Stereoselective Synthesis of Atropisomeric Bipyridine N,N′-Dioxides by Oxidative Coupling

Article abstract of DOI:10.1021/acs.orglett.9b01687

Bipyridine N,N′-dioxide is a structural fragment found in many bioactive compounds. Furthermore, chiral analogues secured their place as powerful Lewis base catalysts. The scope of the existing methods for the synthesis of atropisomeric bipyridine N,N′-di

Full text of DOI:10.1021/acs.orglett.9b01687

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Stereoselective Synthesis of Atropisomeric Bipyridine N,N′-Dioxides
by Oxidative Coupling
†
‡
‡,§
Aleksandr E. Rubtsov,*,‡
Yasuaki Fukazawa, Vladimir Yu. Vaganov, Sergei A. Shipilovskikh,
,
†
and Andrei V. Malkov*
†
Department of Chemistry, Loughborough University, Loughborough LE11 3TU, U.K.
Department of Chemistry, Perm State University, Bukireva 15, Perm 614990, Russia
‡
§
Institute of Chemical Technology, Ural Federal University, Mira 19, Yekaterinburg 620002, Russia
S Supporting Information
*
ABSTRACT: Bipyridine N,N′-dioxide is a structural fragment
found in many bioactive compounds. Furthermore, chiral
analogues secured their place as powerful Lewis base catalysts.
The scope of the existing methods for the synthesis of
atropisomeric bipyridine N,N′-dioxides is limited. Herein, we
present a practical, highly chemo- and stereoselective method
for oxidative dimerization of chiral pyridine N-oxides using O as a terminal oxidant. A series of 13 axially chiral bipyridine
2
N,N′-dioxides were synthesized in up to 75% yield.
eterocyclic N-oxides, including their bis-heterocyclic
Scheme 1. Synthesis of Bipyridine N,N′-Dioxides by
H
analogues, accrued an extensive record of applications
Dimerization of Mononuclear Precursors
1
in drug discovery and natural product chemistry, while chiral
mono-N-oxides and N,N′-dioxides become important players
in asymmetric catalysis due to their distinct Lewis basic
2
properties. A selection of the most efficient N,N′-dioxide
organocatalysts is shown in Figure 1. Except for some
direct oxidative coupling of N-oxides 10 (Scheme 1) was
7
8
realized for making 6 and its analogues.
Synthesis of 6 involves low-temperature deprotonation of
the monomeric pyridine N-oxide followed by oxidation with
molecular iodine to trigger dimerization. In some instances, the
atropisomers were formed with excellent diastereoselectivity;
however, the yields suffered from the formation of substantial
quantities of the respective 2-iodopyridine N-oxide as a
byproduct. In addition to the diastereoselectivity issues, direct
coupling of pyridine N-oxides 10, depending on the reaction
Figure 1. Axially chiral bipyridine-N,N′-dioxides.
9
conditions, can afford up to three products: bipyridines 8,
9
a,10
7b,c,10e,11
3
4
5
mono-N-oxides 11,
1
and N,N′-dioxides 9
(Scheme
derivatives of 2, 4, and 5, such compounds are obtained
by coupling of the monomeric pyridine precursors. Typically,
the synthesis of N,N′-dioxides relies on a transition-metal
mediated coupling of 2-halopyridines 7 (Scheme 1) followed
by N-oxidation and separation into enantiomers or diater-
eoisomers, as appropriate. Compounds 1−3 were synthesized
). Therefore, demand for a robust and efficient method for
coupling of pyridine N-oxides still has not been fulfilled.
12
Herein, we present a practical, highly chemo- and
diastereoselective method for oxidative dimerization of
6
by this route (Scheme 1, 7 → 8 → 9). Since the preparation
Received: May 14, 2019
of 2-halopyridines requires a synthetic detour, an alternative
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01687
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
lithiated pyridine N-oxides employing oxygen as a terminal
oxidant.
Deprotonation of 16a was carried out with LDA (1.3 equiv)
at −78 °C. Quenching with MeOD after 5 min revealed 78% D
incorporation. For the oxidation of the anion, molecular iodine
The chemoselectivity in the formation of mono-N-oxide 11
or N,N′-dioxide 9 from the deprotonated monomeric pyridine
N-oxide 10 is controlled by the interplay between two different
reaction manifolds. Thus, a nucleophilic addition of α-
metalated N-oxide to a neutral 10 followed by elimination of
metal hydroxide leads to 11, whereas oxidation of the anion to
7
c,8b
was assessed first following the literature methods.
