Synthesis of Heterocycle-fused Pyridine N-Oxides from Oximes and Diazo Compounds via RhIII-Catalyzed C-H Activation and Annulation

Article abstract of DOI:10.1002/adsc.201500125

A Rh^III-catalyzed tandem C-H activation and C-N bond formation reaction between oximes and diazo compounds for the synthesis of heterocycle-fused pyridine N-oxides has been developed. The reaction exhibits good functional group tolerance and regioselectivity. After simple transformation, the 1-substituted, 1,3-disubstituted, 1,4-disubstituted and 1,3,4-trisubstituted heterocycle-fused pyridines were all obtained in high efficiency. Moreover, this strategy has also been expanded to the synthesis of a key intermediate for the construction of one potential anti-HIV agent.

Full text of DOI:10.1002/adsc.201500125

COMMUNICATIONS
DOI: 10.1002/adsc.201500125
Synthesis of Heterocycle-fused Pyridine N-Oxides from Oximes
III
À
and Diazo Compounds via Rh -Catalyzed C H Activation and
Annulation
Peng Sun,+a Youzhi Wu,+a Tie Yang,a Xiaoming Wu,a Jinyi Xu,a Aijun Lin,a,*
and Hequan Yaoa,*
a
State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal Chemistry, School of Pharmacy,
China Pharmaceutical University, Nanjing, 210009, People’s Republic of China
Fax: (+86)-25-8327-1042; e-mail: ajlin@cpu.edu.cn or hyao@cpu.edu.cn
+
These authors contributed equally to this work.
Received: February 6, 2015; Revised: May 19, 2015; Published online: July 17, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500125.
III
scribed by Shin (Scheme 1, b);[7] however, the oximes
are prepared from halogenated aromatic ketones or
aldehydes with terminal alkynes in several steps, and
only 3-substituted or 1,3-disubstituted products could
be achieved. To address these shortcomings, nickel[8]-,
rhodium[9]-, or palladium[10]-catalyzed intermolecular
annulations between oximes and internal alkynes af-
fording 3,4-disubstituted or 1,3,4-trisubstituted isoqui-
noline N-oxides have been explored (Scheme 1, c).
The major limitation of these reactions was the
À
Abstract: A Rh -catalyzed tandem C H activation
À
and C N bond formation reaction between oximes
and diazo compounds for the synthesis of heterocy-
cle-fused pyridine N-oxides has been developed.
The reaction exhibits good functional group toler-
ance and regioselectivity. After simple transforma-
tion, the 1-substituted, 1,3-disubstituted, 1,4-disub-
stituted and 1,3,4-trisubstituted heterocycle-fused
pyridines were all obtained in high efficiency. More-
over, this strategy has also been expanded to the
synthesis of a key intermediate for the construction
of one potential anti-HIV agent.
À
Keywords: C H activation; diazo compounds; het-
erocycle-fused pyridine N-oxides; oximes; RhIII-cat-
alysis
Pyridine N-oxides and their derivatives constitute
a core skeleton of various natural products,[1] pharma-
ceutical agents,[2] ligands[3] and functional organic ma-
terials.[4] Methods for the rapid access to and function-
alization of these compounds have attracted continu-
ous synthetic interest. Oxidation of pyridines is one of
the most frequent ways at the early stage, even
though the pre-synthesis of pyridines and the risk of
over-oxidation of some sensitive groups could restrict
the substrate scope and diversity (Scheme 1, a).[5] Re-
cently, significant progress has been made in many
protocols for constructing pyridine N-oxides employ-
ing transition-metal catalysis.[6] Gold- or silver-cata-
lyzed intramolecular electrophilic cyclizations of
Scheme 1. Synthesis of compounds containing pyridine N-
oximes offering isoquinoline N-oxides have been de- oxides.
Adv. Synth. Catal. 2015, 357, 2469 – 2473
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2469

COMMUNICATIONS
Peng Sun et al.
Table 1. Optimization of conditions[a]
narrow scope of the internal alkynes, which may
impact their further applications.
