Water as the Reaction Medium for Intermolecular C-H Alkane Functionalization in Micellar Catalysis

Article abstract of DOI:10.1021/acscatal.6b03669

A series of alkanes C_nH_2n+2 have been functionalized in water as the reaction medium, using a silver-based catalyst, upon the insertion of carbene (CHCO₂Et from N₂CHCO₂Et) groups into the carbon-hydrogen bonds of hexane, cyclohexane, or 2-methylbutane, among others. The regioselectivity toward the distinct reaction sites is identical to that found in neat alkane, the water-based system allowing the use of a much shorter excess of the hydrocarbon. This is the first example of the intermolecular functionalization of alkanes with this strategy in water. The functionalized alkanes partially undergo the incorporation of a second carbene unit to provide α-(acyloxy)acetates, in an unprecedented tandem reaction of this nature.

Full text of DOI:10.1021/acscatal.6b03669

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Letter
Water as reaction medium for intermolecular C-
H alkane functionalization in micellar catalysis
Maria Alvarez, Riccardo Gava, Manuel R. Rodríguez, Silvia G Rull, and Pedro J. Pérez
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ACS Catalysis
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Water as reaction medium for intermolecular C-H alkane functionali-
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a,§
a,§
a,§
a,§
a,
María Álvarez, Riccardo Gava, Manuel R. Rodríguez, Silvia G. Rull, and Pedro J. Pérez *
a
Laboratorio de Catálisis Homogénea, Unidad Asociada al CSIC. CIQSO-Centro de Investigación en Química Soste-
nible and Departamento de Química. Universidad de Huelva, 21007 Huelva, Spain
ABSTRACT: A series of alkanes C H
have been functionalized in water as the reaction medium, using a silver-based
n
2n+2
catalyst, upon insertion of carbene (CHCO Et from N CHCO Et) groups into their carbon-hydrogen bonds of hexane,
2
2
2
cyclohexane or 2-methylbutane, among others. The regioselectivity toward the distinct reaction sites is identical to that
found in neat alkane, the water-based system allowing the use of a much shorter excess of the hydrocarbon. This is the
first example of the intermolecular functionalization of alkanes with this strategy in water. The functionalized alkanes
partially undergoes a incorporation of a second carbene unit to provide α-(acyloxy)acetates, in an unprecedented tandem
reaction of this nature.
KEYWORDS. Alkane functionalization C-H activation catalysis in water carbene transfer copper and silver
catalysts
In spite of water being the solvent in Nature, modern
chemistry have mostly relied in the use of organic, non-
natural solvent for nearly all aspects: synthesis, catalysis,
separation or purification procedures are mostly carried
tiveness of ruthenium-, rhodium-, and cobalt-based cata-
lysts for the cyclopropanation of olefins in aqueous me-
1
out in petrochemical-derived solvents. Within catalytic
applications, such use is probably the result of several
drawbacks derived from low solubility and stability of
many transition metal complexes employed as catalysts or
the reactivity of water itself toward many transfor-
2
mations. However, in the last decades several strategies
3
have been employed toward that end, since the use of
water instead of an organic solvent contributes to a dra-
matic decrease of the so-called Environmental Factor or E-
4
factor, introduced by Sheldon. Thus, several strategies
have been developed toward that end such as the design
of water-soluble catalysts, the use of biphasic catalysis
(with one solvent being water), or the addition of surfac-
tants that provide hydrophobic vesicles where a large
concentration of catalyst and reactants triggers the reac-
tion. The latter methodology has been mainly developed,
5
,6
in recent years, by the group of Lipschutz, showing that
with the appropriate surfactant and water as the sole
solvent, a number of interesting metal-catalyzed organic
transformations take place under milder conditions with
the same catalysts employed in organic solvents.
Scheme 1. Top: Previous intramolecular function-
alization of activated C-H bonds by carbene inser-
tion in water. Bottom: the intermolecular, non-
activated-alkane C-H bond functionalization in
water.
