A Class of N-O-Type Oxidants to Access High-Valent Palladium Species

Article abstract of DOI:10.1021/acs.organomet.8b00712

This article presents a new class of mild reagents that is capable of oxidizing palladacycle(II) complexes to high-valent palladium species, promoting the formation of C-N bonds in stoichiometric and catalytic conditions. The weak N-O bond and the extremely electron-withdrawing benzenesulfonate group on the oxygen atom of the oxidant are crucial moieties to ensure the desired activity. The oxidation mechanism could involve outer-sphere single-electron transfer processes, opening the possibility for a complementary reactivity of Pd(IV) species.

Full text of DOI:10.1021/acs.organomet.8b00712

Article
pubs.acs.org/Organometallics
Cite This: Organometallics XXXX, XXX, XXX−XXX
A Class of N−O-Type Oxidants To Access High-Valent Palladium
Species
Manuel Nappi and Matthew J. Gaunt*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom
S
* Supporting Information
ABSTRACT: This article presents a new class of mild
reagents that is capable of oxidizing palladacycle(II) complexes
to high-valent palladium species, promoting the formation of
C−N bonds in stoichiometric and catalytic conditions. The
weak N−O bond and the extremely electron-withdrawing
benzenesulfonate group on the oxygen atom of the oxidant are
crucial moieties to ensure the desired activity. The oxidation
mechanism could involve outer-sphere single-electron transfer
processes, opening the possibility for a complementary reactivity of Pd(IV) species.
The innately strong and unselective reactivity of the
hypervalent iodonium salts and other oxidants can sometimes
limit the scope of Pd(IV)-catalyzed C−H functionalization to
substrates that are not susceptible to oxidative degradation.
Therefore, the design of milder oxidative conditions to obtain
the Pd(IV) intermediate would be beneficial.10−12 Herein, we
report the discovery of a mild reagent capable of oxidizing
palladacycle(II) complexes to high-valent palladium species,
triggering the formation of C−N bonds in stoichiometric and
catalytic conditions. The weak N−O bond and the electron-
withdrawing benzenesulfonate group on the oxygen atom of
the oxidant are crucial moieties to ensure the desired activity
(Scheme 1b).
INTRODUCTION
■
Palladium-catalyzed processes represent essential tools for the
synthetic chemist. A myriad of distinct Pd-catalyzed trans-
formations are routinely found as key steps in target-oriented
syntheses, affording complex natural products, pharmaceutical
lead compounds, fluorescent compounds, functional advanced
materials, and other high-value commercial products. The
involvement of Pd(IV) complexes in C(sp3)−H functionaliza-
tion protocols has been implicated in several new synthetic
methodologies and many important advances have been made
in the last 20 years.1,2 Typically, strong oxidants such as
hypervalent iodonium salts (e.g., PhI(OAc)2),3 MeCOOOt-
Bu,4 K2S2O8,5 Selectfluor,6 AgOAc,7 Ce(SO4)2,8 NFSI,9 and
N-fluoro-2,4,6-trimethylpyridinium triflate8 are used in stoi-
chiometric amounts to promote the formation of Pd(IV)
intermediates through oxidation of [Pd(II)] palladacycle
complexes (Scheme 1a), allowing the development of several
carbon−heteroatom bond-forming methodologies.
RESULTS AND DISCUSSION
■
In recent years, our group has developed a series of Pd-
catalyzed C(sp3)−H functionalization methods for aliphatic
amines, exploiting the innate coordinating ability of the amine
nitrogen to mediate substrate−catalyst interactions.13−17 In the
case of Pd(IV) methodologies, PhI(OAc)2 was successfully
employed for the formation of C−N and C−O bonds,
delivering aziridines and acetoxylation products, depending
on the substrates and conditions used (Scheme 2a).13
Recently, we reported a palladium(II)-catalyzed γ-C−H
amination process in which cyclic secondary alkyl amines are
converted to highly substituted azetidines.17 The use of a
benziodoxole tosylate as an oxidant, in combination with
AgOAc, was crucial in delivering the azetidines. We proposed
that the dissociative ionization and subsequent nucleophilic
attack of the tosylate at the carbon atom bearing the
palladium(IV) group forms the C−OTs bond, which in turn
Scheme 1. Oxidants To Access High-Valent Palladium
Species in C(sp3)−H Functionalization Reactions
Special Issue: The Roles of Organometallic Chemistry in Pharma-
ceutical Research and Development
Received: October 1, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.8b00712
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Scheme 2. Use of Pd(IV) Chemistry in C(sp3)−H
Functionalizations of Secondary Aliphatic Amines
Table 1. Stoichiometric Studies on the New N−O-Type
Oxidants
a
a
entry Pd cycle oxidant N-heterocycles (yield, %)
−OAc (yield, %)
1
2
3
4
5
1a
1b
1a
1a
1b
2a
2a
2b
2c
2c
3 (0)
5 (0)
3 (10)
3 (83)
5 (80)
4 (0)
6 (0)
4 (15)
4 (0)
6 (0)
is displaced by the proximal amino group to form the azetidine
(Scheme 2b). Guided by the discovery of the dissociative
ionization mechanism, we wondered if a novel class of oxidant
containing the tosylate group could be used to prompt the C−
N bond formation. In particular, we speculated that the key I−
O bond of the benziodoxole can be replaced with an N−O
bond contained in the N-hydroxyl derivatives (Scheme 2c).