As a result, exploiting new strategies for the con-
struction of pyridine N-oxides and their derivatives
with a versatile operation for divergent synthesis is of
foremost interest. In 2013, Glorius[11] reported a pio-
neering RhIII-catalyzed intermolecular cyclization re-
action employing diazo compounds as an alkyne
equivalent for the synthesis of pyridine and isoquino-
line N-oxides (Scheme 1, d). After transformation,
the functionalized 1,3,4-trisubstituted isoquinoline N-
oxides could be obtained. Despite this successful
work, the formation of heterocycle-fused pyridine N-
oxides and their derivatives[12] with diazo compounds
was never mentioned. Compared to aryl or alkene
substrates, heterocyclic compounds remain a challenge
Entry
Solvent
Additive/Base
Yield [%][b]
1
2
3
4
5
6
7
8
MeOH
DMF
AgSbF6(10 mol%)
AgSbF6(10 mol%)
AgSbF6(10 mol%)
AgSbF6(10 mol%)
AgSbF6(10 mol%)
AgSbF6(10 mol%)
Ag2CO3(10 mol%)
AgTFA(10 mol%)
AgOAc(10 mol%)
/
K2CO3(2.0 equiv)
Na2CO3(2.0 equiv)
Cs2CO3(2.0 equiv)
NaOAc(2.0 equiv)
NaOAc(2.0 equiv)
60
23
trace
56
trace
35
73
47
49
50
DMSO
toluene
dioxane
MeCN
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
9
À
in C H bond functionalization owing to the existence
of the heteroatoms, such as N, O and S, which could
easily bind to the metals, resulting in catalyst poison-
10
11
12
13
14
15
31
66
15
À
ing, a decrease in the catalytic activity, or even the C
86(83[c])
79[d]
H activation being directed to an unwanted posi-
tion.[13] To broaden the utility of diazo compounds in
organic synthesis, and also as part of our ongoing pro-
gram to the development of transition-metal-cata-
[a]
Reaction conditions: 1a (0.50 mmol), 2a (1.0 mmol),
(Cp*RhCl2)2 (0.0125 mmol), solvent (2.0 mL), 808C, 12 h
under air atmosphere.
lyzed C H functionalization of heterocycles,[14]
À
[b]
Yield was determined by 1H NMR using dibromome-
thane (d=4.80) as an internal standard.
Isolated yield.
herein, we report a RhIII-catalyzed annulation reac-
tion between heteroaryl oximes and diazo compounds
to synthesize heterocycle-fused pyridine N-oxides.
Furthermore, the ester groups were readily function-
alized via simple operations, providing a great plat-
form to introduce versatile species and making
[c]
[d]
1.0 mol% of (Cp*RhCl2)2 was used.
a facile entry to the 1-substituted, 1,3-disubstituted, Table 2. Substitutions on the aryl unit with varying
1,4-disubstituted and 1,3,4-trisubstituted heterocycle- electronic properties were reacted with 2a, providing
fused pyridines, which expand their applicability to the corresponding 3ba–3 fa in 85–89% yields. A
a large extent.
strong electron withdrawing group (NO2) at the 5-po-
Our initial study focused on the reaction between sition failed to yield the desired product, with starting
1-(benzofuran-2-yl)ethanone oxime 1a and ethyl 2- materials recovered. Phenyl, alkynyl and alkenyl sub-
diazo-3-oxobutanoate 2a. The desired product 4- stituted 1g, 1h and 1i produced the corresponding
(ethoxycarbonyl)-1,3-dimethyl-benzofuro[2,3-c]pyri-
products 3ga–3ia in 77–89% yields. It is noteworthy
dine 2-oxide 3aa was obtained in 60% yield with con- that the substrates bearing other important heterocy-
ditions using 2.5 mol% (Cp*RhCl2)2 and 10 mol% cles, such as furan, thiophene and N-protected pyrrole
AgSbF6 in MeOH at 808C (entry 1). Attempts to op- could also furnish the desired products 3ka, 3la and
timize the reaction conditions employing various sol- 3ma in 90%, 93% and 71% yields. When ethyl
vents, additives and bases are summarized in Table 1. ketone derived oxime 1n was examined, the corre-
The solvents screening indicated that MeOH was the sponding product 3na was obtained in 91% yield,
best solvent for this reaction (entries 1–6). Next, in- while phenyl substituted substrate failed to yield the
vestigation of additives showed that the silver salt was desired product. We next turned our attention to as-
not necessary (entry 10), and we were pleased to find sessing the scope and limitation of the diazo com-
that when 2.0 equiv of NaOAc was used, the yield of pounds. Methyl, tert-butyl or benzyl substituted diazo
3aa was promoted to 86% (entry 14). The use of compounds provided 3ab–3ad in 82–89% yields. R2
Pd(OAc)2, Pd2(dba)3 and Cu(OTf)2 as catalyst proved with various alkyl or aryl groups delivered the corre-
to be inappropriate (see Supporting Information for sponding products 3ae–3ag in 76–87% yields. 3ah
details). The reaction outcome slightly decreased could be obtained in 98% yield when 3-diazopentane-
when 1 mol% of (Cp*RhCl2)2 was tested (entry 15).
