A catalyst-controlled selective synthesis of pyridines and pyrroles

Article abstract of DOI:10.1039/c4sc00125g

We have developed a dual reaction manifold that enables the selective synthesis of both pyridines and pyrroles from the common substrates α-diazo oxime ethers. The strong propensity of 1,3-dienyl nitrenes for 4π-electrocyclization to give pyrroles could be diverted to 6π-electrocyclization via a 1,6-hydride shift or prototropic isomerization, leading to the exclusive formation of pyridines by employing metal nitrene complexes derived from α-diazo oxime ethers under Rh(ii) catalysis. Furthermore, an orthogonal catalytic system has been identified that promotes the selective formation of 1H-pyrroles from the same substrates by redirecting the reactivity of vinyl 2H-azirine intermediates. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4sc00125g

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A catalyst-controlled selective synthesis of
pyridines and pyrroles†
Cite this: Chem. Sci., 2014, 5, 2347
a
b
*
Yaojia Jiang and Cheol-Min Park
We have developed a dual reaction manifold that enables the selective synthesis of both pyridines and
pyrroles from the common substrates a-diazo oxime ethers. The strong propensity of 1,3-dienyl nitrenes
for 4p-electrocyclization to give pyrroles could be diverted to 6p-electrocyclization via a 1,6-hydride
shift or prototropic isomerization, leading to the exclusive formation of pyridines by employing metal
nitrene complexes derived from a-diazo oxime ethers under Rh(II) catalysis. Furthermore, an orthogonal
catalytic system has been identified that promotes the selective formation of 1H-pyrroles from the same
substrates by redirecting the reactivity of vinyl 2H-azirine intermediates.
Received 13th January 2014
Accepted 12th February 2014
DOI: 10.1039/c4sc00125g
www.rsc.org/chemicalscience
Metal nitrenes have drawn considerable interest due to their transition metal catalyst would lead to an alteration of their
diverse reactivity.1–5 Catalytic C–H amination based on metal chemoselectivity towards 6p-electrocyclization to provide pyri-
nitrenes has recently emerged as a powerful tool that allows the dines.32–45 In addition, the challenges included the identica-
introduction of nitrogen functionality into inert C–H bonds and tion of catalysts with the ability to catalyze sequential
efficient access to a variety of synthetically important amino formations of metal carbenes and nitrenes from a-diazo oxime
compounds.6–13 Meanwhile, through a disparate mechanism, ethers in a consecutive catalytic cycle. Furthermore, the devel-
metal nitrenes derived from aryl and vinyl azides have been opment of a catalytic platform that allows exclusive formation
shown to provide facile access to indoles and other fused of either pyridines or pyrroles46–53 from common substrates is
N-heterocycles,14–19 which are core motifs in pharmaceuticals, highly desirable. Herein, we describe the successful develop-
natural products, and functional materials.20–22 Recently, Driver ment of such a reaction manifold [eqn (1)].
et al. reported the synthesis of pyrroles and indoles by the
metal-catalyzed rearrangement of 1,3-dienyl azides and aryl
azides, respectively.23,24
Cascade reactions offer great advantages for organic
synthesis with respect to the reduction of waste, step efficiency,
and alleviating time and efforts in handling intermediates.25–29
In this regard, we have described a catalytic cascade synthesis of
pyrroles from a-diazo oxime ethers under Rh(II) catalysis.30
Encouraged by these results, we became interested in the
reactivity of 1,3-dienyl nitrenes as a platform for N-heterocycle
(1)
We began our exploration for the synthesis of pyridines by
screening various metal salts, employing a-diazo oxime ether 1a
synthesis, which could be readily accessible from a-diazo oxime as a substrate (Table 1).53–56 The use of Cu(OTf) gave pyridine 2a
ethers via in situ formation of 2H-azirines. These nitrene inter-
mediates could potentially participate in two alternative path-
ways: (a) 4p-electrocyclization,24,31 or (b) 6p-electrocyclization
via a 1,6-hydride shi or prototropic isomerization. However,
the strong propensity of 1,3-dienyl nitrenes for 4p-electro-
cyclization to give pyrroles intrigued us as to whether the
modulation of the reactivity of nitrenes with an optimal
in a moderate yield, while Ag and Co catalysts resulted in the
formation of a mixture of pyridine 2a and pyrrole 3a (entries 1–
3). To further optimize the selectivity for pyridine, we examined
Rh(II) complexes bearing ligands with different steric and elec-
tronic attributes (entries 4–7) and found that Rh(II) complexes
with both electron withdrawing and sterically bulky ligands
gave moderate yields. Gratifyingly, Rh(OAc)2 provided pyridine
2a in a 73% yield. The oxidation of dihydropyridine appears to
be rapid as there was no observation of dihydropyridine.
