Copper-mediated synthesis of N-alkenyl-α,β-unsaturated nitrones and their conversion to tri- and tetrasubstituted pyridines

Article abstract of DOI:10.3762/bjoc.11.226

A Chan-Lam reaction has been used to prepare N-alkenyl-α,β-unsaturated nitrones, which undergo a subsequent thermal rearrangement to the corresponding tri- and tetrasubstituted pyridines. The optimization and scope of these transformations is discussed. I

Full text of DOI:10.3762/bjoc.11.226

Copper-mediated synthesis of N-alkenyl-α,β-unsaturated
nitrones and their conversion to tri- and
tetrasubstituted pyridines
Dimitra Kontokosta, Daniel S. Mueller, Dong-Liang Mo, Wiktoria H. Pace,
Rachel A. Simpson and Laura L. Anderson*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 2097–2104.
Department of Chemistry, University of Illinois at Chicago, 845 W.
Taylor St., Chicago, IL 60607, U.S.A
doi:10.3762/bjoc.11.226
Received: 11 August 2015
Accepted: 20 October 2015
Published: 04 November 2015
Email:
Laura L. Anderson* - lauralin@uic.edu
* Corresponding author
This article is part of the Thematic Series "Copper catalysis in organic
synthesis".
Keywords:
Chan–Lam; copper; nitrone; oxygen transfer; pyridine
Guest Editor: S. R. Chemler
© 2015 Kontokosta et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A Chan–Lam reaction has been used to prepare N-alkenyl-α,β-unsaturated nitrones, which undergo a subsequent thermal rearrange-
ment to the corresponding tri- and tetrasubstituted pyridines. The optimization and scope of these transformations is discussed.
Initial mechanistic experiments suggest a reaction pathway involving oxygen transfer followed by cyclization.
Introduction
While most applications of the Chan–Lam reaction are focused undergo a copper-catalyzed rearrangement to α,β-epoxyimines
on the synthesis of aryl ethers and aryl amines, our group has such as 4 [8]. Reduction of these products in the presence of a
been interested in the use of the Chan–Lam reaction for the syn- Lewis acid gave tetrahydroquinolines such as 5 (Scheme 1A).
thesis of O-alkenyl oximes and hydroxylamines, as well as These studies encouraged us to consider if similar N-alkenyl-
N-alkenyl and N-arylnitrones [1-5]. We have discovered that nitrones 8 could be accessed by a Chan–Lam coupling and
when this transformation is performed with oxime and hydrox- transformed into the corresponding substituted pyridines 9
amic acid substrates, these reactive intermediates can be (Scheme 1B).
accessed and subsequently rearrange to a variety of challenging
organic fragments and heterocyclic products [6-13]. Specifi- Pyridines are important heterocycles that are often found in bio-
cally, we reported that N-arylnitrones 3 can be prepared by a logically active molecules [14-21]. Due to the high demand for
Chan–Lam coupling of 1 and 2 and that these compounds these compounds, there are many methods for preparing substi-
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tory insertion. This route is appealing due to the modularity of
the Chan–Lam coupling process, and proceeds through a
pathway that is distinct from the Liebeskind copper-catalyzed
C–N bond coupling and electrocyclization (Scheme 2).
Scheme 1: Use of a Chan–Lam reaction for the synthesis of tetrahy-
droquinolines and potential extension to pyridines [8].
tuted pyridines through condensation reactions [22-26],
cycloadditions [27-30], functionalization of parent pyridine
structures [31-38], fragment couplings [39-42], and transition
metal-catalyzed C–H bond functionalization of α,β-unsaturated
imines and oximes [43-50]. We were inspired by the copper-
catalyzed coupling of protected α,β-unsaturated oximes and
alkenylboronic acids developed by Liebeskind and coworkers
due to its modularity and control of regioselectivity and
Scheme 2: Examples of pyridine synthesis from oxime precursors
[51,52].
