Borane-Catalyzed Stereoselective C–H Insertion, Cyclopropanation, and Ring-Opening Reactions

Article abstract of DOI:10.1016/j.chempr.2020.06.035

Lewis acidic boranes have been shown to be effective metal-free catalysts for highly selective reactions of donor-acceptor diazo compounds to a range of substrates. The reactions of α-aryl α-diazoesters with nitrogen heterocycles indole or pyrrole selectively generate C3 and C2 C–H insertion products, respectively, in good to excellent yields even when using unprotected indoles. Alternatively, benzofuran, indene, and alkene substrates give exclusively cyclopropanated products with α-aryl α-diazoesters, whereas the reactions with furans lead to ring-opening. Comprehensive theoretical calculations have been used to explain the differing reactivities and high selectivities of these reactions. Overall, this work demonstrates the selective metal-free catalytic reactions of α-aryl α-diazoesters with (hetero)cycles and alkenes. This simple, mild reaction protocol represents an alternative to the commonly used precious metal systems and may provide future applications in the generation of biologically active compounds. Efficient and facile routes to heterocyclic compounds are highly desirable because of their remarkable biological importance and applications in drugs approved by the Food and Drug Administration. Current synthetic routes frequently use precious metal-catalyzed reactions. The problems associated with the limited resources of precious metals as well as their toxicities can be avoided through metal-free approaches. Our investigations on the reactivities of diazoesters toward the (hetero)arenes reveal that by using Lewis acidic triarylboranes as a catalyst, we can selectively effect C–H insertion, cyclopropanation, or ring-opening in good to excellent yields. Main group, or metal-free, catalysis has become a burgeoning field; yet, this flourishing field is still in its nascent stage. The work described herein represents a step toward improving the applicability of main group catalysis by employing metal-free approaches in the functionalization of organic compounds. This work demonstrates the highly selective metal-free catalytic reactions of α-aryl α-diazoesters with a range of (hetero)cycles and olefins using Lewis acidic boranes. The simple, mild reaction protocol employed represents an alternative to the commonly used precious metal systems and may provide future applications in the generation of biologically active compounds.

Full text of DOI:10.1016/j.chempr.2020.06.035

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Article
Borane-Catalyzed Stereoselective C–H
Insertion, Cyclopropanation, and Ring-
Opening Reactions
Ayan Dasgupta, Rasool
Babaahmadi, Ben Slater, Brian
F. Yates, Alireza Ariafard,
Rebecca L. Melen
melenr@cardiff.ac.uk
HIGHLIGHTS
Borane-catalyzed regio- and
diastereo-selective reactions
Selective C–H insertion,
cyclopropanation, or ring-
opening reaction
57 examples with isolated yields
up to 92%
Detailed DFT analysis to explain
reaction mechanisms and
selectivity
This work demonstrates the highly selective metal-free catalytic reactions of a-aryl
a-diazoesters with a range of (hetero)cycles and olefins using Lewis acidic boranes.
The simple, mild reaction protocol employed represents an alternative to the
commonly used precious metal systems and may provide future applications in the
generation of biologically active compounds.
Dasgupta et al., Chem 6, 1–18
September 10, 2020 ª 2020 The Author(s).
Published by Elsevier Inc.
https://doi.org/10.1016/j.chempr.2020.06.035

Please cite this article in press as: Dasgupta et al., Borane-Catalyzed Stereoselective C–H Insertion, Cyclopropanation, and Ring-Opening Re-
actions, Chem (2020), https://doi.org/10.1016/j.chempr.2020.06.035
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Borane-Catalyzed Stereoselective
C–H Insertion, Cyclopropanation,
and Ring-Opening Reactions
Ayan Dasgupta,1 Rasool Babaahmadi,2 Ben Slater,3 Brian F. Yates,2 Alireza Ariafard,2
and Rebecca L. Melen1,4,
*
SUMMARY
The Bigger Picture
Efficient and facile routes to
heterocyclic compounds are
highly desirable because of their
remarkable biological importance
and applications in drugs
Lewis acidic boranes have been shown to be effective metal-free
catalysts for highly selective reactions of donor-acceptor diazo com-
pounds to a range of substrates. The reactions of a-aryl a-diazoest-
ers with nitrogen heterocycles indole or pyrrole selectively generate
C3 and C2 C–H insertion products, respectively, in good to excellent
yields even when using unprotected indoles. Alternatively, benzo-
furan, indene, and alkene substrates give exclusively cyclopropa-
nated products with a-aryl a-diazoesters, whereas the reactions
with furans lead to ring-opening. Comprehensive theoretical calcu-
lations have been used to explain the differing reactivities and
high selectivities of these reactions. Overall, this work demon-
strates the selective metal-free catalytic reactions of a-aryl a-diazo-
esters with (hetero)cycles and alkenes. This simple, mild reaction
protocol represents an alternative to the commonly used precious
metal systems and may provide future applications in the genera-
tion of biologically active compounds.
