Site-Selective C–H Benzylation of Alkanes with N-Triftosylhydrazones Leading to Alkyl Aromatics

Full text of DOI:10.1016/j.chempr.2020.06.031

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Article
Site-Selective C–H Benzylation of Alkanes with
N-Triftosylhydrazones Leading to Alkyl
Aromatics
Zhaohong Liu, Shanshan Cao,
Weijie Yu, Jiayi Wu, Fanhua Yi,
Edward A. Anderson, Xihe Bi
bixh507@nenu.edu.cn
HIGHLIGHTS
Silver-catalyzed site-selective C–H
benzylation of unactivated
alkanes
First intermolecular C(sp3)–H
insertions with donor carbene
Reductive alkylation of aryl
aldehydes by alkanes
The first intermolecular C(sp3)–H insertion with donor carbene was achieved by
employing N-triftosylhydrazones as the donor carbene source together with
electron-deficient silver ion and the weakly coordinating TpBr3 ligand. The reaction
proceeds with excellent site selectivity for 3ꢀ C–H bonds, and thus provides a
complementary way for synthesizing alkyl aromatics from abundant and low-cost
alkanes.
Liu et al., Chem 6, 1–15
August 6, 2020 ª 2020 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2020.06.031

Please cite this article in press as: Liu et al., Site-Selective C–H Benzylation of Alkanes with N-Triftosylhydrazones Leading to Alkyl Aromatics,
Chem (2020), https://doi.org/10.1016/j.chempr.2020.06.031
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Article
Site-Selective C–H Benzylation of Alkanes
with N-Triftosylhydrazones
Leading to Alkyl Aromatics
Zhaohong Liu,1,4 Shanshan Cao,1,4 Weijie Yu,1 Jiayi Wu,1 Fanhua Yi,1 Edward A. Anderson,2
and Xihe Bi1,3,5,
*
SUMMARY
The Bigger Picture
The direct and selective
Alkanes are an abundant and valuable resource for transformation
into value-added fine chemicals. However, selective functionaliza-
tion of specific C(sp3)–H bonds in alkanes for alkyl-alkyl bond forma-
tion is a significant challenge because of their intrinsic inertness and
the small differences in reactivity among various C(sp3)–H bonds.
Here, we report a silver-catalyzed site-selective C(sp3)–H benzyla-
tion of simple alkanes using N-triftosylhydrazones as a convenient
carbene precursor, which enables the synthesis of high value-added
alkylated aromatics. A one-pot two-step protocol starting from al-
dehydes was also realized, thereby constituting a formal reductive
alkylation of aryl aldehydes by alkanes. Experimental investigations
and DFT calculations reveal that the role of the [TpBr3Ag]2 catalyst is
3-fold: it modulates the carbene reactivity, inhibits carbene dimer-
ization, and avoids over insertion of the product. All three aspects
are crucial for the success of this first site-selective intermolecular
insertion of donor carbenes into C(sp3)–H bonds of simple alkanes.