However, only the respective 2-iodopyridine N-oxide was
obtained in high yield (entry 1). The length of deprotonation
had no effect on the reaction outcome (entries 2 and 3).
Previously, we reported a single example of oxidative coupling
of deprotonated 16b in a modest yield in the presence of
7c,10e
radical species results in dimerization product 9.
Pursuing our longstanding interest in chiral N,N′-dioxide
11b,13
oxygen, but reproducibility was low.
We now undertook a
1
1b,13
catalysts for asymmetric C−C bond formation,
we
more detailed investigation of this reaction. Allowing the
deprotonation to run for 30 min (or longer) and then
focused on developing a simple and practical method for
selective oxidative coupling of pyridine N-oxides.
Synthesis of chiral monomeric N-oxides 16a−o was
accomplished in three steps from commercially available
introducing O
material being quantitatively recovered (entry 4). However,
when O was applied immediately after addition of 16a to
2
gave no coupling product, with starting
2
ketones 12 by Kro
̈
hnke annulation of 13 and (1R)-myrtenal
LDA, dioxide 17a formed as a single diastereoisomer (dr >
25:1) in 71% yield (81% based on the recovered starting
material). The reaction was complete in under 15 min. At
higher temperatures, the yield of 17a dropped slightly (entries
6 and 7) due to competing nucleophilic addition route to give
the respective bipyridine mono-N-oxide (see Scheme 1).
Mechanistically, the reaction is likely to resemble oxidative
coupling of lithium enolates and proceed through single-
1
4 to afford pyridines 15 that were further oxidized with m-
14
CPBA to 16 (Scheme 2). Next, N-oxide 16a was selected as
a model substrate for developing conditions for its oxidative
dimerization into 17a (Table 1).
Scheme 2. Synthesis of Atropisomeric Bipyridine N,N′-
Dioxides
15
electron oxidation. The key factor appears to be formation of
16
highly ordered organolithium aggregates, where two pyridine
units are favorably aligned to form a C−C bond. Comparison
of the results in entries 4 and 5 suggests that the kinetically
formed complexes at the early stages adopt a correct geometry
for coupling, whereas within 30 min they rearrange into more
stable but nonreactive complexes. Lithium seems to play a
crucial part in holding the heterocyclic units together. Thus,
addition of 12-crown-4 to LDA disrupts formation of
aggregates and shuts down the reaction (entry 8). Likewise,
a less Lewis acidic potassium (KHMDS) was not competent
either (entry 9).
With the optimal conditions identified (Table 1, entry 5),
the scope and limitations of this protocol were explored next
(
Table 2). In most cases, the reactions were performed on a
a
Table 2. Scope of Oxidative Dimerization (16 → 17)
b
entry
16, R
(S )-17
a
yield of 17 (brsm) (%)
Table 1. Optimization of the Oxidative Dimerization
Protocol (16a → 17a)
a
1
2
3
4
5
6
7
8
9
16a, Ph
16b, 3,5-(CF ) -C H
3
17a
17b
17c
17d
17e
17f
17g
17h
17i
17j
17k
17l
17m
17n
17o
70 (81)
45 (74)
59 (70)
38 (89)
65 (87)
48 (81)
35 (82)
SM
40 (76)
44 (63)
32 (88)
75 (75)
49 (68)
SM
3
2
6
T
time before addition of
oxidant (h)
yield of
16c, 3,5-Me -C H
2
6
3
entry
base
LDA
oxidant (°C)
17a (%)
16d, 4-ClC H4
6
b
1
2
3
4
5
6
7
8
I2
I2
I2
O2
O2
O2
O2
O2
−78
−78
−78
−78
−78
0
16
2
0
0.5
0
0
0 (80)
0 (85)
0 (81)
SM
70 (81)
60 (72)
55 (65)
SM
16e, 4-FC H4
6
b
LDA
LDA
LDA
LDA
LDA
LDA
16f, 3-NO C H
4
2
6
b
16g, 4-MeOC H4
6
16h, 2-MeOC H4
6
c
d
16i, 2-naphthyl
16j, 2-furyl
16k, 2-thienyl
16l, CF3
16m, tBu
16n, iPr
e
d
10
11
12
13
14
15
f
d
rt
−78
0
0
LDA, 12-
crown-4
9
KHMDS
O2
−78
0
SM
a
The reactions were carried out in dry THF, and solution of 16a was
16o, CN
23
added to 1.3 equiv of base. Where t = 0, the oxidant was applied
immediately after addition of 16a. LDA = lithium diisopropylamide,
KHMDS = potassium bis(trimethylsilyl)amide, SM = starting
a
The reactions were carried out in dry THF on a 1−5 mmol scale
using 1.3 equiv of LDA at −78 °C for deprotonation. A balloon with
was attached immediately after combining the reactants. In all
cases, the dr of 17 was >25:1. Configuration S was established for
7g by X-ray analysis and was extrapolated to all other dioxides 17.