With the optimized reaction conditions in hand, we pro-
ceeded to survey the scope of the reaction (Table 2). First, we
examined the regioselectivity of the reaction by employing
substrate 1b bearing two different substituents (R2 and R3). The
subjection of 1b bearing methyl and isobutyl groups to the
aDivision of Chemistry and Biological Chemistry, Nanyang Technological University,
Singapore 637616, Singapore
bDepartment of Chemistry, UNIST (Ulsan National Institute of Science and
Technology), Ulsan 689-798, Korea. E-mail: cmpark@unist.ac.kr
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4sc00125g
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Table 1 Optimization of pyridine synthesis
the nitrene from reacting at the benzylic site without prior
isomerization. The potential isomerization during the forma-
tion of a 2H-azirine intermediate was ruled out by an exami-
nation of the alkene conguration of the isolated 2H-azirine
intermediate (see ESI† for NOE experiment). From these
experimental results, we propose that the reaction mechanism
is dissected into thermodynamic and kinetic pathways
depending on the type of substituents for R2 (Scheme 1). For
substrates where R2 ¼ aryl group, isomerization of the nitrene
intermediate B to C via a prototropic isomerization of the
benzylic proton provides a more thermodynamically stable
1-azatriene D. On the other hand, for those where R2 ¼ alkyl
group, a 1,6-hydride shi from the substituents syn to the
nitrenes is favored to afford kinetic 1-azatriene H.
A variety of fused bicyclic pyridines were readily prepared in
good yields by incorporating the desired size of ring into
different alkenes (Table 2, 2e–g). We also examined the tolera-
bility of the R1 group and found that various types of substitu-
ents could be accommodated (2h–k). The reaction with
substrates bearing electron-rich aryl (1h) and heteroaryl (1i)
groups proceeded smoothly to give the corresponding pyridines
in 72% and 64% yields, respectively. Also, those with vinyl and
alkyl groups reacted well to give pyridines (2j and 2k, respec-
tively). Different esters can be prepared by employing corre-
sponding oxime ethers. Thus, pyridine with a benzyl ester (2l)
could be prepared in good yield by using benzyl oxime ether.
Next, we explored the feasibility of the synthesis of pyrroles
from the same substrates, a-diazo oxime ethers. A successful
catalyst would promote multiple sequential rearrangements
initiated by the generation of carbenoid A, which undergoes
rearrangement to give vinyl azirine B. The subsequent isomer-
ization and substituent shi leads to the formation of 1H-
pyrrole 3a (Scheme 2). Due to the competitive formation of 2H-
pyrrole 3a0, the ability of a catalyst to promote the migration of
the gem-substituents on intermediate C is crucial. While
conversion was sluggish with Ni(0) providing the 2H-azirine
intermediate as the major product (Table 3, entry 1), a
substantial improvement was obtained by the use of Ni(II)
catalysts along with concomitant formation of 3a0 (entry 2,
62%). While the addition of various ligands did not signicantly
Yieldb [%]
Entrya
Catalystd
2a
3a
1
2
3
4
5
6c
7
Cu(OTf)
Ag(OAc)
53
25
28
45
57
61
73
—
38
31
—
—
—
—
Co(OAc)2
Rh2(p)4
Rh2(Piv)4
Rh2(esp)2
Rh2(OAc)4
a
Reaction conditions: 1a (0.1 mmol), catalyst (2 mol%), PhCl (1.0 mL),
130 ꢀC, 24 h. b NMR yields. c Methyl 2,2-dimethyl-5-phenyl-2H-pyrrole-4-
carboxylate (16%).
tetramethyl-1,3-benzenedipropionate, Piv ¼ pivalate.