conversion of simple alkanes into
value-added specialty chemicals
is a dream reaction because
alkanes are low cost and readily
obtained by reforming petroleum
feedstocks. Metal carbenoid-
induced alkylation of C(sp3)–H
bond is one of the most versatile
strategies toward this goal. Here,
we report the first site-selective
insertion reaction of donor
carbene into C–H bonds of simple
alkanes leading to alkyl aromatics,
which are among the most
important building blocks in the
chemical industry. The reaction
extends the carbene-induced C–H
insertion to low-reactive donor-
only carbene for the first time,
which may provide a new way for
the resource and high value
INTRODUCTION
The selective catalytic activation of strong, neutral C(sp3)–H bonds under mild con-
ditions to construct C–C and C–X bonds is of great value for both academic and in-
dustrial fields.1–6 However, the direct functionalization of alkane C–H bonds, and
especially the formation of C(sp3)–C(sp3) bonds,7–10 remains a challenging objective
for modern organic synthesis, because of the high bond-dissociation energies
(BDEs), low acidities, and only slight differences in reactivity among the various
alkane C–H bonds.11–13 Among the few strategies available, metallocarbene-trig-
gered C(sp3)–H alkylation, in which high site selectivity is possible without the
need for a directing group in the substrate, has emerged as a key strategy to form
such alkyl-alkyl bonds in alkanes.14–20 The seminal example of this concept was re-
ported by Scott and DeCicco in 1974, who described a copper-catalyzed insertion
of ethyl diazoacetate into cyclohexane.21 Noels and coworkers subsequently discov-
ered that dirhodium tetracarboxylates were more efficient catalysts compared with
copper,22 with a series of transition metal catalysts having since been applied to the
metallocarbene-triggered alkylation of unactivated C(sp3)–H bonds.23–32 These ex-
amples, which employed acceptor-only carbenes (i.e., featuring electron-with-
drawing carbonyl groups), displayed sufficient reactivity to insert into a range of
C–H bonds but lacked selectivity for substrates containing different C–H bond envi-
ronments. However, the pioneering work of Pe´ rez23–25 and Dias28 revealed that cop-
per and silver complexes with bulky tris(pyrazolyl)borate (Tpx) ligands improved both
reactivity and selectivity in the C–H insertion of alkanes with acceptor carbenes, even
utilization of feedstock alkanes.
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including the most challenging substrate—methane.27 In these transformations, re-
action at the less sterically crowded primary C–H bonds were favored over other
24–26,28,29
electronically preferred C–H bonds.
A notable breakthrough in this area
was achieved by Davies and coworkers, who reported that donor/acceptor carbenes
were less reactive but more selective compared with acceptor-only carbenes.33,34
Most importantly, highly site-selective and stereoselective insertions of donor/
acceptor rhodium carbenoids into 1ꢀ, 2ꢀ, and 3ꢀ C–H bonds in simple alkanes
were recently achieved by the Davies group (Figure 1A).35–39
Despite these impressive advances, the diazo components used in all studies to date
feature an electrophilicity-enhancing electron-withdrawing group (typically an ester)
in the acceptor and donor/acceptor carbenes. The development of equivalent re-
gioselective, non-directed catalytic C–H insertions using less reactive donor-only
carbenes remains an unsolved challenge. Although advances have been made in
C(sp2) –H alkylation by donor carbenes,40–42 insertions into C(sp3)–H bonds have
been restricted to intramolecular versions.43–47 Intermolecular insertions are more
challenging as donor carbenes are typically not sufficiently reactive to undergo
effective reaction14,15 and are instead more prone to undergo dimerization (espe-
cially compared with acceptor-stabilized carbenes).48–51 Furthermore, insertion
into the C–H bonds of the alkane substrate is less electronically favored than the
benzylic C–H bonds of the insertion products,52 which usually leads to undesirable
over insertion. As part of our continued interest in the silver-catalyzed activation
of diazo compounds,53–55 here, we report the realization of intermolecular C(sp3)–
H insertions of donor carbenes into alkanes, employing N-triftosylhydrazones as car-
bene sources together with electron-deficient silver ions and the weakly coordi-
nating TpBr3 ligand (Figure 1B). The reaction proceeds with very high site selectivity
for 3ꢀ C–H bonds, and affords diverse array of alkylated aromatics featuring all-car-
bon b-quaternary centers, which are versatile building blocks that would be hard to
synthesize by traditional methods.56
RESULTS AND DISCUSSION
Identification of a Carbene Insertion Catalyst and Carbene Source