Oxidative insertions of Pd(0) complexes to N−O bonds have
been previously reported in the functionalization of N-
acetoxyimine derivatives by Hartwig and others.18 Therefore,
we speculated that an electron-withdrawing N-tosylate
carbamate could promote the formation of high-valent Pd(IV)
species through the oxidative insertion of the palladacycle(II)
complexes into the reactive N−O bond.
a
Yields determined by 1HNMR spectroscopy using 1,1,2,2-tetra-
chloroethane (TCE) as an internal standard.
Scheme 3. Possible Oxidation Mechanism Involving SET
We began our investigation by synthesizing N-tosylate
carbamate derivative 2a and conducting stoichiometric studies
on the palladacycle(II) complexes (1a and 1b) previously
reported in our group (Table 1).13,17 Unfortunately, none of
the desired N-heterocycle products were observed (entries 1
and 2). We reasoned that decreasing the electron density of the
aromatic ring would weaken the N−O bond, and therefore, we
prepared and tested the 4-nitrobenzenesulfonate derivative 2b.
Pleasingly, when palladacycle 1a was used, aziridine 3 was
obtained in 10% yield along with 15% of the acetoxylated
adduct 4 (entry 3). This is the first time an intramolecular C−
H amination has been achieved for piperidine-type scaffolds.
Indeed, when PhI(OAc)2 was previously employed as oxidant,
acetoxylated products were exclusively observed. Next, we
synthesized the carbamate derivative 2c, which contains an
additional nitro group in the ortho position of the
benzenesulfonate moiety. Under mild reaction conditions, we
were delighted to observe the exclusive formation of the
desired aziridine 3 and azetidine 5 in very good yields from
palladacycles 1a and 1b, respectively (entries 4 and 5).
Significantly, no acetoxylation adducts were detected. From the
reaction mixture, we could also isolated a series of carbamate-
containing byproducts. In particular, ethyl N-methyl carbamate
7 was isolated in 27% yield, along with dimers 8 (15% yield), 9
(14% yield), and 10 (3% yield, Scheme 3). The formation of
these compounds was also observed when similar N-
halocarbamates were exposed to electrochemical reduction
conditions, via two consecutive outer-sphere single-electron
transfer (SET) processes.19 As the 2,4-dinitrobenzenesulfonate
oxidant 2c has also been used as a source for the nitrogen
center radical via single-electron reduction in photochemistry20
and due the formation of the dimeric byproducts in the
reaction conditions, we wondered if outer-sphere single-
electron transfer processes are involved in the formation of
our high-valent Pd intermediates. A possible mechanism is
described in Scheme 3. A first slow single-electron transfer
could occur between carbamate 2c and a palladacycle(II)
complex. The radical anion of the oxidant would immediately
undergo mesolytic fragmentation, yielding the 2,4-dinitro-
benzenesulfonate and the reactive nitrogen-centered radical.
The sulfonate will stabilize the palladium(III), whereas a
second fast single-electron transfer would then afford the
Pd(IV) complex and the corresponding carbamate anion
(reduction potential of a general amidyl radical to the
corresponding anion is very high),21 which will immediately
coordinate with the palladium and yield the Pd(IV)
intermediate 11. This outer-sphere mechanism can be seen
as a formal oxidative insertion into the N−O bond. Finally,
azetidine 5 is obtained via a similar dissociative ionization
mechanism described in Scheme 2b.
