g, 1 mmol) yielded 0.2 g (0.7 mmol, 70%) of 9d
as a colorless solid. mp ) 111-113 °C. TLC: Rf ) 0.15 (EtOAc/
cyclohexane ) 1:2). GC-MS (method A): TR ) 5.43 min, m/z )
1
287. H NMR (400 MHz, CDCl3) δ ) 3.63 (3H, s, COOCH3),
4.07 (3H, s, COOCH3), 7.28-7.44 (5H, m, Ar), 8.60 (1H, s, CH),
11.07 (1H, s, OH). 13C NMR (100.6 MHz, CDCl3) δ ) 52.41
(COOCH3), 53.47 (COOCH3), 128.04 (Ar), 128.61 (Ar), 128.68
(Ar), 131.21 (C-COOMe), 132.02 (C-COOMe), 132.62(Ar),
139.41(C-Ar), 140.89 (CH), 156.27 (C-OH), 165.96 (COOCH3),
169.61 (COOCH3). IR (KBr): ν ) 3179 b, 2957 m, 2919 m, 2850
m, 1747 s, 1685 s, 1448 s, 807 s cm-1. HRMS (FAB), [M + H+],
calcd: 288.0866, found: 288.0906.
Dimethyl 3-Hydroxy-6-phenylpyridine-2,5-dicarboxylate (10d).
Alkyne 5d (0.16 g, 1 mmol) yielded 66 mg (0.23 mmol, 23%) of
10d as a colorless solid. mp ) 108-109 °C. TLC: Rf ) 0.37
(EtOAc/cyclohexane ) 1:2). GC-MS (method A): TR ) 5.38 min,
m/z ) 287. 1H NMR (400 MHz, CDCl3) δ ) 3.71 (3H, s,
COOCH3), 4.06 (3H, s, COOCH3), 7.40-7.50 (5H, m, Ar), 7.72
(1H, s, CH), 10.69 (1H, s, OH). 13C NMR (100.6 MHz, CDCl3) δ
) 52.69 (COOCH3), 53.37 (COOCH3), 127.67(CH), 128.29 (Ar),
128.41 (Ar), 128.61 (Ar), 130.66 (C-COOMe), 132.77 (Ar), 138.86
(C-COOMe), 149.86 (C-Ar), 156.90 (C-OH), 167.25 (COOCH3),
169.48 (COOCH3). IR (KBr): ν ) 3225 b, 3023 m, 2957 m, 1730
s, 1687 s, 1455 s, 798 s cm-1. HRMS (FAB), [M + H+], calcd:
288.0866, found: 288.0845. Anal. calcd for C15H13NO5: C, 62.72;
H, 4.56; N, 4.88; found: C, 62.8; H, 4.9; N, 4.5.
Experimental Section
General Procedure for the Preparation of Compounds 9 and
10. A mixture of alkyne 5 (1 mmol) and 1-aza-1,3-butadiene 6
(1.5-3.0 mmol) was heated to 150 °C under Ar for the time given
(TLC control). The reaction mixture was purified by column
chromatography on silica gel. Two easily separable isomers each
were obtained from alkynes 5d-k as well as 17.
Trimethyl 3-Hydroxy-2,5,6-pyridinetricarboxylate (9a). Alkyne
5a (0.12 mL, 1 mmol) yielded 0.269 g (1 mmol, 99%) of 9a as a
colorless solid. mp ) 124-126 °C. TLC: Rf ) 0.27 (EtOAc/
cyclohexane ) 1:2). GC-MS (method A): TR ) 4.89 min, m/z )
1
269. H NMR (400 MHz, CDCl3) δ ) 3.95 (3H, s, COOCH3),
Methyl 6-Acetyl-3-hydroxy-5-phenylpyridine-2-carboxylate
(9e). Alkyne 5e (0.5 g, 3.47 mmol) yielded 0.194 g (0.72 mmol,
21%) of 9e as a colorless solid. mp ) 136-138 °C. TLC: Rf )
3.96 (3H, s, COOCH3), 4.07 (3H, s, COOCH3), 9.67 (1H, s, CH),
11.02 (1H, s, OH). 13C NMR (100.6 MHz, CDCl3) δ ) 53.19
(COOCH3), 53.25 (COOCH3), 53.69 (COOCH3), 126.98 (CAr),
130.49 (CAr), 134.04 (CAr), 139.91 (CAr), 159.42 (C-OH), 164.89
(COOCH3), 165.34 (COOCH3), 168.82 (COOCH3). IR (KBr): ν
0.24 (EtOAc/light petroleum ) 1:1). GC-MS (method B): TR
)
8.29 min, m/z ) 271. 1H NMR (400 MHz, CD3CN) δ ) 1.99 (3H,
s, CH3), 4.01 (3H, s, COOCH3), 7.33-7.49 (5H, m, Ar), 8.31 (1H,
s, CH), 11.04 (1H, s, OH). 13C NMR (100.6 MHz, CD3CN) δ )
30.43 (CH3), 53.62 (COOCH3), 129.15 (CAr), 129.62 (CAr), 130.25
(CAr), 131.89 (CAr), 133.53 (CAr), 137.02 (CAr), 139.61 (CAr), 141.37
(CAr), 156.55 (C-OH), 170.61 (COOCH3), 201.90 (C(O)CH3). IR
(KBr): ν ) 3037 s, 2967 s, 1746 s, 1696 s, 1678 s, 1397 s, 1178
s, 818 s, 747 s cm-1. HRMS (ESI), [M + H+], calcd: 272.0917,
found: 272.0918.
