Copper-mediated ortho-nitration of (hetero)arenecarboxylates

Article abstract of DOI:10.1002/chem.201403363

Various (hetero)arenecarboxylic acids were converted to the corresponding Daugulis amides and nitrated selectively in the ortho-position in the presence of [CuNO₃(PPh₃)₂] and AgNO₂ at 50 °C. A microwave-assisted saponification allows regenerating the carboxylate group within minutes, which may then be removed tracelessly by protodecarboxylation, or substituted by aryl- or alkoxy-groups via decarboxylative cross-coupling.

Full text of DOI:10.1002/chem.201403363

DOI: 10.1002/chem.201403363
Communication
&
CÀH Activation
Copper-Mediated ortho-Nitration of (Hetero)Arenecarboxylates
Dmitry Katayev, Kai F. Pfister, Timo Wendling, and Lukas J. Gooßen*[a]
protocol for the chelation-assisted ortho-nitration of (hetero)ar-
enes using an easily cleavable directing group remains an im-
portant research target.
Abstract: Various (hetero)arenecarboxylic acids were con-
verted to the corresponding Daugulis amides and nitrated
selectively in the ortho-position in the presence of
[CuNO3(PPh3)2] and AgNO2 at 508C. A microwave-assisted
saponification allows regenerating the carboxylate group
within minutes, which may then be removed tracelessly
by protodecarboxylation, or substituted by aryl- or alkoxy-
groups via decarboxylative cross-coupling.
Directing CÀH functionalizations with carboxylate groups
has proven to be particularly versatile, because they can subse-
quently be removed tracelessly or converted into various func-
tional groups via decarboxylative couplings.[14] In nitrations,
the use of unmodified carboxylates appeared troublesome be-
cause of their tendency to undergo ipso-substitution. It should,
however, be possible to overcome this by their temporary
derivatization.
In 2005, Daugulis introduced the use of 8-aminoquinoline as
a carboxylate-based bidentate directing group for the Pd-cata-
lyzed ortho-CÀH arylation of arenes.[15] This uniquely effective
directing group has enabled a vast number of transition metal-
catalyzed functionalizations of C(sp2)ÀH and C(sp3)ÀH bonds,
forming CÀC, CÀO, CÀN and C-halogen bonds.[16] However, the
critical limitation of this auxiliary is its difficult removal, gener-
ally performed by refluxing it in ethanolic NaOH for up to
72 h.[17]
Aromatic nitro compounds have a long history as intermedi-
ates in organic synthesis.[1] Even today, they are almost exclu-
sively synthesized by electrophilic aromatic nitration of
arenes.[2] This strategy generally leads to mixtures of regioiso-
mers because the position of the nitro group is dictated by
the electronic properties of the substrates. For benzoic acid,
the nitration requires harsh conditions (conc. HNO3/H2SO4), and
gives a complex mixture of regioisomers (o-/m-/p-=19:80:1 at
308C).[3] Modern, regiospecific syntheses of nitroarenes include
the ipso-nitration of aryl halides, pseudohalides, organometallic
compounds,[4] or carboxylates[5] using palladium[6] or copper
catalysts.[7] Alternatively, primary aryl amines[8] or azides[9] can
be oxidized to the corresponding nitro compounds. However,
valuable pre-functionalized arenes are required as starting ma-
terials in all cases.
We envisioned that the conversion of aromatic carboxylates
into the corresponding Daugulis amides might allow their se-
lective ortho-CÀH nitration under unprecedentedly mild condi-
tions. Provided that an efficient saponification method could
be found, the resulting ortho-nitro-arenecarboxylates could
then be further functionalized via decarboxylative couplings
(Scheme 1).