To understand if the first single-electron transfer between
2,4-dinitrobenzenesulfonate oxidant 2c and palladacycle 1b is
feasible, we conducted cyclic voltammetry studies (see the
Supporting Information for details). As expected, the reduction
potentials of the oxidants presented a trend. The tosylated
B
DOI: 10.1021/acs.organomet.8b00712
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Article
derivative 2a showed a reduction wave around −1.2 V in
MeCN (vs AgCl/Ag electrode, 3 M KCl), whereas the 4-nitro
(2b) and 2,4-dinitrobenzenesulfonate (2c) carbamates could
be irreversibly reduced at only −0.40 and −0.25 V,
respectively, confirming that compound 2c is the best oxidant.
Next, electron-rich palladacycle 1b was submitted to CV
studies with two different tetrabutylammonium salts as support
electrolytes. Using 0.1 M solution of NBu4PF6, the electro-
chemical experiment showed one irreversible oxidation with
onset potential at +0.83 V. When the same studies were
performed using NBu4OAc as electrolyte, the oxidation wave
shifted to a more negative value, showing an onset potential of
+0.57 V. This changing oxidation potential can be explained by
the different stabilization of the newly formed high-valent Pd
complexes, as also observed by Sanford and colleagues12,22
(better nucleophiles, such as acetate, will better stabilize the
Pd(IV) species). However, in case of outer-sphere oxidation,
ethyl N-methyl carbamate anion will be formed (via two-
electron reduction), which normally displays a very high
nucleophilicity in comparison to that of the acetate anion.
Therefore, even though the cyclic voltammetry studies suggest
an endergonic single-electron transfer, it is possible that the
real oxidation potential of palladacycle 1b in the reaction
conditions would be lower than +0.57 V (due to a better
stabilization of the high-valent palladium species by the
carbamate anion), enabling the first slow single-electron
transfer to oxidant 2c. Obviously, the classical inner-sphere
oxidative insertion mechanism cannot be ruled out.
Table 2. Catalytic Studies on the Use of New N−O-Type
Oxidants
a
entry 2 (equiv)
solvent temp (°C) additive (equiv) 5 yield (%)
1
2
3
4
5
6
7
8
9
2c (1.5)
2c (1.5)
2c (1.5)
2c (2)
2c (2)
2c (3)
2c (4)
2c (4)
2d (2)
2e (2)
2f (2)
HFIP
HFIP
60
90
120
105
90
90
90
90
90
18
25
34
42
45
51
55
61
41
42
23
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
AgOAc (2)
10
11
90
90
a
Yields determined by 1HNMR spectroscopy using 1,1,2,2-tetra-
chloroethane (TCE) as an internal standard.
Intrigued by the reactivity of our novel N−O-type oxidants,
we next attempted a catalytic reaction for the formation of N-
heterocycles. Initial experiments with a stoichiometric amount
of Pd(OAc)2 showed promising results for azetidine 5
formation (60% yield using HFIP as a solvent), whereas
aziridine 3 was only obtained in moderate yield (30% in
dioxane; see the Experimental Section for details). Therefore,
we focused our attention on morpholinone substrate 12 (Table
2). Solvent, temperature, and stoichiometry of the carbamate
2c were crucial parameters in the optimization studies. Indeed,
the reaction in toluene, at 90 °C with 4 equiv of oxidant 2c and
10 mol % of Pd(OAc)2, provided the desired azetidine 5 in
55% yield (entry 7; 2.5 equiv of the oxidant can be recovered
at the end of the reaction and reused). At this point, we cannot
explain why 4 equiv of the oxidant are needed for optimal
yields. Subsequent screening of additives showed AgOAc as a
good candidate, improving the yield to 61% (entry 8). It is
noteworthy that, while the use of silver additive was not
fundamental in this case, traces of azetidine were obtained in
the absence of AgOAc in our previous methodology.17 In an
attempt to improve the reaction outcome, different carbamate
derivatives were prepared and tested. Variations on the
carbamate group showed little difference in the yield (entries
9 and 10), whereas amide 2f provided the product in only 23%
yield (entry 11). None of the azetidine was obtained when
phthalimide (2g), N-phenyl (2h), or the N-tert-butyl (2i)
derivatives were used as oxidant. Surprisingly, from the
reaction mixture of the N-tert-butyl oxidant 2i, we could
