Carbenoid-mediated N-O bond insertion and its application in the synthesis of pyridines

Article abstract of DOI:10.1039/c2cc36009h

Highly efficient synthesis of 3-hydroxypyridines has been developed based on carbenoid-mediated N-O bond insertion. Treatment of δ-diazo oxime ethers with dirhodium complex Rh₂(tfacam)₄ rapidly provides a variety of pyridines in 5-10 minutes in good to excellent yields.

Full text of DOI:10.1039/c2cc36009h

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ARTICLE TYPE
Carbenoid-mediated N-O Bond Insertion and its Application in the
Synthesis of Pyridines
Xinxin Qi, Lu Dai and Cheol-Min Park*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
remarkable example of N-O bond insertion on isoxazoles and its
40 application to pyridine synthesis.10 In our approach for
intramolecular carbenoid-mediated N-O bond insertion of oxime
ethers, it is noteworthy that the reaction could potentially lead to
two competitive pathways depending on the configuration of
oxime ethers; a) azomethine ylide formation for anti-isomer. b)
45 N-O bond insertion for syn-isomer (eqn (1)). Indeed, the former
has been reported by Padwa and coworkers in which
intramolecular reaction of carbenoid with anti-aldoxime ether
leads to formation of azomethine ylide, which further participates
in 1,3-dipolar cycloaddition.11 We reasoned that this pathway
50 may be suppressed and shunted to N-O bond insertion pathway
by employing syn-isomers. Herein, we wish to report successful
development of this strategy leading to efficient synthesis of 3-
hydroxypyridines.
Highly efficient synthesis of 3-hydroxypyridines has been
developed based on carbenoid-mediated N-O bond insertion.
Treatment of δ-diazo oxime ethers with dirhodium complex
Rh2(tfacam)4 rapidly provides a variety of pyridines in 5-10
10 minutes in good to excellent yields.
Pyridines represent a highly valuable class of azacycles, which
are frequently found in bioactive natural products,
pharmaceuticals, and functional materials.1 As a result, the
development of more efficient synthesis of pyridines continues to
15 draw a great deal of interest from the synthetic community.2
Traditional synthesis of pyridines typically relies on condensation
of amine and carbonyl compounds, which often results in poor
regiochemical control and narrow substitution pattern.3 Over the
years, development of new methods based on cycloaddition
20 reactions and multi-component couplings have been reported.4
Also, transition metal-catalyzed reactions have received much
attention.5
In our recent efforts, we have focused to investigate the
reactivity of α-oximino carbenoids.6 The versatile reactivity of
25 these carbenoid species allowed us to develop the synthesis of
various N-heterocycles; pyrroles via [3+2] cycloaddition,6 2H-
azirines and 2-isoxazolines via 1,5-hydride shift,7 2-
alkoxy/aryloxy-2H-azirines via N-O bond insertion,8 and 2H-
azirines and pyrroles via tandem Wolff rearrangement.9 In
30 particular, the observation of facile N-O bond insertion upon
photolysis of α-diazo oxime ethers prompted us to further
investigate the utility of this novel bond forming process.8 We
reasoned that construction of 6-membered azacycles may be
realized if the analogous N-O bond insertion is successfully
35 developed with δ-diazo oxime ethers.
55
Our synthetic attempts began with screening various catalysts
employing 1a as a substrate (Table 1). The configuration of the
oxime ether was unambiguously determined based on the X-ray
structure of the 4-chlorophenyl analogue.12 While copper
complexes generally provided the desired product in poor yields,
60 dirhodium catalysts gave more promising results. It was noted
that the ability of dirhodium catalysts to promote the N-O bond
insertion highly depends on the nature of their ligands. Whereas
Rh2(OAc)4 in refluxing DCE gave 3-hydroxypyridine 2a in 58%
yield, dirhodium complexes with bulkier ligands resulted in
65 diminished yields (Table 1, entries 5-7). Electron deficient
catalysts such as Rh2(tfa)4 and Rh2(pfb)4 gave 2a in comparable
yields to Rh2(OAc)4. To our delight, the use of Rh2(tfacam)4
provided 2a in quantitative yield. Further optimization of the
reaction conditions revealed that the reaction proceeds with
70 greater efficiency by employing higher temperature with shorter
reaction time; 80°C, 5 min, 100% vs. 50 °C, 1h, 74% (Table 1,
entries 10 and 11, respectively). With respect to solvent effects,
N-O bond insertion has been rarely documented in the
literature. It was only recently that Davies et. al reported a
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