In view of the advances made in the formation of CÀC, CÀO,
CÀN and CÀhalogen bonds by modern chelation-assisted
ortho-CÀH functionalizations,[10] a similar strategy would be ap-
pealing also for the regioselective synthesis of nitroarenes. A
certain amount of progress has recently been made in this
field. Thus, Xu et al. described a palladium-catalyzed regiose-
lective ortho-nitration of aromatic CÀH bonds that proceeds at
100–1308C.[11] Liu’s copper-mediated ortho-nitration of
(hetero)arenes requires similarly high temperatures.[12] The
recent CÀH nitration of arylpyridines by Li and co-workers
works already at 808C, but employs expensive RhIII catalysts.[13]
However, the synthetic value of each of these protocols is
strongly limited because they rely on pyridine-based directing
groups that are hard to remove or derivatize. Therefore, a mild
Scheme 1. ortho-Nitration and further functionalization of carboxylic acids.
FG=functional groups, NH2-Q=8-aminoquinoline, X=CO2H, H, Ar, OR.
We began to examine this synthetic sequence by exploring
the model reaction between 8-aminoquinoline benzamide 1a
and silver nitrite. Various catalysts, solvents and oxidants were
investigated until we found a promising lead system (see Table
S1 in the Supporting Information). The ortho-nitrated product
was obtained in 30% yield already at 508C using 50 mol%
Cu(NO3)2 as the catalyst and N-methylmorpholine N-oxide
(NMO) as the oxidant in propylene carbonate (Table 1, entry 1).
Addition of triphenylphosphine ligand strongly increased the
yields, whereas other phosphines were less effective (entries 2–
5). The use of preformed [CuNO3(PPh3)2][18] furnished the prod-
uct in 78% yield and high selectivity for the ortho-mononitrat-
ed product 2a, along only with unreacted starting material
[a] Dr. D. Katayev, K. F. Pfister, T. Wendling, Prof. Dr. L. J. Gooßen
FB Chemie-Organische Chemie
Technische Universitꢀt Kaiserslautern
Erwin-Schrçdinger-Str. Geb. 54, 67663 Kaiserslautern (Germany)
Fax: (+49)631-205-3921
E-mail: goossen@chemie.uni-kl.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403363.
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Table 1. Optimization of the reaction conditions.[a]
Table 2. Copper-mediated ortho-nitration of (hetero)aromatic quinolinyl
amides.[a]
Entry
Cu salt
Ligand
Solvent
T [8C]
2a [%]
Product
Yield
72%
Product
Yield
52%
1
2
3
4
5
6
7
8
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
[CuNO3(PPh3)2]
[CuNO3(PPh3)2]
[CuNO3(PPh3)2]
[CuNO3(PPh3)2]
[CuNO3(PPh3)2]
[CuNO3(PPh3)2]
[CuNO3(PPh3)2]
–
–
PPh3
P(3-FPh)3
P(3-OMePh)3
PC
PC
PC
PC
PC
PC
MeCN
NMP
DMF
toluene
PC
50
50
50
50
50
50
50
50
50
50
40
50
50
30
68
61
25
PCy3
59
–
–
–
–
–
–
–
–
78(72)[b]
41
2a
2b
29
27
28
65
74
0
58%
58%[b]
9
10
11
12[c]
13
2c
2e
2g
2i
2d
2 f
2h
2j
PC
PC
77%
81%
[a] Reaction conditions: 1a (0.3 mmol), [Cu] (50 mol%), ligand
(100 mol%), AgNO2 (2 equiv), NMO (2 equiv), solvent (2 mL), N2 atmos-
phere. Yields were determined by HPLC analysis using 1-(4-methoxyphe-
nyl)ethan-1-one as internal standard. Q=8-quinolinyl, PC=propylene car-
bonate. [b] Yield of isolated product. [c] Air atmosphere.
39%
68%[b]
(entry 6). Other regioisomers or doubly nitrated products were
not detected under these conditions. Among all solvents
tested, propylene carbonate was by far the most effective (en-
tries 6–10). The best results were obtained at 508C, but even
at 408C, the yields remained satisfactory (entry 11). Control ex-
periments revealed that the presence of air has no adverse
effect on the reaction outcome (entry 12), and that the reac-
tion does not take place in the absence of copper (entry 13).
