Rhodium(II)-catalyzed c-h functionalization of electron-deficient methyl groups

Article abstract of DOI:10.1021/jacs.6b01941

Enantioselective C-H functionalization of relatively electron-deficient methyl sites was achieved with the combination of 2,2,2-trichloroethyl aryldiazoacetates and tetrakis(triarylcyclopropanecarboxylate) dirhodium catalysts. The substrate scope of the transformation was relatively broad, and C-H functionalization products were furnished with excellent levels of enantioselectivity. As a strategic reaction, crotonate derivatives give 1,6-dicarbonyl compounds, which are useful for further diversification.

Full text of DOI:10.1021/jacs.6b01941

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Communication
Rhodium (II)-Catalyzed C–H Functionalization
of Electron-Deficient Methyl Groups
Liangbing Fu, David M. Guptill, and Huw M. L. Davies
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b01941 • Publication Date (Web): 11 Apr 2016
Downloaded from http://pubs.acs.org on April 11, 2016
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Rhodium(II)-Catalyzed C–H Functionalization of Electron-
Deficient Methyl Groups
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Liangbing Fu, David M. Guptill and Huw M. L. Davies*
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
hmdavie@emory.edu
Supporting Information Placeholder
ABSTRACT: Enantioselective C–H functionalization of relatively electron-deficient methyl sites was achieved with the combina-
tion of 2,2,2-trichloroethyl (TCE) aryldiazoacetates and tetrakis(triarylcyclopropanecarboxylate) dirhodium catalysts. The substrate
scope of the transformation was relatively broad, and C–H functionalization products were furnished with excellent levels of enan-
tioselectivity. As a strategic reaction, crotonate derivatives give 1,6-dicarbonyl compounds, which are useful for further diversifica-
tion.
The development of new C–H functionalization methods repre-
sents an area of pronounced interest because these methods
have the potential to streamline the synthesis of complex tar-
gets.1,2 The most established and widely utilized C–H function-
alization methods either rely on the use of directing groups3 or
involve radical reactions.4 The most versatile enantioselective
method to date, however, has been C–H functionalization by
means of carbene-induced C–H insertion.5,6 Enantioselective
intramolecular versions of these C–H insertions were developed
in the 1980’s and have seen widespread use in the synthesis of
complex targets.5a-c The advent of donor/acceptor rhodium car-
benes has given life to enantioselective intermolecular C–H
insertion as a synthetically useful process.5c-e Indeed, carbene-
induced intermolecular C–H functionalization has been shown
to be complementary to some classic strategic reactions of or-
ganic synthesis.5e For example, C–H functionalization of silyl
ethers generates 3-siloxy esters (aldol surrogate) (Scheme 1a).7
Alternatively, allylic C–H functionalization of silyl vinyl ethers
generates protected 1,5-dicarbonyl compounds (Michael addi-
tion surrogate) (Scheme 1b).8 Herein, we report the C–H func-
tionalization of crotonate derivatives and related compounds
which offer a novel approach for the enantioselective synthesis
of 1,6-dicarbonyl derivatives (Scheme 1c).
erwise reacted unselectively, as well as those simply too unre-
active for effective C–H functionalization. For example, this
catalyst/reagent combination makes possible the regio- and
stereoselective functionalization of n-alkanes at C-2.11 In this
paper, we describe that this combination also results in effective
C–H functionalization of relatively electron-deficient methyl
sites, such as ethyl crotonate and related compounds.
Scheme 1. Strategic Reactions Using C–H Functionalization
The exploration of the C–H functionalization of ethyl croto-
nate (2) was initiated by comparing the reactions of the methyl
ester 1a and the TCE ester 1b, catalyzed by Rh2(R-p-PhTPCP)4
(Table 1). The reaction of methyl aryldiazoacetate 1a, did gen-
erate some of the desired C–H functionalization product 3a but
the yield was low (15%, entry 1). In contrast, the reaction with
the TCE aryldiazoacetate gave the desired product 3b in 74%
isolated yield with 95% ee (entry 2). The related catalysts,
Rh2(R-TPCP)4 and Rh2(R-p-BrTPCP)4 gave similar but slightly
inferior results compared to Rh2(R-p-PhTPCP)4 (entries 3 and
4) whereas the most widely used catalyst Rh2(S-DOSP)4 gave
low yield (entry 5).