We first examined the intermolecular reaction of 2-methylbutane with N-triftosylhy-
drazone 1a to identify an effective carbene insertion catalyst; the initial choice of the
N-triftosylhydrazone was based on our previous work,57,58 where this hydrazone de-
rivative could inhibit carbene dimerization by slowly generating donor diazo com-
pounds in situ under mild conditions. Many well-known carbene C(sp3)–H bond
insertion catalysts, such as Rh2(S-DOSP)4, FeTPP, CoTPP, and CuOTf, were found
to be inactive (Figure 2, entries 1–4). In contrast, we were pleased to find that elec-
tron-deficient silver salts, including AgOTf, AgPF6, AgSbF6, and AgBF4, gave the
corresponding tertiary C–H bond insertion product, albeit in low yields (18%–40%)
due to substantial carbene dimerization (>50% stilbene was formed in Figure 2, en-
tries 5–8, also see Table S1). Noting that silver catalysts with weakly coordinating
counter ions were able to activate the carbenic carbon toward electrophilic
C(sp3)–H insertion, we turned our attention to the bulky and weakly coordinating
tris(pyrazolyl)borate (Tp) silver complexes.25–28 To our delight, C–H insertion prod-
ucts were obtained in high yields with a 98:2 regioisomeric ratio (r.r.) of 2:3 in favor of
insertion into the tertiary C–H bond, without the formation of primary C–H insertion
product 4 (entries 9–11). Unexpectedly, when the reaction was performed with
TpBr3Cu, a known acceptor carbene X–H insertion catalyst,23,24,59 only trace
amounts of C–H insertion product were formed (entry 12). The expected site-
selectivity trend (tertiary >> secondary; no primary) was also observed with other
1Department of Chemistry, Northeast Normal
University, Changchun 130024, China
2Chemistry Research Laboratory, University of
Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK
3State Key Laboratory of Elemento-Organic
Chemistry, Nankai University, Tianjin 300071,
China
4These authors contributed equally
5Lead Contact
*Correspondence: bixh507@nenu.edu.cn
https://doi.org/10.1016/j.chempr.2020.06.031
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Figure 1. Site-Selective Intermolecular C–H Functionalization of Alkanes with Metallocarbenes
(A) Site-selective C(sp3)–H alkylation of simple alkanes by carbene-induced C–H insertion: advantages and challenges.
(B) This work: ligand-enabled silver-catalyzed site-selective C–H benzylation of alkanes with N-triftosylhydrazones as the donor carbene precursor,
leading to alkyl aromatics.
EWG, electron-withdrawing group; EDG, electron-donating group; r.r., regioisomeric ratio of 3ꢀ, 2ꢀ and 1ꢀ C–H bonds; Triftosyl, 2-(trifluoromethyl)
benzenesulfonyl.
N-sulfonylhydrazones 1b–1d, albeit with lower yields (entries 13–15). On the basis of
these results, [TpBr3Ag]2 was selected as the optimum catalyst for tertiary C–H bond
functionalization of non-activated alkanes (entry 11). Notably, a different and rela-
tively modest selectivity (primary > secondary > tertiary) was observed by the Pe´ rez
and Dias groups using TpAg-based catalysts for 2-methylbutane insertion with sta-
bilized carbenes derived from ethyl diazoacetate.25,28
Scope of N-Triftosylhydrazones as the Carbene Source
Having determined optimum conditions for tertiary C–H functionalization with donor
metallocarbenes, the scope of the reaction was evaluated with a range of substrates
(Figure 3). Initially, a series of aryl N-triftosylhydrazones were tested, which revealed
excellent functional group tolerance. As shown in Figure 3A, highly selective C–H
functionalization of the tertiary site of 2-methylbutane could be achieved in
28%–89% yield, with the regioselectivity ratio ranging from 10:1 to 20:1. The
electronic nature of the substituents on the aryl ring of N-triftosylhydrazone had a
significant impact on yield: aryl hydrazones featuring electron-withdrawing groups
(6–10, 15–22) gave higher yields than those with electron-neutral (5, 11–13) and
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Figure 2. Identification of Catalyst and Carbene Source for Donor Carbene Insertion into Non-
activated sp3 C–H bonds
Reaction conditions: N-Sulfonylhydrazone 1a–1d (0.3 mmol), NaH (0.6 mmol), 2-methylbutane
(5.0 mL) and CH2Cl2 (5.0 mL) were stirred at room temperature for 1 h. Then, the catalyst was added,
and the mixture was stirred at 60ꢀC for 48 h under argon atmosphere. The regioisomeric ratio (r.r.)
and yields of product were determined by 1H NMR spectroscopic analysis of the crude reaction
mixture using CH2Br2 as an internal standard. The isolated yield is given in parentheses.
electron-donating (14) groups; in most cases, virtually a single regioisomer was
observed (r.r. R 20:1). The reaction efficiency was not compromised by the position
or degree of substitution on the phenyl ring of the hydrazone, but the presence of an
ortho substituent led to a modest reduction in site selectivity (16–25, 10:1–16:1 r.r.).
