Palladium-Catalyzed C-H Functionalization of Ferrocenecarboxylic Acid by using 8-Aminoquinoline as a Removable Directing Group

Article abstract of DOI:10.1002/adsc.201500791

A mild and efficient palladium-catalyzed synthetic method for the C-H functionalization of N-(quinolin-8-yl)ferrocenecarboxamide has been developed. Various aryl iodides containing I, NO₂, CN, COMe, CO₂Et, and NH functionalities and also alkyl iodides underwent the Pd-catalyzed intermolecular carbon-carbon bond forming reaction with ferrocenecarboxamide successfully which led to a diverse array of bis(aryl/alkyl)ferrocenecarboxamides in 34-92% yields. Cross-coupling of the ferrocenyl C-H bond with aryl iodides can also be achieved utilizing an economical Ni catalyst. Additionally, selective monoalkylation of ferrocenecarboxamide was studied using sodium bicarbonate as base and dibenzylphosphoric acid as additive under Pd-catalyzed reaction conditions. Subsequently, removal of the directing group, 8-aminoquinoline, from bis(aryl)ferrocenecarboxamides led to bis(aryl)ferrocenes bearing versatile methyl ester and carboxaldehyde functional groups.

Full text of DOI:10.1002/adsc.201500791

FULL PAPERS
DOI: 10.1002/adsc.201500791
À
Palladium-Catalyzed C H Functionalization of Ferrocene-
carboxylic Acid by using 8-Aminoquinoline as a Removable
Directing Group
Moh. Sattar,a Praveen,a Ch. Durga Prasad,a Ajay Verma,a Shailesh Kumar,a
and Sangit Kumara,*
a
Department of Chemistry, Indian Institute of Science Education and Research (IISER), Bhopal, MP – 462 066, India
E-mail: sangitkumar@iiserb.ac.in
Received: August 23, 2015; Revised: October 15, 2015; Published online: January 5, 2016
Dedicated to Professor Harkesh B. Singh, IIT Bombay on the occasion of his 60th birthday.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500791.
Abstract: A mild and efficient palladium-catalyzed monoalkylation of ferrocenecarboxamide was stud-
À
synthetic method for the C H functionalization of ied using sodium bicarbonate as base and dibenzyl-
N-(quinolin-8-yl)ferrocenecarboxamide has been de- phosphoric acid as additive under Pd-catalyzed reac-
veloped. Various aryl iodides containing I, NO2, CN, tion conditions. Subsequently, removal of the direct-
COMe, CO2Et, and NH functionalities and also alkyl ing group, 8-aminoquinoline, from bis(aryl)ferro-
iodides underwent the Pd-catalyzed intermolecular cenecarboxamides led to bis(aryl)ferrocenes bearing
carbon-carbon bond forming reaction with ferro- versatile methyl ester and carboxaldehyde functional
cenecarboxamide successfully which led to a diverse groups.
array of bis(aryl/alkyl)ferrocenecarboxamides in 34–
92% yields. Cross-coupling of the ferrocenyl C H Keywords: biaryls; C C cross coupling; ferrocenes;
bond with aryl iodides can also be achieved utilizing ligand-directed C H functionalization; nickel cata-
an economical Ni catalyst. Additionally, selective lysts; palladium catalysts
À
À
À
Introduction
philes followed by substitution reactions with various
electrophiles. A significant advantage of this approach
Functionalized ferrocenes have attracted considerable is the presence of ortho-directing groups for the met-
interest in catalysis, materials science and as compo- allation, which allow the precise control of regioselec-
nents of polymers, molecular switches, drugs, and sen- tivity or stereoselectivity for the synthesis of 1,2-di-
sors.[1–6] Most applications involve the use of di-, tri- substituted ferrocenes.[8] On the other hand, organo-
or even higher substituted ferrocenes such as tetra- lithium reagents are highly reactive and impose re-
phenyl-substituted ferrocenes which can be used as strictions related to functional group tolerance. Partic-
molecular switches for complexations,[2a] bis(4-bromo- ularly, coupling partners containing functionalities
phenyl)ferrocene which is used as the precursor for such as NO2, I, CN, CO2Et, CHO and NH, which are
the synthesis of redox-active conjugated polymers,[2b] important for further functionalization in the post-
also aryl ring-containing ferrocenes exhibit potential modification strategy, have not been documented.
antitumor activities,[3b,c,d] and 2-silylated/germylated/ Moreover, ortho-lithiation and Friedel–Crafts reac-
phosphorylated arylferrocenes are effective precur- tions are not viable routes to construct arylferrocenes
À
sors for enantioselective C H functionalization of due to the poor reactivity of the aryl halides in these
metallocenes.[7]
reactions.