The transfer of a carbene group from a diazocompound
catalyzed by a transition-metal complex is a well-known
tool for the incorporation of such moiety to an array of
dia, including the asymmetric version. Since then, a num-
ber of catalytic systems for the olefin cyclopropanation in
7
10 11
,
substrates. For decades those transformations were run
water have been described.
Additionally, N-H bonds
in organic solvents, until in the last decade first Nishiya-
12
have also been functionalized with this methodology.
8
9
ma . and shortly after Charette demonstrated the effec-
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In contrast, the functionalization of carbon-hydrogen
bonds by metal-mediated carbene insertion remains un-
Table 1. Screening of stability of copper-catalysts
Tp Cu(L) in water toward carbene and nitrene
transfer.
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x
13
described in water as solvent. This methodology has
been resurrected in this century in such a way that even
highly energetic C-H bonds such as those of methane and
a,b
1
4
light alkanes have been modified. However, in water as
reaction medium only a few examples of the intramolecu-
lar functionalization have been described. Thus, the
1
5
16
groups of Afonso and Che have reported (Scheme 1)
the respective use of Rh- or Ru-based catalysts for the
intramolecular insertion of a carbene group into a carbon-
hydrogen bond, that in addition is somewhat activated by
the presence of a neighboring heteroatom. To our
knowledge, there is no report on the functionalization of
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Catalyst
Reactant Medium
Yield
Ms
Tp Cu(thf)
c
2
>95
(98:2)
EDA
CH Cl
2
d
alkanes C H
with diazo compounds, i. e., under inter-
n
2n+2
Ms
Tp Cu(thf)
>95
(
molecular conditions and in the absence of activating
EDA
EDA
H O
2
d
d
98:2)
H O/
2
Ms
Tp Cu(thf)
>95
(98:2)
TPGS-750-M
82
Br3
Tp Cu(NCMe)
e
EDA
EDA
EDA
CH Cl
2 2
d
d
(
60:40)
77
Br3
Tp Cu(NCMe)
Scheme 2. Trispyrazolylborate ligands employed
in this work.
H O
2
(
60:40)
H O/
2
79
Br3
Tp Cu(NCMe)
groups. In this contribution we report on the catalytic
d
TPGS-750-M
f
PhI=NTs CH Cl
2 2
(58:42)
95
x
capabilities of a Tp -containing (Scheme 2) silver catalyst
Br3
Tp Cu(NCMe)
capable of promoting the modification of several linear,
Br3
Tp Cu(NCMe)
branched and cyclic alkanes upon inserting CHCO Et
PhI=NTs
PhI=NTs
H
2
O
> 95
2
units from N =CHCO Et (ethyl diazoacetate, EDA) in
2
2
H O/
2
Br3
Tp Cu(NCMe)
> 95
water as the solvent, in the first example of this transfor-
mation (Scheme 1).
TPGS-750-M
a
1
3
General procedures: (a) cyclopropanation: o,01 mmol
of catalyst, 1 mmol EDA, 5 mmol styrene, 5 mL H O; (b)
We have been involved in a research program focused
in the use of group 11 metal-based catalysts for several
transformations involving the functionalization of car-
bon-hydrogen bonds of unmodified alkanes and cycloal-
kanes upon the formal insertion of carbene, nitrene or
oxo units, albeit organic solvents were employed in all
cases. Actually, the solvent was, in most of the examples,
the targeted substrate, and thus a large excess was em-
ployed relative to the other reactant. Thus, the use of
water as the reaction medium could allow a decrease of
such excess of the alkane and decrease the E-factor. Our
first concern when facing the incorporation of water as
the reaction medium was the stability of the catalysts. In
a first approach, we chose two reactions as probes for the
test of the catalytic capabilities in water of some of our
already reported catalysts. They were the olefin cyclopro-
panation reaction with ethyl diazoacetate (EDA) and the
styrene aziridination with PhI=NTs (Table 1).