approved by the Food and Drug
Administration. Current synthetic
routes frequently use precious
metal-catalyzed reactions. The
problems associated with the
limited resources of precious
metals as well as their toxicities
can be avoided through metal-
free approaches. Our
investigations on the reactivities
of diazoesters toward the (hetero)
arenes reveal that by using Lewis
acidic triarylboranes as a catalyst,
we can selectively effect C–H
insertion, cyclopropanation, or
ring-opening in good to excellent
yields. Main group, or metal-free,
catalysis has become a
INTRODUCTION
The presence and availability of d-orbitals on transition metals has rendered them
indispensable for a vast number of transformations in which synergic bonding and
back-bonding interactions are central to their chemistry. It is these bonding proper-
ties that allow metal-carbene complexes to play an important role in organometallic
and synthetic chemistry.1 In particular, one area that remains at the forefront of both
academic and industrial research is the use of metal carbene complexes as interme-
diates in the functionalization of electron-rich oxygen and nitrogen heterocycles that
are omnipresent in nature.2 One popular method to generate such complexes is the
catalytic decomposition of diazo compounds.3 The metal-carbene complex can sub-
sequently be used in a plethora of carbene transfer reactions including C–H inser-
tion4 and cyclopropanation5 (Scheme 1A). (Di)rhodium complexes6 are typically
the metal catalyst of choice although other precious metal catalysts such as gold,7
ruthenium,8 palladium,9 and iridium10 can be employed. Of the first-row transition
metals, copper11 is also commonly used, and recently, the earth-abundant metal,
iron,12 has also been shown to be an effective catalyst for carbene transfer reactions.
Recently, it has been shown that the photocatalyzed activation of diazo-compounds
is also possible for cyclopropanation or C–H activation of olefins and
heteroarenes.13
burgeoning field; yet, this
flourishing field is still in its
nascent stage. The work
described herein represents a
step toward improving the
applicability of main group
catalysis by employing metal-free
approaches in the
functionalization of organic
compounds.
Although rhodium is typically used, one major pitfall includes its high cost and
inherent toxicity.14 One field of research that has flourished over the last decade is
Chem 6, 1–18, September 10, 2020 ª 2020 The Author(s). Published by Elsevier Inc.
1
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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Scheme 1. Previous and Current Work
(A) Previous work on metal-carbene transfer reactions and borane activation of dinitrogen compounds.
(B) Work described herein. CAAC, cyclic (alkyl)(amino)carbene; ArF, C6F5, 2,4,6-F3C6H2, or 3,4,5-F3C6H2.
main group chemistry in which current studies aim to unearth new reactivities and se-
lectivities using metal-free compounds, thereby providing alternative (or comple-
mentary) catalysts to those based on the d-block elements.15 One area that has
1Cardiff Catalysis Institute, School of Chemistry,
received attention is the applications of Lewis-acidic-fluorinated triarylboranes in
small-molecule activation and catalysis following the seminal work of Piers in 1996
who showed that B(C6F5)3 could be used as an effective catalyst for hydrosilylation
reactions.16 Later, this borane and its derivatives were also employed as the Lewis
acid component of frustrated Lewis pairs (FLPs) to effect metal-free hydrogenation.17
More recently, the use of boranes for the activation of N–N bonded compounds has
garnered momentum,18 particularly since the groundbreaking work by Braunschweig
Cardiff University, Main Building, Park Place,
Cardiff CF10 3AT, UK
2School of Natural Sciences-Chemistry, University
of Tasmania, Private Bag 75, Hobart, Tasmania
7001, Australia
3Department of Chemistry, University College
London, London WC1H 0AJ, UK
4Lead Contact
on the first-ever metal-free activation of dinitrogen in 2018.19 Specifically, BArF
*Correspondence: melenr@cardiff.ac.uk
https://doi.org/10.1016/j.chempr.2020.06.035
3
(ArF = C6F5, 2,4,6-F3C6H2, 3,4,5-F3C6H2) have been reported to activate metal
2
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dinitrogen compounds20 and diazo compounds.21,22 The latter, however, are typi-
cally stoichiometric, whereby the carbene generated inserts into a B–C bond, leading
to a-functionalized carbonyl compounds.21,23 We have recently employed this reac-
tivity in the metal-free synthesis of asymmetric 3,3-disubstituted benzofuran-2(3H)-
ones from the reaction between a-aryl a-diazoacetates and triarylboranes.21
Recently, there have been a few reports that show that B(C6F5)3 can activate diazo-
compounds in a catalytic manner. Specifically, a-aryl a-diazoesters have been
demonstrated to be suitable substrates for insertion and nucleophilic substitution re-
actions (Scheme 1A). In 2016, Zhang reported the ortho-selective C–H alkylation of
unprotected phenols with a-aryl a-diazoesters using 5 mol % B(C6F5)3.24 Mechanistic
studies revealed that the high selectivity for the ortho-position was due to a
hydrogen-bond directed process involving the O–H group of the phenol, thereby ex-
plaining why substrates such as anisole did not work well for these reactions.
