Metal-Free C-H Functionalization of Alkanes by Aryldiazoacetates

Article abstract of DOI:10.1021/acs.orglett.6b03681

Thermally induced reactions of donor/acceptor diazo compounds generate carbene intermediates capable of C-H functionalization reactions of alkanes. A variety of C-H insertion products were obtained in moderate to good yields and in certain cases with good site selectivity, favoring the functionalization of the more highly substituted C-H bond.

Full text of DOI:10.1021/acs.orglett.6b03681

Letter
pubs.acs.org/OrgLett
Metal-Free C−H Functionalization of Alkanes by Aryldiazoacetates
Cecilia Tortoreto, Daniel Rackl, and Huw M. L. Davies*
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
*
S Supporting Information
ABSTRACT: Thermally induced reactions of donor/acceptor diazo
compounds generate carbene intermediates capable of C−H functionaliza-
tion reactions of alkanes. A variety of C−H insertion products were
obtained in moderate to good yields and in certain cases with good site
selectivity, favoring the functionalization of the more highly substituted C−
H bond.
n recent years, the development of new methods to achieve
Scheme 1
I
selective C−H functionalization reactions has become a very
1
,2
active research area. One particularly useful method has been
3
the insertion of metal carbenes into C−H bonds. Donor/
acceptor-substituted metal carbenes have been shown to be
capable of highly site-selective and stereoselective intermolec4-
ular C−H functionalization of a wide range of substrates.
These carbenes are most commonly derived from the
corresponding aryldiazoacetates or vinyldiazoacetates under
metal-catalyzed conditions. Dirhodium tetracarboxylates have
been the most widely used catalysts for C−H functionalization
reactions, and they are very active catalysts that are capable of
efficient reactions at ambient temperature or below.
intermolecular C−H insertions than the traditional methyl
8
esters. All four substrates gave high yields of the C−H
functionalization products 2 when the reactions with cyclo-
hexane were conducted over 12−48 h. In the case of
methoxyphenyl derivatives 1c and 1d, the yields of 2c and 2d
were roughly equivalent, but in the case of p-bromo derivatives
1a and 1b, the yield of the trichloroethyl ester 2b was higher
than that of the methyl ester 2a.
Because of the cost and scarcity of rhodium, there has been
considerable interest in developing earth-abundant catalysts for
5
the decomposition of diazo compounds. These catalysts are
generally not as reactive as the dirhodium catalysts and in some
5
cases require quite forcing conditions (80 °C). The use of
these more forcing conditions could be of concern because we
In order to obtain further information about the relative rates
of C−H functionalization of cyclohexane, the reactions were
followed by in situ IR monitoring (ReactIR). Figure 1 compares
the rates of decomposition of the four substrates 1a−d. The
6
,7
have already demonstrated that the purely thermal reactions
of aryldiazoacetates in the absence of catalysts can result in
high-yielding transformations such as cyclopropanation and N−
6b
−1
H insertion reactions. Therefore, the possibility exists that the
metal-catalyzed reactions conducted under forcing conditions
may have a significant thermal background reaction. Con-
sequently, we decided to determine the type of C−H
functionalization reactions that can be carried out under purely
thermal conditions and the inherent site selectivity of the
reactions of these free carbenes. These results would provide
useful background information for future studies on the
development of new catalysts for site-selective carbene
reactions.
signals for the diazo functionality (at ∼2090 cm ) decreased
over time, following first-order kinetics. As seen previously in
the thermal cyclopropanation of aryldiazoacetates, the p-
methoxy derivatives 1c and 1d are more reactive than the p-
bromo derivatives 1a and 1b. The nature of the ester group also
influences the thermal reaction, as the trichloroethyl derivatives
1b and 1d are about 2−3 times more reactive that the
corresponding methyl esters 1a and 1c. Thus, 1c has a half-life
of 92 min at 80 °C, whereas 1d has a half-life of 39 min. These
results indicate that a significant background thermal reaction
would be a distinct possibility in attempted metal-catalyzed
reactions under extended forcing conditions.