2
aziridination: o,01 mmol of catalyst, 0,2 mmol PhINTs, 5
mL of water. A commercial solution (5%) of the surfac-
tant from Aldrich was employed when needed (5 mL).
b
Yields quantified by NMR with internal standards upon
extraction with ethyl acetate. See Supporting Infor-
mation. Reference 17. cis:trans ratio of cyclopropanes.
c
d
e
f
Reference 18. Reference 19.
water, or in water containing the surfactant, and the ole-
fin was then added. Finally the carbene or nitrene precur-
sor was incorporated (N =CHCO Et or PhI=NTs, respec-
2
2
tively) in one portion and the mixture stirred for 1-4 h at
room temperature. At the end of the reaction, the prod-
ucts are extracted with several portions of ethyl acetate
and the collected fractions dried with MgSO . Elimination
4
of volatiles led to the crude products that were identified
and quantified by NMR with internal standards (see Sup-
porting Information for details).
The reactions were performed under two different con-
ditions. The first set was carried out in water as the sol-
vent whereas a second group of reactions was carried out
in water with the so-called Lipshutz surfactant, TPGS-
The results are shown in Table 1, where the reaction
17 18 19
outcome already reported . . in dichloromethane as the
solvent has also been incorporated for the sake of com-
parison. Clearly, the already described excellent catalytic
5
,6
7
50-M as an additive. The latter methodology has pro-
Ms
Br3
behavior of the catalysts Tp Cu(thf) and Tp Cu(NCMe)
in organic media can be extended to water as solvent with
no difference neither in activities nor in diastereoselectiv-
ities, the latter referred to the relative ratio of cis and
vided spectacular results in a number of metal-catalyzed
transformations in water. The protocol was the same in
both cases: the catalysts were suspended in deoxygenated
(by intensive bubbling of a N stream for a long period)
2
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trans cyclopropanes obtained. Thus, these copper-based
quence of the elevated concentration of the nascent
product 1 in the micelle that favors its interaction with
the catalyst and further EDA as well as the availability of
1
2
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catalyst not only survive in water but also behave, from a
catalytic point of view, as if they were in an organic sol-
vent.
H O (that was adventitious in the purely organic system).
2
It is worth mentioning that in neat cyclohexane as the
Such observation of identical behavior in the organic
medium or in this water-containing system along with the
lack of any effect of Lipshutz’s surfactant has led us to the
assumption that the reaction takes place inside a micelle
formed by the olefin in water, with the catalyst dissolved
therein. Regarding the carbene and nitrene precursors,
(
CF3)2,Br
substrate, this silver catalyst Tp
Ag(thf) leads to
>95% yield into 1, with 10 mL of cyclohexane whereas in
9
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EDA is soluble in water whereas PhI=NTs poorly dis-
solves in the mixture of water and olefin, the reaction
being thus quite slow, albeit productive. It is worth men-
tioning that the products derived from the activation of
water in both processes, i.e. HOCH CO Et (carbene inser-
2
2
tion into OH) or TsNH were not formed in significant
2
amounts, reinforcing the proposal of micellar catalysis
within the olefin phase.
After the above results, we then focused in the func-
tionalization of C-H bonds of unreactive hydrocarbons, i.
e., lacking of any functional or activating group. Cyclo-
hexane was chosen as the probe for the reaction with EDA
in water as solvent, following the strategy developed with
Scheme 3. Functionalization of cyclohexane in
water
x
unsaturated substrates. An array of Tp ML catalysts, with
the H O-based system only 0.5 mL of the cycloalkane are
2
M being Cu or Ag, were tested, as detailed in Scheme 3.
None of the copper complexes gave significant amounts
of the expected product, ethyl 2-cyclohexylacetate (1 in
Scheme 3): EDA was essentially converted into a mixture
of diethyl fumarate and maleate, as well as minor, but
detectable amounts of HOCH CO Et as the result of water
added to 5 mL of water. The effect of the presence of the
surfactant TPGS-750-M in the reaction mixture was also
investigated, the yield into 1 being similar albeit that of 2
decreased from 20% to 6%. Reaction workup consisted of
extraction of the products with diethyl ether and analysis
of the organic solution by GC, using calibration curves
previously developed with pure samples of the products
2
2
activation. When moving to silver complexes, the situa-
,
Br
tion was somewhat similar with Tp* Ag as the catalyst:
after 14 h at room temperature, only small amounts of the
desired product were observed, and EDA was not fully
(CF3)2,Br
consumed. But the use of Tp
Ag(thf) provided a
significantly different reaction outcome, since under the
same reaction conditions 45% yield (referred to EDA) of
the functionalized product was obtained, all EDA being
consumed (as inferred from GC studies). In addition, a
second product identified as 2-ethoxy-2-oxoethyl 2-
cyclohexylacetate was identified in the reaction mixture
in 20% yield (also referred to EDA, each molecule formal-
ly derives from two molecules of the diazo compound and
20
(see Supporting Information for full description).
