A First Example of Cobalt-Catalyzed Remote C H Functionalization of 8-Aminoquinolines Operating through a Single Electron Transfer Mechanism

Article abstract of DOI:10.1002/adsc.201600161

The development of new C H functionalization protocols based on inexpensive cobalt catalysts is currently attracting significant interest. Functionalized 8-aminoquinoline compounds are high-potential building blocks in organic chemistry and pharmaceutical compounds and new facile routes for their preparation would be highly valuable. Recently, copper has been applied as catalyst for the functionalization of 8-aminoquinoline compounds and found to operate through a single electron transfer (SET) mechanism, although requiring elevated reaction temperatures. Herein, we described the first example of a cobalt-catalyzed remote C H functionalization of 8-aminoquinoline compounds operating through a SET mechanism, exemplified using a practical and mild nitration protocol. The reaction uses inexpensive cobalt nitrate hexahydrate [Co(NO₃)₂?6 H₂O] as catalyst and tert-butyl nitrite (TBN) as nitro source. This methodology offers the basis for the facile preparation of many new functionalized 8-aminoquinoline derivatives. (Figure presented.).

Full text of DOI:10.1002/adsc.201600161

FULL PAPERS
DOI: 10.1002/adsc.201600161
À
A First Example of Cobalt-Catalyzed Remote C H Functionali-
zation of 8-Aminoquinolines Operating through a Single Electron
Transfer Mechanism
Christopher J. Whiteoak,+a,b,* Oriol Planas,+a Anna Company,a and Xavi Ribasa,*
a
Grup de Química Bioinspirada, Supramolecular i Catàlisi (QBIS-CAT), Institut de Química Computacional i Catàlisi
(IQCC) and Departament de Química, Universitat de Girona, Campus de Montilivi, 17071 Girona, Catalonia, Spain
E-mail: xavi.ribas@udg.edu
Current address: Bimolecular Sciences Research Centre, Faculty of Health and Wellbeing, City Campus, Sheffield Hallam
b
University, Sheffield, S1 1WB, U.K.
E-mail: C.Whiteoak@shu.ac.uk
+
These authors contributed equally to this work.
Received: February 6, 2016; Revised: March 2, 2016; Published online: April 15, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600161.
À
Abstract: The development of new C H functionali- of 8-aminoquinoline compounds operating through
zation protocols based on inexpensive cobalt cata- a SET mechanism, exemplified using a practical and
lysts is currently attracting significant interest. Func- mild nitration protocol. The reaction uses inexpen-
tionalized 8-aminoquinoline compounds are high-po- sive cobalt nitrate hexahydrate [Co(NO3)2·6H2O] as
tential building blocks in organic chemistry and phar- catalyst and tert-butyl nitrite (TBN) as nitro source.
maceutical compounds and new facile routes for This methodology offers the basis for the facile prep-
their preparation would be highly valuable. Recently, aration of many new functionalized 8-aminoquino-
copper has been applied as catalyst for the function- line derivatives.
alization of 8-aminoquinoline compounds and found
to operate through a single electron transfer (SET)
mechanism, although requiring elevated reaction Keywords: 8-aminoquinolines; C H functionaliza-
À
temperatures. Herein, we described the first example tion; cobalt; homogeneous catalysis; nitration; nitro-
À
of a cobalt-catalyzed remote C H functionalization gen oxides
Introduction
on a single electron transfer (SET) based remote Cu-
catalyzed C-5 chlorination.[5,6] Since this initial report
The 8-aminoquinoline scaffold is an important motif other Cu-catalyzed functionalizations have been de-
found in a variety of compounds (Scheme 1a), includ- scribed; remote C-5 sulfonylation,[7] C-2 alkylation[8]
ing pharmaceutical drugs (e.g., the antimalarial drugs and more recently remote C-5 chalcogenation[9,10] and
pamaquine and tafenoquine),[1] ligands for coordina- C-5 amination.[11] Besides Cu-catalyzed protocols, Fe-
tion chemistry[2] and more recently as a successful di- catalyzed C-4 and C-5 allylation,[12] Rh-catalyzed C-7
recting group for a number of metal-catalyzed trans- alkenylation[13] and Pd-catalyzed C-5/C-7 chlorina-
formations.[3] As a result, new methodologies for fur- tion[6] have also been described, thus expanding the
ther functionalization of readily accessible 8-amino- toolbox for the preparation of novel 8-aminoquinoline
quinoline compounds are potentially very important derivatives. Unfortunately though, all of these reports
developments in organic synthesis. There are many suffer from the requirement of elevated temperatures
À
reports of metal-catalyzed C H functionalization of and/or high catalyst loadings and as a result the devel-
simple quinolines,[4] whilst in comparison, there are opment of catalytic protocols which are operative
À
very few concerning C H functionalization reactions under milder conditions still remains a challenge.
