Reductive Cleavage of Aromatic and Heteroaromatic Ester Functions via Copper-Catalyzed Proto-Decarbomethoxylation

Article abstract of DOI:10.1021/acs.orglett.8b00930

An unprecedented catalytic reductive cleavage of aromatic and heteroaromatic methyl ester functions was successfully achieved with a cheap, nontoxic, and air-stable Cu(OAc)₂ catalyst. This reaction is fast, features good functional group tolerance, does not require inert atmosphere or anhydrous solvent, and can be scaled up to 1 g. Moreover, carboxylic acids and t-butyl esters also reacted smoothly under these conditions.

Full text of DOI:10.1021/acs.orglett.8b00930

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Reductive Cleavage of Aromatic and Heteroaromatic Ester Functions
via Copper-Catalyzed Proto-Decarbomethoxylation
Jeanne Fichez, Guillaume Prestat, and Patricia Busca*
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS, Universite
France
́
Paris Descartes, Paris 75006,
S
* Supporting Information
ABSTRACT: An unprecedented catalytic reductive cleavage
of aromatic and heteroaromatic methyl ester functions was
successfully achieved with a cheap, nontoxic, and air-stable
Cu(OAc)2 catalyst. This reaction is fast, features good
functional group tolerance, does not require inert atmosphere
or anhydrous solvent, and can be scaled up to 1 g. Moreover,
carboxylic acids and t-butyl esters also reacted smoothly under
these conditions.
sters are widely recognized as ubiquitous organic functions
that can be found in synthetic building blocks as well as in
from copper-catalyzed decarboxylation are of major impor-
tance: (i) decarboxylative cross-coupling reactions for C−C
bond formation, especially as a Suzuki alternative for biaryl
synthesis,9,10 and (ii) the use of carboxylic acid as traceless
directing groups for C−H activation.11,12
More recently, nickel-catalyzed reductive defunctionalization
of phenyl esters was reported for the first time by the group of
Rueping (Scheme 1, eq 2).13 Whereas phenyl esters can be
advantageously used in cross-coupling reactions, mainly limited
to nickel catalysis,14,15 methyl esters are more attractive from an
atom-economic point of view. Surprisingly, and to the best of
our knowledge, there was no report dealing with catalytic
reductive removal of methyl esters when we started our
investigation. The very first example was actually disclosed by
Rueping, while we were preparing this paper, who described the
nickel-catalyzed conversion of methyl esters into stannane
derivatives.16
Given the fundamental synthetic interest in the reduction of
aryl esters and the green advantage of methyl versus phenyl
esters, it would be highly desirable to develop a method to
remove methyl esters via a catalytic process using a cheap,
nontoxic, and air-stable catalyst such as copper. We report
herein the first example of copper-catalyzed reductive cleavage
of aryl and heteroaryl methyl esters (Scheme 1, eq 3). This
reaction represents an attractive pathway for the late-stage
defunctionalization of high-value polyfunctionalized natural or
synthetic aromatic esters.
E
natural products. Consequently, reductive removal of esters
represents an important class of transformations in synthetic
organic chemistry. In recent years, metal-catalyzed defunction-
alization, in general, and decarboxylation, in particular, have
attracted great interest.1 Discovered in 1930, the stoichiometric
decarboxylation of benzoic acids using Cu2O has been
extensively studied during the mid-20th century by Shepard,2
Nilsonn,3 and Cohen.4 The potential of this reaction remained
underexploited until major breakthroughs were achieved over
the past decade with the development of catalytic versions
using various ligands: 1,10-phenanthroline for Gooßen,5
TMEDA for Cahiez,6 or TEA for Cai (Scheme 1, eq 1).7
Microwave heating was also reported to significantly reduce
reaction times.8 Currently, two main applications emerging
Scheme 1. Metal-Catalyzed Proto-decarbo(metho)xylation
of (Hetero)aryls
For our initial investigation of methyl ester defunctionaliza-
tion, inspired from previous studies on protodecarboxyla-
tion,2−8 we chose methyl 2-nitrobenzoate (o-1a) and methyl 2-
methoxybenzoate (o-1b) as models of activated and deactivated
substrates, respectively. After examination of various copper
Received: March 21, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00930
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
sources and amounts, ligands, solvents, and heating conditions,
we were pleased to find that 0.1 equiv of Cu(OAc)2 and 1 equiv
of 1,10-phenanthroline as a ligand in a mixture of 3:1 NMP/
quinoline at 160 °C and 170 W for 1 h were the optimal
reaction conditions (for details, see Tables S1 and S2 in the
Supporting Information (SI)). Before proceeding further,
control experiments were performed and demonstrated (i)
that the desired product is not formed in the absence of copper
and (ii) that the yield is significantly lowered when the ligand
or the microwave activation is missing (for details, see Table S3
in the SI).
