Synthesis of 3-hydroxypyridines using ruthenium-catalyzed ring-closing olefin metathesis

Article abstract of DOI:10.1021/ol8023117

(Chemical Equation Presented) New synthetic routes to substituted 3-hydroxypyridines 6 are presented. Ring-closing olefin metathesis (RCM)/elimination and RCM/oxidation/ deprotection of nitrogen-containing dienes 4 are the key processes of the routes. An

Full text of DOI:10.1021/ol8023117

ORGANIC
LETTERS
2009
Vol. 11, No. 3
515-518
Synthesis of 3-Hydroxypyridines Using
Ruthenium-Catalyzed Ring-Closing
Olefin Metathesis
Kazuhiro Yoshida,* Fumihiro Kawagoe, Kazushi Hayashi, Shingo Horiuchi,
Tsuneo Imamoto,* and Akira Yanagisawa*
Department of Chemistry, Graduate School of Science, Chiba UniVersity, Yayoi-cho,
Inage-ku, Chiba 263-8522, Japan
kyoshida@faculty.chiba-u.jp; imamoto@faculty.chiba-u.jp; ayanagi@faculty.chiba-u.jp
Received October 6, 2008
ABSTRACT
New synthetic routes to substituted 3-hydroxypyridines 6 are presented. Ring-closing olefin metathesis (RCM)/elimination and RCM/oxidation/
deprotection of nitrogen-containing dienes 4 are the key processes of the routes. An application of RCM/oxidation/deprotection to the synthesis
of 3-aminopyridine 13f is also described.
3-Hydroxypyridines are important structural units found in
numerous bioactive compounds.1 However, the lack of
general synthetic methods for 3-hydroxypyridines has ham-
pered in-depth studies of them.2
and are limited to the synthesis of 2-pyridones.12
We have recently focused our efforts on the develop-
ment of new methods13 for the synthesis of carbocyclic
aromatic compounds using RCM and have reported that
substituted phenols 3 can be synthesized in excellent yields
The synthesis of heterocyclic aromatic compounds using
ring-closing olefin metathesis (RCM), which is one of the
most powerful reactions to form carbon-carbon double
bonds in cyclic compounds,3,4 has attracted much attention.5,6
However, the majority of the reports concerns the synthesis
of five-membered heterocyclic aromatic compounds, such
as furans,7 benzofurans,8 pyrroles,9 and indoles.10The syn-
thesis of six-membered heterocyclic aromatic compounds
using RCM is little reported, and most of the available
reports concern the construction of quinoline rings.11
Reports on the construction of pyridine rings are even rarer
(4) For reports on the pharmaceutical application of RCM on a
multikilogram scale (>400 kg of cyclized product), see: (a) Nicola, T.;
Brenner, M.; Donsbach, K.; Kreye, P. Org. Process Res. DeV. 2005, 9,
513–515. (b) Yee, N. K.; Farina, V.; Houpis, I. N.; Haddad, N.; Frutos,
R. P.; Gallou, F.; Wang, X.-J.; Wei, X.; Simpson, R. D.; Feng, X.; Fuchs,
V.; Xu, Y.; Tan, J.; Zhang, L.; Xu, J.; Smith-Keenan, L. L.; Vitous, J.;
Ridges, M. D.; Spinelli, E. M.; Johnson, M.; Donsbach, K.; Nicola, T.;
Brenner, M.; Winter, E.; Kreye, P.; Samstag, W. J. Org. Chem. 2006, 71,
7133–7145. (c) Tsantrizos, Y. S.; Ferland, J.-M.; McClory, A.; Poirier, M.;
Farina, V.; Yee, N. K.; Wang, X.-J.; Haddad, N.; Wei, X.; Xu, J.; Zhang,
L. J. Organomet. Chem. 2006, 691, 5163–5171.
(5) For a review, see: Donohoe, T. J.; Orr, A. J.; Bingham, M. Angew.
Chem., Int. Ed. 2006, 45, 2664–2670.
(6) (a) Arisawa, M.; Nishida, A.; Nakagawa, M. J. Organomet. Chem.
2006, 691, 5109–5121. (b) Donohoe, T. J.; Fishlock, L. P.; Procopiou, P. A.
Chem.sEur. J. 2008, 14, 5716–5726.
(1) Schmidt, A. Curr. Org. Chem. 2004, 8, 653–670.
(2) (a) Lu, J.-Y.; Arndt, H.-D. J. Org. Chem. 2007, 72, 4205–4212, and
references cited therein. (b) Lu, J.-Y.; Keith, J. A.; Shen, W.-Z.; Schuermann,
M.; Preut, H.; Jacob, T.; Arndt, H.-D. J. Am. Chem. Soc. 2008, 130, 13219–
13221.
(7) For reports on the RCM/elimination protocol, see: (a) Bassindale,
M. J.; Hamley, P.; Leitner, A.; Harrity, J. P. A. Tetrahedron Lett. 1999,
40, 3247–3250. (b) Donohoe, T. J.; Fishlock, L. P.; Lacy, A. R.; Procopiou,
P. A. Org. Lett. 2007, 9, 953–956. (c) Donohoe, T. J.; Kershaw, N. M.;
Orr, A. J.; Wheelhouse, K. M. P.; Fishlock, L. P.; Lacy, A. R.; Bingham,
M.; Procopiou, P. A. Tetrahedron 2008, 64, 809–820. (d) Donohoe, T. J.;
Ironmonger, A.; Kershaw, N. M. Angew. Chem., Int. Ed. 2008, 47, 7314–
7316. For a report on the RCM/oxidation protocol, see: (e) Robertson, J.;
Kuhnert, N.; Zhao, Y. Heterocycles 2000, 53, 2415–2420.
(3) For a comprehensive review, see: (a) Handbook of Metathesis;
Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, Germany, 2003. For reviews,
see: (b) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–4450. (c)
Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012–3043. (d) Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29. (e) Hoveyda, A. H.;
Zhugralin, A. R. Nature 2007, 450, 243–251
.
10.1021/ol8023117 CCC: $40.75
Published on Web 12/31/2008
2009 American Chemical Society