À
of 8-aminoquinolines. The first reports of C H func-
In this work we demonstrate a new methodology
tionalization protocols using 8-aminoquinoline as sub- for the functionalization of 8-aminoquinolines using
strate came from Stahl and co-workers, who reported nitration as an example, providing potentially valua-
Adv. Synth. Catal. 2016, 358, 1679 – 1688
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1679

FULL PAPERS
Christopher J. Whiteoak et al.
À
Scheme 1. (a) Examples of compounds containing the 8-aminoquinoline scaffold; arrow indicating the C H bond selectively
activated when using the 8-aminoquinoline directing group. (b) Expected and observed nitration products from this work.
ble products for further elaboration (vide infra) or ap- previous nitration protocols, the main disadvantage of
plication. Nitro compounds are key synthons in or- these methodologies is the necessity for a pre-func-
ganic synthesis as a result of their high-potential for tionalized substrate. Since these early developments
further transformation[14] and therefore nitrated deriv- and with the advent of directing groups, a number of
À
atives of 8-aminoquinoline compounds may be of sig- metal-catalyzed direct C H nitration protocols have
nificant interest. The classical methodology for nitra- been reported, particularly based on Pd[20] and Cu.[21]
tion is based on a mixed acid H2SO4/HNO3 protocol. Although the field is rapidly developing, selective ni-
À
Albeit a simple and successful procedure, it suffers tration of C H bonds still remains a significant chal-
from many drawbacks including the use of harsh reac- lenge.
tion conditions, poor functional group compatibility,
Nitrogen dioxide (NO2) is an atom economic and
regioselectivity problems and possible over-nitra- therefore highly attractive nitrating agent, but its ex-
tion.[15] As a result of these issues, efforts have been treme reactivity (due to its open-shell nature) and
directed towards the development of new nitration toxicity have restricted its use to date. One way of
protocols.[16] Nitration using mixtures of Cu(NO3)2 overcoming the issues associated with the handling of
and acetic anhydride has long been known, although NO2 is to generate it in situ, in a stoichiometric
the requirement for stoichiometric amounts of Cu has manner. This can be achieved through the use of
limited the application of this procedure.[17] In the cheap, commercially available tert-butyl nitrite
search for more favorable protocols, one of the most (TBN), which can convert into the tert-butoxy radical
promising routes that has emerged is the transition and NO2 in the presence of air at room tempera-
metal-catalyzed transformation of aryl halides, tri- ture.[22,23] Recently there have been a number of re-
flates and nonaflates reported by Saito and co-work- ports pertaining to the use of TBN in nitration proto-
ers (Cu-catalyzed)[18] and later Buchwaldꢁs methodol- cols, although examples using metal catalysts are still
ogy (Pd-catalyzed)[19] using nitrite salts as the nitro rare.[24,25]
source. Although solving many of the drawbacks of
1680
asc.wiley-vch.de
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 1679 – 1688

À
FULL PAPERS
A First Example of Cobalt-Catalyzed Remote C H Functionalization
À
The field of Co-catalyzed C H activation has re- Results and Discussion
cently started to receive significant attention as inter-
est in replacing second and third row transition Initially, nitration of 1 in 2,2,2-trifluoroethanol (TFE),
metals with cheaper, more abundant first row transi- using 20 mol% Co(OAc)2 with TBN as nitro source at
tion metals gathers pace.[26] To this end, we have re- 1008C was attempted (Table 1, entry 1). To our disap-
cently become interested in exploiting the potential of pointment none of the expected aromatic nitration
À
Co for the development of new C H functionaliza- products were observed, instead traces of products
tion protocols.[27] We surmised that the use of TBN from nitration of the quinoline directing group at the
and Co-catalysis may permit the nitration of the aro- C-5 position (1a) were found. The same reaction at
matic moiety of 1 (Scheme 1b), using directing group room temperature afforded increased yields to 12%
principals. This conversion has been previously suc- of nitration product 1a and a further unexpected 7-ni-
cessfully realized using Cu as catalyst.[28] As will be tration product, 1b, in 4% yield (Table 1, entry 2). En-
described (vide infra), this was not the case and in- couraged by these low but promising yields, the effect
stead unexpected nitration of the aminoquinoline di- of changing the solvent was investigated (Table 1, en-
recting group was observed (Scheme 1b, products 1a tries 3–9), whereby it was found that the best results
and 1b), thus providing a new remote Co-catalyzed were obtained when acetic acid was used (Table 1,
protocol for the functionalization of 8-aminoquinoline entry 4). Use of acetic acid as solvent furnished an
compounds, which we propose operates through an overall yield of the two quinoline nitration products
SET mechanism, similar to Cu-catalyzed 8-aminoqui- of 49%, in a similar ratio to that observed when using
À
noline C H functionalizations.
