Concise synthesis of bicyclic pyridinol antioxidants

Article abstract of DOI:10.1021/ol102217c

The recently reported bicyclic pyridinols 1 and 2 are highly effective antioxidants exhibiting 88- and 28-fold greater potency, respectively, than α-tocopherol when assayed for their ability to suppress the autoxidation of methyl linoleate. Described herein is a short, economical, and scalable strategy for the synthesis of this novel group of antioxidants, as well as analogues 3-6. Key reactions involved the cyclocondensation reaction of lactam acetals with enaminone 7 and selective functionalizaton of the heterocyclic systems.

Full text of DOI:10.1021/ol102217c

ORGANIC
LETTERS
2
010
Vol. 12, No. 22
189-5191
Concise Synthesis of Bicyclic Pyridinol
Antioxidants
5
Jun Lu, Xiaoqing Cai, and Sidney M. Hecht*
Center for BioEnergetics, The Biodesign Institute, and Department of Chemistry,
Arizona State UniVersity, Tempe, Arizona 85287, United States
sidney.hecht@asu.edu
Received September 15, 2010
ABSTRACT
The recently reported bicyclic pyridinols 1 and 2 are highly effective antioxidants exhibiting 88- and 28-fold greater potency, respectively, than
r-tocopherol when assayed for their ability to suppress the autoxidation of methyl linoleate. Described herein is a short, economical, and
scalable strategy for the synthesis of this novel group of antioxidants, as well as analogues 3-6. Key reactions involved the cyclocondensation
reaction of lactam acetals with enaminone 7 and selective functionalizaton of the heterocyclic systems.
4
,5
The importance of antioxidants in human health has been
attracting increasing attention as accumulating evidence has
demonstrated that reactive oxygen species and other free
radicals are implicated in a variety of biological phenomena,
including aging, mutation, carcinogenesis, and other dis-
the oxidation of methyl linoleate in benzene solution.
However, reported syntheses of the bicyclic pyridinols having
annulated five-membered or six-membered rings required 11
and 6 steps, respectively, and proceeded in moderate yields.
The key step in the reported annulation process consists of
an intramolecular inverse electron demand Diels-Alder
reaction in diphenyl ether at reflux. From a synthetic point
of view, the synthesis of azaindole and dihydropyrrolopy-
ridine systems presents a unique challenge. A frequently
1
,2
eases. R-Tocopherol (R-TOH), a form of vitamin E, is
perhaps the best known natural antioxidant. By transferring
its phenolic H atom to propagating lipid radicals, it quenches
4,5
3
6,7
lipid peroxidation. The development of synthetic radical-
scavenging antioxidants with activity superior to R-TOH is
an ongoing aim of many studies.
employed strategy for azaindole synthesis starts with a
substituted pyridine and appends a pyrrole ring. However,
the electron-deficient nature of the pyridine ring limits the
6-Amino-3-pyridinols have been synthesized and demon-
8
strated to be very efficient antioxidants. In particular, the bicyclic
pyridinols 1 and 2 (Figure 1) displayed 88- and 28-fold larger
inhibition rate constants, respectively, than R-TOH in quenching
application of this method for indole formation. Another
(
4) Wijtmans, M.; Pratt, D. A.; Valgimigli, L.; DiLabio, G. A.; Pedulli,
G. F.; Porter, N. A. Angew. Chem., Int. Ed. 2003, 42, 4370–4373
5) Wijtmans, M.; Pratt, D. A.; Brinkhorst, J.; Serwa, R.; Valgimigli,
L.; Pedulli, G. F.; Porter, N. A. J. Org. Chem. 2004, 69, 9215–9223
(6) Popowycz, F.; Routier, S.; Joseph, B.; M e´ rour, J.-Y. Tetrahedron
2007, 63, 1031–1064
.
(
(
(
(
1) Kohen, R.; Nyska, A. Toxicol. Pathol. 2002, 30, 620–650
2) Marnett, L. J. Carcinogenesis 2000, 21, 361–370
3) Burton, G. W.; Ingold, K. U. Acc. Chem. Res. 1986, 19, 194–201.
.
.
.
.
10.1021/ol102217c  2010 American Chemical Society
Published on Web 10/12/2010