by RCM of 5-hydroxy-1,7-octadien-3-ones 1, followed by
dehydration-tautomerization of 5-hydroxy-2-cyclohex-
enones 2 (eq 1).13d In this paper, we report the synthesis
of 3-hydroxypyridines 6 by applying the aforementioned
method to nitrogen-containing substrates 4, where 1,6-
dihydro-2H-pyridin-3-ones 5were produced as target
intermediates of RCM (eq 2).
Table 1. Synthesis of 1,6-Dihydro-2H-pyridin-3-ones 5 by RCMa
Scheme 1
As shown in Scheme 1, our retrosynthetic analysis revealed
that substrates 4 could be prepared by the vinylation of esters
7. The synthesis of 7 was envisioned to involve the allylation
(8) For reports on the direct synthesis using RCM, see: (a) Fujimura,
O.; Fu, G. C.; Grubbs, R. H. J. Org. Chem. 1994, 59, 4029–4031. (b) van
Otterlo, W. A. L.; Morgans, G. L.; Madeley, L. G.; Kuzvidza, S.; Moleele,
S. S.; Thornton, N.; de Koning, C. B. Tetrahedron 2005, 61, 7746–7755.
(9) For reports on the RCM/elimination protocol, see: (a) Kinderman,
S. S.; Doodeman, R.; Van Beijma, J. W.; Russcher, J. C.; Tjen, K. C. M. F.;
Kooistra, T. M.; Mohaselzadeh, H.; Van Maarseveen, J. H.; Hiemstra, H.;
Schoemaker, H. E.; Rutjes, F. P. J. T. AdV. Synth. Catal. 2002, 344, 736–
748. (b) Declerck, V.; Ribiere, P.; Martinez, J.; Lamaty, F. J. Org. Chem.
2004, 69, 8372–8381. For reports on the RCM/oxidation protocol, see: (c)
Evans, P.; Grigg, R.; Monteith, M. Tetrahedron Lett. 1999, 40, 5247–5250.
(d) Dieltiens, N.; Stevens, C. V.; De Vos, D.; Allaert, B.; Drozdzak, R.;
Verpoort, F. Tetrahedron Lett. 2004, 45, 8995–8998.
a Ring-closing olefin metathesis was carried out with 4 and ruthenium
catalyst (10, 7.5 mol %) in toluene. b Isolated yield by silica gel
chromatography. c 4e was recovered in 28% yield. d 4e was recovered in
9% yield. e The yield is the sum of the yields of 5h (58%) and 11h (34%),
which would be formed by oxidizing 5h in air. f 4i was recovered in 57%
yield. g Catalyst 10 was added over 2 h. 4i was recovered in 73% yield.
h 4i was recovered in 66% yield. i 4i was recovered in 48% yield.
(10) For reports on the direct synthesis using RCM, see: (a) Arisawa,
M.; Terada, Y.; Nakagawa, M.; Nishida, A. Angew. Chem., Int. Ed. 2002,
41, 4732–4734. (b) Arisawa, M.; Terada, Y.; Takahashi, K.; Nakagawa,
M.; Nishida, A. J. Org. Chem. 2006, 71, 4255–4261.
(11) For a report on the direct synthesis using RCM, see: (a) Arisawa,
M.; Theeraladanon, C.; Nishida, A. Heterocycles 2005, 66, 683–688. For a
report on the RCM/elimination protocol, see: (b) Theeraladanon, C.;
Arisawa, M.; Nishida, A.; Nakagawa, M. Tetrahedron 2004, 60, 3017–
3035. For reports on the RCM/oxidation protocol, see: (c) Arisawa, M.;
Theeraladanon, C.; Nishida, A.; Nakagawa, M. Tetrahedron Lett. 2001, 42,
8029–8033. (d) Bennasar, M. L.; Roca, T.; Monerris, M.; García-Díaz, D.
Tetrahedron Lett. 2005, 46, 4035–4038. (e) Bennasar, M. L.; Roca, T.;
Monerris, M.; García-Díaz, D. J. Org. Chem. 2006, 71, 7028–7034.
of amino acid derivatives 8 or the coupling of allyl amines
9 with R-bromo esters. In fact, a series of 4 with various
516
Org. Lett., Vol. 11, No. 3, 2009