TFE as solvent. Thereafter, the Co source was opti-
Table 1. Optimization of reaction conditions.[a]
Entry
Solvent
“Co-source”
Conversion [%][b]
1a [%][b]
1b [%][b]
1[c]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18[d]
19[e]
20[f]
TFE
TFE
CHCl3
acetic acid
DMF
toluene
1,4-dioxane
EtOAc
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(acac)3
>99
55
38
60
45
34
33
44
33
25
29
87
61
40
51
74
trace
12
7
36
–
15
18
11
6
13
19
65
44
21
32
20
–
–
4
trace
13
–
6
6
3
2
5
5
22
17
10
13
7
–
25
2
THF
acetic acid
acetic acid
acetic acid
acetic acid
acetic acid
acetic acid
acetic acid
acetic acid
acetic acid
acetic acid
acetic acid
CoCl2
Co(NO3)2·6H2O
Co(BF4)2·6H2O
Co(acac)2
Co(OAc)2·4H2O
CoBr2
–
<1
>99
14
Co(NO3)2·6H2O
Co(NO3)2·6H2O
Co(NO3)2·6H2O
74
9
46
71
17
[a]
Reaction conditions: 1 (50 mg, 0.2 mmol), Co source (0.04 mmol, 20 mol%), TBN (53 mL, 90%, 2.0 equiv., 0.4 mmol), sol-
vent (1.5 mL), room temperature, 18 h.
Conversions and yields calculated from H NMR spectra of the crude reaction mixture using 1,3,5-trimethoxybenzene as
[b]
1
internal standard.
At 1008C.
4.0 equiv, TBN.
No TBN used.
[c]
[d]
[e]
[f]
10 mol% Co(NO3)2·6H2O.
Adv. Synth. Catal. 2016, 358, 1679 – 1688
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1681

FULL PAPERS
Christopher J. Whiteoak et al.
mized (Table 1, entries 10–16), where it was found sible to obtain the nitration product from 8-aminoqui-
that Co(NO3)2·6H2O was the optimal catalyst noline, 4, indicating the importance of the ancillary
(Table 1, entry 12), furnishing a combined yield of benzoyl group. The lack of desired product from 4
87% of both nitration products and also giving an ex- could be a result of the formation of highly reactive
cellent mass balance. The use of weakly coordinating diazonium compounds, which further react and result
anions such as tetrafluoroborate and nitrate appears in a complex mixture of products.
to be beneficial as these Co sources provided signifi-
Thereafter, a range of substrates bearing differently
cantly higher yields of the nitro products than Co substituted ancillary groups were synthesized
sources with stronger coordinating anions (e.g., Cl, (Table 2, compounds 6–16). In most cases it was possi-
Br, acetate and acetylacetonate). In the absence of ble to obtain excellent to quantitative overall yields
a Co source, no conversion was observed, highlighting of the nitration products. Confirmation of the struc-
the importance of Co to the conversion (Table 1, tures of the major 5- and minor 7-nitrated products
entry 17). In the absence of TBN, using was obtained from X-ray crystal structures of 11b and
Co(NO3)2·6H2O as catalyst, 11% of nitrated products 15a (see the Supporting Information, Figures S140–
was observed, indicating that the nitrate ligand can S142). There are however several notable exceptions
also act as nitro source (Table 1, entry 19), which is where the reaction was quenched; if a p-nitro group
likely as a result of the formation of HNO3 in situ. was included on the benzoyl ancillary (6) or if the an-
Subsequently the effect of increasing the TBN loading cillary group containsed a trifluoromethyl group (12),
to 4.0 equivalents was investigated, which resulted in no conversion was observed. These results suggest
quantitative conversion and yield of the nitro prod- that ancillary groups containing strong electron-with-
ucts (Table 1, entry 18). drawing moieties are unsuitable for use in the nitra-
To check if 20 mol% of Co(NO3)2·6H2O was neces- tion reaction.
