Catalytic C(sp3)-H alkylation via an iron carbene intermediate

Article abstract of DOI:10.1021/jacs.7b07602

The catalytic transformation of a C(sp³)-H bond to a C(sp³)-C bond via an iron carbene intermediate represents a long-standing challenge. Despite the success of enzymatic and small molecule iron catalysts mediating challenging C(sp³)-H oxidations and aminations via high-valent iron oxos and nitrenes, C(sp³)-H alkylations via isoelectronic iron carbene intermediates have thus far been unsuccessful. Iron carbenes have been inert, or shown to favor olefin cyclopropanation and heteroatom-hydrogen insertion. Herein we report an iron phthalocyanine-catalyzed alkylation of allylic and benzylic C(sp³)-H bonds. Mechanistic investigations support that an electrophilic iron carbene mediates homolytic C-H cleavage and rebounds from the resulting organoiron intermediate to form the C-C bond; both steps are tunable via catalyst modifications. These studies suggest that for iron carbenes, distinct from other late metal carbenes, C-H cleavage is partially rate-determining and must be promoted to effect reactivity.

Full text of DOI:10.1021/jacs.7b07602

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Communication
Catalytic C(sp3)–H Alkylation via an Iron Carbene Intermediate
Jennifer R Griffin, Chloe I Wendell, Jacob A Garwin, and M. Christina White
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b07602 • Publication Date (Web): 12 Sep 2017
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Catalytic C(sp )–H Alkylation via an Iron Carbene Intermediate
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Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801, United States
3
ABSTRACT: The catalytic transformation of a C(sp )–
Figure 1. Challenges of iron carbene C–H activation.
3
H bond to a C(sp )–C bond via an iron carbene interme-
diate represents a long-standing challenge. Despite the
success of enzymatic and small molecule iron catalysts
mediating challenging C(sp )–H oxidations and amina-
3
3
tions via high-valent iron oxos and nitrenes, C(sp )–H
alkylations via isoelectronic iron carbene intermediates
have thus far been unsuccessful. Iron carbenes have
been inert, or shown to favor olefin cyclopropanation
and heteroatom-hydrogen insertion. Herein we report an
iron phthalocyanine-catalyzed alkylation of allylic and
3
benzylic C(sp )–H bonds. Mechanistic investigations
support that an electrophilic iron carbene mediates ho-
molytic C–H cleavage and rebounds from the resulting
organoiron intermediate to form the C–C bond; both
steps are tunable via catalyst modifications. These stud-
ies suggest that for iron carbenes, distinct from other late
metal carbenes, C–H cleavage is partially rate-
determining and must be promoted to effect reactivity.
benes, C–H cleavage is partially rate-determining and
tunable via catalyst modifications.
Iron carbene complexes have been generated stoi-
chiometrically at low temperatures, isolated , and/or
demonstrated to undergo C–H insertion in a separate
step at elevated temperatures (e.g. 80°C) . We hypoth-
esized that one reason these reactions are not catalytic is
due to the distinct energetic requirements for each step.
At the elevated temperatures needed for C–H insertion,
thermal decomposition of the diazoester or metal car-
bene into a free carbene may occur. Literature reports
claiming iron-catalyzed C–H alkylation with methyl
5
a
5
b,c
Iron is one of the most abundant elements, totaling
one-third of the Earth’s mass, and is emerging as an im-
1a-f
portant metal for homogenous catalysis . Iron small
molecule catalysts have been demonstrated to catalyze
challenging C–H oxidation and amination processes via
6a
phenyldiazoacetate at 80˚C are ambiguous because this
diazoester is reported and observed by us (Supplemen-
tary Information, SI) to show significant non-metal me-
diated alkylation reactivity at this temperature .
We hypothesized that with iron, there is a higher ki-
netic barrier to C–H insertion than in rhodium and cop-
per systems where metallocarbene formation is rate de-
1
b,1c,1d,1f,
high-valent metal oxos and nitrenes
no iron catalyst has been demonstrated to alkylate
. In contrast,
6b
3
C(sp )–H bonds via an isoelectronic metallocarbene in-
termediate.
Naturally occurring and engineered P450 enzymes
form only inert carbenes or carbenes active for lower
energy processes than C–H alkylation (e.g. cyclopropa-
4a,7,8
termining
. This difference may explain the predomi-
nance of lower energy pathways in iron carbene reac-
tions, such as competitive dimerization to furnish ole-
fins . Reactivity and selectivity of metal carbenes is
2
nations, heteroatom-hydrogen bond insertions) (Fig. 1).
7
Small molecule iron catalysts capable of forming car-
benes also fail to catalyze C–H alkylation, favoring al-
ternative reaction pathways . Curiously, nearly all other
4e,9a
highly tunable ; therefore, we aimed to electronically
3
and sterically tune the catalyst and carbene precursor to
form a metallocarbene intermediate reactive enough to
insert into C(sp )–H bonds at temperatures that mitigate
deleterious pathways and do not decompose the diazo-
precursor.