Donor/acceptor rhodium carbenes behave as highly electro-
philic intermediates and undergo C–H functionalization in a
concerted asynchronous manner, characterized by positive
charge build-up at carbon.9 Hence, electron rich allylic and
benzylic C–H bonds, or those α to oxygen or nitrogen are acti-
vated toward carbene insertion.5 Recently, we have discovered
that the inherent substrate biases can be overcome by employ-
ing our new class of dirhodium catalysts – derived from the
triphenylcyclopropane carboxylate (TPCP) ligand.10 These ste-
rically demanding complexes tend to favor functionalization of
less crowded C–H bonds.10b During these studies, we discov-
ered that aryldiazoacetates bearing the 2,2,2-trichloroethyl
(TCE) ester are more robust and react more cleanly than those
with the corresponding methyl ester.10c The combination of
TPCP catalysts and the TCE esters of donor/acceptor carbenes
enables the functionalization of substrates that would have oth-
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Table 1. Summary of Optimization Studiesa,b
substituents were competent substrates, though to varying de-
1
grees. The reactions to form 12a-c occured with high levels of
enantioselectivity (93-99% ee), but the overall yield was greatly
influenced by the nature of the internal substituent. Similar to
the methyl derivative 9, described in Scheme 2, a methoxy
group is well tolerated and 12a was efficiently formed (88%).
However in the case of the siloxy derivative 11b, the C-H func-
tionalization product 12b was isolated in a lower 50% yield,
due to the occurrence of a competing cyclopropanation product
(isolated in 30% yield). In the case of the bromo derivative 12c,
the overall yield of the reaction was low, presumably because
the methyl site is no longer sufficiently reactive even for the
TCE ester 1b. More highly conjugated substrates were also
good substrates, as illustrated by the formation of 12d-h. Again
the enantioselectivity was high (92-97% ee), except for the case
of the 3-siloxy derivative 12f (58% ee). Particularly noteworthy
is the reaction to form the trienoate 12e in 80% yield and 92%
ee. The reaction is compatible with the Weinreb amide (11g)
and oxazolidinone (11h) though the isolated yield of the
Weinreb amide product 12g was relatively low (35%). So far,
the transformation using the standard reaction conditions is
limited to the indicated unsaturated carbonyl systems. An un-
saturated ketone is prone to epoxide formation by the rhodium
carbene and unsaturated N,N-dimethyl amide or phenylsulfone
did not give the desired product.
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aReaction conditions: The diazo compound (0.8 mmol) in 1.2
mL dichloromethane (DCM) was added over 3 h to a solution of
the substrate (2.0 equiv.) and catalyst (0.5 mol%) in 0.5 mL DCM
at reflux. bFor details about the optimization of relative concentra-
tion and addition time of the diazo compound, see supporting
c
d
information. Isolated yield. Determined by chiral HPLC of the
Table 2. C–H Functionalization of Electron-Deficient Me-
thyl Groupsa
e
1
isolated product. Yield determined by H NMR using trichloro-
ethylene as the internal standard.
C–H functionalization at electron rich allylic positions is
known to be sensitive to steric effects.5c Therefore the reactions
of differentially substituted crotonate derivatives (Scheme 2)
were compared to the established reaction with E-crotonate 2.
The reaction of ethyl (Z)-but-2-enoate 4 gave the desired C–H
insertion product 5 as the Z isomer, in 49% yield and 97% ee,
as well as the cyclopropane 6, which was formed in 17% yield
with 93% ee. This result is consistent with previous studies that
have shown that the delicate balance between C–H functionali-
zation and cyclopropanation is dependant on alkene geometry.5e
When ethyl 3-methylbut-2-enoate 7 was utilized, the more ac-
cessible primary methyl group was functionalized preferentially
with a high level of enantioselectivity (97%). The lower yield
(38%) in this case is presumably due to steric interference. Fi-
nally, when methyl (E)-2-methylbut-2-enoate 9 was used as the
substrate, the more accessible primary methyl group was again
functionalized preferentially to form 10 in good yield and high
level of enantioselectivity (78% yield, 98% ee).
aReaction conditions: 1b (0.8 mmol) in 1.2 mL DCM was add-
ed over 3 h to a solution of the substrate (1.6 mmol, 2.0 equiv.)
b
and catalyst (0.5 mol%) in 0.5 mL DCM at reflux. Cyclopro-
panation by-product was isolated in 30% yield.