sary, the catalyst loading was lowered to 10 mol% and
To investigate whether the strongly electron-with-
it was found that the combined yield of the nitrated drawing ancillary groups were unreactive or poisoning
quinolines was reduced (Table 1, entries 12 vs. 20). It the catalyst, competitive reactions were performed
should be noted that throughout this study only mon- (Scheme 2). In a single reaction vial, trifluoromethyl
onitration products have been observed (either 5- or (12) and methyl (13) containing substrates were react-
7-nitro-8-aminoquinoline) and that elevated tempera- ed at the same time and it was found that the conver-
tures appear to be highly detrimental to the reaction sion of 13 proceeded in similar yield to that in the ab-
outcome. After this optimization, it was decided that sence of 12 (Scheme 2a). This result indicates that 12
the optimal conditions for further substrate scoping did not convert due to it being unreactive rather than
would be 20 mol% Co(NO3)2·6H2O and 4.0 equiva- poisoning the catalyst.
lents of TBN in acetic acid at room temperature. This
In a similar manner, the reason why the substrate
optimized protocol is adventitious over traditional ni- containing the tert-butyl group (15), which afforded
tration procedures as it avoids the use of highly corro- significantly reduced nitration products, was investi-
sive H2SO4 and HNO3 as reagents.
gated. Again, the related substrate bearing the methyl
The optimized nitration protocol was then used containing ancillary was used for the competition and
with a number of other structurally related substrates little inhibition of the formation of the nitration prod-
(Figure 1, substrates 2–5). In all cases it was not possi- ucts of 13 was observed (Scheme 2b). We therefore
ble to achieve the desired nitration products, thus in- propose that the tert-butyl group is preventing the Co
dicating the necessity for the secondary amide and from coordinating to the amide through steric effects;
quinoline in the substrate. Importantly, it was not pos- indeed, the less sterically demanding isopropyl con-
taining substrate (14) could be successfully converted
(Table 2). From the results obtained in this study it
was decided to continue using the benzoyl ancillary
group for future studies as a result of the high yields,
low cost and easy installation/cleavage (vide infra).
After ancillary group optimization, the potential for
the reaction protocol to be transferred to a gram-
scale and upgrading of the nitrated products was in-
vestigated (Scheme 3). We were pleased to find that
when starting from 1.89 g of 1 it was possible to
obtain attractive isolated yields of product 1a (1.35 g,
61%) and also a sufficient amount of product 1b
(410 mg, 18%) to perform the upgrading experiments.
The gram-scale experiments also led us to find a new
facile route for isolation of the products, as it was
Figure 1. Unsuccessful substrates using the optimized reac-
tion conditions.
1682
asc.wiley-vch.de
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 1679 – 1688

À
FULL PAPERS
A First Example of Cobalt-Catalyzed Remote C H Functionalization
Table 2. Screening of different ancillary groups.[a,b,c]
[a]
Reaction conditions: substrate (0.5 mmol), Co(NO3)2·6H2O (29.1 mg, 0.1 mmol, 20 mol%), TBN (267 mL, 90%,
4.0 equiv., 2.0 mmol), acetic acid (3.5 mL), room temperature, 18 h.
Conversions and yields calculated from H NMR spectra of the crude reaction mixture using 1,3,5-trimethoxyben-
zene as internal standard.
Isolated yields in parenthesis.
[b]
[c]
1
found that 1a was significantly less soluble in ethanol using Pd/C and H2 (1 atm). These diamines may in
than 1b, permitting easy separation (see the Support- the future find a wide range of applications, given
ing Information for details).
that their ease of synthesis should make them rela-
With analytically pure samples in hand, reactions tively cheap synthetic precursors for increasing molec-
targeting the removal of the ancillary group and re- ular complexity, compared with other substituted 8-
duction of the nitro groups to amines were attempted aminoquinolines.