d
p
¼
peruorobutyrate, esp
¼
a,a,a0,a0-
Table 2 Substrate scope of pyridine synthesisa
a
Reaction conditions: 1 (0.2 mmol), catalyst (2 mol%), PhCl (2.0 mL),
b
130 ꢀC, 24 h. Benzyl oxime ether.
reaction conditions led to the formation of 2b as a single isomer
in which the C–N bond formation occurred at the methyl group,
which is syn to the nitrene. To our surprise, 1d bearing a p-
bromobenzyl group in place of an isobutyl group gave 2d,
resulting from the reaction at the benzylic site. This observation
clearly rules out a reaction mechanism based on a direct C–H
insertion because of the geometric constraint, which prevents Scheme 1 Proposed reaction mechanism for pyridine formation.
2348 | Chem. Sci., 2014, 5, 2347–2351
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Table 4 Substrate scope of pyrrole synthesisa
Scheme 2 Proposed reaction mechanism for 1H-pyrrole formation.
Table 3 Optimization of pyrrole synthesis
Yieldb [%]
Entrya
Catalystf
3a
3a0
2a
1c,d
2
Ni(cod)2/PPh3
Ni(acac)2
Ni(acac)2/dppf
Ni(acac)2/dppe
NiCl2(dppp)
Ni(acac)2/PPh3
Ni(acac)2/P(oTol)3
NiCl2(PPh3)2
10
62
60
60
66
78
67
82
11
13
23
6
—
—
6
—
—
—
—
21
—
—
—
3e
4d
5e
6d
7d
8
6
a
Reaction conditions: 1a (0.1 mmol), catalyst (10 mol%), PhCl (1.0 mL),
130 ꢀC, 36 h. b NMR yields. c Methyl 2-(2-methylprop-1-en-1-yl)-3-phenyl-
d
e
2H-azirine-2-carboxylate (72%). 20 mol% ligand. 10 mol% ligand.
f
cod
¼
cyclooctadiene, acac
¼
acetylacetonate, dppe
¼
1,2-
bis(diphenylphosphino)ethane, dppp
¼
1,3-bis(diphenylphosphino)
propane, dppf ¼ 1,10-bis(diphenylphosphanyl)ferrocene, oTol ¼ tri(o-
tolyl)phosphine.
improve the yield, we were gratied to nd that the use of NiCl2
with PPh3 as ligand gave 3a in 82% yield (entry 8).
With the optimized conditions in hand, we surveyed the
substrate scope of the synthesis of pyrroles (Table 4). Overall,
the pyrrole formation proceeded smoothly with good to excel-
lent yields. First, we examined the migratory aptitude of the
germinal substituents of the intermediate 2H-pyrroles. While
a
Reaction conditions: 1 (0.2 mmol), catalyst (10 mol%), PhCl (2.0 mL),
130 ꢀC, 36 h.
substrates bearing similar primary alkyl substituents resulted group participates in selective migration (3j). The examination
in the formation of a mixture (3b and 3bb), selective migration of electronic inuence on the migratory aptitude revealed that
was observed with more disparate substituents such as t-Bu and the migration of electron decient substituents is disfavored
benzylic groups (3c and 3d). In contrast to Rh(II) catalysis, it is of (3k, 3l vs. 3m). Also, the reaction with a heterocyclic substrate
note that the formation of pyridine 2d was completely sup- proceeds selectively to provide the pyrrole with a heterocyclic
pressed under Ni(II) catalysis. Bicyclic pyrroles can be readily substituent (3n). The reaction also proceeded well with various
prepared by employing cyclic substrates (3e, 3f, 3h, and 3i). types of substituents for R1 such as aryl, heteroaryl, and alkyl
Consistent with the migratory aptitude, vinyl groups (regardless groups (3o–r).
of being acyclic or endocyclic) smoothly undergo migration over
In summary, a dual reaction manifold that allows for the
the alkyl groups (3g–i). It is noteworthy that an indole 3h was selective synthesis of both pyridines and pyrroles from the
formed through spontaneous oxidation. Likewise, an alkyne common substrates a-diazo oxime ethers has been developed.