Scheme 2. Synthesis of Pyridinol 1
Figure 1. Structures of R-tocopherol and tocopherol-like antioxi-
dants 1 and 2.
strategy applied to the preparation of azaindoles is through
a coupling reaction followed by intramolecular cycliza-
9
,10
tion.
The dihydropyrrolopyridine structure is usually
generated from the azaindole by Pd-catalyzed hydrogenation
1
1
which typically proceeds sluggishly.
In the context of research projects ongoing in our labora-
tory, we sought to develop a concise, practical, and economi-
cal route to this novel group of antioxidants, which might
also be amenable to the facile preparation of structural
analogues. A pyridine structure with a fused five- or six-
membered ring was constructed in one step by the cyclo-
condensation of lactam/amide acetals with enaminone 7. The
bicyclic structures so obtained were then easily functionalized
to afford several desired analogues.
dihydro-1H-pyrrolo[2,3-b]pyridine (9) was prepared in 62%
yield by treatment of enaminone 7 with lactam acetal 8 in
14
t-BuOH/t-BuONa at 90 °C. The bromination of 9 was first
attempted using NBS as the bromination reagent in concen-
1
5
2 4
trated H SO /TFA. However, the bromination conditions
proved to be too harsh, affording dibrominated byproduct
as well as the desired monobrominated product. Since these
were difficult to separate, another method was sought. 1,3-
Dibromo-5,5-dimethylhydantoin (13) was chosen for the
1
6
selective bromination of 9. The reaction was carried out
at 0 °C in chloroform and afforded 12 in 82% yield; no
dibrominated byproduct was observed. In the final step, the
hydroxylation of 12 to afford pyridinol 1 could be achieved
Scheme 1. Retrosynthetic Analyses of Pyridinols 1 and 2
5
as reported previously, albeit only in modest yield.
The low yield of the final step prompted us to consider
other strategies for the conversion of bromide 12 to the
corresponding pyridinol 1. The hydroxylation of aryl
halides in high yields has been reported by Buchwald et
1
7
al. by using KOH in the presence of a Pd catalyst. This
approach was attempted using compound 12 (Scheme 3).
Due to the instability of 1 toward air oxidation, we also
(
7) Popowycz, F.; M e´ rour, J.-Y.; Joseph, B. Tetrahedron 2007, 63, 8689–
707.
8) Song, J. J.; Reeves, J. T.; Gallou, F.; Tan, Z.; Yee, N. K.; Senanayake,
C. H. Chem. Soc. ReV. 2007, 36, 1120–1132.
9) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689–
8
(
(
6
690.
(
(
10) M e´ rour, J.-Y.; Joseph, B. Curr. Org. Chem. 2001, 5, 471–506.
11) Clemo, G. R.; Swan, G. A. J. Chem. Soc. 1945, 603–607.
A retrosynthetic analysis, shown in Scheme 1, suggested that
pyridinols 1 and 2 could be prepared from 1,4,6-trimethylpyr-
rolo[2,3-b]pyridine (9) or 1,5,7-trimethylpiperidinyl[2,3-b]py-
ridine (11) by functional group transformations. The formation
of 9 and 11 was envisioned by a cyclocondensation reaction of
enaminone 7 with lactam acetals 8 and 10, respectively.
The synthesis of 1 is shown in Scheme 2; the formation
of the dihydropyrrolopyridine (azaindoline) intermediate
constitutes the key step. Accordingly, 1,4,6-trimethyl-2,3-
(12) Gao, Y.; Zhang, Q.; Xu, J. Synth. Commun. 2004, 34, 909–916.
(
13) McBride, L. J.; Kierzek, R.; Beaucage, S. L.; Caruthers, M. H.
J. Am. Chem. Soc. 1986, 108, 2040–2048.
(14) This reaction was reported previously, although 9 was obtained in
only low yield (24%) by treatment of 7 with 8 at 120–130 °C. See: Jotwani,
P.; Singh, J.; Anand, N. Indian J. Chem. 1988, 27B, 166.
12
13
(
15) (a) Duan, J.; Zhang, L. H.; Dolbier, W. J., Jr. Synlett 1999, 1245–
1246. (b) Mal, P.; Lourderaj, U.; Venugopalan, P. P.; Moorthy, J. N.;
Sathyamurthy, N. J. Org. Chem. 2003, 68, 3446–3453.
(
16) Alam, A.; Takaguchi, Y.; Ito, H.; Yoshida, T.; Tsuboi, A.
Tetrahedron 2005, 6, 1909–1918.
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Org. Lett., Vol. 12, No. 22, 2010