(Scheme 3). Reduction of 1a using Pd/C and H2 (1
There are currently few inexpensive derivatives of
atm) results in selective formation of 1c in 86% isolat- the 8-aminoquinoline scaffold commercially available.
ed yield, whereby the amide remains unaffected. The To further study the versatility of our Co-catalyzed
(benza)amide ancillary groups of both 1a and 1b can methodology, 5-substituted-8-nitroquinolines were
be easily removed by heating the compounds in boil- prepared through Skraup reactions,[29] and were sub-
ing acidic ethanol to furnish the desired 5-nitro-8-ami- sequently reduced using Pd/C and H2, before addition
noquinoline (A) and 7-nitro-8-aminoquinoline (B), of the ancillary benzoyl group (see the Supporting In-
respectively, in excellent yields. The nitro-8-aminoqui- formation for details of the preparation of 17, 18, and
nolines can then be easily converted into the corre- 19). Substrates 1a and 1c were prepared during this
sponding diamines in excellent yield as exemplified work (Scheme 3). Applying the optimized reaction
by the conversion of A to 5,8-diaminoquinoline (C) conditions to these substrates furnished 17b, 18b and
Adv. Synth. Catal. 2016, 358, 1679 – 1688
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1683

FULL PAPERS
Christopher J. Whiteoak et al.
Scheme 2. Reactions performed to investigate the nature of the inactivity/poor activity of substrates 12 (a) and 15 (b). Yields
1
calculated from H NMR spectra of the crude reaction mixture using 1,3,5-trimethoxybenzene as internal standard and are
based on conversion of the corresponding substrate. Reaction conditions: substrate (0.5 mmol; 0.25 mmol of each substrate),
Co(NO3)2·6H2O (29.1 mg, 0.1 mmol, 20 mol%), TBN (267 mL, 90%, 4.0 equiv., 2.0 mmol), acetic acid (3.5 mL), room tem-
perature, 18 h.
19b in good to excellent isolated yields, with selective a strong oxidizing species in acid media[30,31] and as
formation of the 7-nitro products (Table 3). In line a result a SET from the quinoline occurs to yield
with the exclusive mononitration observed previously a cationic quinoline radical and Co(II). Subsequently,
(Table 2), when the substrate contained a nitro sub- NO2, generated in situ from TBN, reacts with the
stituent, it was not possible to convert 1a, with only quinoline radical and a concerted proton transfer/de-
trace amounts of product obtained. The amine con- metallation step provides the nitration product and
taining substrate, 1c, derived from 1a, also failed to Co(II)X2. This proposed mechanism is similar to the
give the desired product, suggesting interference of Cu(II)-catalyzed chlorination of 8-aminoquinolines
the primary amine in the catalysis. When this sub- reported by Stahl and co-workers, in that the key in-
strate was dimethylated at the amine (1d), it was pos- termediate is a cationic quinoline radical species.[5] To
sible to obtain the nitrated product 1db in an 80% the best of our knowledge this work represents the
isolated yield. This result indicates that the amine of first example of a SET remote functionalization of 8-
1c should be pre-functionalized before further nitra- aminoquinoline using Co. The absence of activity
tion is attempted. Compound 1db contains amine, when strong electron-withdrawing groups are present
nitro and amide functionalities which can be derivat- in the substrate structure (1a, 6 and 12) further indi-
ized independently making it an excellent candidate cates the plausibility of the proposed cationic quino-
for further upgrading.
line radical species. To further highlight this effect
Taking into account all the observations during this a competitive reaction between 17 and 19 was per-
study, the SET based mechanism depicted in formed (Scheme 5a), where it was observed that 19b
Scheme 4 is proposed. Initially Co(II) coordinates to was obtained in >99% yield and 17b in 41%, with re-
the substrate, and is oxidized to Co(III) by the tert- spect to the individual starting substrates, confirming
butoxy radical generated through the decomposition the preference for substrates containing electron-do-
of TBN with O2. The resulting Co(III) species is nating substituents as would be expected for the pro-
1684
asc.wiley-vch.de
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 1679 – 1688

À
FULL PAPERS
A First Example of Cobalt-Catalyzed Remote C H Functionalization
Scheme 3. Gram-scale nitration reaction and subsequent upgrading of nitrated products obtained; Isolated yields reported.
Reaction conditions for gram-scale nitration reaction: 1 (1.89 g, 7.6 mmol), Co(NO3)2·6H2O (443 mg, 1.5 mmol, 20 mol%),
TBN (4.1 mL, 90%, 4.0 equiv., 30.4 mmol), acetic acid (50 mL), room temperatrure, 18 h.
posed SET mechanism. Furthermore, a kinetic iso-
tope experiment (KIE) revealed (Scheme 5b) a kH/kD
Table 3. Screening of different 8-aminoquinoline scaf-
folds.[a,b,c]
value of 0.97, indicating that the rate-limiting step is
À
not a C H activation and adding further evidence for
the proposed mechanism.