We next investigated various directing groups in order to
find out whether other carboxylic acid derivatives would give
comparable results (Figure 1). However, at best traces of prod-
68%[b]
62%
61%[b]
62%
2k
2l
76%[b]
79%
74%
76%
2m
2o
2n
2p
84%
74%
Figure 1. Directing groups screened in the copper-mediated ortho-nitration.
2q
2s
2u
2r
2t
2v
uct were obtained using acyl triazole (3), amide (4, 5) or ester
(6) directing groups. These experiments confirm that both the
quinoline moiety and the amide NH group are mandatory,
which underlines the unique properties of the Daugulis amide.
Having thus found an efficient method for the ortho-nitra-
tion of carboxylic acid derivatives, we next investigated its
scope. Table 2 shows that a variety of aromatic quinolinyl
amides were successfully converted into the ortho-nitrated
products. Both electron-rich and electron-poor benzamides
were smoothly converted, and various functional groups are
tolerated, including ethers (2 f, 2i), esters (2p), and halides (2c,
2k, 2m). Notably, the method is also applicable to five- and
six-membered heterocycles, including pyridine (2r), quinolone
(2s), thiophene (2t, 2v), and furan (2u) derivatives.
52%
49%
51%
43%
[a] Reaction conditions: 1 (1 mmol), propylene carbonate (6 mL), NMO
(2 equiv), AgNO2 (2 equiv), [CuNO3(PPh3)2] (50 mol%), N2 atmosphere,
508C, 48 h, Yield of isolated products. [b] At 708C.
In all cases, the nitration was highly regioselective, and only
in few cases, trace amounts of bis(nitration) products were ob-
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served. Interestingly, the furyl- and thiophene-3-carboxamides
(2u and 2v) were selectively nitrated at the 2-position.
The mechanism of the reaction was investigated by a series
of control experiments. In a competition experiment between
the deuterated and non-deuterated starting materials [D5]1a
and 1a performed under the optimized reaction conditions,
a kinetic isotope effect (KIE) of 2.7 was observed, confirming
that the CÀH bond activation is rate-determining (Scheme 2).
The reaction was also conducted in the presence of the radical
quenchers p-benzoquinone or 2,2,6,6-tetramethylpiperidine-N-
oxyl (TEMPO). In both cases, the yields were only slightly de-
creased, suggesting that the reaction does not involve radical
steps. These findings are in contrast to those for the copper-
promoted pyridine-directed nitration, which has a KIE of 6.5
and has been shown to involve radical steps.[12]
we found that the amide can cleanly be saponified to the cor-
responding carboxylic acid within only seven minutes with
dilute NaOH at 1508C under microwave conditions. Alterna-
tively, the directing group can also tracelessly be removed in
a convenient one-pot microwave-assisted process involving
saponification with LiOH, neutralization with trifluoroacetic
acid, and protodecarboxylation at 1758C at a copper cata-
lyst.[21] For the example in Scheme 4, the overall process thus
allows the selective production of 3-nitrotoluene (8h), an
isomer inaccessible via electrophilic nitration of toluene.
The carboxylate group was also successfully converted into
other functionalities. A decarboxylative cross-coupling of 7h
with 4-bromotoluene in the presence of a Pd/Cu system[22]
gave the corresponding biaryl 9h, and its decarboxylative ipso-
etherification[23] with tetraethoxysilane and a Ag/Cu system
provided 2-nitrotol-4-yl ethyl ether (10h).
In conclusion, an efficient copper-mediated chelation-assist-
ed CÀH nitration of (hetero)aromatic carboxylic acid derivatives
was developed that proceeds under unprecedentedly mild
conditions. The nitration was selectively directed into the
ortho-position by a Daugulis 8-aminoquinoline auxiliary. In
combination with an efficient protocol for the cleavage of the
amide directing group and subsequent decarboxylative ipso-
functionalizations or traceless removal of the carboxylate
group, the reaction concept opens up a wealth of opportuni-
ties for the regioselective synthesis of aromatic compounds.
Based on these findings and the detailed mechanistic
studies by Ribas[19] and Stahl,[20] a mechanism involving aryl–
CuIII species appears reasonable for this ortho-CÀH nitration
(Scheme 3).