In the first set of experiments, the reactions were carried out
with our optimized conditions (method A), and when the
yields were less than 50%, a second set of experiments was
performed using 0.4 equiv of Cu(OAc)2 (method B). In order
to properly benchmark our protocol against previous reports on
decarboxylation of benzoic acids,5−8 we have chosen a wide
panel of substituted methyl benzoates that systematically
include ortho, meta, and para derivatives.
To our delight, the reaction proceeded smoothly in
reasonable to quantitative yields for all of the substrates,
regardless of the substituents’ electronic nature on the aromatic
ring. In that respect, aromatic methyl esters proved to be
indeed prone to undergo proto-decarbomethoxylation under
our conditions, whereas these functional groups remained
stable under Gooßen6 or Rueping9 reductive conditions.
Furthermore, a large variety of functional groups, including
nitro 1a, methoxy 1b, methyl 1c, hydroxy 1d, amino 1e,
dimethylamino 1f, cyano 1g, formyl 1h, chloro 1i, and fluoro 1j
were well tolerated under these conditions, which demonstrates
the generality of our method. Very few exceptions were the p-
nitro (p-1a) and o-methoxy (o-1b) derivatives, which under-
went over-reactions that, despite a full conversion of the
substrates, lowered the yield of the desired product (Table 1,
entries 3 and 4, respectively). Although disappointing, the 26%
yield obtained for the ester o-1b is consistent with the
optimized 24% yield obtained by Gooßen for the correspond-
ing decarboxylation of 2-methoxybenzoic acid.5
For all the other substrates, as described in previous studies
for related decarboxylation of benzoic acids,5−8 a marked steric
and electronic ortho effect can be observed for substrates
bearing neutral or electron-donating groups in the ortho
position, which afford better yields than their meta and para
analogues (Table 1, entries 7−18). This effect seems to be
offset by the presence of electron-withdrawing groups that are,
on the contrary, preferred in the para position (Table 1, entries
19−27). These observations support the hypothesis of a
negative charge on the carbon ipso to the carboxylate in the
transition state,13 except for fluorine-containing compounds
that led to mixed results (Table 1, entries 28−30). In a few
cases, methyl esters led to yields better than those reported for
their carboxylic acid counterparts: 87% vs 81% for the para-
cyano (p-1g) and 91% vs 64% for the para-formyl (p-1h)
derivatives (Table 1, entries 21 and 24).8
To further assess the practicality of our protocol, we
performed control experiments with the substrate o-1i.
Anhydrous conditions are not essential, as they do not lead
to any increase of the yield (Table 1, entry 31 vs 25), and the
reaction can be successfully scaled up to 1 g (150 mmol) with
an even better yield of 63% (Table 1, entry 32 vs 25), which
strengthens the advantages of this new reduction method.
We finally explored the applicability of our conditions to
pharmaceutically relevant heteroaromatic methyl esters and
other types of simple aromatic esters (Table 2).
With these fully optimized conditions in hand, we then
examined the scope and limitations of the reaction (Table 1).