isolate ethyl N-methyl carbamate 7 in 62% yield. A plausible
explanation for the formation of carbamate 7 in the reaction
conditions is described in Scheme 4a. After the first single-
electron transfer between palladacycle 1b and oxidant 2i and
mesolytic fragmentation of the corresponding radical anion,
the newly formed unstable nitrogen-centered radical 13
undergoes a 1,2-methyl shift to form the stable α-amino
Scheme 4. Evidence for the Formation of N-Centered
Radicals
radical 14. Another equivalent of carbamate 2i immediately
oxidizes the α-amino radical 14 to the corresponding iminium
ion (Ered around −1.0 V),23 which will hydrolyze to yield ethyl
N-methyl carbamate 7 and acetone. Because the second
electron transfer, and hence the formation of the carbamate
anion, could not happen (no dimeric byproducts were detected
in this case), the key Pd(IV) complex 11 was not formed,
preventing the synthesis of the desired azetidine via the
dissociative ionization mechanism. Consequently, the for-
mation of carbamate 7 can be considered as a positive evidence
for the presence of nitrogen-centered radical 13 and therefore
for the single-electron transfer between oxidant 2i and
C
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mL, 63 mmol, 1.05 equiv). The resulting clear suspension was stirred
overnight at room temperature and then diluted with H2O (50 mL)
and extracted with CH2Cl2 (3 × 50 mL). The combined organic
extracts were dried (MgSO4) and concentrated in vacuo to yield ethyl
hydroxy(methyl)carbamate (7.1 g, 99% yield) as a colorless oil that
was used without further purification. To a stirred solution of ethyl
hydroxy(methyl)carbamate (3.4 g, 28.5 mmol, 1.0 equiv) in CH2Cl2
(200 mL) at 0 °C were added NEt3 (5.1 mL, 37.1 mmol, 1.3 equiv)
and 2,4-dinitrobenzenesulfonyl chloride (8.0 g, 29.9 mmol, 1.05
equiv). The resulting orange solution was stirred at 0 °C for 3 h and
then diluted with 0.5 M aqueous citric acid (100 mL) and extracted
with CH2Cl2 (2 × 100 mL). The combined organic extracts were
washed with saturated aqueous NaHCO3 (100 mL) and brine (100
mL), dried (MgSO4), and concentrated in vacuo. The resultant
orange solid was collected by filtration on a sintered funnel and then
triturated and washed with Et2O (2 × 100 mL) to provide oxidant 2c.
When necessary, the product was purified by flash chromatography
using petroleum ether/ethyl acetate as eluent.
palladacycle 1b. A computational investigation of these
pathways is ongoing and will be reported in due course. It is
noteworthy that the catalytic reaction to form aziridine 4 was
not successful. We believe the difference in catalytic reactivity
in the formation of 3 and 5 can be possibly ascribed to the
carbonyl group modulating the nucleophilicity of the
coordinating nitrogen atom, thereby rendering catalytically
inactive bisamine Pd(II) complexes less stable.24
Moreover, when 2 equiv of TEMPO was introduced in the
standard reaction conditions, no azetidine product was
observed (Scheme 4b). As a control experiment, the same
amount of TEMPO was added to the standard acetoxylation
reaction with PhI(OAc)2 as oxidant. In this case, acetoxylated
product 6 was obtained in 42% yield (62% yield without
TEMPO), suggesting that in the previous experiment TEMPO
inhibited the reaction through the quenching of a radical
species.
In conclusion, we have discovered a new class of oxidants to
access high-valent palladium species. The weak N−O bond
and the extremely electron-withdrawing benzenesulfonate
group on the oxygen atom of the oxidant are crucial moieties
to ensure the desired activity. Palladacycle(II) complexes could
be stoichiometrically oxidized to the Pd(IV) species, which
promoted the synthesis of N-heterocycles such as azetidine and
aziridine. A preliminary catalytic version is also presented,
where the azetidine product is obtained in good yield. Cyclic
voltammetry experiments and the isolation of carbamate
byproduct in the reaction conditions suggest the possibility
of outer-sphere SET processes involved in the oxidation
mechanism. Overall, we believe that these mild oxidants will
find important applications in other C−H functionalization
processes, especially in the case of substrates that are
susceptible to oxidative degradation.