achieved in 5 steps and 18.1% overall yield, as compared
to the previous reported route which required 11 total steps
and provided 1 in 5.8% yield. Further, the new route
proceeds through a stable O-acetate derivative that can
be stored conveniently.
Scheme 3. Synthesis of 1 and the Corresponding Analogues
5
Using an Alternative Route
Pyridinol 2, having a fused six-membered ring, was
synthesized using a similar strategy (Scheme 4). The
Scheme 4
.
Synthesis of Pyridinols with Fused Six-Membered
Rings
attempted to convert this compound to its acetate ester 4
following the in situ formation of 1. This strategy would
also permit easy scale-up and storage of the intermediates
prior to conversion to the unstable pyridinol. At first, 12
was treated with KOH in 1:1 H
presence of Pd dba and ligand 14 at 100 °C, followed
by the addition of Ac O. Unexpectedly, we obtained
-azaindole 6 in 45% yield, rather than 7-azaindoline 4.
2
O-1,4-dioxane in the
2
3
2
7
Presumably, 4 was quickly oxidized to 6 under Pd-
catalyzed hydroxylation conditions in spite of efforts to
maintain an inert atmosphere. Although 6 was obtained
unexpectedly, we reasoned that its corresponding pyridinol
cyclocondensation of 7 with 10 afforded 11 in 59% yield.
Bromide 15 was prepared from 11 in 86% yield. Hydroxy-
lation of 15, followed by acetylation of the nascent OH
group, afforded 5 in 55% yield. Finally, pyridinol 2 was
3
might also prove to be an interesting antioxidant.
Accordingly, pyridinol 3 was prepared from 6 by hy-
drolysis with K CO in methanol in 97% yield. The desired
-azaindoline 4 was prepared readily from azaindole 6
4
obtained by treatment with LiAH in 95% yield. This method
2
3
provided 2 in 26.5% overall yield (four total steps), while 2
was obtained previously in 3.3% overall yield over six steps.
In summary, we have developed an efficient strategy for
the synthesis of bicyclic pyridinols. To overcome their
instability, the corresponding acetate esters were prepared.
Two 7-azaindole analogues were also prepared by this
procedure and are expected to have interesting properties as
novel antioxidants. The biological evaluation of these and
related antioxidants is in progress in our laboratory.
7
by reduction. The reduction of azaindole has been
achieved in low yield previously by Pd-catalyzed hydro-
1
1
genation. Since NaCNBH
3
in acetic acid media has
recently been reported to effect the facile reduction of
1
8
indole to the corresponding indoline, we applied this
method in our azaindole system. Compound 4 was
obtained in 92% yield. For deacetylation to provide 1,
4
we employed LiAH in THF to remove the acetyl group
reductively rather than by hydrolysis, so that this reaction
could be carried out at low temperature to facilitate
isolation of the final product. The synthesis of 1 was thus
Acknowledgment. This work was supported in part by a
grant from the Friedreich’s Ataxia Research Alliance
FARA).
(
(
17) Anderson, K. W.; Ikawa, T.; Tundel, R. E.; Buchwald, S. L. J. Am.
Chem. Soc. 2006, 128, 10694–10695.
18) (a) Yang, J. S.; Liau, K. L.; Li, C. Y.; Chen, M. Y. J. Am. Chem.
Supporting Information Available: Experimental details
and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(
Soc. 2007, 129, 13183–13192. (b) Papageorgiou, G.; Corrie, J. E. T.
Tetrahedron 2007, 63, 9668–9676. (c) Zhang, Q.; Peng, Y.; Wang, X. I.;
Keenan, S. M.; Arora, S.; Welsh, W. J. J. Med. Chem. 2007, 50, 749–754.
OL102217C
Org. Lett., Vol. 12, No. 22, 2010
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