The initial study explored the thermal reaction of donor/
acceptor carbenes in refluxing cyclohexane, comparing the
reaction of the p-bromophenyl-1a,b and p-methoxyphenyldia-
zoacetates 1c,d (Scheme 1). p-Bromophenyl derivative 1a is the
most widely used substrate in the rhodium-catalyzed reactions,
and p-methoxyphenyl derivative 1c is known to be more
thermally labile. Both the methoxy and trichloroethyl (TCE)
esters were examined because recently the trichloroethyl esters
have been shown to give much cleaner metal-catalyzed
After the high-yielding thermal C−H functionalization of
cyclohexane was established, the general scope of the reaction
with cycloalkanes was examined (Scheme 2). The reaction of p-
methoxyphenyldiazoacetates 1c and 1d gave the C−H insertion
Received: December 9, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03681
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
decomposition of the diazo compounds with the more
electron-deficient aryl groups were lower, and these substrates
needed extended times to achieve full conversion (up to 96 h).
The site selectivity and diastereoselectivity of the reaction
were also explored in order to determine the inherent reactivity
profile of the free donor/acceptor carbene. The reaction of
2
,2,2-trichloroethyl (p-bromophenyl)diazoacetate 1b with 4-
ethyltoluene was tested first (Scheme 3). The thermal reaction
Scheme 3. Reactivity of 1b with 4-Ethyltoluene
Figure 1. ReactIR measurements of the rates of thermal decom-
position of 1a−d in refluxing cyclohexane 2.
Scheme 2. Thermally Induced C−H Functionalization of
Cycloalkanes
gave a 2:1 mixture of the secondary (18) and primary (19) C−
H insertion products in a combined yield of 22%, along with a
3
8% yield of cyclopropanation. In comparison, the Rh (S-
2
DOSP) -catalyzed reaction has been shown to favor 18 in a
4
6
.6:1 ratio, whereas the bulky catalyst Rh (R-pPhTPCP)
2
8a,10
4
strongly favors 19 in an 11:1 ratio.
Importantly, no
cyclopropanation product is oberved in the prescence of
dirhodium catalysts. Establishing the inherent site selectvity of
the free carbene will be useful in evaluating the effectiveness of
new catalysts in controlling metallocarbene-induced C−H
functionalization.
Competition studies were also conducted with substrates
containing tertiary C−H bonds. The reactions favor the tertiary
site with small amounts of other C−H functionalization
products (Scheme 4). The thermal reaction of 1d with p-
cymene gave a 24% yield of insertion into the tertiary C−H
Scheme 4. Reactivity of 1d with p-Cymene and Adamantane
a
Cyclopentane (1.5 mL), hexafluorobenzene (1.5 mL).
products 4−9 in moderate to good yields, as shown in entries
1
−3. 2,2,2-Trichloroethyl ester 1d generally gave higher yields
of C−H insertion products than methyl ester 1c because it
minimizes the formation of secondary products derived from
9
either carbene dimerization or intramolecular C−H insertion.
The reaction with cyclohexane was examined with a variety of
trichloroethyl aryldiazoacetates resulting in the formation of the
C−H insertion products 10−17 in 36−87% yield. The rates of
B
DOI: 10.1021/acs.orglett.6b03681
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Organic Letters
Letter
bond (20) along with smaller amounts of insertion into the
primary site (21) as well as considerable quantities of
cyclopropanated compound. Again, the Rh (S-DOSP) -cata-
Scheme 6. Reactivity of 1d with Acyclic Alkanes
2
4
lyzed reaction favors the sterically more congested position,
while Rh (R-pPhTPCP) inverts the selectivity. Reaction of 1d
2
4
with adamantane gave rise to a 34% yield of the tertiary C−H
insertion product 22. These results contrast with the competing
steric and electronic control of the rhodium-catalyzed reactions,
confirming that electronic factors are inherently predominant
1
1
over steric factors. However, when bulky catalysts are used, a
strong preference for the primary C−H insertion site over a
secondary C−H insertion site can be achieved and the natural
12
selectivity overwritten.
