Displacement of Dinitrogen by Oxygen: A Methodology for the Catalytic Conversion of Diazocarbonyl Compounds to Ketocarbonyl Compounds by 2,6-Dichloropyridine-N-oxide

Article abstract of DOI:10.1021/acs.orglett.7b03912

Dirhodium(II) catalyzed dinitrogen extrusion from diazocarbonyl compounds by 2,6-dichloropyridine-N-oxide forms ketocarbonyl compounds in near-quantitative yields. Reactions occur at room temperature, and the pyridine product does not coordinate with dirhodium(II) to inhibit catalysis. Anhydrous tricarbonyl compounds, as well as dicarbonyl compounds, are conveniently prepared by this methodology, and they have been used in situ for catalytic ene and aldol transformations.

Full text of DOI:10.1021/acs.orglett.7b03912

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Displacement of Dinitrogen by Oxygen: A Methodology for the
Catalytic Conversion of Diazocarbonyl Compounds to Ketocarbonyl
Compounds by 2,6-Dichloropyridine‑N‑oxide
Yang Yu,† Qiang Sha,‡ Hui Cui,† Kory S. Chandler,† and Michael P. Doyle*,†
†Department of Chemistry, University of Texas at San Antonio, San Antonio, Texas 78249, United States
‡Department of Chemistry, College of Sciences, Nanjing Agricultural University, Nanjing, China 210095
S
* Supporting Information
ABSTRACT: Dirhodium(II) catalyzed dinitrogen extrusion
from diazocarbonyl compounds by 2,6-dichloropyridine-N-
oxide forms ketocarbonyl compounds in near-quantitative
yields. Reactions occur at room temperature, and the pyridine
product does not coordinate with dirhodium(II) to inhibit
catalysis. Anhydrous tricarbonyl compounds, as well as
dicarbonyl compounds, are conveniently prepared by this
methodology, and they have been used in situ for catalytic ene
and aldol transformations.
Scheme 1. Oxygen Transfer Reactions
icinal tricarbonyl compounds have proven to be versatile
1
Vsynthetic building blocks.
The carbon of the middle
carbonyl group is highly electrophilic, providing sufficient
reactivity for carbon−carbon bond formation with even
moderately reactive nucleophiles under mild conditions.2−5
Access to these vicinal tricarbonyl compounds has been
provided by oxidation of 1,3-dicarbonyl compounds,6 but is
most conveniently provided by oxidative conversion of the
disubstituted diazomethane formed by diazo transfer to a β-
ketocarbonyl compound, typically, but not limited to, β-
ketoesters and β-ketoamides.7 The diazo transfer reaction of β-
ketocarbonyl compounds occurs by its well-developed base
promoted reaction with organic sulfonyl azides in high yields
under mild conditions.8 The oxidative dinitrogen extrusion step
is less well developed, although several methods have been
used.9 One is reaction with dimethyldioxirane (DMDO),
formed from acetone and oxone,10 that when applied to,
typically, α-diazo-β-ketoesters can form the anhydrous form of
2,3-diketoesters quantitatively or in high yield; however, since
oxone is a somewhat indiscriminate oxidant, DMDO is usually
formed separately and then added to the diazo compound.
DMDO is commonly used for small-scale reactions.11 An
alternative to DMDO is the use of tert-butyl hypochlorite,12 but
with this method the hydrate of the tricarbonyl compound is
the product. Since the hydrate significantly reduces the
electrophilic reactivity of the vicinal carbonyl compound,4
alternative methods are sought to allow large-scale production
of vicinal tricarbonyl compounds avoiding water or other
common nucleophiles that reduce their reactivity.