Table 2. Synthesis of 3-Hydroxypyridines 6 by Eliminationa
Table 3. Synthesis of 3-Hydroxypyridines 6 by Oxidation/
Deprotectiona
a Reaction was carried out with 5 and DBU (2.0 equiv) in DMF at
room temperature for 1 h. b Isolated yield by silica gel chromatography.
substitution patterns could be readily prepared with these
routes.14
The results of RCM of 4 with Grubbs’ second-generation
catalyst 1015 are summarized in Table 1.16 As expected,
cyclized products 5a-d having a p-toluenesulfonyl group
attached to nitrogen were formed in good to excellent yields
a Oxidation was carried out with 5 and DDQ (1.2 equiv) in dioxane at
room temperature for 30 min. Deprotection was carried out with 11 and
10% Pd/C (20 wt % substrate) in methanol at room temperature for 4 h
under H2 (1 atm). b Isolated yield by silica gel chromatography. c DDQ
(1.6 equiv) was used.
by the RCM of 4a-d at 60 or 80 °C (Table 1, entries 1-5).
On the other hand, the RCM of 4e having a benzyl group
attached to nitrogen resulted in corresponding cyclized
product 5e in moderate yields, together with the recovery of
a small amount of 4e (Table 1, entries 6 and 7). These results
could be attributed to deactivation of the catalyst by
coordination of the electron-rich amine moiety of 4e and 5e.17
Therefore, increasing the steric hindrance of the substituent
around the nitrogen atom was expected to affect the
conversion rate of the reaction. In fact, the bulkier the
substituent introduced at R2 position, the higher the yield of
5 (Table 1, entries 8-12). Other difficulties arose in the
formation of a tetrasubstituted double bond by RCM. When
the reaction of N-benzyl diene 4i having two methyl groups
at R1 and R5 positions was carried out at 80 °C for 30 min,
desired product 5i was obtained in only 28% yield (Table 1,
entry 13). Prolonged reaction times with slow addition of
the catalyst did not improve the results (Table 1, entry 14),
and increasing the temperature to 110 °C also gave low yields
(34-35%) (Table 1, entries 15 and 16).
(12) For reports on the RCM/elimination protocol, see: (a) Donohoe,
T. J.; Fishlock, L. P.; Procopiou, P. A. Org. Lett. 2008, 10, 285–288. (b)
Donohoe, T. J.; Fishlock, L. P.; Procopiou, P. A. Synthesis 2008, 2665–
2667. For reports on the RCM/oxidation protocol, see: (c) Chen, Y.; Zhang,
H.; Nan, F. J. Comb. Chem. 2004, 6, 684–687. (d) Stead, D.; O’Brien, P.;
Sanderson, A. J. Org. Lett. 2005, 7, 4459–4462.
(13) (a) Yoshida, K.; Imamoto, T. J. Am. Chem. Soc. 2005, 127, 10470–
10471. (b) Yoshida, K.; Kawagoe, F.; Iwadate, N.; Takahashi, H.; Imamoto,
T. Chem. Asian J. 2006, 1, 611–613. (c) Yoshida, K.; Horiuchi, S.; Iwadate,
N.; Kawagoe, F.; Imamoto, T. Synlett 2007, 1561–1564. (d) Yoshida, K.;
Toyoshima, T.; Imamoto, T. Chem. Commun. 2007, 3774–3776. (e) Yoshida,
K.; Takahashi, H.; Imamoto, T. Chem.-Eur. J. 2008, 14, 8246–8261. (f)
Yoshida, K.; Shishikura, Y.; Takahashi, H.; Imamoto, T. Org. Lett. 2008,
10, 2777–2780. (g) Yoshida, K.; Narui, R.; Imamoto, T. Chem.-Eur. J.
2008, 14, 9706–9713.
(14) See the Supporting Information for details of the synthesis of 4.
(15) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953–956. (b) Trnka, T. M.; Morgan, J. P.; Sanford, M. S.; Wilhelm,
T. E.; Scholl, M.; Choi, T.-L.; Ding, S.; Day, M. W.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 2546–2558.
(16) Bellosta and Cossy reported the formation of 1,6-dihydro-2H-
pyridin-3-one 5 by RCM in their 3-oxoazacycloalk-4-ene synthesis. See:
Taillier, C.; Hameury, T.; Bellosta, V.; Cossy, J. Tetrahedron 2007, 63,
4472–4490.
(17) Compain, P. AdV. Synth. Catal. 2007, 349, 1829–1846.
(18) Applying the same reaction conditions in Table 2 to 5e resulted in
no reaction.
Org. Lett., Vol. 11, No. 3, 2009
517