a
Table 1. Scope of Substituted Methyl Benzoates
b
entry
substrate
R
product
yield (%)
1
2
o-1a
m-1a
p-1a
o-1b
m-1b
p-1b
o-1c
m-1c
p-1c
o-1d
m-1d
p-1d
o-1e
m-1e
p-1e
o-1f
o-NO2
m-NO2
p-NO2
o-OMe
m-OMe
p-OMe
o-Me
2a
2a
2a
2b
2b
2b
2c
2c
2c
2d
2d
2d
2e
2e
2e
2f
80 [84] (A)
44 (A), 32 (B)
c
3
39 (A), 34 (B)
d
4
26 (A), 50 (B)
5
29 (A), 65 [61] (B)
50 (B)
6
7
26 (A), 60 [72] (B)
24 (A), 39 (B)
15 (A), 53 (B)
99 [95] (A)
8
m-Me
p-Me
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
o-OH
m-OH
p-OH
o-NH2
m-NH2
p-NH2
o-NMe2
m-NMe2
p-NMe2
o-CN
51 (A), 96 [99] (B)
53 (A), 83 (B)
0 (A), 72 [70] (B)
0 (A), 55 (B)
0 (A), 36 (B)
21 (A), 59 [64] (B)
15 (A), 55 (B)
0 (A), 38 (B)
87 (A)
m-1f
p-1f
2f
2f
o-1g
m-1g
p-1g
o-1h
m-1h
p-1h
o-1i
2g
2g
2g
2h
2h
2h
2i
m-CN
p-CN
o-CHO
m-CHO
p-CHO
o-Cl
75 (A)
95 [87] (A)
49 (A), 53 (B)
45 (A), 58 (B)
88 [91] (A)
54 (A)
m-1i
p-1i
m-Cl
2i
65 (A), 85 [76] (B)
73 (A)
p-Cl
2i
o-1j
o-F
2j
46 (A), 63 (B)
37 (A), 79 (B)
27 (A), 73 [75] (B)
m-1j
p-1j
m-F
2j
p-F
2j
e
o-1i
o-Cl
2i
50 (A)
f
o-1i
o-Cl
2i
63 (A)
Satisfyingly, all of the desired products were obtained in
moderate to quantitative yields. Furyl 1k and thienyl 1l
derivatives reacted smoothly in good yields with 0.1 equiv of
Cu(OAc)2, leading to 61 and 72% of desired products 2k and
2l, respectively (Table 2, entries 1 and 2). Although pyridyl 1m
and naphthyl 1n substrates failed to react nicely with 0.1 equiv
of catalyst, and they both furnished 99% of the corresponding
products when 0.4 equiv was used (Table 2, entries 3 and 4).
Benzoic acid 1o and the tert-butylbenzoate 1p were the most
reactive substrates, affording benzene 2o in 87 and 99% yields,
a
Method A: methyl benzoate 1a−i (1 mmol), Cu(OAc)2 (0.1 mmol),
1,10-phenanthroline (1 mmol), NMP (2.5 mL), quinoline (0.8 mL),
μW (160 °C/170 W), 1 h. Method B: method A with 0.4 mmol of
b
Cu(OAc)2 instead of 0.1 mmol. Isolated yields indicated in brackets
[] are consistent with those determined by GC or NMR using
c
tetradecane (0.1 mmol) as the internal standard. Aniline was
d
identified in 66% yield. Phenol was identified in 72% yield.
e
f
Performed under anhydrous conditions. Performed on a 1 g (150
mmol) scale.
B
DOI: 10.1021/acs.orglett.8b00930
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Scope of Other (Hetero)aromatics
Scheme 2. Proposed Mechanism for the Copper-Catalyzed
Proto-decarbomethoxylation
phenyl esters with a chemoselectivity that depends on the
amount of catalyst. This new transformation represents an
attractive strategy for the late-stage defunctionalization of high-
value natural or synthetic aromatic esters. It also paves the way
for the use of methyl esters as relevant substrates for cross-
coupling reactions. Further studies in this direction are
currently ongoing in our laboratory and will be reported in
due course.
a
Method A: substrates 1k−s (1 mmol), Cu(OAc)2 (0.1 mmol), 1,10-
phenanthroline (1 mmol), NMP (2.5 mL), quinoline (0.8 mL), μW
(160 °C/170 W), 1 h. Method B: method A with 0.4 mmol of
b
Cu(OAc)2 instead of 0.1 mmol. Isolated yields indicated in brackets
[] are consistent with those determined by GC using tetradecane (0.1
mmol) as the internal standard.
ASSOCIATED CONTENT
■
S
* Supporting Information
respectively (Table 2, entries 5 and 6). On the contrary, methyl,
ethyl, and phenyl benzoates that were less reactive required 0.4
equiv of Cu(OAc)2 to react properly (Table 2, entries 7−9).
These differences observed in reactivity highlight that chemo-
selective reduction could be achieved by this method. On the
basis of our observations, and the conclusions of previous
studies,17,18 the mechanism could be described as follows
(Scheme 2): reduction of the copper acetate by quinoline4a
gives the catalytically active complex I, demethylation of the
ester by the nucleophilic solvent (S) or an acetate anion
(methyl acetate was isolated through distillation) affords the
copper-benzoate II, decarboxylation occurs through the
transition state III17 which leads to the insertion of the metal
into the aryl−carboxyl bond and provides the aryl−copper
species IV. The last step was extensively studied by Cohen, who
demonstrated that quinoline acts as a major source of hydrogen
by being involved in copper-catalyzed C-H activation.4b
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00930.
Full optimization tables and detailed experimental data,
including general methods, synthetic procedures, purifi-
1
cation methods, characterization data, and H and 13C
NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: patricia.busca@parisdescartes.fr.