Although these boranes are moisture sensitive (due to their strong Lewis acidic char-
acter that often results in B–C bond protonolysis), water in combination with B(C6F5)3
was found to be a suitable catalyst for the O–H insertion reactions of water with a-aryl
a-diazoesters.25 Interestingly, mechanistic studies indicate that in this case,
B(C6F5)3$nH2O acts as a Brønsted acid rather than a Lewis acid catalyst to facilitate
a nucleophilic substitution mechanism. In a very similar vein, water could be replaced
by azide for this type of nucleophilic substitution, but the mechanism was proposed
to proceed through Lewis acid activation of the N2 functionality.26 Finally, Prabhu
et al. have demonstrated the use of catalytic B(C6F5)3 toward C–C bond functional-
ization of aryl-allyl alcohols using donor-acceptor carbenes, which was suggested
to progress through borane activation of the diazo functionality followed by
borane-carbene adduct formation.27
As can be seen above, several different modes of activation of diazo-compounds us-
ing B(C6F5)3 have been proposed, and a few computational studies have shed some
light on the probable reaction mechanisms. Density functional theory (DFT) studies
reported by Stephan28 for the reaction of Ph2CN2 with B(C6F5)3 revealed the mech-
anism for this reaction is the initial activation of the N2 functionality through Lewis
adduct formation. This is followed by N2 release to generate a carbene-borane
adduct (calculated to be exergonic by about 53 kcal/mol).28 Subsequent, computa-
tional studies by Wu29 on the B(C6F5)3 activation of diazoesters also revealed N2
release, but in this case, activation of the carbonyl to generate a borane-diazoester
conjugated adduct was more favorable than activation of the N2 functionality.29 The
electron-withdrawing effect of Lewis acidic B(C6F5)3 makes this adduct susceptible
toward selective electrophilic attack.
It was our hypothesis that we could utilize Lewis acidic boranes as an effective cata-
lyst in the activation of diazo compounds for a range of reactions as an alternative to
metal-catalyzed processes. Herein, we report the high regio- and diastereo-selec-
tive C–H insertion, cyclopropanation, and ring-opening reactions of a range of sub-
strates including indoles, benzofurans, indenes, pyrroles, styrenes, and furans under
mild conditions (Scheme 1B). In particular, we showcase that these reactions work
well on unprotected indoles contrary to many metal-catalyzed reactions, thereby
removing the requirement for additional reaction steps (protection and deprotec-
tion) in chemical synthesis. We also report the mechanisms of these reactions using
comprehensive DFT studies to fully understand both our observed regio- and
diastereoselectivity.
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Scheme 2. Scope of C–H Insertion of N-Heterocycles
Conditions: diazoester (1 equiv), indole/pyrrole (1.1 equiv), and B(C6F5)3 (10 mol %) in CH2Cl2 (1.5 mL) at 45ꢀC. Bottom right: solid-state structures of 2f
(left) and 2w (right). Thermal ellipsoids are drawn at 50% probability. H atoms omitted for clarity. All the yields reported are isolated yields.
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RESULTS AND DISCUSSION
a-Aryl a-diazoesters (1a–e, Scheme 2; Figures S1–S11) bearing electron-with-
drawing and electron-donating functional groups were initially prepared using stan-
dard literature procedures.30 Addition of fluorinated triarylboranes BArF (ArF
=
3
C6F5, 2,4,6-F3C6H2, or 3,4,5-F3C6H2) to 1 led to the rapid release of N2. As demon-
strated in our previous studies, as well as those by Stephan, under stoichiometric
conditions, the resulting carbene inserts into one of the B–C bonds, ultimately lead-
ing to a boron enolate.21,22c If, however, the loading of borane is reduced to 10 mol
%, then dimerization of the carbene is observed by 1H NMR spectroscopy and X-ray
diffraction. These promising results demonstrated that boranes can be used as a
catalyst to activate diazo-compounds and indicated that they could be used as an
alternative to metal carbenes as intermediates in the functionalization of various
organic compounds. This prompted us to explore the reactivity of a-aryl a-diazoest-
ers (1a–e) with various heterocycles, indenes, and styrenes catalyzed by boranes.