Table 2 shows the results of the elimination of 5 to yield
3-hydroxypyridines 6. After screening numerous reaction
conditions, we found that treatment of 5a with 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) in DMF at room
temperature produced the desired 3-hydroxypyridine 6a in
71% yield (Table 2, entry 1). Similarly, the reaction of 5b-d
also furnished corresponding products 6b-d in good yields
(Table 2, entries 2-4).
Scheme 2
We employed an oxidation/deprotection strategy for 5e-i,
which have a benzyl group attached to nitrogen.18 The results
are summarized in Table 3. When the oxidation of 5e was
performed with DDQ in dioxane, betaine19 11e was formed.
Treatment of 11e with a catalytic amount of palladium on
carbon under hydrogen deprotected the benzyl group to
produce desired 3-hydroxypyridine 6e in 68% yield (Table
3, entry 1).20 The generality of the oxidation/deprotection
was demonstrated in the synthesis of other 3-hydroxypy-
ridines from 5f-i, and the yields were 68-82% in two steps
(Table 3, entries 2-5).
Finally, we examined an extension of the above-mentioned
strategy to the synthesis of 3-aminopyridine 13. The oxida-
tion/deprotection of oxime 12f, which was prepared by
reacting RCM product 5f with hydroxylamine hydrochloride,
successfully furnished the corresponding 3-aminopyridine 13f
(Scheme 2).
In summary, we have presented a synthetic method for
substituted 3-hydroxypyridines 6 which involved RCM/
elimination and RCM/oxidation/deprotection of nitrogen-
containing dienes 4. RCM/oxidation/deprotection was also
confirmed to be effective for the synthesis of 3-aminopyridine
13. Considering the wide range of utility of these heterocyclic
aromatic compounds, the development of these general
synthetic methods has great significance. The method
presented in this paper offers advantages in terms of
simplicity, flexibility, and avoidance of the formation of
inseparable regioisomers.
Acknowledgment. We appreciate the financial support
from the Futaba Electronics Memorial Foundation, Research
for Promoting Technological Seeds from JST, and a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan.
(19) (a) Shapiro, S. L.; Weinberg, K.; Freedman, L. J. Am. Chem. Soc.
1959, 81, 5140–5145. (b) Muller, C.; Diehl, V.; Lichtenthaler, F. W.
Tetrahedron 1998, 54, 10703–10712. (c) Anastasia, L.; Anastasia, M.;
Allevi, P. J. Chem. Soc., Perkin Trans. 1 2001, 2404–2408.
(20) The deprotection conditions of 11 to 6 were reported by Allevi
and co-workers. See ref 19c.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL8023117
518
Org. Lett., Vol. 11, No. 3, 2009