ORCID
Guillaume Prestat: 0000-0002-3948-1476
Patricia Busca: 0000-0003-1284-8183
Notes
In summary, we have developed the first catalytic reductive
cleavage of aromatic and heteroaromatic methyl esters. This
new reaction involves a cheap, nontoxic, air- and moisture-
stable Cu(OAc)2 catalyst in combination with an inexpensive
phenanthroline ligand. The practicality of this protocol that
does not require anhydrous conditions was demonstrated from
small (1 mmol) to larger (150 mmol) scale. This versatile
method proved to be compatible with a large variety of
functional groups and is not hampered by heteroaromatic
scaffolds. This copper-catalyzed reduction can also be applied
to aromatic carboxylic acid or the parent tert-butyl, ethyl, or
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge the Centre National de la
■
Recherche Scientifique, the Minister
̀
e de l’Enseignement
ieur, de la Recherche et de l’Innovation, and the Agence
Nationale de Recherches sur le Sida et les Hepatites Virales
(Grant No. ANRS ECTZ204422) for financial support of this
work. We also thank the Ecole Doctorale Medicament,
Super
́
́
́
Toxicologie, Chimie, Imageries for the Ph.D. grant to J.F.
C
DOI: 10.1021/acs.orglett.8b00930
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
4282−4285. (h) Chatupheeraphat, A.; Liao, H.-H.; Srimontree, W.;
Guo, L.; Minenkov, Y.; Poater, A.; Cavallo, L.; Rueping, M. J. Am.
Chem. Soc. 2018, 140, 3724−3735.
(16) Yue, H.; Zhu, C.; Rueping, M. Org. Lett. 2018, 20, 385−388.
(17) (a) Perry, G. J. P.; Larrosa, I. Eur. J. Org. Chem. 2017, 2017,
3517−3527. (b) Font, M.; Quibell, J. M.; Perry, G. J. P.; Larrosa, I.
Chem. Commun. 2017, 53, 5584−5597.
(18) (a) Gooßen, L. J.; Rodríguez, N.; Linder, C.; Lange, P. P.;
Fromm, A. ChemCatChem 2010, 2, 430−442. (b) Xue, L.; Su, W.; Lin,
Z. Dalton Trans. 2011, 40, 11926−11936.
REFERENCES
■
(1) Modak, A.; Maiti, D. Org. Biomol. Chem. 2016, 14, 21−35.
(2) (a) Shepard, A. F.; Winslow, N. R.; Johnson, J. R. J. Am. Chem.
Soc. 1930, 52, 2083−2090. (b) Cairncross, A.; Roland, J. R.;
Henderson, R. M.; Sheppard, W. A. J. Am. Chem. Soc. 1970, 92,
3187−3189.
(3) (a) Nilsson, M.; Kulonen, E.; Sunner, S.; Frank, V.; Brunvoll, J.;
Bunnenberg, E.; Djerassi, C.; Records, R. Acta Chem. Scand. 1966, 20,
423−426. (b) Bjorklund, C.; Nilsson, M.; Pedersen, C.; Norin, T. Acta
̈
Chem. Scand. 1968, 22, 2585−2588. (c) Chodowska-Palicka, J.;
Nilsson, M.; Liaaen-Jensen, S.; Rasmussen, S. E.; Shimizu, A. Acta
Chem. Scand. 1970, 24, 3353−3361. (d) Chodowska-Palicka, J.;
Nilsson, M.; Rømming, C.; Svensson, S.; Koskikallio, J.; Kachi, S. Acta
Chem. Scand. 1971, 25, 3451−3456.
(4) (a) Cohen, T.; Schambach, R. A. J. Am. Chem. Soc. 1970, 92,
3189−3190. (b) Cohen, T.; Berninger, R. W.; Wood, J. T. J. Org.
Chem. 1978, 43, 837−848.
(5) Gooßen, L. J.; Thiel, W. R.; Rodríguez, N.; Linder, C.; Melzer, B.
Adv. Synth. Catal. 2007, 349, 2241−2246.
(6) Cahiez, G.; Moyeux, A.; Gager, O.; Poizat, M. Adv. Synth. Catal.
2013, 355, 790−796.
(7) Li, Z.; Fu, Z.; Zhang, H.; Long, J.; Song, Y.; Cai, H. New J. Chem.
2016, 40, 3014−3018.
(8) Gooßen, L. J.; Manjolinho, F.; Khan, B. A.; Rodríguez, N. J. Org.
Chem. 2009, 74, 2620−2623.
(9) For reviews, see: (a) Gooßen, L. J.; Rodríguez, N.; Gooßen, K.