To explore further the influence of electron withdrawing
groups on C–H functionalization reactions, substrates contain-
ing electron-deficient benzylic methyl groups (13) were also
evaluated (Table 3). Toluene derivatives with p-
ethoxycarbonyl, p-bromo, p-methoxycarboalkenyl and p-
ethoxycarboalkynyl groups were all good substrates, undergo-
ing C–H functionalization in high yields (77-89%) and with
high levels of enantioselectivity (96-98% ee). The only excep-
tions were p-nitrotoluene and m-nitrotoluene, which failed to
give rise to the desired product, presumably because they are
too electron deficient.
Scheme 2. Effect of Substitution on Ester Substrates
The scope of the reaction was then explored with more elab-
orate substrates (Table 2). Crotonate derivatives with internal
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was easily manipulated in a variety of ways to give products
Table 3. Functionalization of Electron-Deficient Aromatic
Methyl Groupsa
with oxygen functionality in a 1,6- or 1,4-orientation. Selective
hydrogenation of 3b generated the saturated product 17 in 92%
yield. The TCE ester could be selectively deprotected with zinc
in acetic acid to form the acid 18 in 95% yield, or the two ester
groups could be reduced to the diol 19 in essentially quantita-
tive yield. Ozonolysis of 3b generated the aldehyde 20 in 86%
yield. Pinnick-lindgren-kraus oxidation of 20 followed by TCE
deprotection generated the known succinic acid derivative 21,
and this compound was used to determine the absolute configu-
ration of 21 by comparison of its optical rotation with the re-
ported value.12
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aReaction conditions: 1b (0.8 mmol) in 1.2 mL DCM was add-
ed over 3 h to a solution of the substrate (1.6 mmol, 2.0 equiv.)
and catalyst (0.5 mol%) in 0.5 mL DCM at reflux.
The reaction is applicable to a variety of aryldiazoacetates as
illustrated in Table 4. When TCE arydiazoacetates bearing p-
tBu or p-CF3 were tested, again, 11a turned out to be a better
behaving substrate compared to 2 (16a, b vs 16a', b'). To fully
explore the potential of the scope of arydiazoacetates, substrate
11a was used to react with a variety of other diazo acetates.
Both electron-rich and electron-deficient para-substituents on
the phenyl ring were compatible, generating 16a'-c' in 60-82%
yield and high levels of enantioselectivity (89->99% ee). The
meta-bromo substituent was also tolerated and 16d' was formed
in 87% yield and 88% ee. TCE aryldiazoacetate bearing an o-
bromo on the phenyl ring gave only trace amount of the prod-
uct, presumably because it’s sterically more hindred, and inter-
feres with intermolecular C-H insertion. Notably, the C–H
functionalization could be carried out with the pyridyl deriva-
tive 15e to form 16e' in 48% yield and 92% ee.
Scheme 3. Synthetic Utilities of the Transformation
In conclusion, the enantioselective C–H functionalization of
relatively electron-deficient methyl sites was achieved by use of
the combination of 2,2,2-trichloroethyl (TCE) aryldiazoacetates
and the bulky dirhodium TPCP catalysts. The substrate scope of
the transformation was relatively broad, and various 1,6-
dicarbonyl derivatives were readily furnished. These studies
demonstrate that C–H functionalization can be used for key
disconnection strategies.
Table 4. Scope of TCE Aryldiazoacetatesa
ASSOCIATED CONTENT
Supporting Information
Synthetic details and spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
hmdavie@emory.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support was provided by NSF under the CCI Center for
Selective C–H Functionalization (CHE-1205646). We also wish
to thank The Novartis Institutes for Biomedical Research and
AbbVie for support of our work on C–H functionalization.
aReaction conditions: 15a-e (0.4 mmol) in 1.0 mL DCM was
added over 3 h to a solution of the substrate (0.80 mmol, 2.0
equiv.) and catalyst (0.5 mol%) in 0.4 mL DCM at reflux.
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