) 3155 b, 2846 s, 1728 s, 1657 s, 1555 s, 1505 s, 965 s cm-1
.
HRMS (FAB), [M + H+], calc: 270.0608, found: 270.0611. Anal.
calcd for C11H11NO7: C, 49.08; H, 4.12; N, 5.20; found: C, 49.3;
H, 4.0; N, 5.2.
Dimethyl 3-Hydroxypyridine-5,6-dicarboxylate (9b). Alkyne
5a (0.06 mL, 0.5 mmol) yielded 61 mg (0.29 mmol, 58%) of 9b as
a colorless solid. mp ) 133-135 °C. TLC: Rf ) 0.12 (EtOAc/
light petroleum ) 1:1). GC-MS (method A): TR ) 4.85 min, m/z
) 211. 1H NMR (400 MHz, CD3CN) δ ) 3.85 (3H, s, COOCH3),
3.86 (3H, s, COOCH3), 7.47 (1H, d, J ) 2.7, CH), 8.15 (1H, bs,
Methyl 5-Acetyl-3-hydroxy-6-phenylpyridine-2-carboxylate
(10e). Alkyne 5e (0.5 g, 3.47 mmol) yielded 0.198 g (0.73 mmol,
21%) of 10e as a light yellow solid. mp ) 101-103 °C. TLC: Rf
) 0.41 (EtOAc/cyclohexane ) 1:2). GC-MS (method B): TR
)
(30) A different approach to the nosiheptide core structure has been
detailed. (a) Umemura, K.; Noda, H.; Yoshimura, J.; Konn, A.; Yonezawa,
Y.; Shin, C. G. Bull. Chem. Soc. Jpn. 1998, 71, 1391. (b) See also ref 8b.
8.19 min, m/z ) 271. 1H NMR (400 MHz, CD3CN) δ ) 2.21 (3H,
s, CH3), 3.99 (3H, s, COOCH3), 7.44 (5H, s, Ar), 7.51 (1H, s, CH),
J. Org. Chem, Vol. 72, No. 11, 2007 4209

Lu and Arndt
10.56 (1H, s, OH). 13C NMR (100.6 MHz, CD3CN) δ ) 30.44
(CH3), 53.76 (COOCH3), 126.13 (CH), 129.35 (Ar), 129.61 (Ar),
129.63 (Ar), 131.33 (C-COOMe), 139.75 (Ar), 142.32 (C-CH),
148.86 (C-Ar), 157.73 (C-OH), 170.25 (COOCH3), 202.54 (C(O)-
CH3). IR (KBr): ν ) 2899 s, 2899 w, 2850 w, 1744 s, 1697 s,
1201 s, 849 s, 809 s cm-1. HRMS (ESI), [M + H+], calcd:
272.0917, found: 272.0918.
Methyl 3-Hydroxy-5-phenylpyridine-2-carboxylate (10k).
Alkyne 5k (0.11 mL, 1 mmol) yielded 55 mg (0.24 mmol, 24%)
of 10k as a colorless solid. mp ) 83-86 °C. TLC: Rf ) 0.13
(EtOAc/cyclohexane ) 1:2). GC-MS (method B): TR ) 7.16 min,
m/z ) 229. 1H NMR (400 MHz, CD3CN) δ ) 4.00 (3H, s,
COOCH3), 7.44-7.51 (3H, m, Ar), 7.53, 7.54 (1H, d, J ) 4.6,
CH), 7.64-7.66(2H, m, Ar), 8.26, 8.27 (1H, d, J ) 4.6, CH), 11.18
(1H, s, OH). 13C NMR (100.6 MHz, CDCl3) δ ) 53.65 (COOCH3),
129.32 (CAr), 129.62 (CAr), 130.07 (CAr), 130.39 (CAr), 131.51 (CAr),
135.76 (CAr), 138.89 (CAr), 142.14 (CAr), 157.00 (C-OH), 171.57
(COOCH3). IR (KBr): ν ) 2955 w, 2921 s, 2852 s, 1744 s, 1694
s, 1245 s, 863 s, 807 s cm-1. HRMS (ESI), [M + H+], calcd:
230.0812, found: 230.0810.