thermal oxidative dedinitrogenation of aryldiazocarbonyl
compounds in good yield, but DMSO was used as the solvent,
and the minimum temperature employed was 50 °C for
treatment with these normally reactive diazo compounds.13
Previously, diazoesters had been employed for copper catalyzed
oxygen atom abstraction from a variety of N-oxides;14 good to
high pyridine yields were obtained for reactions performed at
60 °C with a large excess of the diazo compound. Our interest
is in generating a methodology for the construction of vicinal
tricarbonyl compounds that could be performed with a mild
oxidant under mild conditions avoiding water or other common
nucleophiles that would reduce their electrophilic reactivity in
subsequent reactions. We now report the efficient generation of
anhydrous vicinal di- and tricarbonyl compounds by
dirhodium(II) catalyzed reactions between diazocarbonyl
One approach to the replacement of the dinitrogen of diazo
compounds by oxygen has been oxygen atom transfer (Scheme
1). Dimethyl sulfoxide has been recently reported to effect
Received: December 15, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03912
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
compounds and 2,6-dichloropyridine-N-oxide, and their
applications for carbon−carbon bond formation.
2,6-Dichloropyridine-N-oxide (2b) was optimum in its rate of
transfer and convenience. However, the oxygen transfer to 1a
using 2b did not occur with copper(II) triflate14 at 60 °C over
24 h in DCE, the conditions preciously used by Chang using
selected aryldiazoacetates.
The cause for the relative ease of oxygen transfer with 2,6-
disubstituted pyridine-N-oxides is proposed to be an outcome
of weak coordination with the pyridine-N-oxide and the
structure of rhodium(II) carboxylates whose oxygen ligands
provide a barrier to association by its pyridine product (eq 1).
By recognizing the differences in stabilities of diazocarbonyl
compounds (acceptor−acceptor, donor−acceptor, and accept-
or),15 we selected α-diazo-β-ketoesters as model substrates for
dinitrogen replacement by oxygen. These diazo compounds are
much more stable than diazoacetates or aryldiazoesters that
have been previously employed for this transformation. Their
thermal stabilities and resistance to catalytic dinitrogen loss
have been described.9c,16 Treatment of methyl 2-diazo-3-
oxobutanoate (methyl diazoacetoacetate, MDAA, 1a) with
either DMSO or pyridine-N-oxide resulted in no apparent
reaction at room temperature over 24 h, and even in refluxing
1,2-dichloroethane (DCE, 82 °C) this diazo compound
exhibited negligible reaction. The addition of rhodium acetate
to form an intermediate metal carbene was ineffective with
pyridine-N-oxide at room temperature, and very slow
dinitrogen extrusion was observed at the much higher
temperature of refluxing DCE. Since our goal was oxygen
transfer that could occur at or below room temperature, we
searched for an oxygen transfer reagent that could allow
complete reaction to occur within a reasonable time period, and
the results of this search are given in Table 1. Pyridine-N-oxide
and para-substituted pyridine-N-oxides (para-OMe, −Me, −Cl,
NO2) underwent slow rhodium acetate catalyzed oxygen
transfer with MDAA in refluxing DCE but were unreactive at
room temperature. In contrast, 2,6-disubstituted pyridine-N-
oxides underwent smooth oxygen transfer at room temperature
with rates of reaction that were dependent on the substituents.
The coordinating ability of pyridine with rhodium(II)
carboxylates is very strong,17 but the electron-rich chloride
substituents at the 2- and 6-positions can be expected to block
this association.
Equilibrium associations were determined by UV/vis spec-
troscopy for 2,6-dichloropyridine-N-oxide (Figure 1) and for
a
Table 1. Screening Reaction Conditions for 1a
Figure 1. UV/vis spectrum for the coordination between 2,6-
dichloropyridine-N-oxide and Rh2(oct)4. Spectral changes accompany-
ing sequential additions of 2,6-dichloropyridine-N-oxide (0.30 M in
DCM, from 0.20 to 2.0 equiv) to Rh2(oct)4 (1.20 × 10−2 M) in 2.5 mL
of anhydrous DCM at 23 °C.