Conclusions
In conclusion, a new practical room-temperature Co-
catalyzed remote nitration protocol for the prepara-
tion of 5- and 7-nitro-8-aminoquinolines using easily
installable and removable ancillary groups has been
developed. The protocol is proposed to operate
À
through a previously unreported remote C H func-
tionalization route based on a SET mechanism for the
described 8-aminoquinoline substrates. This new
methodology is intended to inspire further work into
the development of new facile and mild catalytic
routes for the preparation of newly functionalized 8-
aminoquinoline compounds. Indeed, we are now
working towards the installation of other functional
groups using this radical-based protocol and also the
application of the products obtained in this study, in
particular the utilization of differently substituted 8-
[a]
Reaction
conditions:
substrate
(0.5 mmol),
Co(NO3)2·6H2O (29.1 mg, 0.1 mmol, 20 mol%), TBN
(267 mL, 90%, 4.0 equiv., 2.0 mmol), acetic acid (3.5 mL),
room temperature, 18 h.
Isolated yields reported.
Selectivity >99% in all cases.
À
aminoquinolines as directing groups in C H activa-
tion protocols.
[b]
[c]
Adv. Synth. Catal. 2016, 358, 1679 – 1688
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1685

FULL PAPERS
Christopher J. Whiteoak et al.
Scheme 4. Proposed mechanism for the nitration reaction at C-5.
Scheme 5. (a) Competition reactions performed to investigate relative reactivity of substrates 17 and 19. Yields calculated
1
from H NMR spectra of the crude reaction mixture using 1,3,5-trimethoxybenzene as internal standard and are based on
conversion of corresponding substrate. Reaction conditions: substrate (0.5 mmol; 0.25 mmol of each substrate),
Co(NO3)2·6H2O (29.1 mg, 0.1 mmol, 20 mol%), TBN (267 mL, 90%, 4.0 equiv., 2.0 mmol), acetic acid (3.5 mL), room tem-
perature, 18 h. (b) Summary of kinetic isotope experiment (KIE); for further details see the Supporting Information.
1686
asc.wiley-vch.de
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 1679 – 1688

À
FULL PAPERS
A First Example of Cobalt-Catalyzed Remote C H Functionalization
[6] For an expanded substrate scope see the more recent
Experimental Section
paper by Xie and co-workers: H. Guo, M. Chen, P.
Jiang, J. Chen, L. Pan, M. Wang, C. Xie, Y. Zhang, Tet-
rahedron 2015, 71, 70.
General Procedure for Cobalt-Catalyzed Nitration
Reactions
[7] See: a) H.-W. Liang, K. Jiang, W. Ding, Y. Yuan, L.
Shuai, Y.-C. Chen, Y. Wei, Chem. Commun. 2015, 51,
16928; b) H. Qiao, S. Sun, F. Yang, Y. Zhu, W. Zhu, Y.
Dong, Y. Wu, X. Kong, L. Jiang, Y. Wu, Org. Lett.
2015, 17, 6086; c) J. Wei, J. Jiang, X. Xiao, D. Lin, Y.
Deng, Z. Ke, H. Jiang, W. Zeng, J. Org. Chem. 2016,
DOI: 10.1021/acs.joc.5b02509; d) J. Xu, C. Shen, X.
Zhu, P. Zhang, M. J. Ajitha, K.-W. Huang, Z. An, X.
Liu, Chem. Asian J. 2016, DOI: 10.1002/asia.201501407.
[8] X.-F. Xia, S.-L. Zhu, Z. Gu, H. Wang, RSC Adv. 2015,
5, 28892.
A 10-mL vial was charged with 0.5 mmol of substrate,
Co(NO3)2·6H2O (29.1 mg, 20 mol%, 0.1 mmol), tert-butyl ni-
trite (TBN) (267 mL, 90%, 4.0 equiv., 2.0 mmol) and 3.5 mL
of acetic acid. The vial was sealed and the reaction stirred at
room temperature for 18 h. After this period the reaction
mixture was diluted with ethyl acetate (30 mL) and extract-
ed using brine (20 mL). The aqueous layer was then extract-
ed with ethyl acetate (2”30 mL), the organic layers com-
bined, dried over magnesium sulfate and the solvent re-
moved under reduced pressure. The crude reaction mixture
was purified by column chromatography, using dichlorome-
thane as eluent unless stated, providing analytically pure ni-
trated products.