Methyl 6-Acetyl-3-hydroxypyridine-2-carboxylate (9m). Alkyne
5m (0.156 mL, 2 mmol) yielded 0.21 g (1.07 mmol, 54%) of 9m
as a colorless solid. mp ) 120-122 °C. TLC: Rf ) 0.35 (EtOAc/
cyclohexane ) 1:2). GC-MS (method B): TR ) 6.30 min, m/z )
195. 1H NMR (400 MHz, CDCl3) δ ) 2.71 (3H, s, COCH3), 4.08
(3H, s, COOCH3), 7.43, 7.45 (1H, d, J ) 8.8, CHCHCOH), 8.18,
8.2 (1H, d, J ) 8.8, CHCHCOH), 11.11 (1H, s, OH). 13C NMR
(100.6 MHz, CDCl3) δ ) 25.16 (C(O)CH3), 53.26 (COOCH3),
126.58 (CH), 127.95 (CCHCHCOH), 128.64 (CCOOMe), 145.97
(CC(O)Me), 161.3 (C-OH), 169.68 (COOMe), 198.2 (C(O)Me).
IR (KBr): ν ) 3192 b, 2968 m, 2925 m, 2855 m, 1699 s, 1681 s,
1574 s, 851 s cm-1. HRMS (FAB), [M + H+], calcd: 196.0604,
found: 196.0587. Minor isomer 10m: GC-MS (method B): TR )
6.55 min, 195 (M+)
Methyl 5-Bromo-3-hydroxy-6-phenylpyridine-2-carboxylate
(9h). Alkyne 5h (90 mg, 0.497 mmol) yielded 49 mg (0.16 mmol,
32%) of 9h as a colorless solid. mp ) 103-104 °C. TLC: Rf )
0.30 (EtOAc/cyclohexane ) 1:2). GC-MS (method B): TR ) 7.53
min, m/z ) 307, 308. 1H NMR (400 MHz, CDCl3) δ ) 4.03 (3H,
s, COOCH3), 7.42-7.63 (5H, m, Ar), 7.75 (1H, s, CH), 10.69 (1H,
s, OH). 13C NMR (100.6 MHz, CDCl3) δ ) 53.28 (COOCH3),
125.69(C-Br), 128.03 (Ar), 128.73 (Ar), 129.48 (Ar), 130.80 (Ar),
136.46 (CH), 138.51 (C-COOMe), 150.36 (C-Ar), 157.23 (C-OH),
169.74 (COOCH3). IR (KBr): ν ) 3171 b, 2957 m, 1683 s, 1504
m, 1434 s, 1207 s, 801 s cm-1. HRMS (FAB), [M+], calcd:
306.9844, found: 306.9843 [79Br]. Anal. calcd for C13H10BrNO3:
C, 50.67; H, 3.27; N, 4.55; found: C, 50.8; H, 3.6; N, 4.2.
Methyl 6-Bromo-3-hydroxy-5-phenylpyridine-2-carboxylate
(10h). Alkyne 5h (90 mg, 0.497 mmol) yielded 25 mg (0.08 mmol,
16%) of 10h as a colorless solid. mp ) 100-101 °C. TLC: Rf )
0.19 (EtOAc/cyclohexane ) 1:2). GC-MS (method A): TR ) 5.31
min, m/z ) 307, 308. 1H NMR (400 MHz, CDCl3) δ ) 4.07 (3H,
s, COOCH3), 7.33-7.51 (5H, m, Ar), 8.48 (1H, s, CH), 11.07 (1H,
s, OH). 13C NMR (100.6 MHz, CDCl3) δ ) 53.44 (COOCH3),
127.63 (CAr), 128.38 (CAr), 128.61 (CAr), 128.95 (CAr), 129.20 (CAr),
133.34 (CAr), 139.99 (CAr), 143.37 (CAr), 157.00 (C-OH), 169.96
(COOCH3). IR (KBr): ν ) 3128 b, 1746 s, 1681 s, 1504 s, 1360
s, 898 s, 811 s cm-1. HRMS (FAB), [M+], calc: 306.9844, found:
306.9882 [79Br].
Methyl 6-Benzoyl-3-hydroxypyridine-2-carboxylate (9n). Alkyne
5n (0.25 g, 1.92 mmol) yielded 0.365 g (1.42 mmol, 74%) of 9n
as a light yellow solid. mp ) 94-96 °C. TLC: Rf ) 0.38 (EtOAc/
cyclohexane ) 1:2). GC-MS (method B): TR ) 8.09 min, m/z )
1
257. H NMR (400 MHz, CD3CN) δ ) 3.92 (3H, s, COOMe),
7.43-7.48 (2H, m, Ar), 7.46, 7.49 (1H, d, J ) 8.8, CH), 7.56-
7.61 (1H, m, Ar), 8.05-8.07 (2H, m, Ar), 8.11,8.13 (1H, d, J )
8.8, CH), 10.93 (1H, s, OH). 13C NMR (100.6 MHz, CD3CN) δ )
53.58 (COOCH3), 127.33 (CH), 128.70 (Ar), 129.25 (C-COOMe),
131.20 (CH), 131.64 (Ar), 133.41 (Ar), 137.10 (Ar), 147.09 (C-
C(O)Ar), 160.91 (C-OH), 170.23 (COOMe), 191.79 (C(O)-Ar).
