Direct Transformation of Esters into Arenes with 1,5-Bifunctional Organomagnesium Reagents

Article abstract of DOI:10.1002/anie.201505414

A direct transformation of carboxylic acid esters into arenes with 1,5-bifunctional organomagnesium reagents is described. This efficient and practical method enables the one-step defunctionalization of various carboxylic acid esters to prepare benzene, anthracene, tetracene, and pentacene derivatives. A double nucleophilic addition of the 1,5-organodimagnesium reagent to the ester is followed by an immediate 1,4-elimination reaction that leads to the direct [5+1] formation of a new aromatic ring.

Full text of DOI:10.1002/anie.201505414

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201505414
German Edition: DOI: 10.1002/ange.201505414
Organomagnesium Reagents
Direct Transformation of Esters into Arenes with 1,5-Bifunctional
Organomagnesium Reagents
Achim Link, Christian Fischer, and Christof Sparr*
Dedicated to Professor Steven V. Ley on the occasion of his 70th birthday
Abstract: A direct transformation of carboxylic acid esters into
arenes with 1,5-bifunctional organomagnesium reagents is
described. This efficient and practical method enables the one-
step defunctionalization of various carboxylic acid esters to
prepare benzene, anthracene, tetracene, and pentacene deriv-
atives. A double nucleophilic addition of the 1,5-organo-
dimagnesium reagent to the ester is followed by an immediate
1,4-elimination reaction that leads to the direct [5+1] forma-
tion of a new aromatic ring.
O
rganomagnesium reagents have an ideal reactivity for
carbon–carbon bond forming reactions, as is evident from the
enduring relevance of Grignard chemistry.[1] In recent years,
we have experienced a dramatic improvement in the acces-
sibility of organomagnesium compounds by the emergence of
mild halogen–metal exchange methods. Seminal studies by
Knochel and co-workers have shown that Grignard reagents
bearing various reactive functional groups can be readily
prepared and utilized.[2] Compared to the insertion of
Scheme 1. a) Double halogen–metal exchange to form (1Z,4Z)-1,5-
dimetalla-1,4-pentadiene 3. b) Direct transformation of carboxylic acid
ester 4 into arene 6 through the double addition of (1Z,4Z)-1,5-
dimetalla-1,4-pentadiene 3 followed by a 1,4-elimination.
À
elemental magnesium into the C X bond, these exchange
An analogous [5+1]-formation of an aromatic ring with
known methods would require several stages and harsh
reaction conditions.[5] Given the high availability of carboxylic
acid esters, a mild one-step process would give expedient
access to compounds typically prepared by transition-metal-
catalyzed cross-coupling reactions from complementary sub-
strates.[6] Intrigued by this prospect, we evaluated the
feasibility of a direct conversion of esters into arenes with
1,5-bifunctional organomagnesium compounds.
We started our investigations with the development of
a concise synthesis of (1Z,4Z)-1,5-diiodopenta-1,4-diene (1a)
from readily available starting materials (Scheme 2).[7] Two
equivalents of ethynylmagnesium bromide (7) were added to
ethyl formate (8), followed by diiodination with N-iodo-
succinimide. The subsequent (Z)-selective double alkyne
reduction with diimide and a trifluoroacetic acid mediated
dehydroxylation with triethylsilane provided (1Z,4Z)-1,5-
diiodopenta-1,4-diene (1a) in 41% yield over four steps.[8]
reactions are characterized by an exceptional range of
applications. For instance, Oshima et al. and researchers at
Banyu Pharmaceuticals have reported on the highly efficient
conversion of (Z)-alkenyliodides without chelating groups to
form the corresponding alkenylmagnesium compounds by
using lithium trialkylmagnesates (R3MgLi).[3] These magne-
siations proceed with complete retention of double-bond
configuration and without undesired elimination reactions.
Considering this remarkable advancement, we anticipated
the development of new synthetic methods based on bifunc-
tional organomagnesium compounds resulting from a double
halogen–metal exchange.[4] A stereospecific double halogen–
metal exchange of (1Z,4Z)-1,5-dihalopenta-1,4-diene 1 with
an exchange reagent 2 would lead to a 1,5-bifunctional
organomagnesium reagent 3 (Scheme 1a). A subsequent
double nucleophilic addition of reagent 3 to carboxylic acid
ester 4 generates cyclohexa-2,5-dienolate 5, which is directly
transformed into an arene by means of a 1,4-elimination
reaction (Scheme 1b).
[*] A. Link, C. Fischer, Dr. C. Sparr
Department of Chemistry, University of Basel
St. Johanns-Ring 19, 4056 Basel (Switzerland)
E-mail: christof.sparr@unibas.ch
Scheme 2. Synthesis of (1Z,4Z)-1,5-diiodopenta-1,4-diene 1a. a) THF,
Homepage: http://www.chemie.unibas.ch/~sparr
=
RT; b) N-Iodosuccinimide, AgNO3, acetone, RT; c) KO2CN NCO2K,
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201505414.
pyridine, AcOH, MeOH, RT, then aqueous HCl; d) Et3SiH, CF3CO2H,
CH2Cl2, 08C; 41% over four steps.
