Triarylborane-Catalyzed Alkenylation Reactions of Aryl Esters with Diazo Compounds

Article abstract of DOI:10.1002/anie.202007176

Herein we report a facile, mild reaction protocol to form carbon–carbon bonds in the absence of transition metal catalysts. We demonstrate the metal-free alkenylation reactions of aryl esters with α-diazoesters to give highly functionalized enyne products. Catalytic amounts of tris(pentafluorophenyl)borane (10–20 mol %) are employed to afford the C=C coupled products (31 examples) in good to excellent yields (36–87 %). DFT studies were used to elucidate the mechanism for this alkenylation reaction.

Full text of DOI:10.1002/anie.202007176

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Accepted Article
Title: Triarylborane Catalysed Alkenylation Reaction of Aryl Esters with
Diazo-Compounds
Authors: Ayan Dasgupta, Katarína Stefkova, Rasool Babaahmadi,
Lukas Gierlichs, Alireza Ariafard, and Rebecca Melen
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202007176
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10.1002/anie.202007176
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Triarylborane Catalyzed Alkenylation Reaction of Aryl Esters with
Diazo-Compounds
Ayan Dasgupta+, Katarína Stefkova+, Rasool Babaahmadi, Lukas Gierlichs, Alireza Ariafard*, and
Rebecca L. Melen*
Abstract: Herein we report a facile, mild reaction protocol to form
carbon-carbon bonds in the absence of transition metal catalysts. We
demonstrate the metal-free alkenylation reactions of aryl esters with
α-diazoesters to give highly functionalized enyne products. Catalytic
amounts of tris(pentafluorophenyl)borane (10–20 mol%) are
employed to afford the C=C coupled products (31 examples) in good
to excellent yields (36–87%). DFT studies have been undertaken to
elucidate the mechanism for this alkenylation reaction.
Diazo compounds have found a multitude of applications in
synthetic chemistry and are versatile intermediates that can
rapidly functionalize organic compounds in a single step.[1,2] In
particular, diazo compounds and N-tosylhydrazones (diazo
precursors) have attracted much attention as carbonyl
equivalents in the construction of carbon-carbon double bonds.[3]
Transition metal catalysts, such as palladium, are typically used
in reactions with diazo compounds to synthesize C=C bonds.[4]
Two mechanistic approaches are generally accepted being (i)
migratory insertion of a palladium carbene species (generated
from the diazo compound) followed by β-hydride elimination, or
(ii) nucleophilic attack of a diazo compound on a transition metal–
carbene species followed by β-elimination (Figure 1a). More
recently, more abundant first row metals such as copper or iron
have been employed with diazo-compounds.[ 5 , 6 ] Of particular
Figure 1. General representation of benzylic alkenylation.
relevance is the recent report of FeCl2 catalyzed alkenylation of
benzylic C(sp3)–H bonds with diazoesters in the presence of an
oxidant (Figure 1b). Nonetheless, metal-free approaches are
comparatively rare. In 2015, the first transition metal free gem-
difluoroolefination of diazo acetates with difluorocarbene reagents
was reported (Figure 1c).[7] Herein we investigate the alkenylation
of benzylic sp3 centers using tris(pentafluorophenyl)borane
[B(C6F5)3] as the catalyst (Figure 1d) as a new route to generate
conjugated organic compounds. Over the past decade the use of
B(C6F5)3 and related triarylboranes have grown in popularity as
catalysts for a range of transformations.[8] Importantly, the ester
substituted enyne and diene products generated in the reaction
are usually made by metal catalyzed Sonogashira cross-coupling
reactions.[9] These compounds are common starting materials for
