A new and flexible synthesis of 4-hydroxypyridines: Rapid access to caerulomycins A, e and functionalized terpyridines

Article abstract of DOI:10.1002/chem.200900939

A simple new protocol for the preparation of substituted 4-hydroxypyridines form inexpensive commercially available reagents was reported. The synthetic sequence involved three stages with an intramolecular aldol-type condensation of readily available ena

Full text of DOI:10.1002/chem.200900939

COMMUNICATION
DOI: 10.1002/chem.200900939
A New and Flexible Synthesis of 4-Hydroxypyridines: Rapid Access to
Caerulomycins A, E and Functionalized Terpyridines
Jyotirmayee Dash[a, b] and Hans-Ulrich Reissig*[a]
Dedicated to Professor Johann Mulzer on the occasion of his 65th birthday
Pyridine derivatives belong to the most versatile heterocy-
cles found in natural products and pharmaceuticals.[1] Substi-
tuted pyridine derivatives have also been used as reagents in
organic synthesis and for new materials.[2] For example,
functionalized 2,2’-bipyridines and 2,2’:6’,2’’-terpyridines
have received considerable attention as ligands in transition-
metal catalysis and as building blocks in supramolecular
chemistry.[3] Although there are many methods available for
the synthesis of specifically functionalized pyridines,[4] many
of these involve fairly complex synthetic pathways associat-
ed with low yields. In particular, there is no simple route to
fluoroalkyl-substituted pyridines which are potential insecti-
cides and herbicides.[5]
The synthetic sequence involves three stages with an in-
tramolecular aldol-type condensation of readily available
enamides as key step.[7] The first step is a simple condensa-
tion of diketones 1 and 2 with aqueous NH3 and catalytic
SiO2 to give (Z)-enaminones 3 or 4 in almost quantitative
yield.[8] In order to avoid regioselectivity problems, only
symmetric 1,3-diketones were used so far. These precursors
3 or 4 were acylated with in situ generated acid chlorides to
provide (Z)-enamides[9] 5 in high yield (Scheme 2, Table 1).
Herein, we report a simple new protocol for the prepara-
tion of substituted 4-hydroxypyridines from inexpensive
commercially available reagents (Scheme 1).[6] This flexible
three-component/three-step method also provides an effi-
cient access to the antibiotics caerulomycin A, E and their
novel hybrid analogues.
Scheme 2. Synthesis of 4-hydroxypyridine derivatives 6 and 7. a) 25% aq.
NH3, SiO2 (cat.), RT, 12 h; b) SOCl2, Et3N, CH2Cl2; c) TMSOTf, iPr2NEt,
1,2-dichloroethane, d) NaH, NfF, THF. TMSOTf=Trimethylsilyltrifluoro-
methane sulfonate; NfF=nonafluorobutanesulfonyl fluoride.
Scheme 1. A new synthetic approach to 4-hydroxypyridine derivatives.
Intermediates 5 were finally treated with trimethylsilyl tri-
flate and Hꢀnig base in 1,2-dichloroethane at reflux temper-
ature which induce an aldol-type condensation reaction with
the amide as electrophilic moiety to afford 4-hydroxypyri-
dines 6. In most cases, the crude products were treated with
sodium hydride and nonafluorobutanesulfonyl fluoride
(NfF) to provide the less polar, easily isolable pyridyl 4-nona-
flates 7a–h, which are direct precursors for palladium-cata-
lyzed cross couplings[7,10] as illustrated in an example
(Scheme 3). The scope of the new method was investigated
by preparing a small library of model compounds (Table 1).
[a] Dr. J. Dash, Prof. Dr. H.-U. Reissig
Institut fꢀr Chemie und Biochemie, Freie Universitꢁt Berlin
Takustrasse 3, 14195 Berlin (Germany)
Fax : (+49)30-83855367
E-mail: hans.reissig@chemie.fu-berlin.de
[b] Dr. J. Dash
Indian Institute of Science Education and Research Kolkata
Mohanpur Campus, Mohanpur 741252, Nadia, West Bengal (India)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900939.
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Table 1. Preparation[a] of (Z)-enamides 5 and their conversion into 4-hy-
droxypyridines 6 and pyridyl 4-nonaflates 7.