The strong preference for tertiary substitution was maintained for N-triftosylhydra-
zones derived from naphthyl (27) and heteroaryl aldehydes (28), albeit the latter pro-
ceeded in lower yield (28%).
Scope of the Alkane
With hydrazone reactivity explored, we next studied the scope of the alkane to
determine the effect of sterics and multiple potential insertion points on site
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Figure 3. Substrate Scope of the Silver-Catalyzed C(sp3)–H Insertion
Reaction conditions: N-Triftosylhydrazone (0.3 mmol), NaH (0.6 mmol), [TpBr3Ag]2 (2.5 mol %), alkane (5.0 mL) and CH2Cl2 (5.0 mL), 60ꢀC, 48 h, under an
argon atmosphere. For compounds 8–10, 12–14, 26–28, and 59, 5.0 mol % [TpBr3Ag]2 was used. For compounds 42–45, 2.0 equiv alkane was used. The
r.r. of 3ꢀ and 2ꢀ C–H insertion was determined by 1H NMR spectroscopic analysis of the crude material. For 60, 2:1 refers to selectivities toward the
tertiary and secondary sites of cis-decalin. All yields are isolated yields.
selectivity (Figure 3B). Both symmetric and unsymmetric alkanes were found to un-
dergo highly selective tertiary C–H alkylation with hydrazone 1a, affording the
desired alkylarenes (29–32, 34, and 35) in generally high yields. The exception was
an alkane featuring a tert-butyl group on the carbon atom adjacent to the tertiary
center (33) where no reaction was observed, emphasizing the sensitivity of the sys-
tem to the steric environment around the tertiary site (c.f. 31,32 versus 33). This
was further confirmed by the absence of benzyl C–H bond insertion products (the re-
action of cumene afforded the corresponding insertion product in only 10% NMR
yield, for details see Figure S2). In the absence of a tertiary C–H bond, functionaliza-
tion of secondary C–H sites also proved possible; for example, n-hexane underwent
high-yielding insertion (82%) but displayed relatively poor secondary site selectivity
(36, C2:C3 = 3:1 r.r.). The reaction of 2,6,10,14-tetramethylpentadecane, which fea-
tures subtly different tertiary centers, afforded insertion products at both 3ꢀ C–H
bonds, with a modest favoring of the less hindered position (37). Nonetheless, this
result further illustrates the power of the [TpBr3Ag]2 catalyst in donor carbene inser-
tion into the tertiary sites of unactivated C(sp3)–H bonds, irrespective of the number
of other C–H bonds. It is also noteworthy that the alkylarene products of all these
reactions would be inaccessible through traditional Friedel-Crafts alkylation using
primary haloalkanes due to competing rearrangements, polysubstitution, or mis-
matched regiodirecting effects.56
Pleasingly, the reaction could be readily extended to secondary and tertiary C–H
bonds for a range of cycloalkanes (Figure 3C). The formation of secondary carbene
C–H insertion products of 5–8-membered rings proceeded in excellent yield
(38–41); on the other hand, the reaction of N-triftosylhydrazones with adamantane
and 1,3-dimethyladamantane afforded only the tertiary C–H bridgehead insertion
products 42–45 (55%–83% yield) with no observation of reaction at the secondary
C–H bonds. This result further emphasizes the exquisite site selectivity for tertiary
C–H bonds in the absence of steric effects, regardless of the number of secondary
C–H bonds. The scope of secondary C–H insertion was further explored using
various N-triftosylhydrazones and cyclohexane, which furnished the corresponding
alkylated products 46–59 in good to excellent yields. Interestingly, carbene insertion
into cis-decalin produced both tertiary and secondary CÀH insertion products 60 in
66% yield with 2:1 ratio favoring the former. Conversely, trans-decalin only pro-
duced secondary CÀH insertion products, potentially due to 1,3-diaxial interactions