Transition metal (TM)-catalyzed C H functionali-
À
Consequently, there is a permanent interest in new
strategies for the derivatization of ferrocene. The zation of cyclopentadienyl rings is an atom economi-
most common methods of functionalization of ferro- cal alternative approach for structural diversification.
cene are Friedel–Crafts reactions and the use of orga- Although C H functionalization of ferrocenes by var-
nolithium reagents, which generate potent nucleo- ious transition metals have been presented in the lit-
À
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Palladium-Catalyzed C H Functionalization of Ferrocenecarboxylic Acid
À
Scheme 1. C H functionalization of N-(quinolin-8-yl)ferrocenecarboxamide.
À
À
erature, limited reports on the catalytic C H func-
Here we present a Pd- or Ni-catalyzed C H func-
tionalization of ferrocenes are available.[9–13] Shibata tionalization of readily accessible N-(quinolin-8-yl)fer-
et al. have presented an elegant Ir-catalyzed method- rocenecarboxamide for the synthesis of diversely sub-
ology for the alkenylation and alkylation of ferro- stituted bis(arylated), bis(alkylated), and monoalky-
cenes.[6a,b,11]
lated ferrocenecarboxamides (Scheme 1). Additional-
À
Oxazoline ligand-directed C H arylation of ferro- ly, the 8-aminoquinoline directing group has
cenes has been studied using Pd(II) complexes, none- been removed and thereby synthesized bis(aryl)ferro-
theless, a stoichiometric amount of the expensive Pd- cenecarboxamides were transformed into bis(aryl)fer-
catalyst is required, additionally reactions are poor rocenecarboxaldehydes and esters.
yielding and showed poor substrate scope.[12] Ferro-
cenes bearing oxazoline directing groups are either
expensive or difficult to synthesize. Also conversion Results and Discussion
of oxazoline to acid/ester or aldehyde is difficult be-
cause of the stability of ferrocene under harsh reac- For optimization of the reaction conditions, ferro-
tion conditions. On the other hand, functionalities cenes with various amide directing groups (1a–1f)
such as ester and CHO are desirable for further trans- were synthesized and treated with iodobenzene in the
formation at later stages.
presence of a base, additives, and TM catalysts in var-
The pioneering work of Chatani,[14] Daugulis,[15] and ious solvents. N-Isopropyl-, N-methoxy-, and N-phe-
others[16,17] in the area of ligand-directed TM-cata- nylferrocenecarboxamides 1a–1c failed to give any C
À
À
lyzed C H arylation and alkylation, as well as several H arylated product with iodobenzene in the presence
formidable applications in total synthesis served as of Pd(OAc)2 catalyst, Cs2CO3 and AgOAc in toluene
our inspiration for this work. The substrate containing at 1208C (entries 1–3, Table 1).
bidentate ligand would bind tightly to the catalyst in
N-2-Pyridylferrocenecarboxamide 1d bearing a coor-
À
À
close proximity of the C H bond and hence enhances dinating N-atom provided a 54% yield of the C H
À
the functionalization of C H bond under mild reac- functionalized
bis(phenyl)-N-2-pyridylferrocenecar-
tion conditions. Also bidentate ligand strategies boxamide 2a (entry 4, Table 1). N-(2-Methylthiophe-
enable economically viable transition metals such as nyl)ferrocenecarboxamide having a methylthio coor-
À
Cu and Ni to act as catalysts for the functionalization dinating group failed to yield C H arylated ferrocene,
of C H bonds. Additionally, the bidentate directing unexpectedly (entry 5, Table 1). Next, the ferrocene-
À
group can be transformed or removed to obtain vari- carboxamide having an 8-aminoquinoline directing
ous synthetically useful functional groups on ferro- group yielded 83% of arylated ferrocence 3a. More-
cene.