Angew. Chem., Int. Ed. 2008, 47, 3100−3120. (b) Rodríguez, N.;
Gooßen, L. J. Chem. Soc. Rev. 2011, 40, 5030−5048. (c) Cornella, J.;
Larrosa, I. Synthesis 2012, 44, 653−676.
(10) For selected examples, see: (a) Gooßen, L. J.; Deng, G.; Levy, L.
M. Science 2006, 313, 662−664. (b) Gooßen, L. J.; Rodríguez, N.;
Melzer, B.; Linder, C.; Deng, G.; Levy, L. M. J. Am. Chem. Soc. 2007,
129, 4824−4833. (c) Gooßen, L. J.; Zimmermann, B.; Knauber, T.
Angew. Chem., Int. Ed. 2008, 47, 7103−7106. (d) Gooßen, L. J.;
Rodríguez, N.; Linder, C. J. Am. Chem. Soc. 2008, 130, 15248−15249.
(e) Gooßen, L. J.; Zimmermann, B.; Linder, C.; Rodríguez, N.; Lange,
P. P.; Hartung, J. Adv. Synth. Catal. 2009, 351, 2667−2674.
(f) Gooßen, L. J.; Rodríguez, N.; Lange, P. P.; Linder, C. Angew.
Chem., Int. Ed. 2010, 49, 1111−1114. (g) Tang, J.; Biafora, A.;
Gooßen, L. J. Angew. Chem., Int. Ed. 2015, 54, 13130−13133.
(h) Zhao, S.; Liu, Y.-J.; Yan, S.-Y.; Chen, F.-J.; Zhang, Z.-Z.; Shi, B.-F.
Org. Lett. 2015, 17, 3338−3341. (i) Chen, L.; Ju, L.; Bustin, K. A.;
Hoover, J. M. Chem. Commun. 2015, 51, 15059−15062. (j) Patra, T.;
Nandi, S.; Sahoo, S. K.; Maiti, D. Chem. Commun. 2016, 52, 1432−
1435.
(11) For a review, see: (a) Zhang, F.; Spring, D. R. Chem. Soc. Rev.
2014, 43, 6906−6919. (b) Biafora, A.; Gooßen, L. J. Synlett 2017, 28,
1885−1890. (c) Wei, Y.; Hu, P.; Zhang, M.; Su, W. Chem. Rev. 2017,
117, 8864−8907.
(12) For selected examples, see: (a) Chiong, H. A.; Pham, Q.-N.;
Daugulis, O. J. Am. Chem. Soc. 2007, 129, 9879−9884. (b) Bhadra, S.;
Dzik, W. I.; Gooßen, L. J. Angew. Chem., Int. Ed. 2013, 52, 2959−2962.
(c) Quan, Y.; Xie, Z. J. Am. Chem. Soc. 2014, 136, 15513−15516.
(d) Pan, S.; Zhou, B.; Zhang, Y.; Shao, C.; Shi, G. Synlett 2016, 27,
277−281. (e) Biafora, A.; Krause, T.; Hackenberger, D.; Belitz, F.;
Gooßen, L. J. Angew. Chem., Int. Ed. 2016, 55, 14752−14755.
(13) Yue, H.; Guo, L.; Lee, S.-C.; Liu, X.; Rueping, M. Angew. Chem.,
Int. Ed. 2017, 56, 3972−3976.
(14) For a review, see: Takise, R.; Muto, K.; Yamaguchi, J. Chem. Soc.
Rev. 2017, 46, 5864−5888.
(15) For selected examples, see: (a) Amaike, K.; Muto, K.;
Yamaguchi, J.; Itami, K. J. Am. Chem. Soc. 2012, 134, 13573−13576.
(b) Muto, K.; Yamaguchi, J.; Musaev, D. G.; Itami, K. Nat. Commun.
2015, 6, 7508. (c) LaBerge, N. A.; Love, J. A. Eur. J. Org. Chem. 2015,
2015, 5546−5553. (d) Guo, L.; Rueping, M. Chem. - Eur. J. 2016, 22,
16787−16790. (e) Guo, L.; Chatupheeraphat, A.; Rueping, M. Angew.
Chem., Int. Ed. 2016, 55, 11810−11813. (f) Pu, X.; Hu, J.; Zhao, Y.;
Shi, Z. ACS Catal. 2016, 6, 6692−6698. (g) Yue, H.; Guo, L.; Liao, H.-
H.; Cai, Y.; Zhu, C.; Rueping, M. Angew. Chem., Int. Ed. 2017, 56,
D
DOI: 10.1021/acs.orglett.8b00930
Org. Lett. XXXX, XXX, XXX−XXX