in this conformational locked system (for details see Figures S2–S4) Also noteworthy
is the compatibility of the catalytic system with ketone-derived N-triftosylhydra-
zones, albeit in these cases only donor/acceptor carbenes (featuring an electron-
withdrawing group CO2Me or CF3 adjacent to the hydrazone) produced C–H inser-
tion products in excellent yields (61 and 62). In their absence, the reaction failed to
yield even trace amounts of the desired product (e.g., 63), which demonstrated that
the additional electron-donating group greatly attenuated the electrophilicity of
carbene. However, the donor carbenes do not yet match donor/acceptor carbenes
in terms of scope, selectivity, and functional group compatibility.35,36 For example,
substrates containing other functionalities such as bromo and ester functional
groups (1-bromo-3-methylbutane and 4-methylpentyl hexanoate) only yield trace
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Figure 4. One-Pot Reductive Alkylation of Aromatic Aldehydes Using Alkanes as the Alkylating
Agent
˚
Reaction conditions: aryl aldehyde (0.3 mmol), N-triftosylhydrazide (0.3 mmol), 4 A MS (30 mg), NaH
(0.6 mmol), [TpBr3Ag]2 (2.5 mol %), alkane (5.0 mL) and C6F6 (5.0 mL), 60ꢀC, 48 h, argon atmosphere.
The r.r. was determined by 1H NMR spectroscopic analysis of the crude material. Yields are isolated
yields. For compounds 2 and 6, CH2Cl2 (5.0 mL) was used as the co-solvent. For compounds 8, 9, 23
and 27, [TpBr3Ag]2 (5.0 mol %) was used.
amount of the desired products, probably due to the halophilicity and oxophilicity of
silver salt.60
Intramolecular C(sp3)–H Insertion
Finally, we evaluated the catalytic efficiency of [TpBr3Ag]2 in promoting intramolec-
ular C–H insertion reactions. Indanes are important carbocyclic motifs found in com-
pounds displaying antitumor, antiallergic, anticonvulsant, herbicidal, and antimicro-
bial activities.61 To our delight, indane derivatives 64–66 were obtained in moderate
to excellent yield using N-triftosylhydrazones with an o-alkyl substituent (Figure 3D);
although related intramolecular C(sp3)–H bond insertions of gold carbenes have
been reported, a Thorpe-Ingold effect is typically required to position the C–H
bond closer to the carbene center47; in the present case, no such constraint is
required, which even enabled insertion into primary C–H bonds (65).
One-Pot Hydrazone Synthesis and C–H Functionalization
The N-triftosylhydrazones used in this reaction are readily derived from the corre-
sponding carbonyl compounds. We questioned whether C–H insertion could be
achieved directly from the carbonyl precursor in a one-pot process. Pleasingly, a
sequenced reaction of 4-chlorobenzaldehyde with N-triftosylhydrazide gave the
desired C–H insertion product 2 in 53% yield with >20:1 site selectivity. The addition
˚
of 4 A MS into the reaction mixture dramatically improved the product yield to 95%
(for details, see Table S2). Under these modified conditions, a range of aromatic al-
dehydes, as well as linear and cycloalkanes, reacted smoothly to give the corre-
sponding alkylarenes in 33% to 95% yields with excellent tertiary C–H insertion
selectivity (Figure 4). From a synthetic perspective, this process effectively corre-
sponds to a direct reductive alkylation of carbonyls using unactivated alkanes as al-
kylating agents. This is an attractive alternative to existing multistep approaches to
synthesize alkylated arenes, and again avoids the regioselectivity and reactivity
problems typically encountered in Friedel-Crafts alkylation.56
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Figure 5. Gram-Scale C–H Insertion and Further Transformations
Reaction conditions:
(A) KBr (0.5 equiv), oxone (3.0 equiv), MeNO2, RT, 24 h.
(B) NBS (1.5 equiv), CCl4, reflux, overnight.
(C) LiBr (1.0 equiv), NaIO4 (25 mol %), AcOH, 110ꢀC, 36 h.