over, a slightly better yield (93%) of 3a was obtained
Our group has utilized aryl amide substrates for in- in the absence of AgOAc (entry 7, Table 1). The use
tramolecular carbon-carbon and carbon-heteroatom of silver acetate alone offered a comparatively low
(nitrogen, oxygen, sulfur, and selenium) bond forming yield of 3a (entry 8, Table 1). Next, various bases such
reactions for the synthesis of various heterocycles via as NaHCO3, Na2CO3, and K2CO3 were screened in
[18]
À
functionalization of carbon-halogen or C H bonds.
the Pd-catalyzed reaction, nonetheless, all proved to
À
Nonetheless, C H functionalization of aryl amides for be less effective (entries 9–11, Table 1). The reaction
an intermolecular carbon-carbon coupling reaction can also be carried out in t-BuOH and t-amylOH sol-
has not been achieved.
vents, albeit with low yields (45 and 40%, respective-
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Moh. Sattar et al.
Table 1. Optimization for arylation of ferrocene carboxamide.[a]
Entry
TM
DG
Base
Solvent
Yield[%][b]
1[c]
2[c]
3[c]
4[c]
5[c]
6[c]
7
8
9
10
11
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
PdCl2
1a
1b
1c
1d
1e
1f
1f
1f
1f
1f
1f
1f
1f
1f
1f
1f
1f
1f
1f
1f
1f
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
AgOAc
NaHCO3
Na2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NaHCO3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
t-BuOH
t-amyl-OH
DCE
toluene
toluene
toluene
toluene
toluene
toluene
toluene
NR
NR
NR
2a [54]
NR
3a [83]
3a [92]
3a [74]
3a [47]
3a [24]
3a [55]
3a [45]
3a [40]
3a [84]
NR
3a [38]
3a [44]
NR
NR
3a [50]
3a [78]
12
13
14
15
16
17
PdCl2 (ACN)2
NiCl2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
18[d]
19[d]
20[e]
21[f]
[a]
Amide 1 (0.1 mmol, 35.6 mg), PhI (0.3 mmol, 33 mL), Pd(OAc)2 (10 mol%, 2 mg) Cs2CO3 (0.25 mmol, 86 mg) in toluene
(1.5 mL) at 1208C for 8–16 h unless otherwise noted.
Isolated yields.
1.1 equiv. of AgOAc and Cs2CO3 were used.
Reaction was carried out at 1208C for 18 h.
[b]
[c]
[d]
[e]
[f]
Reaction at 1408C, for 18 h.
Reaction at 1608C, for 18 h. NR=no reaction.
ly) being obtained (entries 12 and 13, Table 1). 1,2-Di- switching the base from Cs2CO3 to NaHCO3 and ele-
chloroethane provided a comparable yield (84%) of vating temperature from 140 to 160 8C, the yield of
3a as obtained from toluene (entry 4 vs. 7, Table 1). the product increased by 28% (entry 21, Table 1).
Among various Pd catalysts screened, Pd(OAc)2 was
observed to be effective for C H functionalization of 10 mol% of Pd(OAc)2, 2.5 equiv. of Cs2CO3 in toluene
1f (entries 14–17, Table 1).
After screening of various conditions, we chose
À
to study the substrate scope of the reaction
Next, an economically viable Ni(II) catalyst was ex- (Scheme 2). Also Ni(OTf)2 as catalyst in the presence
À
plored for C H functionalization of ferrocenecarbox- of NaHCO3 in toluene at 1608C was also employed in
amide 1f (entries 18–21, Table 1). Disappointingly, selected examples. As evident from the Scheme 2, p-
À
substitution of Pd(II) with Ni(II) failed in the C H methyl-, p-ethyl-, p-tert-butyl- and p-trifluoromethyl-
functionalization of 1f under the optimized reaction phenyl iodides successfully reacted with N-(quinolin-
conditions. Elevating the temperature to 1408C pro- 8-yl)ferrocenecarboxamide 1f to form 2,5-bis(4-alkyl-
vided a moderate yield of 3a under the optimized re- benzene)-1-N-(quinolin-5-yl)ferrocenecarboxamides
action conditions (entry 20, Table 1). Furthermore, on 3b–3e in 70–80% yields under Pd-catalyzed reaction
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Palladium-Catalyzed C H Functionalization of Ferrocenecarboxylic Acid
Scheme 2. Substrate scope with regard to aryl/heteroaryl iodides. Unless otherwise stated, isolated yields using 10 mol% of
Pd(OAc)2 in toluene are given.