With an expedient access to the ortho-nitro-carboxamides in
hand, we went on to examine the cleavage of the 8-amino-
quinoline group. Scheme 4 displays the hydrolysis of the Dau-
gulis amide 2h and follow-up chemistry for the example of 2-
nitro-4-toluic acid (7h). After elaborate reaction development,
Experimental Section
Synthesis of 2-nitro-N-(quinolin-8-yl)benzamide (2a)
A 20 mL vessel was charged with 8-benzoylaminoquinoline 1a
(248 mg, 1.00 mmol), CuNO3(PPh3)2 (325 mg, 0.50 mmol), and
AgNO2 (311 mg, 2.00 mmol). In a glovebox, N-methylmorpholine N-
oxide (242 mg, 2.00 mmol) was added and the vessel was sealed.
Propylene carbonate (6 mL) was added via syringe, and the mix-
ture was stirred at 508C for 48 h. After cooling to room tempera-
ture, the mixture was diluted with dichloromethane (50 mL), fil-
tered, washed with aqueous 20% ammonium hydroxide (20 mL),
water (20 mL) and brine (20 mL), and dried over MgSO4. The sol-
vent was removed in vacuum, and product 2a was isolated from
the residue by flash column chromatography (SiO2, ethyl acetate/n-
hexane gradient) as a yellow solid (210 mg, 72%). M.p. 1998C,
1H NMR (400 MHz, CDCl3): d=10.19 (brs, 1H), 8.90 (dd, J=6.4,
2.4 Hz, 1H), 8.76 (dd, J=4.1, 1.6 Hz, 1H), 8.20 (dd, J=8.3, 1.8 Hz,
1H), 8.14 (d, J=8.3 Hz, 1H), 7.74–7.81 (m, 2H), 7.57–7.70 (m, 3H),
7.47 ppm (dd, J=8.3, 4.3 Hz, 1H); 13C NMR (101 MHz, CDCl3): d=
164.2, 148.3, 146.7, 138.3, 136.4, 134.1, 133.8, 133.0, 130.8, 128.6,
127.9, 127.4, 124.7, 122.4, 121.8, 117.1 ppm; IR (neat): n˜ =3338 (m),
1673 (s), 1518 (vs), 1482 (s), 1424 (m), 1356 (vs), 1325 (s), 1132 (w)
cmÀ1; MS (ESI): m/z: 293.9 [MH+]; elemental analysis calcd (%) for
C16H11N3O3: C 65.53, H 3.78 N 14.33; found: C 65.28, H 3.84, N 14.31.
Scheme 2. Intermolecular kinetic isotope effect (KIE).
Scheme 3. Proposed mechanism of the ortho-nitration.
Acknowledgements
We thank J. Pollini and Dr. F. Menges for technical assistance
and the DFG (SFB TRR88 “3MET”) and the Swiss National Sci-
ence Foundation (fellowship to D. K.) for financial support.
Scheme 4. Follow-up functionalization reactions of ortho-nitrotoluic acid.
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Keywords: carboxylic acids
homogeneous catalysis · nitration
·
CÀH activation
· copper ·
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Received: May 2, 2014
Published online on && &&, 0000
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COMMUNICATION
&
CÀH Activation
D. Katayev, K. F. Pfister, T. Wendling,
L. J. Gooßen*
&& – &&
Mild and selective: In the presence of
[CuNO3(PPh3)2], aromatic and heteroaro-
matic 8-aminoquinolinyl amides under-
go selective ortho-CÀH nitration under
exceptionally mild conditions. A micro-
wave-assisted cleavage of the amide di-
recting group allows regeneration of
the carboxylate group within minutes.
The carboxylate may be tracelessly re-
moved in situ, or substituted by aryl or
alkoxy groups in decarboxylative pro-
cesses (see scheme; NH2Q=8-amino-
quinoline, X=CO2H, H, Ar, OR).
Copper-Mediated ortho-Nitration of
(Hetero)Arenecarboxylates
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