(D) FeCl2 (10 mol %), n-C8H17N3 (2.0 equiv), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.2 equiv),
H2O (2.0 equiv), trifluoroacetic acid, 60ꢀC.
To illustrate the practicality of the process, multigram-scale syntheses of 2 and 39
were carried out. As shown in Figure 5A, a 10 mmol scale reaction of N-triftosylhy-
drazone 1a and 2-methylbutane proceeded very well in the presence of [TpBr3Ag]2,
affording 2 in high yield (92%, 1.81 g). For this process, the concentration was
increased from 0.03 M to 0.1 M, and 1.2 mol % silver catalyst was sufficient. Similarly,
the one-pot reaction of 4-chlorobenzaldehyde with cyclohexane on a 20 mmol scale
also produced the desired alkylarene 39 in high yield. Owing to the presence of
benzylic C–H bonds, alkylarenes can undergo a variety of powerful synthetic trans-
formations. For example, benzylic oxidation of alkylarene 39 by KBr/oxone pro-
duced ketone 67 in 86% yield.62 39 also underwent smooth radical-mediated C–H
bromination with N-bromosuccinimide (68), and C–H acetoxylation with acetic
63
acid / NaIO4 (69) in good yields. The contrasting benzylic C–H functionalization
selectivity of these transformations, compared with the carbene insertion, is of
note. In addition, N-alkylaniline 70 could be readily derived from alkylarene 39 via
an FeCl2-catalyzed C(sp2)–C(sp3) bond-cleavage process (Figure 5B).64
Mechanistic Investigations and Computational Studies
Kinetic Isotope Effect
To gain insight into the reaction mechanism, kinetic isotope effect (KIE) experiments
were performed. The reaction of N-triftosylhydrazone 1a with a 1:1 mixture of cyclo-
hexane and cyclohexane-d12 afforded the C–H and C–D insertion products 39 and
D-39, respectively, in a 3:1 ratio (Figure 6, also see Figures S5–S8). The measured
kH/kD value is in good agreement with values determined in previously reported
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Figure 6. KIE Experiment
rhodium-catalyzed C–H insertion reactions,34,44 suggesting a primary kinetic
isotope effect.65
Density Functional Theory (DFT) Calculations
The crucial role of the TpBr3 ligand in both the reactivity and site selectivity of the
C(sp3)–H insertion stimulated us to explore the origin of its effects using DFT calcu-
lations. Computations were performed with M06-2X/6-31+G(d,p)-SDD (Ag and Br)
corrected energies with the SMD (CH2Cl2) solvent model on B3LYP/6–31G(d,p)-
SDD (Ag and Br) calculated geometries, using Gaussian 09 (for details on computa-
tional methods see Data S1 and S2). Figure 7A presents an energy profile for the
insertion of donor diazo compound 1a–1, generated from N-triftosylhydrazone 1a
on treatment with base, into the 1ꢀ, 2ꢀ, and 3ꢀ CÀH bonds of 2-methylbutane. First,
the silver-catalyzed elimination of N2 from diazo compound 1a–1 occurs via TSI with
an energy barrier of 15.9 kcal/mol to form the silver carbene IntI, which constitutes
the rate-determining step.66 The calculated AgÀC distance in IntI is 2.05 A, indi-
˚
cating single bond character, which renders the carbene-carbon atom electrophilic
(Figure 7B).67 The LUMO of IntI, which comprises an out-of-phase combination of
the Cp-p* orbital and the Ag dp orbital (Figure 7B), further illustrates the electro-
philic nature of the carbon atom with a large coefficient on this atom. This car-
bene-carbon LUMO character has also been used to explain the reactivity of the
acceptor-only carbene coordinated to the Ag(3,5-(CF3)2PyrPy) moiety.67 To improve
understanding of the key role of TpBr3 in the reactivity of donor carbenes, and to
rationalize site selectivity and chemoselectivity, atom-condensed local electrophi-
licity indexes68 of IntI and IntI-AgOTf (generated from 1a–1 with TpBr3Ag and
AgOTf, respectively) were determined (Figure 7C). To our surprise, this revealed
that the electrophilicity of the carbene carbon of IntI is less than that of IntI-AgOTf.