b
c
material. Yield of 2-iodopyridine N-oxide. dr > 25:1, no mono-N-
d
e
O
2
oxide 11 formed. Yield based on recovered starting material. Mono-
N-oxide 11 formed (5%). Mono-N-oxide 11 formed (8%).
f
a
1
b
Isolated yield; brsm = yield based on recovered starting material.
B
DOI: 10.1021/acs.orglett.9b01687
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
gram scale, and there was no noticeable difference in the
product yields within the tested range of 1−5 mmol scale. For
the substrates with aromatic substituents 16b−g,i, the reaction
followed the same trend as for the parent 16a. Configuration of
Table 3. Oxidative Coupling vs Nucleophilic Addition/
a
Elimination Process
the chiral axis in 17g was established as S by X-ray analysis
a
(
see the Supporting Information for details), which was
extrapolated to all other N,N′-dioxides. However, N-oxide 16h,
with the methoxy group in the o-position capable of chelating
Li, failed to produce the coupling product, which likely
resulted from formation of complexes with unfavorable
alignment of the pyridine units (entry 8). Substrates with
heterocyclic substituents 16j and 16k mirrored reactivity of the
aromatic analogues to furnish the respective N,N′-dioxides
T
yield of 9
1
b
entry
10, R , R2
(°C)
N
or O
yield of 11 (%)
(%)
2
2
1
2
3
4
5
6
7
10a, Ph, H
10a, Ph, H
10b, Ph, Br
10b, Ph, Br
10b, Ph, Br
10c, Ph, Ph
10c, Ph, Ph
−78
−78
−78
0
−78
−78
0
O2
N2
O2
O2
N2
O2
N2
92
93
0
0
0
69
(
entries 10 and 11). For N-oxides with aliphatic substituents,
c
the reaction outcome depended on the presence of an α-C−H
c
c
bond in the substituent. Thus, substrates 16l (CF ) and 16m
30
47
3
(tBu) lacking any C−H bond reacted uneventfully (entries 12
80
0
0
0
60
c
and 13), whereas 16n (iPr) proved unreactive, even though a
MeOD quench 5 min after deprotonation revealed 75% D
incorporation in the 2-position of the pyridine ring and none in
the iPr group. The reason for such an anomalous behavior is
not clear at the moment.
0
a
The reactions were carried out in dry THF on a 0.4−0.6 mmol scale,
unless stated otherwise, using 1.3 equiv of LDA at −78 °C for
deprotonation. A balloon with O was attached immediately after
2
b
c
The coupling of 2-cyanopyridine 16o resulted in a low yield
of the N,N′-dioxide 17o. In this instance, the starting material
was fully consumed through competing side reactions.
The prerequisite to quickly intercept the kinetically formed
complexes of 2-lithiopyridine N-oxides prompted us to briefly
examine their electrochemical oxidation (Scheme 3). The
combining the reactants. Isolated yield. Yield based on recovered
starting material.
sterically hindered 2,5-diphenylpyridine N-oxide 10c in the
presence of O gave only N,N′-dioxide 9c, while no product
2
was formed under inert atmosphere (entries 6, 7). Bromide in
position 5 appears to mark a borderline case. Under O at −78
2
°
C, only N,N′-dioxide 9b was formed (entry 3); at 0 °C, both
Scheme 3. Electrochemical Synthesis of Atropisomeric
Bipyridine N,N′-Dioxides
reaction manifolds exhibited similar rates slightly favoring
oxidative dimerization (entry 4). Naturally, under N , only
2
mono-N-oxide 11b was attained (entry 5). The results indicate
that the steric size of the substituent in position 5, along with
the reaction temperature and the reaction atmosphere, strongly
influence the preferred pathway. As a follow up, cross-coupling
of two different pyridine N-oxides was examined under
conditions favoring a nucleophilic addition/elimination route
10c
(
Scheme 4). Pyridine N-oxides 10b or 10d were added to a
Scheme 4. Cross-Coupling of Two Different Pyridine N-
Oxides
reaction was carried out in THF at ambient temperature
employing LiBF as an electrolyte. It was found essential to use
4
Ph PO (1.5 equiv), presumably acting as a sacrificial electron
3
acceptor to prevent reduction of pyridine N-oxide. The best
yields were attained when LDA was added in three portions
with 5 min intervals. In these cases, the yields were on par with
those obtained under O atmosphere. The N,N′-dioxides 17a,
2
1
7e, and 17f were attained as single diastereoisomers.