the synthesis of heterocycles such as pyran-2-ones through a
simple metal- or borane- catalyzed cyclization reaction.[10,11]
Such pyran-2-ones are omnipresent in many bioactive natural
products which display inter alia antimicrobial, anti-HIV, and
antitumor activity.[12]
Initially, we reacted dimethyl 2-diazomalonate (1a) with 1-(4-
fluorophenyl)-3-(trimethylsilyl)prop-2-yn-1-yl-4-fluorobenzoate
(2a) in a 1:1.1 ratio in trifluorotoluene (TFT) solvent (Table 1). In
the absence of a borane catalyst no reaction occurred after 22 h
at 65 °C (Table 1, entry 1). However, the addition of 20 mol% of
a fluorinated triarylborane resulted in loss of N2 from 1a and the
benzylic alkenylation of the aryl-alkynyl ester 2a with loss of 4-
fluorobenzoic acid to generate the C=C coupled enyne product
dimethyl
2-(1-(4-fluorophenyl)-3-(trimethylsilyl)prop-2-yn-1-
ylidene) malonate (3a). A range of borane catalysts were trialed
in the reaction including B(2,4,6-F3C6H2)3, B(3,4,5-F3C6H2)3, and
B(C6F5)3 giving the product in 41%, 25%, and 78% isolated yields
respectively when using a 20 mol% catalyst loading (Table 1,
entries 2–4). Other Lewis acids such as BF3·OEt2 on the other
hand, showed no conversion after 18 h at 65 °C (Table 1, entry
5). Likewise, the Brønsted acid, PTSA (p-toluenesulfonic acid),
also gave no desired product (Table 1, entry 6). A reduction in
catalytic loading to 10 mol% still gave the product in high yields
(81% after 22 h) whereas reducing the catalytic loading further to
5 mol% resulted in just 42% yield after 22 h (Table 1, entries 7–
8).
[a] Dr. A. Dasgupta, K. Stefkova, L. Gierlichs, Dr. R. L. Melen,
Cardiff Catalysis Institute, School of Chemistry, Cardiff University, Main
Building, Park Place, Cardiff, CF10 3AT, Cymru/Wales, United Kingdom
E-mail: MelenR@cardiff.ac.uk
+Authors contributed equally
[b] R. Babaahmadi, Prof. A. Ariafard, School of Natural Sciences-Chemistry,
University of Tasmania Private Bag 75, Hobart, Tasmania 7001, Australia.
E-mail: alirezaa@utas.edu.au
Supporting information can be found under https://doi.org/xxx. 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 catalogue
at under: http://doixxxx.
1
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10.1002/anie.202007176
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Table 1. Optimization of conditions for the alkenylation reactions of α-diazoester
1a with aryl ester 2a.
Catalytic
loading
(mol%)
Temperature Time Yield
Entry
BAr3
Solvent
(°C)
(h) (%)[a]
1
2
No Catalyst
B(C6F5)3
-
TFT
TFT
65
65
22
18
-
20
78
B(2,4,6-
F3C6H2)3
B(3,4,5-
F3C6H2)3
3
4
20
20
TFT
TFT
65
65
18
18
41
25
5
6
BF3·OEt
PTSA
20
10
10
5
TFT
TFT
65
65
18
22
22
22
22
22
48
22
22
22
22
-
-
7
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
TFT
65
81
42
48
30
30
68
52
45
-
8
TFT
65
9
10
5
TFT
100
100
RT
65
10
11
12
13
14
15
TFT
20
10
10
10
10
TFT
Toluene
CH2Cl2
Hexane
THF
65
65
65
[a] Isolated yield.
Elevating the temperature to 100 °C using 10 and 5 mol%
B(C6F5)3 resulted in side-products and reduced isolated yields of
the product 3a, while reducing the temperature to room
temperature also gave lower yields when using 20 mol% B(C6F5)3
(Table 1, entries 9–11). TFT was found to be the best solvent for
the reaction whereas toluene, dichloromethane, and hexane
showed reduced yield of the product, and THF resulted in no
desired product being formed (Table 1, entries 12–15). Finally, we
investigated the effect of different leaving groups on the ester (R1,
t
table 1 scheme) including 4-FC6H4, CF3, Me, Ph, and Bu. The
t
reaction proceeded in all cases except when R = Bu. However,
the rate of reaction was faster with electron withdrawing groups
therefore we opted to use esters 2 where R1 = 4-FC6H4 or CF3.