wondered if a Chan–Lam route to N-alkenylnitrones would Results and Discussion
allow us to prepare similar intermediates (Scheme 2A) [51]. A Chan–Lam coupling between chalcone oxime 6a and cyclo-
Nakamura and coworkers have reported that N-allenylnitrones hexenylboronic acid (7a) was initially tested using reaction
can be accessed through rearrangements of O-propargylic conditions that we had previously identified as optimal for
oximes and undergo similar electrocyclizations to form analogous N-alkenylnitrone syntheses from fluorenone oxime
pyridines (Scheme 2B) [52]. Herein, we show that N-alkenyl- [7]. Nitrone 8aa was successfully isolated in 40% yield using
nitrones 8 can be prepared through a Chan–Lam coupling of 2 equiv of Cu(OAc)2 and the reaction conditions indicated in
α,β-unsaturated oximes 6 and an alkenylboronic acids 7 and that Table 1, entry 1. Only the E-nitrone isomer was observed and
these compounds undergo a novel thermal rearrangement to the isolated. Decreasing the amount of copper reagent to 1 equiv
corresponding tri- and tetrasubstituted pyridines 9 (Scheme 2C). had little influence on the reaction and a screen of other
This use of α,β-unsaturated oxime reagents for the synthesis of common copper salts only resulted in diminished yields
pyridines is unique from transition metal-catalyzed C–H bond (Table 1, entries 2–7). Further reduction of the copper loading
functionalization processes that require a regioselective migra- to 10–30 mol % of Cu(OAc)2 was tolerated without a decrease
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Table 1: Optimization of Chan–Lam coupling for the synthesis of N-cyclohexenyl-α,β-unsaturated nitrones.a
entry
catalyst
cat. conc
additive
yield (%)b
1
Cu(OAc)2
Cu(OAc)2
CuTC
2 equiv
none
none
none
none
none
none
none
none
none
COE
NBD
COD
1-octene
dba
40
2
1 equiv
46
3
1 equiv
30
4
CuBr
1 equiv
dec
trace
trace
trace
45
5
CuI
1 equiv
6
CuOTf2
1 equiv
7
Cu(TFA)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
1 equiv
8
10 mol %
30 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
9
45
10
11
12
13
14
65
58
72
57
51
aConditions: 6a (1 equiv), 7a (2 equiv), pyridine (5 equiv), Na2SO4 (8–9 equiv), 0.1 M in DCE, 25 °C, air, 18 h. bDetermined by 1H NMR spectroscopy
using CH2Br2 as a reference.
in reaction efficiency (Table 1, entries 8 and 9). The key factor 8ab in only 15% yield (Table 2, entries 6 and 7). Phenyl-substi-
in improving the yield of the transformation was identified as an tuted alkenylboronic acid 7c and monosubstituted alkenyl-
alkene additive. Alkene and alkyne additives have previously boronic acids 7d and 7e, were more efficient reaction partners
been observed to improve similar copper-catalyzed coupling with chalcone oxime and gave the corresponding nitrones in
reactions [53]. As shown in Table 1, entries 10–14, the addition good to excellent yield (Table 2, entries 8–10). Acyclic alkenyl-
of 1.2 equiv of cyclooctadiene (COD), cyclooctene (COE), boronic acids were also incompatible with the optimal condi-
norbornadiene (NBD), 1-octene, and dibenzylideneacetone tions determined for cyclohexenylboronic acid (7a) and
(dba) all improved the yield of the Chan–Lam reaction, but required the use of 1–2 equiv of Cu(OAc)2. The use of both
COD was most efficient.
copper-catalyzed and copper-mediated reaction conditions with
oximes 6 and alkenylboronic acids 7, allowed for the prepar-
ation of a variety of N-alkenyl-α,β-unsaturated nitrones to test
for further reactivity.
Having identified optimal conditions for the synthesis of
N-cyclohexenylnitrone 8aa, the scope of the nitrone synthesis
was explored by varying the oxime and alkenylboronic acid
reagents. As shown in Table 2, chalcone oximes with both elec- The preparation of the N-alkenyl-α,β-unsaturated nitrones
tron-rich and electron-poor aryl substituents, as well as shown in Table 2, allowed for further study of their conversion
heteroaryl substituents, were tolerated for the transformation to tri- and tetrasubstituted pyridines. The preliminary evalua-
with electron-donating substituents providing higher yields tion of this thermal transformation with 8aa indicated that
(Table 2, entries 1–4). A significant increase in reaction effi- DMSO was a more efficient reaction medium than PhMe,
ciency was also observed for dba oxime (Table 2, entry 5). dioxane, or DMF (Scheme 3). As shown in Table 3, all of the
Evaluation of acyclic alkenylboronic acids further highlighted chalcone nitrones were readily converted to the corresponding
the differences between dba oxime and chalcone oximes as pyridines in good yield (Table 3, entries 1–4, 6, 8–10). In
substrates for the Chan–Lam reaction. When dba oxime was contrast, the dba nitrones gave the corresponding pyridines in
treated with but-2-en-2-ylboronic acid, nitrone 8eb was isolated attenuated yields (Table 3, entries 5 and 7). The high density of
in good yield; in contrast, treatment of chalcone oxime with substituents and regiospecificity of the transformation due to the
but-2-en-2-ylboronic acid, resulted in the isolation of nitrone use of the Chan–Lam reaction for the synthesis of the nitrone
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Table 2: Scope of N-alkenyl-α,β-unsaturated nitrone synthesis.a
entry
1
8
yield (%)b
72c
entry
6
8
yield (%)b
15d
8ab
8aa
2
41c
7
68d
8eb
8ba
3
63c
8
57d
8ac
8ad
8ae
8ca
4
5
70e
84c
9
75d
83d
8da
8ea
10
aConditions: 6 (1 equiv), 7 (2 equiv), pyridine (5 equiv), COD (1.2 equiv), Na2SO4 (8–9 equiv), 0.1 M in DCE, 25 °C, air, 18 h. bPercent isolated yield.