Furthermore, formation of bipyridine mono-N-oxides was
not observed, thus making the electrochemical dimerization of
2
-lithiopyridine N-oxides 16 a useful tool for synthesizing 17.
Appearance of bipyridine mono-N-oxides alongside 16a
solution of deprotonated N-oxide 16a at 0 °C under N2
atmosphere. Mono-N-oxides 18ab and 18ad were obtained
in good yield, though with low diastereoselectivity.
(Table 1, entries 6 and 7) raised questions regarding the
factors influencing the competition between the two reaction
manifolds: oxidative coupling vs nucleophilic addition/
elimination sequence. Therefore, coupling of N-oxides 10a−c
with substituents in position 5 of differing sizes was examined
To illustrate the advantage of the oxidative dimerization over
the existing metal-mediated coupling of 2-halopyridines, the
two sequences in the synthesis of atropisomeric (S )-19a were
a
compared (Scheme 5).
(Table 3).
Thus, pure (S )-17a obtained by oxidative coupling of 16a
a
The least sterically congested 2-phenylpyridine N-oxide 10a
furnished only addition/elimination product 11a under both
oxidative and inert atmosphere (entries 1,2). The most
was readily converted to (S )-19a by heating with metallic Zn
in aqueous THF with no erosion of the stereochemical
integrity. On the other hand, a Ni-catalyzed coupling of 2-
a
C
DOI: 10.1021/acs.orglett.9b01687
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 5. Synthesis of Atropisomeric Bipyridines
ACKNOWLEDGMENTS
■
The authors thank the Russian Science Foundation for Grant
No. 18-73-10156. Y.F. and A.V.M. thank the Leverhulme Trust
for the research grant (RGP-2015-351). Y.F. also thanks the
Japanese Government and Loughborough University for a
studentship.
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ASSOCIATED CONTENT
Supporting Information
■
(
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01687.
́
́
̌
́
̌
́
̌
́
2
Experimental procedures; H and 13C NMR spectra for
1
2
new compounds (PDF)
(
(
Accession Codes
5235. (c) Denmark, S. E.; Fan, Y. Tetrahedron: Asymmetry 2006, 17,
CCDC 1905937 and 1909215 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
6
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AUTHOR INFORMATION
Corresponding Authors
■
(
10) (a) Tagawa, Y.; Hama, K.; Goto, Y.; Hamana, M. Heterocycles
*
E-mail: a.malkov@lboro.ac.uk.
E-mail: rubtsov@psu.ru.
1992, 34, 2243. (b) Tagawa, Y.; Hama, K.; Goto, Y.; Hamana, M.
Heterocycles 1995, 40, 809. (c) Kovalev, I. S.; Rusinov, V. L.;
Chupakhin, O. N. Chem. Heterocycl. Compd. 2009, 45, 176. (d) Wang,
H.; Pei, Y.; Bai, J.; Zhang, J.; Wu, Y.; Cui, X. RSC Adv. 2014, 4, 26244.
(e) Jha, A. K.; Jain, N. Eur. J. Org. Chem. 2017, 2017, 4765.
*
ORCID
Sergei A. Shipilovskikh: 0000-0002-8917-2583
Aleksandr E. Rubtsov: 0000-0002-4299-3464
Andrei V. Malkov: 0000-0001-6072-2353
Notes
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Shipilovskikh, S. A.; Rubtsov, A. E.; Elsegood, M. R. J.; Malkov, A. V.
Chem. - Eur. J. 2015, 21, 4551. (c) Peng, X. J.; Huang, P. P.; Jiang, L.
L.; Zhu, J. Y.; Liu, L. X. Tetrahedron Lett. 2016, 57, 5223.
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.9b01687
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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(
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(
17) Furthermore, oxidation of (S )-19a with m-CPBA gave a mere
a
3
:1 mixture of atropisomeric (S )-17a and (R )-17a (see the
a
a
Supporting Information). No racemization of (S )-19a was observed
a
after heating for 1 h at 100 °C in DMSO.
E
DOI: 10.1021/acs.orglett.9b01687
Org. Lett. XXXX, XXX, XXX−XXX