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Table 1: In situ generation of reagent 3[a] and optimization of the reaction
and 5 versus entry 3). A marked improvement in yield was
obtained after optimizing the reaction time and temperature,
and subsequent reactions were carried out for 2 h at À208C.
The best results were obtained by the immediate use of the
in situ prepared reagent 3a and a compensation of decom-
position pathways with an excess of the reagent (Table 1,
entries 9 and 10 versus entry 7).
parameters for the direct ester to arene transformation.[b]
With the optimized reaction conditions in hand, we
explored the substrate scope of the direct transformation of
carboxylic acid esters into benzenes (Table 2). A comparable
outcome was obtained with substrates bearing electron-
withdrawing groups, whereas the lower reactivity of ester
substrates with electron-donating groups was evident from
a lower yield (Table 2, entry 1 versus entries 2–4). Nonethe-
less, phenyl-substituted heterocyclic compounds could be
prepared in synthetically meaningful yields (Table 2, entries 5
and 6). Even alkyl and alkenyl esters were amenable to form
the corresponding benzene derivatives 6g and 6h, thus
highlighting the broad applicability of the method (Table 2,
entries 7 and 8). Furthermore, when using an additional
equivalent of reagent 3a, even a protic substrate was tolerated
and efficiently converted into the corresponding benzene
derivative 6i (Table 2, entry 9, 80%).
Entry
X–M Exchange Reagent (2)
T [8C]
t
Yield [%][c]
1
2
3
4
5
6
7
8
9
10
nBuLi[d]
À40
0
2 h
30 min
30 min
30 min
30 min
30 min
2 h
2 h
2 h
2 h
46
70
70
64
56
69
82
61
70
73
iPrnBu2MgLi[e]
iPrnBu2MgLi
nBu3MgLi
0
0
0
sBunBu2MgLi
iPrnBu2MgLi
iPrnBu2MgLi
iPrnBu2MgLi
iPrnBu2MgLi[f]
iPrnBu2MgLi[g]
À20
À20
À40
À20
À20
[a] Reactions performed with 200 mmol 1a and 200 mmol 2 for 5 min at T.
[b] 100 mmol 4a and in situ generated 3 for t at T followed by aqueous
work-up (HCl 1.0 molLÀ1). [c] Yield of isolated product 6a. [d] Reaction
was performed in Et2O. [e] Purchased from Sigma–Aldrich, No. 683418.
[f] Reagent 3a was kept 2 h at À208C prior the reaction with 4a.
[g] 160 mmol 1a and 160 mmol 2.
Having developed a method for the direct conversion of
carboxylic acid esters into benzene derivatives, we turned our
attention to 1,5-bifunctional diarylmagnesium reagents 3b–
3d for the transformation of esters into anthracene, tetracene,
and pentacene derivatives. The direct addition of metallic
We next explored different methods for the double
metalation to form 1,5-organodimetallic reagents 3
(Table 1, M = Li or Mg). The two-fold iodine–lithium
exchange at À408C described by Jutzi led to a highly
Table 2: Scope of the direct ester to benzene transformation using 1,5-bifunctional
organomagnesium reagent 3a.[a]
reactive dilithium species[9] capable of converting
methyl 4-phenylbenzoate (4a) into p-terphenyl (6a)
in a promising yield of 46% (Table 1, entry 1). Since
no product formation was observed after a trans-
metalation reaction with MgX2 and since the direct
reaction of 1a with elemental magnesium was
ineffective to give the corresponding organomagne-
sium compound, we focused on (Z)-alkenyliodide–
magnesium exchange reactions.[10] However, even
after prolonged reaction times, the reaction of 1a
with iPrMgCl·LiCl resulted mainly in monometala-
tion. In contrast, sBu2Mg·LiCl enabled complete
halogen–metal exchange at both the 1- and 5-
position. Nevertheless, the resulting reagent was
unproductive in the conversion of 4a to the desired
p-terphenyl (6a).[11] Given the extraordinary modu-
lation aptitude of magnesate reagents, we treated 1a
with equimolar amounts of commercially available
heteroleptic iPrnBu2MgLi.[12] Even at 08C, (Z,Z)-
1,4-pentadiene-1,5-diyl 3a[13] was efficiently formed
within 5 min and a significant increase in yield for the
direct carboxylic acid ester to phenyl conversion was
achieved (Table 1, entry 2, 70%). Alternatively,
iPrnBu2MgLi can effortlessly be prepared from
iPrMgCl and two equivalents of nBuLi (Table 1,
entry 3). We further examined nBu3MgLi and sBu-
nBu2MgLi to identify iPrnBu2MgLi as the ideal
Entry
1
Product[b]
Entry
4
Product[b]
Entry
7
Product[b]
6a, 82%
6b, 80%
6d, 57%[c]
6g, 68%
6h, 60%
2
3
5
6
8
9
6e, 72%
6c, 59%
6 f, 68%
6i, 80%[c]
[a] Reactions performed with 100 mmol 4 and in situ generated 3a (from 200 mmol
1a and 200 mmol 2) for 2 h at À208C followed by aqueous work-up (HCl
halogen–metal exchange reagent (Table 1, entries 4 1.0 molLÀ1). [b] Yield of isolated product. [c] From 300 mmol 1a and 300 mmol 2.