pyridine-N-oxide, with both exhibiting relatively low equili-
brium constants (30.2 for 2b and 43.2 for pyridine-N-oxide
with Rh2(oct)4). Strikingly, however, 2,6-dichloropyridine-N-
oxide 2b showed no obvious spectral shifts by UV/vis
O-transfer
reagent
temp
time
(h)
yield 3a
b
1
entry
catalyst
(°C)
(%)
spectroscopy or H NMR spectroscopy, indicating negligible
1
2
3
4
5
2a
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(oct)4
none
23
24
1
0
association with the dirhodium(II) catalyst. This confirmation
of steric inhibition to association with dirhodium(II)
carboxylate catalyst confirms that such bases can be used in
rhodium(II) catalyzed reactions without inhibition of catalytic
activity. 2,6-Dibromo- or 2,6-dimethyl-substituents do not offer
any advantage over the 2,6-dichloro substituents.
2b
2c
23
90
23
1.5
24
1.5
0.67
12
24
82
2d
2e
23
30
23
69
c
6
2b
2b
none
23
94
7
8
23/82
23
0
Rh2(OAc)4
complex
a
Standard reaction conditions: Rh2(OAc)4 (2.0 × 10−3 mmol) was
added to a 1.0 mL DCM solution of 1a (0.20 mmol) and pyridine-N-
oxides 2 (1.0 equiv) at room temperature. NMR yield with 1,3,5-
trimethoxylbenzene as internal standard. 4 Å Molecular sieves (50
b
c
Reactions with methyl diazoacetoacetate were performed at
room temperature using a slight excess of the oxygen transfer
agent. Treatment of MDAA with 2,6-dichloropyridine-N-oxide
at room temperature in air produced only the anhydrous form
of this 2,3-diketoester (>95%) in reactions performed in
mg) were added into a solution of 1a (28.4 mg, 0.20 mmol), 2,6-
dichloropyridine-N-oxide 2b (32.8 mg, 0.20 mmol, 1.0 equiv) in DCM
(1.0 mL). The mixture was stirred for 10 min before the addition of
Rh2(oct)4 (1.56 mg, 2.0 × 10−3 mmol) at room temperature. Reaction
time is 40 min.
B
DOI: 10.1021/acs.orglett.7b03912
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
anhydrous solution. Upon standing the solution absorbed
moisture, but this diketoester was isolated by filtration from
molecular sieves through cotton in 90% yield with an
anhydrous/hydrate ratio of 93:7. This level of the anhydrous
form was similar to that which could be achieved by heating
(90−100 °C) the hydrate of methyl 2,3-dioxobutanoate under
vacuum (∼1 Torr).4
Extension of the optimum conditions to other acceptor−
acceptor diazo compounds showed the generality of the
method (Scheme 2). Formation of the anhydrous tricarbonyl
Scheme 3. Competition Reactions for Some Specific
Substrates
Scheme 2. Oxygen Transfer of Acceptor−Acceptor Diazo
a
Compounds
Scheme 4. Oxygen Transfer of Donor−Acceptor Diazo
a
Compounds
a
4 Å Molecular sieves (50 mg) were added to a 1.0 mL DCM solution
of 1a−h (0.20 mmol) and 2,6-dichloropyridine-N-oxide (1.0 equiv).
The mixture was stirred for 10 min before adding Rh2(oct)4 (2.00 ×
10−3 mmol) at room temperature. Reactions were monitored by TLC.
Yields were determined by 1H NMR with 1,3,5-trimethoxylbenzene as
b
the internal standard. 5 equiv of 2,6-dichloropyridine-N-oxide were
c
used. 10 equiv of 2,6-dichloropyridine-N-oxide were used.
a
compound (3) was quantitative in most cases and was isolated
in very high yield. The metal carbene intermediates formed
from diazo compounds 1g and 1h underwent competing
intramolecular reactions whose importance could be reduced
with the use of excess 2,6-dichloropyridine-N-oxide.
Competing reactions were intramolecular C−H insertion
reactions (eqs 3 and 4) or a 1,4-hydrogen shift (eq 5) (Scheme
3). The formation of benzaldehyde by 1,4-hydride transfer is a
known transformation18 whose competition with oxygen
transfer could be circumvented by increasing the relative
amount of 2,6-dichloropyridine-N-oxide.