C–H Insertion, Cyclopropanation, and Ring-Opening
Indoles are ubiquitous in nature, possess many biological activities, and are common
motifs in many drugs and agrochemicals.31 As such, methods to modify indoles are
highly sought after. One method to achieve this is through a transition-metal-cata-
lyzed carbene transfer reaction to yield C3-substituted compounds.32 We therefore
decided to start our investigations into the borane-catalyzed carbene transfer reac-
tions using N-methylindole as the substrate in reactions with a-aryl a-diazoester 1a
(Scheme 1). Optimization of the reaction conditions (see Table S1) revealed that by
using 10 mol % of the borane B(C6F5)3, 84% yield of the C3-substituted product 2a
could be formed after 22 h in CH2Cl2 at 45ꢀC. Reducing the Lewis acidity by using
B(2,4,6-F3C6H2)3 as a catalyst afforded the desired product in 76% yield, whereas
B(3,4,5-F3C6H2)3 gave 56% isolated yield. Lowering the catalytic loading of
B(C6F5)3 to 5 mol % also led to full conversion albeit with longer reaction times of
32 h. Under the optimized reaction conditions (10 mol % B(C6F5)3, 45ꢀC, CH2Cl2),
various indoles and a-aryl a-diazoesters were investigated in the C–H insertion reac-
tion to give the C3-substituted indole as the sole product (Scheme 2). Indeed, deute-
rium-labeling studies using 1,2-dimethylindole-3-D or 1-methylindole-2-D with 1a
clearly revealed the reaction was proceeding through carbene insertion into the
C–H/D bond at the C3 position (see Figures S67–S76; Scheme S1). The influence
of the electron-donating or electron-withdrawing group attached to the aryl ring
of the a-aryl a-diazoester (1a–e) was investigated but appeared to have little effect
on the rate or yield of the reaction with products 2a–e (Figures S12–S22), displaying
excellent isolated yields from 75% to 85% when reacted with N-methylindole. Like-
wise, indole starting materials bearing substitution on the phenyl ring as well as at
the C2 position were tested including 1,2-dimethylindole, 5-bromo-1-methylindole,
and 1-methyl-2-phenylindole, which afforded the desired C–H insertion products
(2f–t, Figures S23–S55) in excellent yields (up to 90%).
When examining the previous literature, in almost all cases, the scope has been
limited to indoles where the N–H group is protected through alkylation or through
the use of a protecting group.33 Indeed, when metal catalysts such as rhodium are
used, then additional insertion into the N–H bond is often observed as an undesired
side reaction. One example where this has been overcome was reported in 2018
through the use of an engineered variant of myoglobin biocatalysts.34 We therefore
turned our attention to the reactivity of unprotected indoles with a-aryl a-diazoesters
1a–e. Formation of the desired products 2u–y was observed with very good isolated
yields of 60%–72% (Scheme 2; Figures S56–S66). Interestingly, this reaction was
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proved highly regio- and chemoselective with no N–H insertion being observed.
This borane could therefore serve as an alternative to metal catalysts for the selective
C–H insertion in the presence of an N–H group. This can reduce the number of steps
in chemical synthesis due to the reduced need to protect and deprotect the N-atom.
Suitable single crystals for X-ray diffraction of the products 2f and 2w were afforded
from the slow evaporation of a saturated CH2Cl2 solution at room temperature, con-
firming the structures of these products (Scheme 2, bottom; Figures S152 and S153;
Tables S2 and S3). When pyrroles were investigated in this reaction, C–H insertion
was also observed generating alkylation products as observed with transition metal
carbenoids.35 This time, exclusive C2-insertion resulted, consistent with typical elec-
trophilic substitution reactions of pyrroles.36 3a and 3b were generated in 65% and
68% yields, respectively, when 1c and 1e were reacted with N-methylpyrrole
(Scheme 2; Figures S77–S80). If the C2 position is blocked, then very little reaction
takes place, leaving the starting pyrrole as the major species in solution.
The encouraging outcome from the reactions of N-heterocycles with a-aryl a-diazoesters
increased our curiosity to investigate the borane-catalyzed reactions with other (hetero)
cycles including benzofurans and indenes. Again, B(C6F5)3 (10 mol %) was found to be
the best catalyst for these reactions with a single product being isolated after 20 h at
45ꢀC. The crude 1H NMR spectrum of the reaction of 1a with 2,3-benzofuran displayed
two doublets at d = 5.34 ppm and d = 3.79 ppm, indicating that the carbene had added
into the C2, C3 double bond of the benzofuran generating the cyclopropanated product
(Scheme 3). Cyclopropanes are key motifs in biologically active compounds with anti-
biotic, antimicrobial, antitumor, or antiviral activities.37 As above, the most common
way to make such compounds is the transfer of a carbene from a diazocarbonyl com-
pound (usually via a rhodium-carbenoid intermediate) to an olefin.38 Yet, intermolecular
diasteroselective cyclopropanation remains a challenge.39 Using the same optimized re-
action conditions, 2,3-benzofuran and 5-bromobenzofuran were tested for the reaction
with a-aryl a-diazoesters 1 (Scheme 3).The products 4a–f were isolated as a single dia-
stereoisomer in good yields (70%–76%, Scheme 3; Figures S81–S93). Indene also under-
went diastereoselective cyclopropanation with 1a–c and 1e yielding the products 5a–
d in 78%–92% yield (Scheme 3; Figures S94–S102). Slow evaporation of a saturated so-
lution of products 4a and 5c from CH2Cl2 afforded single crystals of the product, which
were measured by X-ray diffraction unambiguously confirming the structure and diaster-
eoselectivity of the reaction (Scheme 3; Figures S154 and S155; Tables S4 and S5).