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Table 3: Scope of the direct transformation of esters into anthracenes, tetracenes,
and pentacenes using 1,5-bifunctional organomagnesium reagents 3b–3d.[a]
(Table 3, entry 8, 55% for three anthracene forma-
tions). With an excess of reagent 3b, esters with
protic functional groups could also be efficiently
converted (Table 3, entries 9 and 10). Particularly
gratifying was that tetracene derivatives substituted
at the 5-position were also obtained in high yields
(Table 3, entries 11 and 12). We furthermore found
that by working in the dark with degassed THF, even
monosubstituted pentacene derivatives were acces-
sible after isolation by crystallization (Table 3,
entries 13 and 14). These synthetically challenging
monosubstituted pentacenes emphasize the advan-
tages of the direct ester to arene transformation. The
mild reaction conditions of the method also allow the
preparation of sensitive compounds in high yields.
In summary, we have developed a method for the
direct transformation of carboxylic acid esters into
the corresponding benzene and acene derivatives by
the use of 1,5-bifunctional organomagnesium
reagents. An in situ iodine–magnesium exchange
with lithium trialkylmagnesates enabled the gener-
ation of dialkenyldimagnesium reagents for the
formation phenyl derivatives. In contrast, the diaryl-
dimagnesium reagents were accessible when using
metallic magnesium from o,o’-dibromodiaryl-
methane precursors, which allowed the efficient
synthesis of anthracenes, tetracenes, and pentacenes.
Treatment of carboxylic acid esters with the 1,5-
bifunctional organomagnesium reagents enabled the
single-step preparation of various arenes under mild
reaction conditions and in yields of up to 99%. We
expect that this method will find a wide range of
applications in discovery chemistry and sustainable
process research, particularly in the synthesis of
organic functional materials. Future studies will
evaluate other selected substrate and reagent classes,
the structure of the 1,5-bifunctional organomagne-
sium reagents, and the mechanism of this practical
preparative method.
Entry Product[b]
Entry Product[b]
Entry Product[b]
1
7
11
6j, 99%
6n, 87%
6r, 61%
2–4
8
12
6k, 97%
6o, 55%[e]
6s, 89%
99%,[c] 94%[d]
5
6
9
13
6l, 99%
6p, 88%[f]
6t, 97%
10
14
6m, 97%
6q, 99%[g]
6u, 82%
[a] Reactions performed with 100 mmol 4 in 1.0 mLTHFand 140 mmol 3 for 4 h at RT
followed by aqueous workup (HCl 1.0 molLÀ1). [b] Yield of isolated product.
[c] 1.00 mmol scale. [d] 10.0 mmol scale. [e] Threefold ester to anthracene trans-
formation with 420 mmol 3b; the third aromatization was induced in a separate step
through treatment with conc. HCl [f] 200 mmol 3b. [g] 240 mmol 3b.
Acknowledgements
We gratefully acknowledge the Swiss National Sci-
ence Foundation for generous financial support,
Novartis AG for an Excellence Scholarship for Life Sciences
and Priv.-Doz. Dr. D. Häussinger for assistance with NMR
spectroscopy. We thank Prof. K. Gademann and Prof. D.
Seebach for helpful discussions.
magnesium to o,o’-dibromodiarylmethanes led to the notably
more stable reagents 3b–3d.[14] To our delight, the union of 3b
and ester 4a resulted in the formation of anthracene
derivative 6j with extraordinary efficiency (Table 3, entry 1,
99%). A more electron-rich aryl ester could also be converted
into the biaryl product in excellent yield (Table 3, entry 2).
The scalability of the reaction was verified by increasing the
reaction scale (Table 3, entries 3 and 4, 1.00 mmol and
10.0 mmol). Moreover, the phenylanthracene with a bromo
substituent and the naphthyl derivative with increased steric
demand could also be obtained in remarkable yields (Table 3,
entries 5 and 6, 99% and 97%). The reaction of an
alkenylester underlines the wide substrate scope (Table 3,
entry 7, 87%) and a triple carboxylic acid ester to arene
transformation highlights the robustness of the reaction
Keywords: acenes · arenes · carboxylic acid esters ·
Grignard reactions · organomagnesium reagents
How to cite: Angew. Chem. Int. Ed. 2015, 54, 12163–12166
Angew. Chem. 2015, 127, 12331–12334
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Received: June 12, 2015
Published online: August 19, 2015
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