The cyclization of enamides 5 was found to be tolerant of
a range of functional groups with different steric demands
including trifluoromethyl, pentadecafluoroheptyl, phenyl, 2-
pyridyl and pentafluorophenyl. The method allows for a
rapid access to 2-aryl pyridines[1] 7c, 6d, 7d, 7 f, 6g, 7g and
2,2’-bipyridines[3] 7h in high yield. Remarkably, this protocol
was employed for the preparation of trifluoromethyl-substi-
tuted pyridyl nonaflates 7a and 7e from the diketones 1 and
2 in good overall yields (41–53%, entries 1 and 5) using just
one column chromatography for purification. The enami-
nones 3 and 4 were treated with trifluoroacetic anhydride in
CH2Cl2 at 08C to provide the enamides 5a and 5e in almost
quantitative yield. The crude products were subjected to
cyclization conditions followed by nonaflation to give 7a
and 7e.
Entry R1 R2
Yield [%][b] 5 Isolated
Yield [%][c]
products
6 and 7
AHCTUNGTERG(NNUN 6/7)
1
2
Me CF3 5a, 93[d]
7a: 53[e]
6b (R4 = H): 63[f]
7b (R4 = Nf): 79[g]
Me C7F15 5b, 73
3
4
Me Ph
5c, 83
7c: 83[h]
The convenient preparation of fluorous[11] pyridine deriva-
tives 6b and 7b bearing a CF3ACHTNUGRTNEUNG(CF2)6 group at C-2 position
6d (R4 =H): 68[f]
7d (R4 =Nf): 73[g]
in high yield (entry 2) further highlights the synthetic poten-
tial of this methodology. Notably pyridine derivatives 7b, 7d
and 7g can serve as promising building blocks for novel flu-
orinated functional materials.[12]
Me C6F5 5d, 77
In order to demonstrate the potential of nonaflate deriva-
tives 7 in palladium-catalyzed reactions, we carried out a
Suzuki coupling[13] of nonaflate derivative 7g with bisboron-
5
6
Et CF3 5e, 97[d]
7e: 41[e]
7 f: 61[h]
ic ester 8 (Scheme 3). Using PdACHTNUGTRENUNG(OAc)2 and dppf in the pres-
Et Ph
5 f, 81
ence of K2CO3 and LiCl in DMF, a novel conjugated fluori-
nated heteroaromatic compound 9 was acquired in 37%
yield (not optimized), thereby enabling an easy access to a
multitude of similar elongated heteroaromatic systems.
We have further expanded the scope of our method to
rapidly prepare caerulomycins A and E (Scheme 4). These
natural products are two of the five caerulomycins isolated
from Streptomyces caeruleus.[14] This class of compounds
contains a 2,2’-bipyridine unit[15–17] and exhibits considerable
cytotoxic and antibiotic properties. By using our approach,
picolinic acid 10 was treated with thionyl chloride to gener-
ate the acid chloride which was coupled with 3 to obtain en-
amide 11 in 82% yield (Scheme 4). Intermediate 11 was
treated with Hꢀnig base and trimethylsilyl triflate to afford
the pyridinol intermediate, which upon subsequent reaction
with methyl iodide smoothly provided the desired 4-me-
thoxy-6-methyl-2,2’-bipyridine (12) in 63% overall yield.
This two-step approach constitutes a remarkably practical
access to the known intermediate 12 of Quꢃguinerꢄs synthe-
sis[16] and is therefore easily amenable to scale-up. Following
the steps of Quꢃguinerꢄs synthesis, 12 was oxidized with
SeO2 in dioxane to give caerulomycin E (13). Subsequent
condensation of this aldehyde with hydroxylamine afforded
caerulomycin A (14, Scheme 4). This new route to 13 and 14
provides clear advantages in the total number of steps and
the overall yield compared to the previously reported ap-
proaches.[15,16]
6g (R4 =H): 67[f]
7g (R4 =Nf): 81[g]
7
8
Et C6F5 5g, 84
Et 2-Py 5h, 86
7h: 51[h]
[a] Conditions unless noted otherwise. [b] SOCl2, Et3N, CH2Cl2, 08C to
RT, 12 h. [c] i) TMSOTf, iPr2NEt, 1,2-dichloroethane, 1008C, 3 d, and/or
ii) NaH, NfF, THF, RT, 7 h. [d] Enamides were prepared using trifluoro-
acetic acid anhydride, CH2Cl2, 08C, 30 min. [e] Yield using a one-column
purification step from 1 and 2. [f] Yield of purified 4-hydroxypyridines 6
using conditions i) of footnote [c]. [g] Nonaflates 7 were prepared from
isolated 6. [h] Steps i) and ii) of footnote [c] were applied without isolat-
ing the intermediate 4-hydroxypyridines.