IR (KBr): ν ) 3067 s, 2916 w, 1679 s, 1577 s, 1219 s, 944 s, 698
s cm-1. HRMS (ESI), [M + H+], calcd: 258.0761, found:
258.0762. Minor isomer 10n (9 mg, 1% as determined by 1H NMR),
GC-MS (method B): TR ) 8.28 min, m/z ) 257.
Methyl 6-Chloro-3-hydroxy-5-phenylpyridine-2-carboxylate
(9i). Alkyne 5i (70 mg, 0.51 mmol) yielded 46 mg (0.17 mmol,
34%) of 9i as a colorless solid. mp ) 108-109 °C. TLC: Rf )
0.28 (EtOAc/cyclohexane ) 1:2). GC-MS (method B): TR ) 7.32
1
min, m/z ) 263. H NMR (400 MHz, CDCl3) δ ) 4.08 (3H, s,
COOCH3), 7.36-7.51 (5H, m, Ar), 8.36 (1H, s, CH), 11.11 (1H,
s, OH). 13C NMR (100.6 MHz, CDCl3) δ ) 53.41 (COOCH3),
128.24 (C-Cl), 128.35 (Ar), 128.99 (Ar), 129.45 (Ar), 131.34 (Ar),
136.27 (C-COOMe), 137.71 (C-Ar), 141.19 (CH), 157.06 (C-
OH), 169.85 (COOCH3). IR (KBr): ν ) 3054 b, 2923 m, 1673 s,
1576 m, 1397 s, 913 s, 812 s cm-1. HRMS (FAB), [M + H+],
calcd: 264.0422, found: 264.0437.
Thiazolylalcohol (27). In a dry Schlenk flask, PdCl2 (10 mg,
0.059 mmol), PPh3 (30.9 mg, 0.118 mmol), and CuI (22 mg, 0.118
mmol) were dissolved in DMF (15 mL) under argon, and the
mixture was stirred for 30 min. Bromothiazole 16 (1.3 g, 5.9 mmol),
3-butyn-2-ol (0.64 mL, 8.8 mmol), and triethylamine (1.6 mL, 11.8
mmol) were added to the mixture. The mixture was heated to 80
°C for 2 h (TLC control), and it turned dark brown. The mixture
was cooled to room temperature, diluted with dichloromethane (50
mL), and filtered through Celite. The pad of Celite was rinsed with
dichloromethane (3 × 10 mL), and the combined filtrates were
concentrated and purified by column chromatography on silica gel
(EtOAc/cyclohexane ) 1:4) to give 0.90 g (4.3 mmol, 90%) of
thiazolylalcohol 27 as a colorless solid. mp ) 94-95 °C. TLC: Rf
Methyl 5-Chloro-3-hydroxy-6-phenylpyridine-2-carboxylate
(10i). Alkyne 5i (70 mg, 0.51 mmol) yielded 20 mg (0.08 mmol,
15%) of 10i as a colorless solid. mp ) 164-165 °C. TLC: Rf )
0.46 (EtOAc/cyclohexane ) 1:2). GC-MS (method B): TR ) 7.30
1
min, m/z ) 263. H NMR (400 MHz, CDCl3) δ ) 4.04 (3H, s,
COOCH3), 7.42-7.67 (5H, m, Ar), 7.54 (1H, s, CH), 10.72 (1H,
s, OH). 13C NMR (100.6 MHz, CDCl3) δ ) 53.25 (COOCH3),
126.61 (CAr), 127.38 (CAr), 128.06 (CAr), 128.12 (CAr), 128.78 (CAr),
129.44 (CAr), 135.81 (CAr), 137.20 (CAr), 157.56 (C-OH), 169.59
(COOCH3). IR (KBr): ν ) 3157 s, 2902 m, 1683 s, 1556 m, 1436
s, 802 s cm-1. HRMS (FAB), [M + H+], calcd: 264.0422, found:
264.0445.