In addition to cyclopropanation of benzofurans and indene, we also trialed the cyclo-
propanation of other olefins (Scheme 4). Initially, styrene was reacted with 1a, 1b,
and 1e under the same conditions described above. Of note, the products were ob-
tained as a single diastereoisomer 6a–c in 81%, 83%, and 70% isolated yields,
respectively (Scheme 4; Figures S103–S109 and S123–S125). Other 1-substituted
olefins also worked with 2-vinylnaphthalene, giving the product 6d in 78% yield (Fig-
ures S110, S111, and S126) when reacted with 1b. Both 1,1-disubstituted (terminal)
and 1,2-disubstituted (internal) olefins were also successful giving the products 6e–h
in 71%–77% yield (Scheme 4; Figures S112–S120, S127, and S128). Again, the 1,2-
disubstituted olefins displayed highly diastereoselective reactions. Importantly,
when trimethyl((2-vinylphenyl)ethynyl)silane was employed, we observed exclusive
reactivity at the alkene functionality and not the alkyne giving 6i (Figures S121,
S122, and S129) in 79% yield as a single diastereoisomer. Limitations of this reaction
were the non-aromatic cyclic olefins including cyclohexene and limonene.
Considering the differing selectivity between the C–H insertion product obtained for
indoles versus cyclopropanation products for indenes and benzofuran, we decided
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Scheme 3. Catalytic Cyclopropanation of Benzofurans and Indenes Using B(C6F5)3
Conditions: diazoester (1 equiv), benzofuran/indene (1.1 equiv), and B(C6F5)3 (10 mol %) in CH2Cl2
(1.5 mL) at 45ꢀC. All the yields reported are isolated yields. Bottom right: solid-state structures of 4a
(left) and 5c (right). Thermal ellipsoids are drawn at 50% probability. H atoms omitted for clarity.
to undertake several competition experiments to investigate the comparative rates
of reactions and selectivity between the different substrates (Figure S151). Using the
optimized reaction condition we performed three competition reactions (Scheme 5)
using equimolar mixture of (1) 1-methylindole and 2,3-benzofuran, (2) 1-methylin-
dole and 1H-indene, and (3) 2,3-benzofuran and 1H-indene with 1 equiv of diazo
compound 1b and 10 mol % B(C6F5)3. The progress of the reactions was monitored
by 1H NMR spectroscopy using mesitylene as an internal standard. Interestingly,
when indole was present, the exclusive formation of the C3 C–H insertion product
(2b) was observed showing 89% and 88% conversion after 22 h. In these cases,
the benzofuran and indene substrates remained untouched, showing no cyclopro-
panation products 4b and 5b, respectively. These results indicate that the indole
is far more reactive (nucleophilic) than the benzofuran and indene substrates.
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Scheme 4. Catalytic Cyclopropanation of Olefins Using B(C6F5)3
Conditions: diazoester (1 equiv), olefin (1.1 equiv), and B(C6F5)3 (10 mol %) in CH2Cl2 (1.5 mL) at
45ꢀC. All the yields reported are isolated yields.
Alternatively, when equimolar mixture of 2,3-benzofuran and 1H-indene were re-
acted with 1b, formation of both the cyclopropanation products 4b and 5b were
observed. In these cases, indene reacts faster than benzofuran, showing a 1:2.9 ratio
of 4b:5b after 22 h.
Finally, we turned our attention to the borane-catalyzed reactions of a-aryl a-diazo-
esters with furan substrates. Indeed, the synthesis and subsequent transformations
of furans is an important area of research.40 Recently, they have received attention
in the area of renewable biomass where the acid-catalyzed thermal dehydration of
sugars provides furan compounds, which may be used as convenient starting mate-
rials in organic synthesis.41 Compared with reactions that involve functionalization of
the furan heterocycle keeping the five membered ring intact, ring-opening reactions
have been less studied42 although recently B(C6F5)3 was shown to be an excellent
catalyst for the tandem ring-opening and hydrosilylation of furans to obtain sili-
con-functionalized products.43 We therefore sought to investigate the tandem
borane-catalyzed carbene transfer and ring-opening reactions of furans. Initially,
1a was reacted with furan in the presence of a Lewis acidic borane catalyst (10 mol
%) generating a single ring-opened product 7a (Scheme 6; Figures S130–S132).