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Table 1 Optimization of reaction conditions
Table 2 Substrate scope of 3-hydroxy pyridine synthesisa
Entry
Catalysta
Solventb
Temp
(°C)
time
Yieldc
(%)
1d
2d
3d
4
Cu(hfacac)2
Cu(OTf)2
DCE
80
80
80
80
80
80
80
80
80
80
50
80
110
1h
25
19
17
58
40
35
51
59
59
100
74
84
76
DCE
1h
2a (92%)
2b (75%)
2e (91%)
2c (64%)
CuOTf
DCE
1h
Rh2(OAc)4
Rh2(Piv)4
DCE
10 min
20 min
20 min
30 min
10 min
10 min
5 min
1h
5
DCE
2d (65%)
2f (83%)
2i (88%)
6
Rh2(Oct)4
Rh2(esp)2
DCE
7
DCE
8
Rh2(tfa)4
DCE
9
Rh2(pfb)4
DCE
10
11
12
13
Rh2(tfacam)4
Rh2(tfacam)4
Rh2(tfacam)4
Rh2(tfacam)4
DCE
DCE
2g (80%)
2j (72%)
2h (87%)
Benzene
Toluene
5 min
5 min
a hfacac = trifluoroacetylacetonate, tfa = trifluoroacetate, pfb =
2k (63%)
2n (86%)
2l (62%)
2o (91%)
perfluorobutyrate, Piv = pivaloate, Oct = octanoate, esp = α,α,α′,α′-
tetramethyl-1,3-benzenedipropionate, tfacam = trifluoroacetamide. b
DCE = dichloroethane. c yields determined by NMR vs. standard. d
5
mol% catalyst.
2m (60%)
DCE turned out to be an optimal solvent (Table 1, entries 10 vs.
12 and 13).
a Isolated yields.
5
With the optimal conditions in hand, we turned our attention to
examine the substrate scope of the reaction. As shown in Table 2,
the intramolecular N-O bond insertion proceeded smoothly to
give a variety of 3-hydroxypyridines in good to excellent yields.
Substrates with common electron withdrawing groups (R3) were
30 expulsion of dinitrogen proceeds to undergo N-O bond insertion
to give intermediate B. For substrates with R3 = ester, ketone, and
phosphonate, elimination of MeOH occurs to form pyridines
retaining the R3 moieties. In contrast, for the substrate with R3 =
sulfone, loss of sulfonyl group leads to formation of 2-
35 methoxypyridine 2d.
10 tolerated well to afford pyridines substituted with the
corresponding functional groups. It is noteworthy that 1d bearing
sulfonyl group provided 2-methoxy-3-hydroxypyridine 2d
resulting from elimination of the sulfonyl group in place of the
methoxy group. Survey of aryl groups with various substituents
15 indicated that the reaction is quite tolerant to steric and electronic
influences (2e-i). In addition, substrates with 2-naphthyl (2j) and
heteroaryl groups such as 2-thienyl (2k) and 2-furyl (2l) moieties
smoothly participated in the reaction to give the corresponding
pyridines in good yields. Encouraged by these results, we also
20 examined those bearing alkyl and alkenyl groups for R1.
Substrates with both tert-Bu and 1-cyclohexenyl groups provided
2m and 2n in 86% and 60% yields, respectively. The cyclization
reaction remained efficient even with substitution on the tether,
providing 2o in 91% yield.
Scheme 1 Proposed reaction mechanism.
In summary, we have developed efficient synthesis of 3-
40 hydroxypyridines based on N-O bond insertion of δ-diazo oxime
ethers. Competitive formation of azomethine ylide could be
25
Based on the observation, a plausible mechanism for the
formation of 3-hydroxypyridine is proposed in Scheme 1. The
reaction initiated by formation of dirhodium carbenoid A with

Page 3 of 4
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8. X. Qi, X. Xu and C.-M. Park, Chem. Commun., 2012, 48, 3996-
3998.
70 9. Y. Jiang, W. C. Chan and C.-M. Park, J. Am. Chem. Soc., 2012, 134,
4104-4107.
10. (a) J. R. Manning and H. M. L. Davies, J. Am. Chem. Soc., 2008,
130, 8602-8603; (b) J. R. Manning and H. M. L. Davies,
Tetrahedron, 2008, 64, 6901-6908.
75 11. A. Padwa, D. C. Dean, M. H. Osterhout, L. Precedo and M. A.
Semones, J. Org. Chem., 1994, 59, 5347-5357.
suppressed by controlling the configuration of oxime ethers and
shunted to the N-O bond insertion pathway. This transformation
features broad functional group tolerance, high efficiency and
very rapid conversion under mild reaction conditions with low
catalyst loading. In addition, the protocol allows for access to 2-
alkoxy-3-hydroxypyridines by employing substrates bearing
sulfonyl group (for example, 2d).
5
We gratefully acknowledge Nanyang Technological University
for funding of this research. We thank Dr. Yongxin Li for X-ray
12. CCDC 895021 (1h) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge
Crystallographic
Data
Centre
via
10 crystallographic analysis.
80
http://www.ccdc.cam.ac.uk/cgi-bin/catreq.cgi.
Notes and references
Division of Chemistry and Biological Chemistry,
School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637371,
15 Singapore.; Fax: +65-6513-2748; Tel: +65-6513-2748; E-mail:
cmpark@ntu.edu.sg
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
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Efficient synthesis of pyridines has been developed based on carbenoidꢀmediated NꢀO bond
insertion of δꢀdiazo oxime ethers.