Further calculations showed that the energy barrier of the coupling of IntI with diazo
compound 1a–1 is 4.7 kcal/mol higher than that for IntI-AgOTf (Figure 7C, for details
see Figure S9). Compared with IntI, IntI-AgOTf is therefore more prone to undergo
carbene dimerization, which is consistent with the experimental results (entries 5
versus 11, Figure 2). The optimized structure of IntI showed that the steric environ-
ment around the silver atom is highly crowed (Figure 7B), which may inhibit carbene
dimerization and enable productive C–H bond insertion.
We suspect that it is very likely that the interaction between the electrophilic silver car-
bene IntI and nucleophilic C(sp3)–H bond is so weak that only the most electronically
favored 3ꢀ C–H bonds can react well, whereby developing positive charge at the insert-
ing carbon atom is best accommodated at the tertiary center. Association of the alkane
substrate with IntI leads to IntII-T/S/P (depending on which C–H bond coordinates).
While IntII-T is marginally favored in this process, it is the subsequent insertion step
that is predominantly site-determining. Indeed, insertion into both the secondary and
tertiary C–H bonds appears to be fewer barriers from IntII-S/T. For the tertiary C–H
bond in particular, association of the substrate with the carbene is predicted to result
in spontaneous (barrierless) insertion, while reaction at the primary C–H bond is disfa-
vored compared with the other environments (TSII-P DGs = 8.1 kcal molÀ1). Selectivity
between the 2ꢀ and 3ꢀ bonds appears computationally to arise from the association
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Figure 7. Mechanistic Studies for Silver-Catalyzed C(sp3)–H Insertion with Donor Diazo Compounds by DFT
(A) Calculated free-energy profiles for the C(sp3)–H insertion of 2-methylbutane by donor silver carbene. Energies are in kcal molÀ1
.
(B) Optimized structure and LUMO of silver carbene complex.
(C) Calculated Fukui values on carbenic carbon Ca (purple) and Ag center (blue color) of the different silver carbene complexes.
step, in which coordination of the tertiary C–H bond is favored. These energy profiles are
consistent with the trend in BDEs,11 and the experimentally observed site selectivity for
the 3ꢀ, 2ꢀ, and 1ꢀ C–H bonds of 2-methylbutane (r.r. 20:1:0).
The C(sp3)–H insertion with donor silver carbene is a concerted but asynchronous pro-
cess, as evidenced (Figure 8) by the large difference between the Ca–H3 and Ca–C3
˚
˚
bond distances in TSII-T (1.18 versus 2.41 A, respectively), TSII-S (1.19 versus 2.32 A),
66,67
˚
and TSII-P (1.20 versus 2.28 A).
However, the difference between these bond
lengths at the transition point lessens as the extent of substitution at the inserting carbon
decreases; in other words, the extent of C–H bond cleavage (and, correspondingly, C–H
bond formation at the carbenic carbon) is greatest for the tertiary C–H bond. This is not
unexpected based on the ability of the insertion center to accommodate the developing
positive charge (3ꢀ > 2ꢀ >> 1ꢀ), as characterized by the natural population analysis (NPA)
charges on intermediates IntII and transition states TSII (Figure 8). These values clearly
illustrate charge gain at the carbenic carbon Ca in TSII-T (À0.68), TSII-S (À0.66), and TSII-
P (À0.63) relative to that in IntI (À0.24), minimal change at the migrating hydrogen, and
loss of charge from the alkane carbons C1 (0.33), C2 (0.34), and C3 (0.40) relative to the
Figure 8. Calculated Energy Barrier (DGs) of 3ꢀ, 2ꢀ, and 1ꢀ C–H Insertion of 2-methylbutane, and
Charge Flow (De) From Alkane Carbon to the Electrophilic Carbene
The values in parentheses correspond to the NPA charges of certain atoms.