Again, reaction optimization showed that mild conditions (45ꢀC in CH2Cl2) were
needed for the reaction to complete, but in this case, the less Lewis acidic borane
2,4,6-trifluorophenylborane [B(2,4,6-F3C6H2)3] was found to be a better catalyst
than B(C6F5)3, giving 61% yield of the product 7a compared with 52%. We then
extended the scope of the reaction to 2-methylfuran and 2,5-dimethylfuran with
a-aryl a-diazoesters 1 to generate the products 7b–i in 64%–82% yields (Scheme
6; Figures S133–S150). In all cases, just a single diastereoisomer was generated,
which could also be confirmed by single-crystal X-ray diffraction analysis for com-
pounds 7a and 7h (Scheme 6, bottom, Figures S156 and S157; Tables S6 and S7).
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Scheme 5. Competition Reactions between Indole, Benzofuran, and Indene
Conditions: diazoester 1b (1 equiv), (hetero)cycle (1 equiv each), and B(C6F5)3 (10 mol %) in CH2Cl2
(1.5 mL) at 45ꢀC. All the yields reported are NMR yields using mesitylene as an internal standard.
Computational Studies
To examine the contrasting products obtained for indole, indene, benzofuran, sty-
rene, pyrrole, and furan-based moieties, we undertook a thorough DFT investigation
of all the potential reaction pathways. We focused upon the driving force for the C–H
insertion product obtained for pyrroles and indoles versus the cyclopropanation
products for styrenes, indenes, and benzofurans versus the ring-opened products
for furans. Calculations were performed at the SMD/M06-2X-D3/def2-TZVP//
CPCM/B3LYP/6-31G(d) level of theory to examine the origin of the contrasting prod-
ucts (Tables S8–S63). Regardless of the substrate, the first step in the reaction is the
same, namely B(C6F5)3 activation of the diazo reagent (Scheme 7, see Figure S158
for the free energy profile). It transpires that formation of species I2 (Scheme 7) is
a prerequisite for all pathways. This can be obtained when B(C6F5)3 binds effectively
with the carbonyl oxygen atom of the diazoester starting material 1 to form interme-
diate I1, as seen in our previous studies.21 The B(C6F5)3 coordination results in the C–
N bond in I1 becoming weaker than that in starting material 1, thereby making N2 a
better leaving group. The weakening of the C–N bond is ascribed to the increased
contribution of the resonance structure I10, as evidenced by the lengthening of the
˚
˚
C–N bond (1.334 A in I1 versus 1.318 A in 1) as well as the shortening of the C–C
˚
˚
bond (1.436 A in I1 versus 1.470 A in 1) (see Figure S158). This facilitates the release
of N2, yielding the key species I2 with an energy barrier of 25 kcal/mol (TS2 in Fig-
ure S158).29 Two resonance structures of I2 (I20 and I200) describe the structure and
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Scheme 6. Catalytic Ring-Opening of Furans
Conditions: diazoester (1 equiv), furan (1.1 equiv), and B(2,4,6-F3C6H2)3 (10 mol %) in CH2Cl2
(1.5 mL) at 45ꢀC. All the yields reported are isolated yields. Bottom: solid-state structures of 7a (left)
and 7h (right). Thermal ellipsoids drawn at 50% probability. H atoms omitted for clarity.
bonding of this key intermediate. This is confirmed by the fact that the C–C bond in
˚
˚
I2 (1.392 A) is significantly shorter than that in I1 (1.436 A) and starting diazo com-
˚
pound 1 (1.470 A). Furthermore, species I2 is highly electron deficient, leading to
its ability to readily react with nucleophiles in an appreciably exergonic fashion giv-
ing intermediates I3a–f (Scheme 7), which then proceed to generate the C–H inser-
tion, cyclopropanated, or ring-opened products. Owing to the electron-deficient
nature of I2, any transition structure for the addition of (hetero)cycles to I2 was diffi-
cult to locate. It should be noted that attempts to locate an associative transition
structure in which a (hetero)cycle serves as a nucleophile and attacks intermediate
I1 were unsuccessful. On the basis of our calculations, this step is energetically highly
favorable, a result which is in agreement with the previous reports by Wu et al.29
At the heart of the contradistinct reactivity between the different nucleophiles is the
competition between forming the cyclopropanation product (P1) versus the C–H
insertion product (P2), or the ring-opened product (P3). Once intermediate I3
(Scheme 7) is formed, it is the branching point for the three different processes:
(1) C–H insertion, (2) ring-opening, and (3) cyclopropanation. The nature of the
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Scheme 7. DFT-Calculated Activation of Diazo Substrates by B(C6F5)3
˚
Bond lengths measured in A.