Exploratory studies were conducted to determine whether
the C−H functionalization reaction could occur in substrates
containing other functional groups (Scheme 5). Reaction of 1d
Scheme 5. Reactivity of 1d with 1,4-Cyclohexadiene and
Mesitylene
obtained as a 1:1 mixture of two diastereoisomers. Similarly to
earlier examples (Schemes 3 and 4) Rh (S-DOSP) -catalysis
2
4
enhanced the natural selectivity, while the latest-generation
dirhodium catalyst Rh [R-3,5-di(p-tBuC H )TPCP] could
2
6
4
4
8
b
severely invert the natural selectivity trend. When 2-
methylpentane was used as a substrate, adduct 30 derived
from the electronically favored insertion into the tertiary C−H
bond was obtained as the major product. The minor adduct 31,
derived from the functionalization of the secondary carbon
(
C2), was obtained as a mixture of diastereomers in a 1.6:1
ratio.
To gain mechanistic insights, a set of experiments was
with 1,4-cyclohexadiene gave a mixture of the C−H insertion
product 23 (30% yield) and cyclopropane 24 (24% yield). This
outcome is different from that of the metal-catalyzed reactions,
which tend to undergo the C−H functionalization cleanly at
performed using reagents 1c and 1d in 1:1 mixtures of
cyclohexane and cyclohexane-d12 (Scheme 7). Mass spectrom-
13
the doubly allylic site. The reaction with mesitylene gave the
two products 25 and 26 derived from benzylic C−H insertion
and aromatic substitution, respectively. A similar product
distribution was reported in an iron-catalyzed reaction of 1c
Scheme 7. Homocoupling and Kinetic Isotope Effect
5a
with mesitylene conducted at 80 °C, and the reported
conditions would probably have been sufficiently vigorous for
the purely thermal reaction to be a competing process.
Among the classic and most challenging substrates to
evaluate the site selectivity of carbene-induced C−H function-
alization have been acyclic alkanes. We recently demonstrated
that the combination of dirhodium TPCP catalysts and TCE
esters of the donor/acceptor carbenes can lead to highly regio-
8b
and steroselective functionalization of n-alkanes at C2.
etry indicated the predominant formation of homocoupling
Therefore, we became intrigued to evaluate whether alkanes
could react thermally with the donor/acceptor carbenes and
what level of site selectivity would be possible. Performing the
reaction of 1d in n-hexane at 80 °C generated two major
products derived from C−H functionalization of the secondary
sites at C2 (adduct 28) and C3 (29) in a 2.4:1 ratio (Scheme
products over cross-coupling products. The measured k /kD
H
values, in the range of 1.9−2.2, are in accordance with
previously reported results for dirhodium-catalyzed C−H
11a
insertion reactions.
The predominant formation of the
homocoupling products advocates for a concerted hydrogen
transfer mechanism. The higher proportion of protonated over
deuterated adducts indicates the occurrence of a primary kinetic
6
). This indicates a modest selectivity due to steric factors.
14
Only traces of the adduct derived from an electronically
isotope effect. A mechanism similar to the one commonly
15
disfavored insertion into the primary −CH bond (27) could
accepted for metal-catalyzed C−H insertion reactions can
therefore be considered for this transformation, including a
concerted nonsynchronous hydride transfer/C−C bond
formation.
3
1
be observed in the H NMR spectrum of the crude reaction
mixture. Moreover, 28 was obtained as a mixture of two
diastereomers in a 1.9:1 ratio, while regioisomer 29 was
C
DOI: 10.1021/acs.orglett.6b03681
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In conclusion, the scope of thermally induced C−H
functionalization of alkanes by metal-free donor−acceptor
carbenes has been described. The process is surprisingly high
yielding in certain cases and can be reasonably site-selective.
The results give a benchmark of the inherent site selectivity of
the free donor/acceptor carbenes, which will be useful for the
evaluation of the efficiency of new catalysts. Furthermore, the
study indicates that background thermal reactions must be
considered in metal-catalyzed C−H insertion reactions of
donor/acceptor diazo compounds conducted at elevated
temperatures.
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AUTHOR INFORMATION
Corresponding Author
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Financial support was provided by NSF under the CCI Center
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Swiss National Science Foundation (early postdoc grant
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