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Our mechanistic study indicates the pyridine formation is 24 H. Dong, M. Shen, J. E. Redford, B. J. Stokes, A. L. Pumphrey
initiated by a 1,6-hydride shi or prototropic isomerization, and T. G. Driver, Org. Lett., 2007, 9, 5191–5194.
depending on the type of substituents. The reaction scope of 25 P. F. Xu and W. Wang, Catalytic Cascade Reactions, Wiley,
these transformations demonstrates that a variety of diverse 2013.
structures of these important N-heterocycles are readily acces- 26 L.-Q. Lu, J.-R. Chen and W.-J. Xiao, Acc. Chem. Res., 2012, 45,
sible from a-diazo oxime ethers with high efficiency.
1278–1293.
¨
27 T. J. J. Muller, Metal Catalyzed Cascade Reactions, Springer,
2010.
Acknowledgements
28 C. Grondal, M. Jeanty and D. Enders, Nat. Chem., 2010, 2,
167–178.
29 K. C. Nicolaou, D. J. Edmonds and P. G. Bulger, Angew.
Chem., Int. Ed., 2006, 45, 7134–7186.
30 Y. Jiang, W. C. Chan and C.-M. Park, J. Am. Chem. Soc., 2012,
134, 4104–4107.
We gratefully acknowledge UNIST (Ulsan National Institute of
Science and Technology) and Nanyang Technological Univer-
sity. We thank Wei Chuen Chan for the assistance with prepa-
ration of several substrates.
31 W. Hinz, R. Alan Jones, S. U. Patel and K. Mary-Helen,
Tetrahedron, 1986, 42, 3753–3758, in part.
32 N. S. Y. Loy, A. Singh, X. Xu and C.-M. Park, Angew. Chem.,
Int. Ed., 2013, 52, 2212–2216.
33 D. G. Stark, L. C. Morrill, P.-P. Yeh, A. M. Z. Slawin,
T. J. C. O'Riordan and A. D. Smith, Angew. Chem., Int. Ed.,
2013, 52, 11642–11646.
Notes and references
1 G. Dequirez, V. Pons and P. Dauban, Angew. Chem., Int. Ed.,
2012, 51, 7384–7395.
2 J. F. Berry, Dalton Trans., 2012, 41, 700–713.
3 C. Wentrup, Acc. Chem. Res., 2011, 44, 393–404.
4 D. Karila and R. H. Dodd, Curr. Org. Chem., 2011, 15, 1507– 34 Z. Shi and T.-P. Loh, Angew. Chem., Int. Ed., 2013, 52, 8584–
1538. 8587.
5 N. Gritsan and M. Platz, Photochemistry of azides: the azide/ 35 C.-H. Lei, D.-X. Wang, L. Zhao, J. Zhu and M.-X. Wang, J. Am.
nitrene interface, John Wiley & Sons Ltd, 2010. Chem. Soc., 2013, 135, 4708–4711.
6 J. L. Roizen, M. E. Harvey and B. J. Du, Acc. Chem. Res., 2012, 36 J. M. Neely and T. Rovis, J. Am. Chem. Soc., 2012, 135, 66–69.
45, 911–922.
37 W. Gati, M. M. Rammah, M. B. Rammah, F. Couty and
G. Evano, J. Am. Chem. Soc., 2012, 134, 9078–9081.
38 C. Wang, X. Li, F. Wu and B. Wan, Angew. Chem., Int. Ed.,
2011, 50, 7162–7166.
39 M. Z. Chen and G. C. Micalizio, J. Am. Chem. Soc., 2011, 134,
1352–1356.
7 T. A. Ramirez, B. Zhao and Y. Shi, Chem. Soc. Rev., 2012, 41,
931–942.
8 R. T. Gephart and T. H. Warren, Organometallics, 2012, 31,
7728–7752.
9 H. Lu and X. P. Zhang, Chem. Soc. Rev., 2011, 40, 1899–1909.
10 F. Collet, C. Lescot and P. Dauban, Chem. Soc. Rev., 2011, 40, 40 I. Nakamura, D. Zhang and M. Terada, J. Am. Chem. Soc.,
1926–1936.
2010, 132, 7884–7886.