) 0.15 (EtOAc/cyclohexane ) 1:2). GC-MS (method B): TR
)
7.22 min, m/z ) 211. 1H NMR (400 MHz, CDCl3) δ ) 1.56 (3H,
d, J ) 6.7, CH3), 2.23 (1H, s, OH), 3.95 (3H, s, COOCH3), 4.77
(1H, q, J ) 6.5, CHCH3), 8.17 (1H, s, CH). 13C NMR (100.6 MHz,
CDCl3) δ ) 23.61 (CHCH3), 52.48 (CH3), 58.59 (CHCH3), 76.44
(C-CCOH), 96.89 (CCOH), 128.64 (CH), 147.16 (C-CCOH),
148.76 (C-COOCH3), 161.22 (COOCH3). IR (KBr): ν ) 3343 b,
2981 s, 2486 s, 2230 s, 1681 s, 1248 s, 928 s, 771 s cm-1. HRMS
(FAB), [M + H+], calcd: 212.0376, found: 212.0416.
Methyl 2-But-1′-yne-3′-oxo-4-thiazolecarboxylate (17). A mix-
ture of IBX (1.57 g, 5.59 mmol) in dry DMSO (10 mL) was added
dropwise to a cooled solution (0 °C) of thiazolylalcohol 27 (0.9 g,
4.3 mmol) in dry THF (10 mL) under argon. The solution was
allowed to warm to room temperature after 2 h and was stirred for
Methyl 3-Hydroxy-6-phenylpyridine-2-carboxylate (9k). Alkyne
5k (0.11 mL, 1 mmol) yielded 0.15 g (0.66 mmol, 66%) of 9k as
a colorless solid. mp ) 107-109 °C. TLC: Rf ) 0.47 (EtOAc/
cyclohexane ) 1:2). GC-MS (method B): TR ) 7.13 min, m/z )
1
229. H NMR (400 MHz, CDCl3) δ ) 4.07 (3H, s, COOCH3),
7.36-7.39 (1H, m, Ar), 7.40, 7.425 (1H, d, J ) 8.8, CH), 7.43-
7.47 (2H, m, Ar), 7.82, 7.84 (1H, d, J ) 8.8, CH), 7.92-7.94 (2H,
m, Ar), 10.71 (1H, s, OH). 13C NMR (100.6 MHz, CDCl3) δ )
53.03 (COOCH3), 126.57 (CAr), 126.84 (CAr), 126.94 (CAr), 128.68
(CAr), 128.79 (CAr), 129.36 (CAr), 138.31 (CAr), 149.48 (CAr), 157.80
(C-OH), 170.16 (COOCH3). IR (KBr): ν ) 3092 b, 2955 m, 1714
s, 1694 s, 1372 s, 805 s cm-1. HRMS (ESI), [M + H+], calcd:
230.0812, found: 230.0811.
4210 J. Org. Chem., Vol. 72, No. 11, 2007

Hetero Diels-Alder Synthesis of 3-Hydroxypyridines
12 h (TLC control). The mixture was diluted with water (60 mL)
and was extracted with diethyl ether (4 × 50 mL). The combined
extracts were dried with sodium sulfate and were evaporated to
dryness. Purification by column chromatography on silica gel
(EtOAc/cyclohexane ) 1:6) gave 0.89 g (4.26 mmol, 99%) of
thiazolylketone 17 as a colorless solid. mp ) 159-160 °C. TLC:
Rf ) 0.39 (EtOAc/cyclohexane ) 1:2). GC-MS (method B): TR )
6.99 min, m/z ) 209. 1H NMR (400 MHz, CDCl3) δ ) 2.44 (3H,
s, C(O)CH3), 3.94 (3H, s, COOCH3), 8.32 (1H, s, CH). 13C NMR
(100.6 MHz, CDCl3) δ ) 32.44 (C(O)CH3), 52.70 (CH3), 79.52
(C-CCC(O)CH3), 90.44 (CC(O)CH3), 130.89 (CH), 146.21
(C-CC(O)CH3), 148.17 (C-COOCH3), 160.71 (COOCH3), 183.06
(C(O)CH3). IR (KBr): ν ) 3078 s, 2204 s, 1728 s, 1673 m, 1453
s, 1231 s, 861 s cm-1. HRMS (FAB), [M + H+], calcd: 210.0219,
found: 210.0219. Anal. calcd for C9H7NO3S: C, 51.67; H, 3.37;
N, 6.69; found: C, 51.7; H, 3.5; N, 6.8.
(C-COOMe), 145.98 (C-C(O)Me), 147.74 (C-COOMe), 151.91
(C-OTf), 160.59 (C-C(N)S), 161.21 (COOMe), 161.91 (COOMe),-
198.88 (C(O)CH3). IR (KBr): ν ) 3100 s, 1740 s, 1716 s, 1423 s,
1221 s, 930 s, 893 s, 798 s cm-1. HRMS (FAB), [M + H+], calcd:
468.9982, found: 468.9959.