4a,4b
4c
4a
late metals, including copper , cobalt , silver , pal-
3
4d
4e
4f
ladium , rhodium , and ruthenium , form metallocar-
benes catalytically active for C–H alkylation. Herein we
report an iron-catalyzed alkylation of allylic and ben-
3
We first evaluated iron catalysts used for metallo-
carbene-mediated cyclopropanations and heteroatom-
zylic C(sp )–H bonds and provide evidence of an iron
carbene intermediate. Distinct from other late metal car-
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hydrogen insertions for the intramolecular alkylation of
. We examined a se-
NaBAr (48%) (Table 1B). Adding the substrate to
3,5b,10
III
allylic C–H bonds (Table 1A)
ries of substituted diazo compounds (acceptor 1, donor-
acceptor 2, acceptor-acceptor 3) with varying degrees of
[Fe Pc] over an hour further increased the yield (53%).
Catalysts with halogenated phthalocyanine ligand
frameworks formed C–H alkylated product in lower
9a
electrophilicity and steric bulk . With iron porphyrin
and phthalocyanine catalysts, diazoester 1 converted to
olefin dimer (4, 93% and 84%, respectively), suggestive
yield than the unsubstituted, commercial catalyst (e.g.
[(Fe Cl Pc)Cl]). Iron (II) phthalocyanine and iron por-
III
8
phyrin complexes gave very little or no C–H alkylation
(see SI), highlighting the significance of the Fe oxida-
9a
III
of iron carbene formation . Bulkier disubstituted car-
bene precursor 2 disfavored dimerization with all cata-
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Table 2. Substrate scope.
9
lysts, but favored ketone product 5 over alkylation .
a
We hypothesized that augmenting the electrophilic-
Table 1. Reaction optimization.
ity of the disubstituted diazo compound would increase
its reactivity by producing a strongly electrophilic metal-
locarbene that could more readily engage in higher ener-
gy C–H insertion pathways. Under rhodium catalysis,
such electrophilic diazo compounds require very active
catalysts to form the metallocarbene; however, once
formed, the resulting carbene is more reactive towards
9a
C–H insertion . Acceptor-acceptor diazoester 3 resulted
in predominately recovered starting material. Upon ex-
13
10
F
amination of the C shifts of the α-carbon of various
tion state and the ligand framework . NaBAr alone
4
gave no product (see SI).
acceptor-acceptor diazo precursors, we observed that
sulfonate esters appeared to be the most electrophilic
and thus investigated their diazoesters (6) for C–H al-
Allylic C–H alkylations are rare under both noble
and base metal catalysis. Specifically, under rhodium
and copper catalysis, chemoselectivity issues arise
wherein cyclopropanation of the olefin competes with
C-H insertion
iron-catalyzed reaction across a range of allylic diaz-
osulfonate esters (Table 2A). Bulky trisubstituted ole-
fins, olefins with proximal, protected oxygen functional-
ity, and styrenyl substrates all undergo alkylation in pre-
parative yields (8-13). Consistent with an electrophilic
9b
kylation reactivity . The catalyst with the greatest π-
accepting character, iron phthalocyanine chloride
III
4a,4e,9
(
[Fe Pc]Cl), formed C–H alkylated δ-sultone product 7
. We investigated the scope of this
in low yield (3%) but with excellent selectivity (97%
rsm).
Examination of non-coordinating counterions to
render the iron catalyst more electrophilic led to a signif-
icant increase in yield with both AgSbF (45%, SI) and
6
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III
metallocarbene intermediate, [Fe Pc]-catalyzed C–H
alkylation is sensitive to substrate electronics (13 vs.
bound carbene intermediate in both the C–H bond cleav-
age and C–C bond formation steps (Fig. 2C, 2D). In
rhodium-catalysis proceeding via metallocarbene inter-
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4c,11
0) . This contrasts observations with metalloradical
1
intermediates invoked in cobalt catalysis, where sub-
4c
strate electronics do not affect reactivity. Chemoselec-
tivity for iron-catalyzed allylic C–H alkylation is main-
tained with more proximal olefins where cyclopropana-
tion would form the geometrically preferred 6-
Figure 2. Mechanistic studies.
9b
membered sultone (14-15). In contrast, rhodium catal-
ysis shows poor chemoselectivity for C–H insertion,
forming cyclopropanated products. We also demonstrate
one example of ethereal C—H alkylation (16).
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Benzylic C(sp )–H bonds were evaluated under
these reaction conditions and shown to readily undergo
alkylation (Table 2B). Substrates containing electron
rich aryl rings are alkylated in high yield (17-18), with
no cyclopropanation observed even for a naphthalene-
III
containing substrate (19). [Fe Pc] promotes C–H alkyla-
tion adjacent to chromene and indole heterocycles (20-
21), and tolerates lactam and thiophene motifs (23-24).