Finally, the synthetic utility of our method is illustrated in
a concise synthesis of terpyridine derivatives (Scheme 5).[3]
We perceived that we could devise novel cytotoxic com-
pounds, which are notably a class of small molecules being
hybrids of two molecules of caerulomycin E or A, sharing a
Scheme 3. Suzuki coupling of pyridyl nonaflate 7g with bisboronic ester 8
leading to fluorinated penta
ACHTUTNGRENNUG(het)aryl compound 9. a) PdACHUTGNTREN(NUNG OAc)2, dppf,
LiCl, K2CO3, DMF, 1008C, 12 h (37%).
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Synthesis of 4-Hydroxypyridines
COMMUNICATION
gen bonds between the carbonyl oxygen and NH. The
1H NMR spectrum of 16 reveals an NH signal at
d
13.57 ppm and an olefinic CH signal at d 5.47–5.48 ppm con-
sistent with the other (Z)-enamides of type 5. Two sets of
NH signals at d 14.40 and d 10.05 ppm and two sets of ole-
finic CH signals at 5.52–5.51 and 7.51 ppm were observed in
the 1H NMR spectrum of isomer 17. We observed that
(Z,Z)-enamide 16 was slowly converted into the major
(Z,E)-enamide 17, which may be attributed to electrostatic
repulsion between the pyridine nitrogen atom and the car-
bonyl oxygen atoms.
The mixture of 16 and 17 was treated with TMSOTf/
iPr2NEt and after subsequent O-methylation terpyridine de-
rivative 18 was obtained in 66% yield (Scheme 5).[19] This
was then oxidized with SeO2 to provide dialdehyde 19 in
69% yield. Condensation of 19 with hydroxylamine afforded
bisoxime 20. Hybrid compounds 19 and 20 were obtained
from dicarboxylic acid 15 in 42 and 30% overall yields, re-
spectively. Functionalized terpyridine derivatives 18, 19 and
20 may also serve as building blocks in supramolecular
chemistry.
In conclusion, we have developed a simple and highly
flexible protocol for the preparation of substituted 4-hydroxy-
pyridines and their corresponding nonaflate derivatives. The
efficacy and versatility of the method allowed a quick access
to fluorinated pyridines, 2,2’-bipyridines as well as 2,2’:6’,2’’-
terpyridines, a class of compounds commonly used as bio-
logical probes and in material science. The corresponding
pyridyl nonaflates can serve as precursors for the synthesis
of extended (hetero)aromatic systems as illustrated in a
Suzuki reaction. The methodology was also successfully ap-
plied to an expedient synthesis of natural products caerulo-
mycins A, E and their novel analogues. Further applications
will be described in due course.
Scheme 4. Synthesis of caerulomycins E (13) and A (14). a) SOCl2, Et3N,
CH2Cl2, 08C to RT, 12 h (82%); b) TMSOTf, iPr2NEt, 1,2-dichloro-
ethane, 1008C, 3 d; c) K2CO3, MeI, acetone, RT, 7 h (63%, 2 steps); d)
SeO2, 1,4-dioxane, 1108C, 2 d; e) NH2OH·HCl, pyridine, EtOH, 708C,
1 h.
common pyridine ring (Scheme 5). This would open new op-
portunities for the discovery of novel bioactive compounds
from privileged natural product-based libraries.[18]
Experimental Section
General procedure for the preparation of enamides 5: To a stirred solu-
tion of the corresponding acid (1.2 mmol) and Et3N (1.5–1.8 mmol) in
CH2Cl2 (1.5 mL), thionyl chloride (1.2 mmol) was added dropwise at 08C
under an argon atmosphere. The reaction was stirred for 30 min and then
a solution of amino ketones 3 or 4 (1 mmol) in CH2Cl2 (1 mL) was added
to the reaction mixture at 08C. The reaction mixture was allowed to
warm up to room temperature over night. The reaction mixture was
quenched with satd. solution of NaHCO3 (2 mL per 1 mmol of acid) and
extracted with CH2Cl2 (3ꢅ2 mL per 1 mmol), dried with Na2SO4 and
concentrated to dryness. The residue was purified by chromatography on
silica gel (hexane/ethyl acetate 8:1 ! 1:1) to afford the corresponding
enamides 5.