Ethyl (((2,4-Dinitrophenyl)sulfonyl)oxy)(methyl)carbamate 2c
1
(76% Yield). H NMR (400 MHz, CDCl3) δ: 8.65 (d, J = 2.3 Hz,
1H), 8.55 (dd, J = 8.7 Hz, J = 2.3 Hz, 1H), 8.42 (d, J = 8.7 Hz, 1H),
4.04 (q, J = 7.1 Hz, 2H), 3.39 (s, 3H),1.1 (t, J = 7.1 Hz, 3H).
Ethyl Methyl(tosyloxy)carbamate 2a (87% Yield). 1H NMR (400
MHz, CDCl3) δ: 7.86 (d, J = 8.7 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H),
3.93 (q, J = 7.1 Hz, 2H), 3.26 (s, 3H), 2.46 (s, 3H), 1.0 (t, J = 7.1 Hz,
3H).
Methyl Methyl(((4-nitrophenyl)sulfonyl)oxy)carbamate 2b (82%
Yield). 1H NMR (400 MHz, CDCl3) δ: 8.40 (d, J = 8.9 Hz, 2H), 8.19
(d, J = 8.9 Hz, 2H), 3.51 (s, 3H), 3.34 (s, 3H).
Methyl (((2,4-Dinitrophenyl)sulfonyl)oxy)(methyl)carbamate 2d
1
(74% Yield). H NMR (400 MHz, CDCl3) δ: 8.67 (d, J = 2.2 Hz,
1H), 8.56 (dd, J = 8.5 Hz, J = 2.2 Hz, 1H), 8.42 (d, J = 8.5 Hz, 1H),
3.61 (s, 3H), 3.39 (s, 3H).
Isobutyl (((2,4-Dinitrophenyl)sulfonyl)oxy)(methyl)carbamate 2e
1
(77% Yield). H NMR (400 MHz, CDCl3) δ: 8.64 (d, J = 2.2 Hz,
1H), 8.55 (dd, J = 8.6 Hz, J = 2.2 Hz, 1H), 8.42 (d, J = 8.6 Hz, 1H),
3.8 (d, J = 6.7 Hz, 2H), 3.38 (s, 3H), 1.89−1.72 (m, 1H), 0.84 (d, J =
6.7 Hz, 6H).
N-(((2,4-Dinitrophenyl)sulfonyl)oxy)-N-methylacetamide 2f
EXPERIMENTAL SECTION
1
■
(52% Yield). H NMR (400 MHz, CDCl3) δ: 8.66 (d, J = 2.2 Hz,
General Information. Proton nuclear magnetic resonance (1H
NMR) spectra were recorded at ambient temperature on a Bruker
AM 400 (400 MHz) or an Avance 500 (500 MHz) spectrometer.
Chemical shifts (δ) are reported in parts per million and quoted to
the nearest 0.01 ppm relative to the residual protons in CDCl3 (7.26
ppm), and coupling constants (J) are quoted in hertz (Hz). Data are
reported as follows: chemical shift (multiplicity, coupling constants,
number of protons). Coupling constants were quoted to the nearest
0.1 Hz and multiplicity reported according to the following
convention: s = singlet, d = doublet, t = triplet, q = quartet, qn =
quintet, sp = septet, m = multiplet, bs = broad. Where coincident
coupling constants have been observed, the apparent (app)
multiplicity of the proton resonance has been reported. Carbon
nuclear magnetic resonance (13C NMR) spectra were recorded at
ambient temperature on a Bruker AM 400 (100 MHz) or an Avance
500 (125 MHz) spectrometer. Chemical shift (δ) was measured in
parts per million and quoted to the nearest 0.1 ppm relative to the
residual solvent peaks in CDCl3 (77.16 ppm). Toluene was dried and
distilled using standard methods. 1,1,2,2-Tetrachloroethane, 1,2-
dichloroethane (DCE), 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP)
were purchased from Acros and Sigma-Aldrich. Pd(OAc)2 (Pd
45.9−48.4%, needles) and AgOAc were purchased from Alfa Aesar.
All reagents were purchased at the highest commercial quality and
used without further purification. Reactions were carried out under an
atmosphere of air. Palladacycles 1a and 1b and morpholinone 12 were
prepared according literature procedures.13,17 Cyclic voltammetry
studies were performed using Electrasyn 2.0 IKA.
1H), 8.60 (dd, J = 8.5 Hz, J = 2.2 Hz, 1H), 8.43 (d, J = 8.5 Hz, 1H),
3.37 (s, 3H), 2.13 (s, 3H).