Chem 6, 1–15, August 6, 2020
11

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corresponding atoms on the 2-methylbutane-carbene complexes. In all three cases, the
bridging H can be regarded as a conduit for charge flow, and the lowest free-energy
values of the three key transition states can be explained by the better charge flow
from the 3ꢀ C–H group of 2-methylbutane to the electrophilic carbene. Taken together,
charge flow from the alkane carbon to the electrophilic carbene center is the dominant
contributor to the site selectivity for 3ꢀ versus 2ꢀ and 1ꢀ CÀH insertion.67 In addition,
DFT methods uB97XD, M06, and B3LYP-D3 with the same basis set 6–31+G(d,p)-
SDD (Ag and Br) were used to calculate the solvation single point energies for compar-
ison (for details see Figures S10–S12). Our computational results indicated that M06-2X,
uB97XD, M06, and B3LYP-D3 functionals give the same trend in the relative energies of
transition states and intermediates, and the site selectivities calculated by uB97XD,
M06, and B3LYP-D3 methods are consistent with those obtained using M06-2X.
Conclusions
A ligand-enabled, silver-catalyzed site-selective C(sp3)–H alkylation of alkanes has
been developed using donor carbenes, generated in situ from N-triftosylhydra-
zones, which enables the synthesis of alkyl aromatics. This chemistry complements
the previous uses of the acceptor-only or donor-acceptor carbenes in proceeding
via a less electrophilic carbenoid intermediate, such that site selectivity is based
more on the association and strength of the inserting C–H bond (and the ability of
the carbon center to accommodate developing positive charge) than on the acces-
sibility of the insertion site. As such, this provides a different basis on which to design
selective C–H insertion processes, and here, provides a new platform for the con-
struction of alkyl-alkyl bonds directly from unactivated C(sp3)–H bonds, without reli-
ance on directing groups. From a synthetic perspective, this reaction offers a simple
means to accomplish the direct reductive alkylation of aryl carbonyl compounds,
thus providing a powerful method for the preparation of alkylarenes, in particular,
those that would be difficult to synthesize by conventional methods. The roles of
the bulky TpBr3 ligand and the silver ion have been elucidated by combining exper-
imental studies and theoretical calculations: modulating the electrophilicity of donor
carbenoids capable of reacting with 3ꢀ C–H bond with high selectivity, sterically in-
hibiting the dimerization of the carbene, and further avoiding over insertion into the
benzylic C–H bond of the product. The significant advances in the methodology and
the deep insights in reaction mechanism would stimulate new ideas for further devel-
opment of carbene-triggered site-selective C–H functionalization of simple alkanes.
EXPERIMENTAL PROCEDURES
Resource Availability
Lead Contact
Further information and requests for resources and reagents should be directed to
and will be fulfilled by the Lead Contact, Xihe Bi (bixh507@nenu.edu.cn).
Materials Availability
This study did not generate new unique reagents.
Data and Code Availability
There is no dataset and code associated with the paper.
Full experimental procedures are provided in the Supplemental Information.
Images of the key spectral and analytical data of the compounds generated in this
study are included in Figures S1–S156 in Supplemental Information.
12
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Article
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2020.06.031.
ACKNOWLEDGMENTS
This work is dedicated to Professor Michael Famulok on the occasion of his 60th
birthday. This work was supported by NSFC (21871043, 21961130376), Department
of Science and Technology of Jilin Province (20180101185JC, 20190701012GH,
20200801065GH), and the Fundamental Research Funds for the Central Universities
(2412019ZD001, 2412020ZD003). E.A.A. thanks the EPSRC for support (EP/
S013172/1). X.B. and E.A.A. thank the Royal Society for a Newton Advanced Fellow-
ship (NAF R1 191210).
AUTHOR CONTRIBUTIONS
Z.L. and S.C. contributed equally to this work. Z.L., S.C., W.Y., F.Y., and J.W. per-
formed the experimental investigations and theoretical calculations. Z.L. and X.B.
conceived the concept, designed the project, analyzed the data, and, together
with E.A.A, discussed the results and prepared this manuscript.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: March 19, 2020
Revised: May 20, 2020
Accepted: June 23, 2020
Published: July 23, 2020
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