2,4-dione 2h was used. Cyclic substrate, 2-diazocyclo-
With the optimized conditions in hand, the sub- hexane-1,3-dione 2i, generated 3ai in 92% yield.
strate scope containing one heteroatom in the hetero- When ethyl 2-diazo-3-oxopropanoate 2j was subject-
cycle was checked, and the results are shown in ed to the optimized reaction conditions, 1,4-disubsti-
2470
asc.wiley-vch.de
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 2469 – 2473

COMMUNICATIONS
Synthesis of Heterocycle-fused Pyridine N-Oxides
Table 2. Substrate scope I[a,b]
We then sought to establish the scope of the het-
erocycles with two heteroatoms, such as thiazoles and
oxazoles, and the results are described in Table 3. The
reaction was amenable to both electron-withdrawing
and electron-donating groups on the aryl unit. 2-
Phenyl thiazole 4a reacted with 2b, affording 5ab in
98% yield. Methyl at the 4-position of the phenyl
group performed smoothly to yield 5bb in 98% yield.
5 db could be obtained in 90% yield with an in-
creased catalyst loading. A substrate with a strong
electron-withdrawing group (CF3) offered 5gb in
98% yield. Diazo with ethyl, tert-butyl and phenyl
group provided the corresponding products 5aa, 5ac
and 5ad in 90%, 98% and 78% yield, respectively.
5ai was obtained in 71% yield when the cyclic diazo
compound 2i was employed. 3-Unsubstituted product
5aj could be accessed in 90% yield with ethanol as
Table 3. Substrate scope II[a,b]
[a]
Reaction conditions:
1 (0.50 mmol), 2 (1.0 mmol);
(Cp*RhCl2)2 (0.0125 mmol), NaOAc (1.0 mmol), in sol-
vent (2.0 mL) at 808C for 12 h under air atmosphere.
Isolated yields.
[b]
tuted product 3aj, 3cj, 3ej and 3gj were obtained in
83–88% yields. After further operations, these com-
pounds could be transformed to the 1-substituted ben-
zofuro[2,3-c]pyridines via reduction and decarboxyla-
tion, which were inaccessible through previously re-
ported methods.[15] Our reaction also gave 3aa in
76% yield (1.08 g) in gram scale (5 mmol) under the
standard conditions.
[a]
Reaction conditions:
4 (0.50 mmol), 2 (1.0 mmol);
(Cp*RhCl2)2 (0.0125 mmol), NaOAc (1.0 mmol), solvent
(2.0 mL), at 708C for 12 h under air atmosphere.
Isolated yields.
0.035 equiv of (Cp*RhCl2)2.
EtOH (2.0 mL) as solvent.
[b]
[c]
[d]
[e]
[f]
ClCH2CH2Cl (2.0 mL) as solvent.
4.0 equiv of NaOAc.
Adv. Synth. Catal. 2015, 357, 2469 – 2473
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2471

COMMUNICATIONS
Peng Sun et al.
the solvent. Oxazole substrate 4h gave the desired
product 5hb in 50% yield, albeit with 4 equiv of base.