one of cyclohexane). We have previously described the
formation of such compounds when employing pure es-
ters as the reactants in their reactions with EDA in the
presence of related silver-based catalysts. According to
To demonstrate that the acyloxyacetate is formed from
the ester, we have performed an experiment with pure 1
(commercial sample) and n-pentane. Under the same
conditions than those shown in Scheme 3, a mixture of 2
and the esters derived from the insertion into the C-H
bonds of pentane was obtained (eq 1). These result unam-
biguously demonstrate that the ester 1 is an intermediate
in the formation of the acyloxyacetate 2.
20
the mechanistic interpretation already proposed, the
reaction requires a H O molecule and eliminates EtOH.
2
However, this is the first time that we (or others) observe
this tandem reaction in which the alkane is first convert-
ed into an ester and this is subsequently transformed into
the α-(acyloxy)acetate. We believe that this is a conse-
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The observance of the catalytic properties of
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(CF3)2,Br
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Tp
Ag(thf) in water toward carbene insertion into
the C-H bonds of cyclohexane led us to test a series of
linear and branched alkanes. Scheme 4 shows the reac-
tion of pentane with EDA using this silver complex as the
catalyst (0,005 mmol of catalyst, 0,2 mmol of EDA, 0,5 mL
-4,22 mmol- of pentane, 5 mL H O, rt, 14 h) a mixture of
2
alkyl-acetates 3a-c derived from the functionalization at
C1, C2 and C-3 reaction sites was obtained with a respec-
tive 38:48:14 ratio of products. This selectivity is similar to
1
4c
that found when using pentane as the unique solvent,
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thus evidencing that the catalyst behavior is not influ-
enced by the change of reaction medium. In addition to
3
a-c, three α-(acyloxy)-acetates 4a-c were also formed as
the result of the silver-catalyzed incorporation of a second
carbene unit onto 3a-c. Figure 1 contains the GC trace of
the reaction mixture, from which an interesting feature
has been extracted: the relative ratio of 3a-c is maintained
in 4a-c, in what we interpret as the absence of any effect
Scheme 5. Functionalization of linear and
branches alkanes in water.
Three other alkanes have been studied, namely hexane,
-methylbutane and 2,3-dimethyl-butane, with a similar
2
behavior being observed: the products derived from the
functionalization of the C-H bonds of the alkanes were
obtained as well as some of the doubly activated deriva-
tives. The overall conversion into functionalized products
ranged within 59-83%, based in EDA. Scheme 5 displays
the products and relative yields obtained. Similarly to the
commented example of pentane, the regioselectivity of
the alkane functionalization was nearly identical to those
previously reported in neat alkane as the reaction me-
Scheme 4. Functionalization of pentane in water
(yields based on EDA).
14c
dia. Also, the relative ratio of alkyl-acetates was main-
tained in the α-(acyloxy)-acetates in all the experiments,
again evidencing the lack of effect of the alkyl chain in the
reactivity of the ester group toward the second incorpora-
tion of a carbene moiety.
(CF3)2,Br
Thus, we have found that the complex Tp
Ag(thf)
catalyzes the intermolecular functionalization of alkanes
in water by carbene transfer from ethyl diazoacetate in
the first example of this transformation in such medium.
Interestingly, the regioselectivity observed, intended as
the relative ratio of products derived from the insertion
into the distinct sites, is nearly identical. Additionally, a
concurrent reaction takes place by the silver-catalyzed
incorporation of a second carbene unit onto the ester
moiety of the alkane functionalized products. This con-
secutive transformation from alkanes is also unprece-
dented, and it is probably the result of the micellar nature
Figure 1. GC trace of the reaction mixture of the
functionalization of pentane
of the alkyl substituent in the reactivity of 3a-c in the
second transformation.