cCu(OAc)2 (10 mol %). dCu(OAc)2 (1–2 equiv), pyridine (10 equiv), no COD. eCu(OAc)2 (10 mol %), no COD.
precursor are noteworthy and provide advantages over pyridine To better understand the conversion of N-alkenyl-α,β-unsatu-
syntheses that require regioselective insertion reactions or rated nitrones 8 to pyridines 9, two mechanistic experiments
nucleophilic additions.
were evaluated (Scheme 4). The conversion of nitrone 8ae to
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Beilstein J. Org. Chem. 2015, 11, 2097–2104.
pyridine 9ae was monitored by 1H and 13C NMR spectroscopy.
Surprisingly, after heating 8ae for 4 h at 140 °C in DMSO-d6, a
1:1:1 mixture of isoxazoline 15ae, enaminoketone 16ae, and
pyridine 9ae was observed [54,55]. Further heating this mix-
ture of intermediates for 4 h resulted in the sole formation of
pyridine 9ae. This experiment suggests that the conversion of
nitrone 8ae to pyridine 9ae proceeds by oxygen transfer to give
16ae and nucleophilic addition of the enamine to the ketone.
This pathway may explain the solvent dependence that was
observed for the transformation (Scheme 3). The lack of any
observation of dihydropyridine N-oxide intermediate 17ae
Scheme 3: Solvent effect on conversion of N-alkenylnitrones to
pyridines.
Table 3: Scope of conversion of N-alkenyl-α,β-unsaturated nitrones to pyridines.a
entry
1
9
yield (%)b
entry
6
9
yield (%)b
71
50
9aa
9ab
9eb
2
3
68
64
7
8
36
87
9ba
9ca
9ac
4
5
76
43
9
71
65
9ad
9ae
9da
9ea
10
aConditions: 8 (1 equiv), 4 Å MS, 0.1 M in DMSO, 140 °C, 6–8 h. bPercent isolated yield.
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Scheme 4: Mechanistic experiments.
suggests that the reaction is not proceeding through an electro-
cyclization and elimination process. A second experiment tested
the electronic effect of this oxygen-transfer process. Unsymmet-
rically substituted dba nitrone 8fa was subjected to the cycliza-
tion conditions and a 1:1 mixture of 9fa:9fa' was observed. This
experiment indicated a lack of any significant electronic prefer-
ence for the oxygen-transfer process.
Supporting Information
Supporting Information File 1
Experimental part.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-11-226-S1.pdf]
Conclusion
Acknowledgements
A new method for the preparation of tri- and tetrasubstituted
pyridines has been developed that hinges on the use of a
Chan–Lam coupling to construct N-alkenyl-α,β-unsaturated
nitrone precursors from the corresponding oximes and alkenyl-
boronic acids. This method is tolerant of a variety of chalcone-
and dba-derived oxime substrates as well as both mono- and
disubstituted alkenylboronic acids. Initial reaction monitoring
experiments suggest that the cyclization of the N-alkenyl-α,β-
unsaturated nitrone to the pyridine occurs through an oxygen
transfer from the nitrone functionality to the β-position of the
conjugated olefin followed by nucleophilic attack of the
enamine.
We acknowledge generous funding from ACS-PRF (DNI-
50491), NSF (NSF-CHE 1212895 and 1464115), and the
University of Illinois at Chicago. We also thank Mr. Furong
Sun (UIUC) for mass spectrometry data.
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