Triisopropylsilyl triflate (0.68 mL, 2.52 mmol) was added
dropwise to a stirring solution of ketone 28 (0.59 g, 1.26 mmol)
and triethylamine (0.3 mL, 5.0 mmol) in dry dichloromethane (10
mL) at 0 °C under an argon atmosphere. The mixture was allowed
to warm to room temperature after 1 h and was stirred for 12 h. A
saturated NaCl solution (20 mL) was added and the mixture was
extracted with dichloromethane (3 × 20 mL). The combined organic
extracts were dried with Na2SO4, concentrated to dryness, and
purified by column chromatography on silica gel (EtOAc/cyclo-
hexane ) 1:12) to give 0.785 g (1.25 mmol, 99%) of enol ether 19
1
as a yellow oil. TLC: Rf ) 0.84 (EtOAc/cyclohexane ) 1:2). H
Methyl 5-(4-(Methoxycarbonyl)thiazol-2-yl)-6-acetyl-3-hy-
droxypyridine-2-carboxylate (18). A solution of thiazolylketone
17 (1.0 g, 4.78 mmol) and 2-methoxycarbonyl-1,3-bis(trimethyl-
siloxy)-1-aza-1,3-butadiene (4.15 g, 14.4 mmol) in toluene (1 mL)
was heated to 180 °C for 3 h under Ar (CAUTION! Use a thick-
walled sealed tube!). After the solution was cooled to room
temperature, the reaction mixture was purified by column chro-
matography on silica gel (EtOAc/light petroleum ) 1:4) to give
888 mg (2.64 mmol, 55%) of ketone 18 and 447 mg (1.33 mmol,
28%) of its 5-acetyl regioisomer 18a as colorless solids.
NMR (400 MHz, CDCl3) δ ) 0.87-1.03 (21H, m, TIPS), 3.98
(3H, s, COOCH3), 4.01 (3H, s, COOCH3), 4.82, 4.86 (1H, d, J )
13.7, CdCH2), 5.07, 5.11 (1H, d, J ) 18.8, CdCH2), 8.27 (1H, s,
CH), 8.36 (1H, s, CH). 13C NMR (100.6 MHz, CDCl3) δ ) 12.40,
17.67, 52.56, 53.18, 100.44, 130.44, 130.52, 131.34, 132.63, 141.02,
144.50, 147.16, 153.42, 154.19, 161.42, 162.1, 162.51. IR (KBr):
ν ) 2942 w, 2857 w, 1741 s, 1695 s, 1434 s, 1223 b, 858 s, 799
s cm-1. HRMS (FAB), [M + H+], calcd: 625.1316, found:
625.1291.
Methyl 6-(2-Bromo-acetyl)-5-(4-methoxycarbonyl-thiazol-2-
yl)-3-trifluoromethanesulfonyloxy-pyridine-2-carboxylate (20).
NBS (0.23 g, 1.3 mmol) was added at room temperature to a
solution of enol ether 19 (0.666 g, 1.1 mmol) in THF/0.5 M
phosphate buffer (6:1, 14 mL, pH 7), and the reaction mixture was
stirred for 30 min (TLC control). The reaction mixture was diluted
with phosphate buffer (pH 7, 20 mL) and was extracted with
dichloromethane (3 × 20 mL). The combined extracts were dried
with Na2SO4, concentrated, and purified by column chromatography
on silica gel (diethyl ether/N-pentane ) 1:3) to yield 0.583 g (1.07
mmol, 97%) of bromoketone 20 as a colorless solid. mp ) 133 °C
(decomp). TLC: Rf ) 0.39 (EtOAc/cyclohexane ) 2:3). 1H NMR
(400 MHz, CDCl3) δ ) 3.99 (3H, s, COOCH3), 4.08 (3H, s,
COOCH3), 4.81 (2H, s, CH2Br), 8.31 (1H, s, CH), 8.40 (1H, s,
CH). 13C NMR (100.6 MHz, CDCl3) δ ) 33.14, 52.71, 53.60,
127.79, 130.76, 133.59, 134.05, 146.51, 148.01, 149.38, 156.04,
159.79, 161.15, 161.64, 191.15. IR (KBr): ν ) 2924 s, 2854 s,
1740 b, 1434 s, 1222 s, 800 s cm-1. HRMS (FAB), [M + H+],
calcd: 546.9087, found: 546.9122 [79Br].