The reaction pathway was proposed just as shown
in Scheme 2, which is similar to Gloriusꢁ work.[11] At
first, substrate 1a coordinates with [RhIII] species fol-
À
lowed ortho C H cleavage to afford A. Insertion of
diazo compound 2a to C Rh generates C via Rh car-
À
bene intermidiate B. Subsequential proton–Rh ex-
change gives intermediate C. Enol intermediate D
can be obtain via simple tautomerism from E. Then
6p electrocyclization or nucleophilic attack by the ni-
trogen atom in D or E, and the elimination of water
leads to the desired product 3aa.
Scheme 4. Synthetic applications.
To gain insight into the utility of the reaction, the
N-oxides were further functionalized. As shown in furo[2,3-c]pyridine 8 was obtained in 54% yield.
Scheme 3, bromine substituted N-oxide could convert After reduction, hydrolysis and Curtis rearrangement,
to compound 6 through a PCl3-mediated reduction 4-NH2 substituted benzofuro[2,3-c]pyridine 9 was ob-
step[16] and a C N cross-coupling reaction in 63% tained in 62% yield, which could serve as a valuable
À
total yield. Utilizing a three step route, including re- precursor for the synthesis of more complex and
duction, hydrolysis and Ag2CO3-mediated decarboxy- useful compounds (see Supporting Information for
lation, 1,3-disubstituted benzofuro[2,3-c]pyridine 7 details).
was obtained in 59% overall yield.[17] When R2 =H,
With the aim to expand the application of our reac-
following the same route, the 1-substituted benzo- tion further, we also successfully provided an alterna-
tive way to synthesize compound 11, a key intermedi-
ate for the construction of potential anti-HIV agent
I.[18] By means of our method, 3aj could be synthe-
sized from readily available starting materials 1a and
2j in 83% yield in 1 mmol scale (Table 2). Then,
treatment of 3aj with TFAA,[19] followed by oxidation
with MnO2 could smoothly provide aldehyde 10 in
96% yield (Scheme 4). Sequential hydrolysis and de-
carboxylation[20] conveniently generated the desired
product 11 in 73% yield (see Supporting Information
for details).
In conclusion, we have identified an efficient
method for the construction of heterocycle-fused pyri-
III
À
dine N-oxides through a Rh -catalyzed tandem C H
activation and cyclization from oximes and diazo
compounds. The reaction exhibited good functional
group tolerance and regioselectivity. Moreover, the
products formed could be transformed to the 1-substi-
tuted, 1,3-disubstituted, 1,4-disubstituted and 1,3,4-tri-
substituted heterocycle-fused pyridines in high effi-
ciency. A key intermediate for the synthesis of a po-
tential anti-HIV agent was also achieved from cheap
and readily available starting materials. Further inves-
tigation on the reaction mechanism and application to
the synthesis of bioactive natural products are in
progress in our laboratory.
Scheme 2. Proposed reaction pathway.
Experimental Section
A
sealed tube was charged with heteroaryl oxime
(0.50 mmol, 1 equiv), (RhCp*Cl2)2 (0.0125 mmol,
2.5 mol%), NaOAc (1 mmol, 2 equiv), diazo (1.0 mmol,
2 equiv) and MeOH (2.0 mL). The reaction mixture was vig-
Scheme 3. Functionalization of heterocycle-fused pyridine
N-oxides.
2472
asc.wiley-vch.de
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 2469 – 2473

COMMUNICATIONS
Synthesis of Heterocycle-fused Pyridine N-Oxides
orously stirred at 808C (oil temperature) for 12 h. After
cooling to room temperature, the reaction mixture was dilut-
ed with ethyl acetate (20 mL) and filtered through a plug of
Celite. The mixture was concentrated in vacuo and purified
by flash chromatography on silica gel to afford the desired
product.
J.-H. Li, M.-K. Wang, R.-Y. Tang, X.-G. Zhang, C.-L.
Deng, Adv. Synth. Catal. 2012, 354, 1890–1896; c) Q.
Ding, D. Wang, X. Sang, Y. Lin, Y. Peng, Tetrahedron
2012, 68, 8869–8905.