1,3-Dioxoisoindolin-2-yl 2,4-Dinitrobenzenesulfonate 2g (66%
Yield). 1H NMR (400 MHz, CDCl3) δ: 8.75 (d, J = 2.2 Hz, 1H), 8.62
(dd, J = 8.6 Hz, J = 2.2 Hz, 1H), 8.47 (d, J = 8.6 Hz, 1H), 7.91−7.82
(m, 4H).
Methyl (((2,4-Dinitrophenyl)sulfonyl)oxy)(phenyl)carbamate 2h
1
(48% Yield). H NMR (400 MHz, CDCl3) δ: 8.67 (d, J = 2.2 Hz,
1H), 8.47 (dd, J = 8.5 Hz, J = 2.2 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H),
8.00 (d, J = 8.4 Hz, 1H), 7.45−7.38 (m, 2H), 7.37−7.32 (m, 1H),
7.18−7.10 (m, 1H), 3.65 (s, 3H).
Ethyl tert-Butyl(((2,4-dinitrophenyl)sulfonyl)oxy)carbamate 2i
1
(61% Yield). H NMR (400 MHz, CDCl3) δ: 8.64 (d, J = 2.3 Hz,
1H), 8.55 (dd, J = 8.7 Hz, J = 2.3 Hz, 1H), 8.37 (d, J = 8.7 Hz, 1H),
4.04 (q, J = 7.1 Hz, 2H), 1.45 (s, 9H),1.1 (t, J = 7.1 Hz, 3H).
Stoichiometric Studies Using Palladacycles. A suspension of
the palladacycle 1 (0.025 mmol, 1 equiv) and oxidant 2 (0.05 mmol, 2
equiv) in 1,2-dichloroethane (0.5 mL) was heated in a sealed tube at
50 °C and stirred for 16 h. The reaction mixture was cooled to room
temperature, filtered through Celite, and eluted with dichloro-
methane. In the case of palladacycle 1a, the solution was extracted
with water (3 × 10 mL) and concentrated in vacuo to deliver aziridine
3 as 2,4-dinitrobenzenesulfonate salt. 1H NMR (400 MHz, CDCl3) δ:
8.42−8.34 (m, 3H), 8.19−8.02 (bs, 1H), 3.03 (dd, J = 7.4 Hz, J = 3.7
Hz, 1H), 2.52 (dd, J = 4.1 Hz, J = 3.7 Hz, 1H), 2.06−1.98 (m, 2H),
1.73 (s, 3H), 1.72−1.65 (m, 1H), 1.63 (s, 3H), 1.55−1.49 (m, 2H),
1.46 (s, 3H), 1.49−1.45 (m, 1H). 13C NMR (125 MHz, CDCl3) δ:
148.3, 148.2, 143.1, 132.0, 126.0, 118.8, 56.2, 48.9, 36.3, 32.3, 27.6,
27.1, 27.0, 23.1, 14.4. When palladacycle 1b was used, the solution
was basified by the addition of a saturated aqueous solution of
NaHCO3. The aqueous solution was further extracted with dichloro-
Typical Procedure for the Synthesis of Oxidants 2.20 To a
stirred suspension of N-methylhydroxylamine hydrochloride (5.0 g,
60 mmol, 1.0 equiv) in THF (100 mL) and H2O (10 mL) were added
NaHCO3 (10.0 g, 120 mmol, 2.0 equiv) and ethyl chloroformate (6
D
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methane (3 × 10 mL), and the combined organic extracts were dried
(MgSO4), filtered, and concentrated in vacuo to deliver azetidine 5.
1H NMR (400 MHz, CDCl3) δ: 4.52 (d, J = 11.5 Hz, 1H), 4.04 (d, J
= 11.5 Hz, 1H), 3.38−3.28 (m, 1H), 3.23 (td, J = 8.3, 4.7 Hz, 1H),
2.35−2.22 (m, 2H), 1.90−1.74 (m, 2H), 1.11 (s, 3H), 1.04 (t, J = 7.5
Hz, 3H), 1.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 175.7, 73.2,
66.2, 49.9, 42.7, 32.5, 25.9, 25.1, 21.1, 8.1.
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Ethyl (((Ethoxycarbonyl)amino)methyl)(methyl)carbamate 8. 1H
NMR (400 MHz, CDCl3) δ: 4.65 (d, J = 7.3 Hz, 2H), 4.23−4.08 (bs,
4H), 3.00 (s, 3H), 1.27 (t, J = 7.0 Hz, 6H).