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of this catalytic system, that provide high concentrations
1
2
3
4
5
6
7
8
9
of reactants and catalyst in a reduced volume. In our
opinion, these findings open a new approach for the cata-
lytic functionalization of hydrocarbons lacking of unsatu-
rations or activating groups, which are desirable raw ma-
terials for future development.
Modern Catalytics Methods for Organic Synthesis with
Diazo Compounds, John Wiley & Sons, New York, 1998; (b)
M. P. Doyle, in Comprehensive Organometallic Chemistry
II; E. W. Abel, F. G. A. Stone, G. Wilkinson, Eds; Pergamon
Press: Oxford, U. K., 1995, Vol 12, pp 421.
(
8) Iwasa, S.; Takezawa, F.; Tuchiya, Y.; Nishiyama, H. Chem.
Commun. 2001, 59–60
ASSOCIATED CONTENT
(
9) Wurz, R. P.; Charette, A. B. Org. Lett. 2002, 4, 4531–4533.
(10) Nicolas, I.; Le Maux, P.; Simonneaux, G. Coord. Chem. Rev.
2008, 252, 727–735.
General methods, synthetic procedures and catalytic
experiments are provided in a pdf file. This material is
available free of charge via the Internet at
http://pubs.acs.org
1
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(11) (a) van Oers, M. C. M.; Abdelmohsen, L. K. E. A.; Rutjes, F.
P. J. T.; van Hest, J. C. M. Chem. Commun. 2014, 50, 4040–
4
043. (b) Morandi, B.; Dolva, A.; Carreira, E. M. Org. Lett.
2
2
012, 14, 2162–2163. (c) Morandi, B.; Carreira, E. M. Science
012, 335, 1471–1474. (d) Nicolas, I.; Maux, P. L.; Simon-
AUTHOR INFORMATION
Corresponding Author
neaux, G. Tetrahedron Lett. 2008, 49, 5793–5795. (e) Es-
tevan, F.; Lloret, J.; Sanaú, M.; Úbeda, M. A. Organometal-
lics 2006, 25, 4977–4984. (f) Wu, H.; Xu, L. W.; Xia, C. G.;
Ge, J.; Zhou, W.; Yang, L. Catal. Commun. 2005, 6, 221–223.
12) Srour, H. F.; Maux, P. Le; Chevance, S.; Carrié, D.; Yondre,
N. Le; Simonneaux, G. J. Mol. Catal. A Chem. 2015, 407,
perez@dqcm.uhu.es (PJP),
(
Author contributions
§
These authors contributed equally to the work
194–203.
(
13) (a) Caballero, A.; Díaz-Requejo, M. M.; Fructos, M. R.;
Notes
Olmos, A.; Urbano, J.; Pérez, P. J. Dalton Trans. 2015, 44,
Authors declare no competing financial interests.
20295-20307. (b) Díaz-Requejo, M. M.; Pérez, P. J. Chem.
Rev. 2008, 108, 3379-3394. (c) Díaz-Requejo, M. M.;
Belderraín, T. R.; Nicasio, M. C.; Pérez, P. J. Dalton Trans.
ACKNOWLEDGMENTS
2006, 5559-5566.
Support for this work was provided by the MINECO
(14)(a) Caballero, A.; Despagnet-Ayoub, E.; Díaz-Requejo, M. M.;
Díaz-Rodríguez, A.; González-Núñez, M. E.; Mello, R.; Mu-
ñoz, B. K.; Solo Ojo, W.; Asensio, G.; Etienne, M.; Pérez, P.
J. Science 2011, 332, 835-838. (b) Fuentes, M. A.; Olmos, A.;
Muñoz, B. K.; González-Núñez, M. E.; Mello, R.; Asensio,
G.; Caballero, A.; Etienne, M.; Pérez, P. J. Chem. Eur. J.
(
CTQ2014-52769-C03-01 and CTQ2014-62234-EXP). M. A.,
R. G. and S. G.-R. thank MINECO for FPI fellowships. M.
R.-R. thanks MEC for FPU fellowship.