A substrate containing a benzodioxole moiety is readily
alkylated (22), despite the activated methylenedioxy
2a
functionality (Fig. 1A).
We investigated the application of this reaction to
the late-stage functionalization of δ-tocopherol, a
chromane antioxidant (Table 2C). Tocopherol derivative
III
5 was subjected to [Fe Pc]-catalyzed C–H alkylation
2
and furnished 26 in 78% yield. The δ-sulfone motif has
been demonstrated to be readily derivitized . Accord-
9b
ingly, a three step elaboration of the δ-sultone via nucle-
ophilic displacement yielded 27, bearing an unsymmet-
rical tertiary center with two new functional group han-
dles, in 44% overall yield.
We next sought to investigate the mechanism and
the involvement of an iron carbene intermediate in this
reaction. We hypothesized that C–H alkylation occurs
via an iron-bound carbene intermediate that, analogous
mediates, varying the carboxylate ligands has been
shown to influence both the intramolecular kinetic iso-
1b,1f
1c,1d
to iron oxos
and iron nitrenes , promotes homolyt-
7
,11,12b
ic cleavage of the C–H bond followed by recombination
with the resulting carbon-centered radical to form the
new C–C bond (Fig. 2A). Alternatively, [Fe Pc] could
tope effect (KIE) of C–H cleavage
tivity of C–C bond formation
change in the KIE with varied ligand electronics:
and the selec-
. We observed a
4
e,9a,13
III
III
Fe Pc] gave the highest KIE (5.0), followed by
serve as a Lewis acid to decompose the diazosulfonate
ester to a free carbene capable of inserting into proximal
C–H bonds. We investigated unligated iron salts and UV
light with no added catalyst, conditions demonstrated to
form reactive free carbenes from acceptor-acceptor di-
[
[
III III
Fe Cl Pc] (4.8) and [Fe Cl Pc] (4.5). These data
8
16
support involvement of the iron complex in the C–H
cleavage step. The larger KIE values for iron versus
rhodium (1.8), support the proposed stepwise versus
12
7
azo species . FeCl and FeCl resulted in predominate-
3
2
concerted mechanism (Fig. 2C) . A stepwise mechanism
ly recovered starting material (Fig. 2B), whereas irradia-
tion of 6 with UV light (254 nm) gave compound 28,
generated from C–H insertion of the free carbene into
the dichloromethane solvent (Fig. 2B). Product 28 is not
accounts for the improved chemoselectivity of iron rela-
tive to rhodium catalysts for C–H insertion over cyclo-
propanation; a stabilized allylic radical is preferred over
the secondary aliphatic radical formed during stepwise
olefin oxidation processes
III
1c,4c
observed under [Fe Pc]-catalysis, which is also run in
dichloromethane. These divergent outcomes support the
.
We also probed the effect of ligand electronics on
the C-C bond forming step. We performed a study on Z-
olefin substrate 32 to determine if scrambling of the
double bond geometry occurred during allylic C–H al-
III
hypothesis that [Fe Pc]-catalyzed C–H alkylation does
not proceed via free carbene intermediates.
We next sought to probe the involvement of an iron-
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kylation (Fig. 2D). Under Rh (OAc) catalysis, no isom-
2
The authors declare no competing financial interest.
4
erization of the olefin was observed, consistent with a
concerted mechanism of C–H insertion. In contrast, un-
der [Fe Pc] catalysis we observed scrambling of olefin
ACKNOWLEDGMENT
III
Financial support provided by the NIGMS MIRA (R35
GM122525). J.R.G is a National Science Foundation and
Springborn Graduate Fellow. C.I.W. is an Illinois Distin-
guished Graduate Fellow. We thank L. Zhu for assistance
with NMR and Dr. J.R. Clark for checking our experi-
mental procedure.
geometry, consistent with a stabilized carbon radical
intermediate. The extent of olefin isomerization is de-
pendent on the electronic substitution of the ligand, with
the electron deficient chlorinated iron catalysts affording
products with less isomerization than the unsubstituted
phthalocyanine (10:1 vs 3:1). Under cobalt porphyrin
catalysis, in the absence of a chiral pocket, isomerization
during functionalization of Z-olefins occurs to a greater
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. Intermolecular KIE stud-
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III
16
gesting that with a more electron deficient iron catalyst,
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7
nitrogen, competes energetically with C–H cleavage .
We report an iron-catalyzed C(sp )–H alkylation via
3
III
a metallocarbene intermediate. [Fe Pc] alkylates allylic
3
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ASSOCIATED CONTENT
8
Supporting Information. The Supporting Information is
available free of charge on the ACS Publications website at
DOI:
(
2
Experimental details and characterization data (PDF)
Spectral data (PDF)
(
(
(
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AUTHOR INFORMATION
Corresponding Author
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*mcwhite7@illinois.edu
Notes
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