11 C.-M. Che, V. K.-Y. Lo, C.-Y. Zhou and J.-S. Huang, Chem. Soc. 41 T. Sakai and R. L. Danheiser, J. Am. Chem. Soc., 2010, 132,
Rev., 2011, 40, 1950–1975.
13203–13205.
12 F. Collet, R. H. Dodd and P. Dauban, Chem. Commun., 2009, 42 F. Sha and X. Huang, Angew. Chem., Int. Ed., 2009, 48, 3458–
5061–5074.
3461.
13 R. Skouta and C.-J. Li, Tetrahedron, 2008, 64, 4917–4938.
14 K. Okamoto, T. Oda, S. Kohigashi and K. Ohe, Angew. Chem.,
Int. Ed., 2011, 50, 11470–11473.
43 S. Liu and L. S. Liebeskind, J. Am. Chem. Soc., 2008, 130,
6918–6919.
44 D. A. Colby, R. G. Bergman and J. A. Ellman, J. Am. Chem.
Soc., 2008, 130, 3645–3651.
´
´
15 I. Cano, E. Alvarez, M. C. Nicasio and P. J. Perez, J. Am. Chem.
Soc., 2011, 133, 191–193.
´
´
´
´
´
45 J. Barluenga, M. A. Fernandez-Rodrıguez, P. Garcıa-Garcıa
16 T. G. Driver, Org. Biomol. Chem., 2010, 8, 3831–3846.
and E. Aguilar, J. Am. Chem. Soc., 2008, 130, 2764–2765.
17 X. Li, Y. Du, Z. Liang, X. Li, Y. Pan and K. Zhao, Org. Lett., 46 M. Zhang, H. Neumann and M. Beller, Angew. Chem., Int. Ed.,
2009, 11, 2643–2646.
2013, 52, 597–601.
18 G. Hajos and Z. Riedl, Curr. Org. Chem., 2009, 13, 791–809.
19 M. Alvarez-Corral, M. Munoz-Dorado and I. Rodriguez-
Garcia, Chem. Rev., 2008, 108, 3174–3198.
47 D. Srimani, Y. Ben-David and D. Milstein, Angew. Chem., Int.
Ed., 2013, 52, 4012–4015.
48 Z. Shi, M. Suri and F. Glorius, Angew. Chem., Int. Ed., 2013,
52, 4892–4896.
20 A. F. Pozharskii, A. Soldatenkov and A. R. Katritzky,
Heterocycles in Life and Society: An Introduction to 49 J. Liu, Z. Fang, Q. Zhang, Q. Liu and X. Bi, Angew. Chem., Int.
Heterocyclic Chemistry, Biochemistry and Applications, Wiley,
2011.
21 J. P. Michael, Nat. Prod. Rep., 2005, 22, 627–646.
22 D. O'Hagan, Nat. Prod. Rep., 2000, 17, 435–446.
Ed., 2013, 52, 6953–6957.
50 W. J. Humenny, P. Kyriacou, K. Sapeta, A. Karadeolian and
M. A. Kerr, Angew. Chem., Int. Ed., 2012, 51, 11088–
11091.
23 L. Jiao-Jie, M. Tian-Sheng and Y. Jin-Quan, Angew. Chem., Int. 51 M. P. Huestis, L. Chan, D. R. Stuart and K. Fagnou, Angew.
Ed., 2008, 47, 6452–6455.
Chem., Int. Ed., 2011, 50, 1338–1341.
2350 | Chem. Sci., 2014, 5, 2347–2351
This journal is © The Royal Society of Chemistry 2014

View Article Online
Edge Article
Chemical Science
52 S. Rakshit, F. W. Patureau and F. Glorius, J. Am. Chem. Soc., 55 X. Qi, L. Dai and C.-M. Park, Chem. Commun., 2012, 48,
2010, 132, 9585–9587. 11244–11246.
53 E. Lourdusamy, L. Yao and C.-M. Park, Angew. Chem., Int. 56 X. Qi, Y. Jiang and C.-M. Park, Chem. Commun., 2011, 47,
Ed., 2010, 49, 7963–7967.
7848–7850.
54 X. Qi, X. Xu and C.-M. Park, Chem. Commun., 2012, 48, 3996–
3998.
This journal is © The Royal Society of Chemistry 2014
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