2014, 20, 11013-11018. (c) Gava, R.; Olmos, A.; Noverges, B.;
REFERENCES
Varea, T.; Álvarez, E.; Belderraín, T. R.; Caballero, A.; Asen-
sio, G.; Pérez, P. J. ACS Catalysis 2015, 5, 3726-3730.
15) (a) Candeias, N. R.; Carias, C.; Gomes, L. F. R.; André, V.;
Duarte, M. T.; Gois, P. M. P.; Afonso, C. A. M. Adv. Synth.
Catal. 2012, 354, 2921–2927. (b) Candeias, N. R.; Gois, P. M.
P.; Afonso, C. a M. J. Org. Chem. 2006, 71, 5489–5497. (c)
Candeias, N. R.; Gois, P. M.; Afonso, C. A. Chem Commun
2005, 2, 391–393.
(
(1) (a) Lipshutz, B. H.; Gallou, F.; Handa, S. ACS Sustain.
Chem. Eng. 2016, 4, 5838-5849.
(
2) (a) Cornils, B. and Herrmann, W. A. Aqueous-Phase Or-
nd
ganometallic Catalysis: Concept and Applications, 2 ed,
Weinheim, Germany, 2004. (b) Joo, F. Aqueous Organome-
tallic Catalysis, Kluwer Academic Publishers, New York,
(16) Ho, C. M.; Zhang, J. L.; Zhou, C. Y.; Chan, O. Y.; Yan, J. J.;
Zhang, F. Y.; Huang, J. S.; Che, C. M. J. Am. Chem. Soc.
2010, 132, 1886–1894
2002.
(3) See for example: (a) Schaper, L. A.; Hock, S. J.; Herrmann,
W. A., Kuhn, F. E. Angew. Chem. Int. Ed. 2013, 52, 270-289.
(17) Díaz-Requejo, Caballero, A.; M. M.; Belderrain, T. R.; Nica-
sio, M. C.; Trofimenko, S.; Pérez, P. J. J. Am. Chem. Soc
2002, 124, 978-983.
(b) Chanda, A.; Fokin, V. V. Chem. Rev. 2009, 109, 725–748.
(c) Li, C.-J. Chem. Rev. 2005, 105, 3095-3165. (d) Li, C. J.
Chem. Rev. 1993, 93, 2023-2035
(18) Yap, G. P. A.; Joves, F.; Urbano, J.; Alvarez, E.; Trofimenko,
S.; Díaz-Requejo, M. M.; Pérez, P. J. Inorg. Chem. 2007, 46,
780-787.
(4) (a) Sheldon, R. A. Green Chem. 2007, 9, 1273-1283. (b)
Sheldon, R. A. Chem. Ind. 1992, 903-906.
(
5) (a) Lipshutz, B. H.; Ghorai, S. Aldrichimica Acta 2012, 45, 3-
6. (b) Lipshutz, B. H.; Ghorai, S. Aldrichimica Acta 2008,
1, 59-72.
6) Lipshutz, B. H.; Ghorai, S. Green Chem. 2014, 16, 3660–
679.
(19) Mairena, M. A.; Díaz-Requejo, M. M.; Belderraín, T.; Nica-
sio, M. C.; Trofimenko, S.; Pérez, P. J. Organometallics
2004, 23, 253-256.
1
4
(
(20) Gava, R.; Fuentes, M. A.; Besora, M.; Belderrain, T. R.;
Jacob, K.; Maseras, F.; Etienne, M.; Caballero, A.; Pérez, P.
J. ChemCatChem 2014, 6, 2206-2210.
3
(7) (a) Cheng, Q.-Q., Doyle, M. P. Adv. Organomet. Chem.
2016, 66, 1-31. (b) Doyle, M. P.; McKervey, M. A.;Ye, T.
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Alkanes are functionalized with ethyl diazoacetate and a silver catalyst in water as the reaction medium leading to
alkyl acetates and minor amounts of α-(acyloxy)-acetates, the latter deriving from a consecutive functionalization
of the formers, in the first example of the intermolecular modification of alkanes by this methodology
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