Diethyl Methylenebis(methylcarbamate) 9. 1H NMR (400 MHz,
CDCl3) δ: 4.94−4.81 (bs, 2H), 4.23−4.08 (m, 4H), 2.95−2.81 (bs,
6H), 1.28 (t, J = 7.0 Hz, 6H).
Diethyl Methylenedicarbamate 10. 1H NMR (400 MHz, CDCl3)
δ: 4.55−4.47 (m, 2H), 4.17−4.09 (m, 4H), 1.30−1.22 (m, 6H).
Stoichiometric Studies Using Pd(OAc)2. In a 10 mL vial
equipped with stir bar, Pd(OAc)2 (11 mg, 0.05 mmol) and oxidant 2c
(17 mg, 0.05 mmol) were combined, followed by the addition of the
solvent (0.5 mL) and 2,2,6,6-tetramethylpiperidine (0.009 mL, 0.05
mmol) or 3,3-diethyl-5,5-dimethylmorpholin-2-one 12 (18.5 mg, 0.05
mmol). Then the vial was sealed under air with a screw cap and
Teflon septum, placed in a preheated oil bath at 60 °C, and stirred for
16 h. The reaction mixture was cooled to room temperature, filtered
through Celite, eluted with dichloromethane, and concentrated in
vacuo. TCE (0.053 mL, 0.05 mmol) was added as an internal
1
standard, and the yields were determined by HNMR spectroscopy.
DCE: 3 = 13% yield, 5 = 25% yield. HFIP: 3 = traces, 5 = 60%.
Dioxane: 3 = 30%, 5 = 56%. Toluene: 5 = 46%; AcOEt: 5 = 26%.
Typical Procedure for Catalytic Studies. In a 10 mL vial
equipped with a stir bar, Pd(OAc)2 (2.2 mg, 0.01 mmol), oxidant 2c
(140 mg, 0.4 mmol), and AgOAc (34 mg, 0.2 mmol) were combined,
followed by the addition of toluene (1.0 mL) and 3,3-diethyl-5,5-
dimethylmorpholin-2-one 12 (18.5 mg, 0.1 mmol). Then the vial was
sealed under air with a screw cap and Teflon septum, placed in a
preheated oil bath at the described temperature, and stirred for 16 h.
The reaction mixture was cooled to room temperature, filtered
through Celite, eluting with ethyl acetate, and then basified by the
addition of a saturated aqueous solution of NaHCO3. The aqueous
solution was further extracted with ethyl acetate (3 × 10 mL), and the
combined organic extracts were dried (MgSO4), filtered, and
concentrated in vacuo. TCE (0.0105 mL, 0.1 mmol) was added as
1
an internal standard, and the yields were determined by H NMR
spectroscopy.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.8b00712.
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of Aliphatic Amines by a Four-Membered-Ring Cyclopalladation
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of aliphatic amines to β-lactams. Science 2016, 354, 851−857.
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Gaunt, M. J. Selective Reductive Elimination at Alkyl Palladium(IV)
by Dissociative Ligand Ionization: Catalytic C(sp3)−H Amination to
Azetidines. Angew. Chem., Int. Ed. 2018, 57, 3178−3182.
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3676−3677.
NMR traces and cyclic voltammetry studies (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: mjg32@cam.ac.uk.
ORCID
Manuel Nappi: 0000-0002-3023-0574
Matthew J. Gaunt: 0000-0002-7214-608X
■
Notes
The authors declare no competing financial interest.
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fluorourethans in acetonitrile. The generation of carbethoxynitrene.
Can. J. Chem. 1984, 62, 768−777.
ACKNOWLEDGMENTS
■
We are grateful to EPSRC (EP/N031792/1), the Royal
Society for a Wolfson Merit Award (M.J.G.), and H2020
European Research Council (Grant No. 702462 to M.N.) for
funding.
̈
(20) Cecere, G.; Konig, C. M.; Alleva, J. L.; MacMillan, D. W. C.
Enantioselective Direct α-Amination of Aldehydes via a Photoredox
Mechanism: A Strategy for Asymmetric Amine Fragment Coupling. J.
Am. Chem. Soc. 2013, 135, 11521−11524.
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Organometallics
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DOI: 10.1021/acs.organomet.8b00712
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