[9] L. Zhu, R. Qiu, X. Cao, S. Xiao, X. Xu, C.-T. Au, S.-F.
Yin, Org. Lett. 2015, 17, 5528.
[10] Note that in ref.[7d] other examples of couplings using
a Cu SET methodology are described; N(SO2Ph)2,
OAc, Br, I and CF3; therefore highlighting the future
1
Full characterization data obtained (including original H,
13C {1H} and COSY NMR spectra for all products and new
compounds) can be found in the Supporting Information.
CCDC 1438116 (11b), CCDC 1438117 (13b) and CCDC
1438118 (15a) contain the supplementary crystallographic
data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
À
potential for SET C H functionalization methodolo-
gies.
[11] H. Sahoo, M. K. Reddy, I. Ramakrishna, M. Baiyda,
Chem. Eur. J. 2016, 22, 1592.
[12] X. Cong, X. Zeng, Org. Lett. 2014, 16, 3716.
[13] J. Zhou, B. Li, F. Hu, B.-F. Shi, Org. Lett. 2013, 15,
3460.
[14] N. Ono, The Nitro Group in Organic Synthesis, Wiley-
VCH, New York, 2001.
Acknowledgements
[15] G. A. Olah, R. Malhotra, S. C. Narang, Nitration: Meth-
ods and Mechanisms, Wiley-VCH, New York, 1989
[16] a) G. Yan, M. Yang, Org. Biomol. Chem. 2013, 11,
2554; b) G. Yan, A. J. Borah, L. Wang, Org. Biomol.
Chem. 2014, 12, 6049.
[17] For representative examples, see: a) K. I. H. Williams,
S. E. Cremer, F. W. Kent, E. J. Sehm, D. S. Tarbell, J.
Am. Chem. Soc. 1960, 82, 3982; b) M. Nakata, S. Wada,
K. Tatsuta, M. Kinoshita, Bull. Chem. Soc. Jpn. 1985,
58, 1801; c) M. N. Gandy, M. J. Piggot, J. Nat. Prod.
2008, 71, 866.
We acknowledge financial support from the ERC for the
Starting Grant ProjectERC-2011-StG-277801 to X.R and
MINECO of Spain for CTQ2013-43012-P to X.R. and A.C.,
and a RyC contract to A.C. We thank the MECD for a FPU
PhD grant to O.P and Generalitat de Catalunya (2014 SGR
862). X.R. also thanks ICREA for ICREA-Acad›mia 2010
and 2015 awards. We are also grateful to X. Fontrodona (X-
ray crystallography), Dr. L. Gómez (HR-MS) and STR-
UdG.
[18] S. Saito, Y. Koizumi, Tetrahedron Lett. 2005, 46, 4715.
[19] B. P. Fors, S. L. Buchwald, J. Am. Chem. Soc. 2009, 131,
12898.
References
[20] For examples of Pd-catalyzed nitration reactions, see:
a) Y.-K. Liu, S.-J. Lou, D.-Q. Xu, Z-Y. Xu, Chem. Eur.
J. 2010, 16, 13590; b) W. Zhang, S. Lou, Y. Liu, Z. Xu,
J. Org. Chem. 2013, 78, 5932; c) J. Dong, B. Jin, P. Sun,
Org. Lett. 2014, 16, 4540; d) W. Zhang, S. Ren, J.
Zhang, Y. Liu, J. Org. Chem. 2015, 80, 5973.
[21] For examples of Cu-catalyzed nitration reactions, see:
a) L. Zhang, Z. Liu, H. Li, G. Fang, B.-D. Barry, T. A.
Belay, X. Bi, Q. Liu, Org. Lett. 2011, 13, 6536; b) J. Liu,
S. Zhuang, Q. Gui, X. Chen, Z. Yang, Z. Tan, Adv.
Synth. Catal. 2015, 357, 732; c) D. Katayev, F. F. Pfister,
T. Wendling, L. J. Gooßen, Chem. Eur. J. 2014, 20,
9902.
[1] J. Recht, E. Ashley, N. White, Safety of 8-Aminoquino-
line Antimalarial Medicines, World Health Organiza-
tion, 2014.
[2] a) J. Yoon, S. A. Wilson, Y. K. Jang, M. S. Seo, K.