4 Å Molecular sieves (50 mg) were added into a 1.0 mL DCM
solution of 6a−d (0.20 mmol), 2,6-dichloropyridine-N-oxide (1.0
equiv). The mixture was stirred for 10 min before adding Rh2(oct)4
(2.00 × 10−3 mmol) at room temperature. Reactions were monitored
by TLC. Yields were determined as isolated yields after flash column
chromatography.
Scheme 5. Applications in C−C Bond Forming Reactions
As expected, applications to donor−acceptor diazo com-
pounds were similar in their quantitative conversions and high
isolated yields (Scheme 4). The major difference from reactions
with acceptor−acceptor diazo compounds was the relative ease
in handling the tricarbonyl compounds, diketoesters being
much less prone to hydrate formation.
2,3-Diketoesters have been employed in a number of
transformations,2,3 and representative reactions were run to
determine if they could be successfully performed in the same
reaction medium that is used to effect oxygen transfer. The ene
reaction with α-methylstyrene (eq 6)4 was performed on 3a
after completion of oxygen transfer. The asymmetric aldol
reaction was performed on 3a (eq 7) after completion of
oxygen transfer by the addition of (L)-proline and cyclo-
hexanone (Scheme 5).
In summary, with catalysis by dirhodium carboxylates 2,6-
dichloropyridine-N-oxide replaces dinitrogen by oxygen in
diazocarbonyl compounds. In this general methodology,
reactions occur at room temperature, produce the anhydrous
C
DOI: 10.1021/acs.orglett.7b03912
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03912.
■
S
Detailed experimental procedures, H and 13C NMR
spectra of new compounds, and UV−vis spectra for
coordination study (PDF)
1
(11) (a) Schutte, J.; Kilgenstein, F.; Fischer, M.; Koert, U. Eur. J. Org.
̈
Chem. 2014, 2014, 5302. (b) Truong, P.; Shanahan, C. S.; Doyle, M. P.
Org. Lett. 2012, 14, 3608. (c) Truong, P.; Xu, X.; Doyle, M. P.
Tetrahedron Lett. 2011, 52, 2093. (d) Adam, W.; Zhao, C. G.; Jakka, K.
Organic Reactions 2008, 1−346. (e) Saba, A. Synth. Commun. 1994, 24,
695.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: michael.doyle@utsa.edu.
ORCID
(12) Rubin, M. B.; Gleiter, R. Chem. Rev. 2000, 100, 1121.
(13) O’Connor, N. R.; Bolgar, P.; Stoltz, B. M. Tetrahedron Lett.
2016, 57, 849.
(14) Jeong, J.; Lee, D.; Chang, S. Chem. Commun. 2015, 51, 7035.
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2861. (b) Bourissou, D.; Guerret, O.; Gabbai, F. P.; Bertrand, G.
Chem. Rev. 2000, 100, 39.
Michael P. Doyle: 0000-0003-1386-3780
Notes
(16) Ford, A.; Miel, H.; Ring, A.; Slattery, C. N.; Maguire, A. R.;
McKervey, M. A. Chem. Rev. 2015, 115, 9981.
The authors declare no competing financial interest.
(17) Drago, R. S.; Tanner, S. P.; Richman, R. M.; Long, J. R. J. Am.
Chem. Soc. 1979, 101, 2897.
(18) Doyle, M. P.; Dyatkin, A. B.; Autry, C. A. J. Chem. Soc., Perkin
ACKNOWLEDGMENTS
■
Support for this research from The Welch Foundation (AX-
1871) is gratefully acknowledged. The HRMS used in this
research is supported by a grant from the National Institutes of
Health (G12MD007591). The National Science Foundation
supported the acquisition of a NMR spectrometer used in this
study (CHE-1625963).
Trans. 1 1995, 619.
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DOI: 10.1021/acs.orglett.7b03912
Org. Lett. XXXX, XXX, XXX−XXX