(hetero)cycles plays the most important role as to which pathway is taken. For all
(hetero)cycles, the cyclopropanation occurs with a much lower barrier than the other
two pathways. This suggests that the cyclopropanated species should be the first
Figure 1. DFT Computed Reaction Pathways for the Reaction of Indole Substrates with
Diazoesters and B(C6F5)3
The relative free energies are given in kcal/mol.
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Figure 2. DFT Computed Reaction Pathways for Benzofuran with Diazoesters and B(C6F5)3
The relative free energies are given in kcal/mol.
kinetic product in all cases. In addition, for all (hetero)cycles, the product obtained
from the C–H insertion pathway is more stable than that obtained from the other
two pathways. In other words, the C–H insertion reaction produces the thermody-
namic product. When examining the reactions of I2 with nucleophiles, for several
cases (furan, benzofuran, indole, indene, and styrene), we were unable to locate I3
as a minimum. This is mainly because the p-donor ability of the -OMe and
-OB(C6F5)3 substituents increase the nucleophilicity of the C=C p-bond in the eno-
late functionality of I3, greatly favoring the C–C coupling process to give the kinetic
cyclopropanated products P1.
Initially, we investigated all possible reaction pathways with indole at the C3 position,
with I2 (Figure 1) assisted by an adventitious (catalytic) water molecule for the C–H inser-
tion pathway. The calculations for indole indicate that once I3a is formed, it can be imme-
diately transformed into cyclopropanated product P1. This product is not stable enough
to remain intact and thus undergoes a reverse transformation to furnish the thermody-
namic C–H insertion product P2 via sequence P1/I3/I4/P2 with an activation barrier
of 15.1 kcal/mol. The strong p-donor ability of the nitrogen atom in the indole signifi-
cantly stabilizes the carbocation center in I3a, resulting in it being unable to form a stable
cyclopropanated product. Alternatively, reaction at the indole C2 position with I2 (see
Figure S159) gives the C–H insertion product with a transition structure that lies
11.7 kcal/mol higher in energy than that for the C3-product. This explains why only
C3 products are observed experimentally for indoles. Indeed, the higher stability of
I3a for the C3-addition product with respect to I3a’ for the C2-addition product forces
the reaction preferentially to yield the C3 products. For indoles, I3a is not able to enter
the ring-opening channel to give P3 due to an extremely endergonic reaction owing to
the disruption of the aromaticity of the heterocycle.
For benzofuran, we similarly compared the relative free energy of all the stationary
points for the three possible pathways: C–H insertion, cyclopropanation, and
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Figure 3. Energy Profiles for the Different Diastereoisomers of the Reaction
Computed reaction pathways for the two possible diastereoisomers for the reaction of diazoesters
with benzofuran-catalyzed B(C6F5)3. The relative free energies are given in kcal/mol.
ring-opening (Figure 2). In this case, the first kinetic cyclopropanated product P1 is
so stable that it does not allow the thermodynamic C–H insertion product P2 to be
formed under the reaction conditions; starting from the cyclopropanated product
P1, formation of the thermodynamic C–H insertion product P2 would need to cross
a very high barrier of 32.6 kcal/mol. Similar to indoles, benzofuran is also unreactive
toward the ring-opening process because of the disruption of the aromaticity of the
six-membered ring in the ring-opened product P3. The same result is observed for
indene and styrene substrates (see Figures S160 and S161) in that the reaction be-
tween the indene or styrene nucleophiles with I2 immediately gives the kinetic cyclo-
propanated product P1 (Figure S163). As with benzofuran, these kinetic products are
too stable to undergo the reverse transformation to afford the thermodynamic C–H
insertion product P2.
We also undertook calculations to explain our observed diastereoselectivity for the
cyclopropanation reactions with benzofurans, indenes, and styrenes. Using benzo-
furan as an example, we found that TSI3-P1(BCF) lies 4.0 kcal/mol lower in energy
than TSI3-P1(BCF)’ and that P1 is thermodynamically more stable than P1’ (Figure 3).
This is presumably because of the reduced steric hindrance in TSI3-P1(BCF) brought
about by the sterically demanding B(C6F5)3 moiety.
Finally, we turned our attention to explaining the contradistinct reactivity of the 5-
membered heterocycles pyrrole and furan that give the C2 C–H insertion and ring-
opened products, respectively. For pyrrole, the energy profile (Figure 4, top)
related to competition between the three pathways indicates that although the
pathways leading to cyclopropanated P1 and ring-opening products P3 are kinet-
ically favored over the C–H insertion pathway, they are not stable thermodynami-
cally; both P1 and P3 energetically lie above I3e. In contrast, the C–H insertion
pathway starting from I3e assisted by an adventitious water molecule by surmount-
ing an activation barrier of 22.8 kcal/mol gives P2 with DGrxn = ꢁ17.5 kcal/mol. The
calculations predict that the presence of an adventitious water molecule is
required as a catalyst for the C–H insertion pathway to occur with an accessible
activation barrier. The direct proton transfers are found to be more energy
demanding with DGz > 30 kcal/mol (see Figure S162). Finally, we calculated the
three possible pathways for the case of furan (Figure 4, bottom). For this hetero-
cycle, the first kinetic product (cyclopropanation, P1) is about 7.7 kcal/mol higher
in energy than the second kinetic product (ring-opening, P3), and thus, the former
can be converted to the latter through a reverse transformation by overcoming an
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Figure 4. DFT Computed Reaction Pathways for Pyrrole and Furan Substrates with Diazoesters and B(C6F5)3
The reaction of pyrrole substrates (top) and furan substrates (bottom). The relative free energies are given in kcal/mol.