Ketone 18: mp ) 217 °C (decomp.). TLC: Rf ) 0.06 (EtOAc/
cyclohexane ) 1:2). GC-MS (method B): TR ) 9.51 min, m/z )
1
336. H NMR (400 MHz, CDCl3) δ ) 2.70 (3H, s, C(O)CH3),
3.95 (3H, s, COOCH3), 4.09 (3H, s, COOCH3), 7.68 (1H, s, CH),
8.34 (1H, s, CH), 11.02 (1H, s, C-OH). 13C NMR (100.6 MHz,
CDCl3) δ ) 27.44 (C(O)CH3), 52.52 (COOCH3), 53.44 (COOCH3),
129.00 (CH), 129.09 (C-COOMe), 129.69 (CH), 134.34 (C-CH),
145.02 (C-C(O)Me), 147.11 (C-COOMe), 159.37 (C-OH),
161.55 (COOMe), 163.32 (C-C(N)S), 169.08 (COOMe), 198.79
(C(O)CH3). IR (KBr): ν ) 3157 s, 2914 s, 2854 s, 1729 m, 1692
m, 1461 s, 1377 s, 1179 w, 890 s cm-1. HRMS (FAB), [M + H+],
calcd: 337.0489, found: 337.0515.
Ketone Isomer 18a: mp ) 186 °C (decomp.). Rf ) 0.17 (minor
isomer). GC-MS (method B): TR ) 9.41 min, m/z ) 336. 1H NMR
(400 MHz, CDCl3) δ ) 2.64 (3H, s, C(O)CH3), 3.93 (3H, s,
COOCH3), 4.09 (3H, s, COOCH3), 7.29 (1H, s, CH), 8.22 (1H, s,
CH), 10.91 (1H, s, C-OH). 13C NMR (100.6 MHz, CDCl3) δ )
30.91 (C(O)CH3), 52.37 (COOCH3), 53.44 (COOCH3), 124.36
(CH), 129.36 (CH), 129.52 (C-COOMe), 138.08 (C-C(N)S),
142.32 (C-C(O)Me), 147.57 (C-COOMe), 159.12 (C-OH), 161.58
(COOMe), 166.51 (C(N)S), 168.85 (COOMe), 201.03 (C(O)CH3).
IR (KBr): ν ) 3124 s, 2958 w, 2922 w, 2852 w, 1743 s, 1704 s,
1454 s, 1216 s, 808 s, 762 s cm-1. HRMS (ESI), [M + H+], calc:
337.0489, found: 337.0492.
Methyl 5-(4-Methoxycarbonyl-thiazol-2-yl)-3-trifluoromethane-
sulfonyloxy-6-(1-triisopropylsilyloxy-vinyl)-pyridine-2-carboxy-
late (19). Trifluoromethanesulfonic anhydride (0.9 mL, 5.4 mmol)
was added dropwise over 10 min to a solution of hydroxypyridine
18 (1.2 g, 3.6 mmol) and triethylamine (1 mL, 7.2 mmol) in dry
dichloromethane (40 mL) at 0 °C under an Ar atmosphere. The
reaction mixture was gradually warmed to room temperature and
was stirred for 12 h. The reaction was quenched by the addition of
phosphate buffer (pH 2, 0.50 M, 20 mL), and the solution was
extracted with dichloromethane (3 × 50 mL), dried with Na2SO4,
and concentrated. Purification by column chromatography on silica
gel (EtOAc/light petroleum ) 1:3) gave 0.81 g (1.7 mmol, 80%
based on recovered starting material) of pyridineketone 28 as a
colorless solid. mp ) 126-128 °C. TLC: Rf ) 0.22 (EtOAc/
cyclohexane ) 1:2). 1H NMR (400 MHz, CDCl3) δ ) 2.78 (3H, s,
C(O)CH3), 3.96 (3H, s, COOCH3), 4.06 (3H, s, COOCH3), 8.20
(1H, s, CH), 8.38 (1H, s, CH). 13C NMR (100.6 MHz, CDCl3) δ )
28.10 (C(O)CH3), 52.61 (COOCH3), 53.46 (COOCH3), 116.94,
120.12 (Tf), 130.56 (C-C(N)S), 132.40 (CH), 133.94 (CH), 141.03
Methyl
6-[2-(1′-allyoxycarbonylamino-2′-tritylsulfanyl-
ethyl)-Thiazol-4-yl]-5-(4-methoxycarbonyl-thiazol-2-yl)-3-trif-
luoromethanesulfonyloxy-pyridine-2-carboxylate (23). A suspen-
sion of thioamide 22 (0.67 g, 1.5 mmol) and anhydrous KHCO3
(0.29 g, 2.9 mmol) in THF (10 mL) was cooled to -40 °C, and
bromoketone 20 (0.51 g, 0.93 mmol) in THF (2 mL) was added
dropwise. After the mixture was stirred for 2 h, it was allowed to
warm to room temperature and was stirred for 48 h. The reaction
mixture was filtered under argon and was cooled to -20 °C. 2,6-
Lutidine (1.2 mL, 10.5 mmol) and trifluoroacetic anhydride (0.6
mL, 4.4 mmol) were slowly added, and the solution was allowed
to stir for 2 h. Brine (50 mL) was added, and the mixture was
extracted with dichloromethane (3 × 50 mL). The combined organic
extracts were dried with Na2SO4. Column chromatography (silica
gel, EtOAc/light petroleum ) 1:5) gave 0.59 g (0.65 mmol, 69%)
of thiazolylpyridine 23 as a yellow, microcrystalline solid. mp )
104 °C (decomp.). TLC: Rf ) 0.33 (EtOAc/cyclohexane ) 1:2).