Using the optimized conditions (10 mol% B(C6F5)3, 65 °C, 18–
22 h, TFT solvent) the scope of the reaction was investigated.
Reactions of a variety of 2-diazomalonates (1a–c) with aryl-
alkynyl esters (2a–g) yielded the products 3a–n in good to very
good isolated yields (63–87%) (Scheme 1). The reaction worked
well with several symmetrical diazoesters 1 as well as p-F, p-Cl,
p-Br and p-CF3 substituents on the aryl group of the aryl-alkynyl
ester 2. In addition, trimethylsilyl (TMS) and phenyl substituents
could be tolerated on the alkyne functionality of 2. Electron
releasing (p-OMe) or strongly electron withdrawing (2,6-F) on the
aryl group of 2h and 2i were unsuccessful giving a complex
mixture of inseparable products. Likewise, the reaction with di-
tert-butyl 2-diazomalonate (1d) was unsuccessful showing only
decomposition of the diazo compound. Single crystals of 3a and
3n suitable for X-ray diffraction could be grown from slow
evaporation of a saturated CH2Cl2 solution (Figure 2).
isolated in lower yields (36–46%) than those obtained for the
symmetrical diazoesters.
Scheme 1. Propargylic alkenylation of aryl-alkynyl and aryl-alkenyl esters using
diazomalonates. Insert shows the synthesis of by-products 4a and 4b. [a] Yield
of by-product formed in the synthesis of 3o. [b] Yield of by-product formed in the
synthesis of 3q. [c] Yield of by-product formed in the synthesis of 3p.
We further examined the scope of this methodology in
reactions with the unsymmetrical α-aryl-diazoesters methyl 2-(4-
chlorophenyl)-2-diazoacetate (1e) and methyl 2-diazo-2-
phenylacetate (1f) with 2a and 2e. The products 3o–q were all
2
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Figure 2. Solid-state structure of compound 3a (left) and 3n (right). Thermal
ellipsoids drawn at 50% probability. Carbon: black; oxygen: red; fluorine: green;
silicon: yellow.
fluorobenzoate (2p). In this case no reaction had occurred even
after 32 h. Compound 6e was crystallized by vapor diffusion using
CH2Cl2/hexane as solvents and the crystals were measured by X-
ray diffraction (Figure 3).
The products were all formed in a 1:0.4 ratio (E:Z) of
diastereoisomers as determined by 1H NMR spectroscopy of the
crude reaction mixture. One reason for the reduced yield of the
C=C coupled product was the observation that a new by-product
4a–b was formed in an approximate 1:1 ratio with the desired
product 3. We attribute the generation of the by-product to the
increased reactivity of the α-aryl-diazoesters 1e and 1f which
rapidly react with the 4-fluorobenzoic acid (5) generated in the
reaction.
diphenyldiazomethane
It
should
be
only
noted
homo-coupling
that
when
of
using
the
Figure 3. Solid-state structure of compound 6e. Thermal ellipsoids drawn at
50% probability. Carbon: black; oxygen: red.
diazocompound was observed. Reactions with an aryl-alkenyl
ester 2j also proved possible generating the diene products 3r
and 3s in 71% and 77% yields respectively.