[7] a) H.-S. Yeom, S. Kim, S. Shin, Synlett 2008, 924–928;
b) H.-S. Yeom, Y. Lee, J.-E. Lee, S. Shin, Org. Biomol.
Chem. 2009, 7, 4744–4752.
[8] W.-C. Shih, C.-C. Teng, K. Parthasarathy, C.-H. Cheng,
Chem. Asian J. 2012, 7, 306–313.
[9] M. Arambasic, J. F. Hooper, M. C. Willis, Org. Lett.
2013, 15, 5162–5165.
[10] B. Li, P. Jiao, H. Zhong, J. Huang, Synlett 2013, 24,
2431–2436.
Acknowledgements
Generous financial support from the Ministry of Education
of China (PSCIRT-1193), the National Natural Science Foun-
dation of China (NSFC21272276), the Natural Science Foun-
dation of Jiangsu Province (BK20140655) and Fundamental
Research Funds for the Central Universities for H. Y. is ac-
knowledged.
[11] Z. Shi, D. C. Koester, M. Boultadakis-Arapinis, F. Glo-
rius, J. Am. Chem. Soc. 2013, 135, 12204–12207.
[12] a) L. Zheng, J. Ju, Y. Bin, R. Hua, J. Org. Chem. 2012,
77, 5794–5800; b) T. K. Hyster, T. Rovis, Chem.
Commun. 2011, 47, 11846–11848; c) P. C. Too, S. H.
Chua, S. H. Wong, S. Chiba, J. Org. Chem. 2011, 76,
6159–6168; d) P. C. Too, Y.-F. Wang, S. Chiba, Org.
Lett. 2010, 12, 5688–5691; e) W. Sun, M. Wang, Y.
Zhang, L. Wang, Org. Lett. 2015, 17, 426–429.
[13] a) Y.-J. Liu, X. Hui, W.-J. Kong, M. Shang, H.-X. Dai,
J.-Q. Yu, Nature 2014, 515, 389–393; b) N. Schrçder, F.
Lied, F. Glorius, J. Am. Chem. Soc. 2015, 137, 1448–
1451; c) D.-T. D. Tang, K. D. Collins, J. B. Ernst, F. Glo-
rius, Angew. Chem. 2014, 126, 1840–1844; Angew.
Chem. Int. Ed. 2014, 53, 1809–1813.
References
[1] a) G. OꢁDonnell, R. Poeschl, O. Zimhony, M. Gunarat-
nam, J. B. C. Moreira, S. Neidle, D. Evangelopoulos, S.
Bhakta, J. P. Malkinson, H. I. Boshoff, A. Lenaerts, S.
Gibbons, J. Nat. Prod. 2009, 72, 360–365; b) G. M.
Nicholas, J. W. Blunt, M. H. G. Munro, J. Nat. Prod.
2001, 64, 341–344.
[2] a) B. Xia, W. Ma, B. Zheng, X. Zhang, B. Fan, Eur. J.
Med. Chem. 2008, 43, 1489–1498; b) B. Reux, T. Neva-
lainen, K. H. Raitio, A. M. P. Koskinen, Bioorg. Med.
[14] a) L. Zhao, Z. Li, L. Chang, J. Xu, H. Yao, X. Wu, Org.
Lett. 2012, 14, 2066–2069; b) Z. Li, L. Ma, J. Xu, L.
Kong, X. Wu, H. Yao, Chem. Commun. 2012, 48, 3763–
3765; c) Y. Su, H. Zhou, J. Chen, J. Xu, X. Wu, A. Lin,
H. Yao, Org. Lett. 2014, 16, 4884–4887.
´
Chem. 2009, 17, 4441–4447; c) K. Walczynski, O. P. Zui-
derveld, H. Timmerman, Eur. J. Med. Chem. 2005, 40,
15–23; d) E. Rajanarendar, S. Raju, M. N. Reddy, S. R.
Krishna, L. H. Kiran, A. R. N. Reddy, Y. N. Reddy,
Eur. J. Med. Chem. 2012, 50, 274–279.