Scheme 5. Synthesis of novel terpyridine derivatives 18, 19, and 20. a)
SOCl2, Et3N, CH2Cl2, 08C to RT, 12 h (92%, 1:2); b) TMSOTf, iPr2NEt,
1,2-dichloroethane, 1008C, 3 d; c) K2CO3, MeI, acetone, RT, 7 h (66%, 2
steps); d) SeO2, 1,4-dioxane, 1108C, 2 d (69%); e) NH2OH·HCl, pyri-
dine, EtOH, 708C, 1 h (71%).
General procedure for cyclization of enamides for the synthesis of nona-
flates 7: Enamide 5 (1.00 mmol) was dissolved in 1,2-dichloroethane
(5.00 mL). Then iPr2NEt (4.00 mmol) and trimethylsilyl triflate (TMS-tri-
flate, 5.00 mmol) were added at 08C. The reaction flask was allowed to
warm up to room temperature and heated under reflux for 3 d and
quenched with satd. NH4Cl solution (5 mL). After extraction with di-
chloromethane (3ꢅ5 mL) the combined organic phases were dried with
Na2SO4 and evaporated to provide the crude pyridinol 6. The crude prod-
uct was dissolved in THF (10 mL) and NaH (3.00 mmol) was added
under an argon atmosphere. Nonafluorobutanesulfonyl fluoride (NfF,
It is noteworthy that the amide coupling of pyridine 2,6-
dicarboxylic acid 15 with 3 gave two bisenamides 16 and 17
in a ratio of 1:2 in 92% yield (Scheme 5). The expected
(Z,Z)-enamide 16 contains hydrogen bonds between the
amide NH and the pyridine lone pair in addition to hydro-
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H.-U. Reissig and J. Dash
2.50 mmol) was added dropwise at room temperature. The mixture was
stirred at room temperature for 7 h, monitored by TLC, and quenched by
slow addition of methanol and water (5 mL). It was extracted with ethyl
acetate (3ꢅ5 mL), dried with Na2SO4 and concentrated to dryness. The
residue was purified by chromatography on silica gel (hexane/ethyl ace-
tate) to give the corresponding nonaflate derivatives 7.
dealing with fluorinated heterocycles, see: M. Schlosser, Angew.
Chem. 2006, 118, 5558–5572; Angew. Chem. Int. Ed. 2006, 45, 5432–
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[6] H.-U. Reissig, J. Dash, PCT Int. Appl. WO 2008074474, 2008 and
H.-U. Reissig, J. Dash, Ger. Offen. DE 102006059710, 2008.
[7] The intramolecular aldol type reaction of enamides is inspired from
our earlier work on alkoxyallene-based approach to pyridines, see:
a) O. Flçgel, J. Dash, I. Brꢀdgam, H. Hartl, H. U. Reissig, Chem.
Eur. J. 2004, 10, 4283–4290; b) J. Dash, T. Lechel, H.-U. Reissig,
Org. Lett. 2007, 9, 5541–5544; C. Eidamshaus, H.-U. Reissig, Adv.
Synth. Catal. 2009, 351, 1162–1166; for a related process leading to
4-quinolones see: J. Huang, Y. Chen, A. O. King, M. Dilmeghani,
R. D. Larsen, M. M. Faul, Org. Lett. 2008, 10, 2609–2612.
[8] Y. Gao, Q. Zhang, J. Xu, Synth. Commun. 2004, 34, 909–916.
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Weintritt, A. Hupperts, J. Org. Chem. 1995, 60, 6637–6641.
[10] T. Lechel, J. Dash, I. Brꢀdgam, H.-U. Reissig, Eur. J. Org. Chem.
2008, 3647–3655.
Acknowledgements
We thank the Alexander von Humboldt-Foundation for a Postdoctoral
Fellowship (to J.D.), the Fonds der Chemischen Industrie and the Bayer
Schering Pharma AG for continuous generous support. The help of Dr.
R. Zimmer and F. Pfrengle (Freie Universitꢁt Berlin) during preparation
of this manuscript is gratefully acknowledged. We thank C. Ehm and P.
Hommes (Freie Universitꢁt Berlin) for experimental contributions.
[11] For the synthesis and application of fluorous pyridine derivatives,
see: C. Rocaboy, F. Hampel, J. A. Gladysz, J. Org. Chem. 2002, 67,
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Keywords: amides · cyclization · heterocycles · natural
products · pyridines · supramolecular chemistry
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Received: April 8, 2009
Published online: June 16, 2009
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