Based upon literature precedent, we believe there are two
possibilities for substrate activation by the borane catalyst either
(i) activation of the carbonyl group on the ester 2 resulting in the
generation of a carbenium ion[10] or, (ii) activation of the diazo
compounds 1 by the borane.[13,14] In order to determine which
pathway is operating, and to investigate the entire reaction
mechanism, we undertook DFT calculations at the SMD/M06-2X-
D3/def2-TZVP//CPCM/ B3LYP/6-31G(d) level of theory using
toluene as the solvent. Figure 4 shows the catalytic cycle
proposed by the DFT calculations into the reaction pathway
shown in Figure 5. It was found that coordination of the borane to
the ester 2 was the initial step of the reaction to give the adduct
I1 via a low energy transition state (TS1) of 3.6 kcal mol-1. This
was calculated to be a lower energy pathway by 13.0 kcal mol-1
than coordination of the borane to the diazo compound, a
transformation which is computed to be endergonic by about 13.6
kcal mol-1 (Figure S144). I1 was found to have an elongated C–O
bond length of 1.502 Å, which results in bond cleavage and the
generation of an electrophilic carbenium ion in salt I2 occurring
with an activation barrier of 13.4 kcal mol-1 through TS2. The
generation of the carbenium ion corroborates the observation that
esters less able to stabilize a positive charge such as 2p were
unsuccessful in these reactions. I2 exists as a close ion pair and
reacts with the diazo substrate 1 as a nucleophile via TS3
(activation barrier 13.8 kcal mol-1) to give the salt I3. The reaction
between I2 and 1 result in the C–N π-bond in the diazo substrate
being interrupted, evidenced by the elongated C–N bond in I3.
The resultant intermediate (I3) also exists as a close ion pair with
a short O–H contact (1.945 Å).
Scheme 2. Benzylic alkenylation of diaryl esters using diazomalonates.
The satisfactory outcome from these reactions led us to
extend our work to demonstrate a broader substrate scope for this
protocol. Rather than alkynyl or alkenyl esters, diaryl esters were
examined for the alkenylation reactions. Using the optimized
reaction conditions, diaryl esters 2k–o reacted with diazoesters
1a–c to afford the C=C bonded products 6a–l in good to excellent
yields of 67–87% (Scheme 2). These reactions proved successful
with symmetrical diaryl esters containing both electron-
withdrawing (p-F) and electron-donating (p-OMe) functionalities
on the aryl ring. In addition, these reactions were also possible
using asymmetrical diaryl esters 2n and 2o.
Limitations included the reaction of esters bearing a
cyclohexyl group such as cyclohexyl(phenyl)methyl 4-
3
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highly functionalized C=C bonded products in the absence of a
metal catalyst. B(C6F5)3 was found to be the most effective
catalyst for the reaction giving the C–C bonded product in good
to excellent yields. Comprehensive DFT studies have been used
to elucidate the reaction mechanism which highlight that the key
role of the catalyst is to activate the aryl ester rather than the
diazomalonate. Importantly, this simple reaction allows complex
ester substituted enyne and diene products to be generated in a
single step. Notably, the products generated are essential
precursors to prepare biologically active heterocyclic molecules.
Acknowledgements
A.D., K.S., and R.L.M. would like to acknowledge the EPSRC for
an Early Career Fellowship for funding (EP/R026912/1). A.A. and
R.B. thank the Australian Research Council (ARC) for project
funding (DP18000904), and the Australian National
Computational Infrastructure and the University of Tasmania for
the generous allocation of computing time
Keywords: alkenylation • diazoester • metal-free catalysis •
Figure 4. Catalytic cycle proposed by DFT calculations.
Figure 5. DFT calculated free energy profile for the reaction. The relative free energies are given in kcal mol-1 and the selected bond distances (in pink) in Å.
Finally, an E2-type elimination reaction through TS4 with an
activation barrier as low as 3.7 kcal mol-1 releases dinitrogen and
4-fluorobenzoic acid (5) as a borane adduct to generate the C=C
double bonded product 3.
tris(pentafluorophenyl)borane
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5
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2 Become 1: Lewis acidic
A. Dasgupta, K. Stefkova, R.
Babaahmadi, L. Gierlichs, A.
Ariafard*, and R. L. Melen*
boranes are employed in the
metal-free
alkenylation
reactions of aryl esters with α-
diazoesters to give highly
functionalized alkene, enyne
and diene products in good to
excellent yields. DFT studies
Page No. – Page No.
Triarylborane Catalysed
Alkenylation Reaction of
Aryl Esters with Diazo-
Compounds
have
elucidated
the
mechanism for the reaction.
6
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