[15] a) K. R. Roesch, R. C. Larock, J. Org. Chem. 1998, 63,
5306–5307; b) D. K. Whelligan, D. W. Thomson, D.
Taylor, S. Hoelder, J. Org. Chem. 2009, 75, 11–15;
c) R. P. Korivi, C.-H. Cheng, Org. Lett. 2005, 7, 5179–
5182; d) T. Fukutani, N. Umeda, K. Hirano, T. Satoh,
M. Miura, Chem. Commun. 2009, 45, 5141–5143; e) N.
Guimond, K. Fagnou, J. Am. Chem. Soc. 2009, 131,
12050–12051; f) D. A. Colby, R. G. Bergman, J. A.
Ellman, J. Am. Chem. Soc. 2008, 130, 3645–3651; g) K.
Parthasarathy, C.-H. Cheng, J. Org. Chem. 2009, 74,
9359–9364; h) K. Parthasarathy, M. Jeganmohan, C.-H.
Cheng, Org. Lett. 2008, 10, 325–328; i) Z.-W. Zhang, A.
Lin, J. Yang, J. Org. Chem. 2014, 79, 7041–7050.
[16] J. W. Pavlik, S. Laohhasurayotin, J. Heterocycl. Chem.
2007, 44, 1485–1492.
[3] For reviews, see: a) V. Derdau, S. Laschat, E. Hupe,
W. A. Kçnig, I. Dix, P. G. Jones, Eur. J. Inorg. Chem.
ˇ
´
1999, 1999, 1001–1007; b) A. V. Malkov, P. Kocovsky,
Eur. J. Org. Chem. 2007, 29–36; for representative ex-
amples, see: c) B. Tao, M. M. C. Lo, G. C. Fu, J. Am.
Chem. Soc. 2001, 123, 353–360; d) F. Pointillart, T.
Cauchy, O. Maury, Y. L. Gal, S. Golhen, O. Cador, L.
Ouahab, Chem. Eur. J. 2010, 16, 11926–11941; e) N.
Takenaka, R. S. Sarangthem, B. Captain, Angew. Chem.
2008, 120, 9854–9856; Angew. Chem. Int. Ed. 2008, 47,
9708–9710.
[4] T. Nishida, A. Fukazawa, E. Yamaguchi, H. Oshima, S.
Yamaguchi, M. Kanai, Y. Kuninobu, Chem. Asian J.
2014, 9, 1026–1030.
[17] P. Lu, C. Sanchez, J. Cornella, I. Larrosa, Org. Lett.
[5] a) D. Limnios, C. G. Kokotos, Chem. Eur. J. 2014, 20,
559–563; b) Y. Ding, W. Zhao, W. Song, Z. Zhang, B.
Ma, Green. Chem. 2011, 13, 1486–1489; c) S. L. Jain, B.
Sain, Chem. Commun. 2002, 38, 1040–1041; d) M. R.
Prasad, G. Kamalakar, G. Madhavi, S. J. Kulkarni, K. V.
Raghavan, Chem. Commun. 2000, 36, 1577–1578; e) W.
Zhao, X. Wang, C. X. Yang, Synth. Commun. 2014, 44,
150–156.
2009, 11, 5710–5713.
[18] M. P. Clark, M. A. Lockwood, F. F. Wagner, M. G.
Natchus, B. C. Doroh, T. L. Johnson, W. A. Tahirovic,
W. Lawrence, J. M. Wiseman, J. W. Skudlarek (Altiris
Therapeutics), WO2009121063, 2009.
[19] C. Fontenas, E. Bejan, H. A. Haddou, G. G. A. Bala-
voine, Synth. Commun. 1995, 25, 629–633.
[20] L. J. Gooßen, W. R. Thiel, N. Rodríguez, C. Linder, B.
Melzer, Adv. Synth. Catal. 2007, 349, 2241–2246.
[6] a) H. Wang, M. Zhu, S. Ye, J. Wu, RSC Adv. 2013, 3,
13626–13629; b) B. Yao, R.-J. Song, Y. Liu, Y.-X. Xie,
Adv. Synth. Catal. 2015, 357, 2469 – 2473
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2473