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activation free energy of 6.6 kcal/mol (energy difference between P1 and TSI3-P3).
In this case, formation of the thermodynamic C–H insertion product P2 requires
surmounting a free energy barrier of 32.1 kcal/mol (energy difference between
P3 and TSI3-I4), which is too high to be attainable under the reaction conditions.
This result rationalizes why for furan, only the ring-opening product is experimen-
tally observed. Furan is more reactive than pyrrole toward ring-opening, likely due
to a higher preference for a carbon atom to form a p-bond with oxygen than with a
nitrogen atom in the reaction.
Conclusions
In conclusion, we have shown that Lewis-acidic-fluorinated triarylboranes can be
used as effective metal-free catalysts for highly selective reactions of donor-
acceptor diazo compounds to a range of substrates. The reactions of a-aryl a-di-
azoesters with the nitrogen heterocycles indole or pyrrole selectively generate
the C3 and C2 C–H insertion products, respectively, in good to excellent yields
even when using unprotected indoles. Alternatively, benzofuran, indene, and
olefin substrates give exclusively the cyclopropanated products with a-aryl a-di-
azoesters, whereas the reactions with furans lead to ring-opening with C=C
bond formation. DFT calculations have been employed to understand the reaction
mechanisms as well as the differing regio- and diastereoselectivities of the sub-
strates. Overall, this work demonstrates the highly selective metal-free catalytic
reactions of a-aryl a-diazoesters with a range of (hetero)cycles and olefins. This
simple, mild reaction protocol represents an alternative to the commonly used
precious metal systems and may provide future applications in the generation of
biologically active compounds.
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, Rebecca Melen (MelenR@cardiff.ac.uk).
Materials Availability
Unique and stable reagents generated in this study will be made available on
request, but we may require a payment and/or a completed Materials Transfer
Agreement if there is potential for commercial application.
Data and Code Availability
Crystallographic data for 2f, 2w, 4a, 5c, 7a, and 7h have been deposited in the Cam-
bridge Crystallographic Data Center (CCDC) under accession numbers CCDC:
1940993, 1939757, 1939753, 1939756, 1939754, and 1939755. These data can be
obtained free of charge from the CCDC at http://www.ccdc.cam.ac.uk/
data_request/cif. Information about the data that underpins the results presented
in this article, including how to access them, can be found in the Cardiff University
data catalog at http://doi.org/10.17035/d.2020.0111365980. All other data are
available from the Lead Contact upon reasonable request.
Representative Procedure for Boron-Catalyzed Reactions
Under a nitrogen atmosphere, the triarylborane (10 mol %) was dissolved in CH2Cl2
(0.5 mL) and added to a CH2Cl2 solution (0.5 mL) of diazoester 1 (0.2 mmol, 1 equiv).
The heteroarene/indene/alkene substrate (0.22 mmol, 1.1 equiv) in CH2Cl2 (0.5 mL)
was then added to the reaction mixture dropwise. The reaction was heated at 45ꢀC
for 18–24 h before all volatiles were removed in vacuo and the crude compound
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purified via column chromatography on silica using hexane/ethyl acetate as eluent.
Full experimental procedures are provided in the Supplemental Information.
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2020.06.035.
ACKNOWLEDGMENTS
We are grateful to the EPSRC (B.S., EP/L000202) and (A.D., EP/R026912/1) for fund-
ing and the awarding of an EPSRC Early Career Fellowship (R.L.M., EP/R026912/1).
A.A., B.F.Y., and R.B. thank the Australian Research Council (ARC) for project fund-
ing (DP180100904) and the Australian National Computational Infrastructure and
the University of Tasmania for the generous allocation of computing time. The au-
thors would also like to acknowledge Dasara Hadri for performing preliminary calcu-
lations into the reaction mechanisms.
AUTHOR CONTRIBUTIONS
A.D. designed the project and performed all of the experimental work. R.B., B.F.Y.,
B.S., and A.A. undertook all the DFT calculations. R.L.M. directed the project. R.L.M.
wrote the manuscript with input from all authors. All authors analyzed the results and
commented on the manuscript.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: February 24, 2020
Revised: May 22, 2020
Accepted: June 25, 2020
Published: July 22, 2020
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