Nehru, B. Hedman, K. O. Hodgson, E. Bill, E. I. Solo-
mon, W. Nam, Angew. Chem. 2009, 121, 1283; Angew.
Chem. Int. Ed. 2009, 48, 1257; b) S. Hong, Y.-M. Lee,
K.-B. Cho, K. Sundaravel, J. Cho, M. J. Kim, W. Shin,
W. Nam, J. Am. Chem. Soc. 2011, 133, 11876.
[3] For examples, see: M. Corbet, F. De Campo, Angew.
Chem. 2013, 125, 10080; Angew. Chem. Int. Ed. 2013,
52, 9896.
[22] tert-Butyl nitrate is a known source of nitrogen monox-
ide, see: P. G. Wang, T. B. Cai, N. Taniguchi, in: Nitric
Oxide Donors: for Pharmaceutical and Biological Ap-
plication, (Eds.: P. G. Wang, T. B. Cai, N. Taniguchi),
Wiley-VCH, Weinheim, 2005.
[4] For a review of quinoline functionalization reactions,
see: T. Iwai, M. Sawamura, ACS Catal. 2015, 5, 5031,
and references cited therein.
[5] A. M. Seuss, M. Z. Ertem, C. J. Cramer, S. S. Stahl, J.
Am. Chem. Soc. 2013, 135, 9797.
Adv. Synth. Catal. 2016, 358, 1679 – 1688
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1687

FULL PAPERS
Christopher J. Whiteoak et al.
[23] In the presence of oxygen the autoxidation of nitrogen
monoxide results in nitrogen dioxide: a) S. Goldstein,
G. Czapski, J. Am. Chem. Soc. 1995, 117, 12078; b) L.
Grossi, S. Strazzari, J. Org. Chem. 1999, 64, 8076; c) B.
Galliker, R. Kissner, T. Nauser, W. H. Koppenol,
Chem. Eur. J. 2009, 15, 6161.
[24] For examples of transition metal free nitration reac-
tions using tert-butyl nitrate see: a) T. Taniguchi, A.
Yajima, H. Ishibashi, Adv. Synth. Catal. 2011, 353,
2643; b) M. Hu, B. Liu, X.-H. Ouyang, R.-J. Song, J.-H.
Li, Adv. Synth. Catal. 2015, 357, 3332; c) S. Maity, T.
Naveen, U. Sharma, D. Maiti, Org. Lett. 2013, 15, 3384;
d) B. Kilpatrick, M. Heller, S. Arns, Chem. Commun.
2013, 49, 514; e) J. Zhao, P. Li, C. Xia, F. Li, RSC Adv.
2015, 5, 32835; f) D. Koley, O. C. Colón, S. N. Savinov,
Org. Lett. 2009, 11, 4172.
79, 8948; b) M. Moselage, J. Li, L. Ackermann, ACS
Catal. 2016, 6, 498; c) D. Wei, X. Zhu, J.-L. Niu, M.-P.
Song,
ChemCatChem.
2016,
DOI:
10.1002/
cctc.201600040.
[27] O. Planas, C. J. Whiteoak, A. Company, X. Ribas, Adv.
Synth. Catal. 2015, 357, 4003.
[28] See refs.[21b,21c]
[29] For a general procedure, see: G. He, S.-Y. Zhang,
W. A. Nack, Q. Li, G. Chen, Angew. Chem. 2013, 125,
11330; Angew. Chem. Int. Ed. 2013, 52, 11124.
[30] Co(III) acetate compounds are strong one-electron oxi-
dizing species, see: J. D. Donaldson, D. Beyersmann,
Cobalt and Cobalt Compounds, in: Ullmannꢀs Encyclo-
pedia of Industrial Chemistry, Wiley-VCH, 2005.
À
[31] Cobalt-catalyzed SET C H activation mechanisms
have been previously implicated, see, for example:
a) J. K. Kochi, R. T. Tang, T. Bernath, J. Am. Chem.
Soc. 1973, 95, 7114; b) X.-K. Guo, L.-B. Zhang, D. Wei,
J.-L. Niu, Chem. Sci. 2015, 6, 7059.
[25] For an example of a metal-catalyzed nitration protocol
using tert-butyl nitrate, see ref.[20d]
[26] For an overview of cobalt-catalyzed C H activation
À
protocols, see: a) L. Ackermann, J. Org. Chem. 2014,
1688
asc.wiley-vch.de
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 1679 – 1688