1H NMR (400 MHz, CDCl3) δ ) 2.64-2.86 (2H, m, CH2CH),
4.02 (3H, s, COOCH3), 4.11 (3H, s, COOCH3), 4.57, 4.58 (2H, d,
J ) 5.6, COOCH2CHdCH2), 4.73 (1H, m. CH2CH), 5.13 (1H, m,
NH), 5.28, 5.30 (1H, d, J ) 10.0, CHdCH2), 5.34, 5.38 (1H, d, J
) 16.8, CHdCH2), 5.95 (1H, m, CHdCH2), 7.28-7.42 (15H, m,
trityl), 7.98 (1H, s, CH), 8.15 (1H, s, CH), 8.34 (1H, s, CHd
CNCOOMe). 13C NMR (100.6 MHz, CDCl3) δ ) 36.77, 52.03,
52.58, 53.41, 65.97, 67.51, 117.95, 120.19, 123.24, 126.97,
J. Org. Chem, Vol. 72, No. 11, 2007 4211

Lu and Arndt
128.09, 129.50, 130.35, 132.25, 132.48, 133.46, 141.62, 144.27,
144.51, 146.95, 150.15, 151.15, 155.01, 161.38, 162.39, 162.45,
171.10. IR (KBr): ν ) 2924 s, 2854 s,1731 s, 1494 m, 1433 s,
1217 s, 886 s, 796 s cm-1. [R]D20 ) -2.1 (c ) 1, CHCl3). HRMS
(FAB), [M + H+], calcd: 911.1155, found: 911.1165.
CH2), 3.39, 3.40, 3.42, 3.43 (1H, q, J ) 5.9, CH2), 3.88 (3H, s,
COOMe), 4.01 (3H, s, COOMe), 5.47 (1H, br, CH), 7.94 (1H, s,
CH), 8.30 (1H, s, CCHS), 8.37 (1H, s, CCHS). 13C NMR (100.6
MHz, CDCl3) δ ) 28.41, 29.04, 29.18, 52.85, 53.94, 60.13, 66.08,
108.46, 121.15, 123.76, 131.96, 133.48, 134.13, 142.22, 145.48,
147.76, 151.65, 162.21, 163.54. IR (KBr): ν ) 2979 s, 2928 s,
Ketal-Protected Building Block (25). A suspension of thioamide
24 (2.45 g, 8.9 mmol) and anhydrous KHCO3 (2.4 g, 24 mmol) in
THF 100 mL was cooled to -40 °C, and bromoketone 20 (3.2 g,
5.9 mmol) in THF (20 mL) was added dropwise to the suspension.
After the mixture was stirred for 2 h, it was allowed to warm to
room temperature and was stirred for 48 h. The reaction mixture
was filtered under argon and was cooled to -20 °C. 2,6-Lutidine
(7.2 mL, 61.9 mmol) and trifluoroacetic anhydride (4.1 mL, 29
mmol) were slowly added, and the solution was allowed to stir for
2 h. Brine (100 mL) was slowly added, and the mixture was
extracted with dichloromethane (3 × 100 mL). The combined
organic extracts were dried with Na2SO4. Column chromatography
(silica gel, EtOAc/cyclohexane ) 1:5) gave 2.56 g (3.54 mmol,
60%) of thiazolylpyridine 25 as a yellow microcrystalline solid.
mp ) 108 °C (decomp.). TLC: Rf ) 0.35 (EtOAc/cyclohexane )
1702 s, 1602 s, 1432 s, 1347 s, 1217 s, 859 s, 798 s cm-1. [R]D20
)
-48.0 (c ) 1, CHCl3). HRMS (FAB), [M + H+], calcd: 725.0686,
found: 725.0712.
Acknowledgment. This work was supported by the Deutsche
Forschungsgemeinschaft and the Fonds der Chemischen Indus-
trie. We thank the Bayer HealthCare AG, Wuppertal (D), for a
donation of equipment. H.-D.A. acknowledges an Emmy-
Noether fellowship, and J.-Y. is a member of the International
Max-Planck Research School for Chemical Biology.
Supporting Information Available: Additional experimental
methods, characterization data, and 1H spectra for compounds 6-25.
This material is available free of charge on the Internet at
http://pubs.acs.org.
1
1:2). H NMR (400 MHz, CD3CN) δ ) 1.33 (9H, s, C(CH3)3),
1.78 (3H, s, CH3), 1.87 (3H, s, CH3), 2.77, 2.8 (1H, q, J ) 12.3,
JO0703505
4212 J. Org. Chem., Vol. 72, No. 11, 2007