conditions. Next, bis(4-substituted benzene)-1-N-(qui-
Synthesis of selected bis(aryl)ferrocenecarbox-
nolin-5-yl)ferrocenamides 3f–3i with electron-donat- amides has also been studied under economical Ni-
ing functional groups such as OCH3, N(CH3)2, and catalyzed reaction conditions and compared with the
electron-withdrawing groups NO2, CN, C(O)CH3, Cl, yields obtained using Pd-catalyst. Bis(aryl)ferrocene-
and even iodo were also obtained in good yields. Sim- carboxamides 3f, 3m, and 3n having electron-donating
ilarly, meta, di-meta, and para-substituted-arylferroce- methyl and methoxy substituents were obtained in
necarboxamides 3l–3q were obtained under the opti- poor yields under Ni-catalyzed reaction conditions as
mized Pd-catalyzed reaction conditions. On the other compared to Pd-catalyst (40, NR, and 10% for Ni cat-
hand, ortho-substituted aryl iodides reacted sluggishly alyst vs. 74, 75, and 69% for Pd catalyst). On the
and only one ortho-methylbenzeneferrocenecarboxa- other hand bis(4-nitrophenyl)ferrocenecarboxamide
mide 3p was obtained in 45% yield under the opti- 3k having electron-withdrawing NO2 groups was ob-
mized conditions while o-NO2-, o-OMe-, and o- tained in 68% yield which is comparable to the yield
CH2CO2H-substituted phenyl iodides were observed (75%) obtained using Pd catalyst.
to be unreactive, presumably due to the steric effect.
After synthesizing various bis(aryl)ferrocenecar-
Next, N-methylindolyl iodide and indolyl iodide boxamides, we explored the synthesis of bis(alkyl)fer-
having acidic NH proton showed compatibility to the rocenecarboxamides and monosubstituted aryl- and
Pd-catalyzed conditions and yielded the respective in- alkylferrocenecarboxamides. Unfortunately, the syn-
dolylferrocenecarboxamides 3u and 3v in 68 and 34% thesis of bis(alkyl)ferrocenecarboxamide and also se-
yields, respectively. A heteroarene, 2-iodothiophene, lective monoarylation of ferrocenecarboxamide 1f
also smoothly reacted with ferrocenecarboxamide 1f could not be accomplished under the optimized reac-
to
form
novel
2,5-bis(thiophenyl)ferro- tion conditions by varying the stoichiometry of alkyl
and aryl iodides. Therefore, we searched for reaction
cenecarboxamide 3w in moderate 56% yield.
Structures of bis(phenyl)-, bis(4-iodophenyl)- and conditions which could provide access to bis(alkyl)-
bis(thiophenyl)ferrocenecarboxamides 3a, 3i and 3w and selective monoaryl- or alkyl-substituted ferroce-
are also determined by single crystal X-ray study necarboxamides (Table 2).
(Figure 1, for details, see the Supporting Information,
The reaction in toluene provided traces or poor
yield of bis(ethyl)ferrocenecaboxamide 4a. The reac-
pages S152–S159).[19]
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Moh. Sattar et al.
Figure 1. ORTEP views of 4-iodophenyl- and 2-thiophenylferrocenecarboxamides 3i and 3w.
tion in tert-amyl alcohol and dichoroethane solvents acetate reacted smoothly with ferrocenecarboxamide
combination (1:1) in the presence of (BnO)2POOH 1f to form bis(alkyl)ferrocenecarboxamides 4b–4i in
additive smoothly provided bis(ethyl)ferrocenecar- the presence of Cs2CO3 in an equimolar mixture of
boxamide 4a in 55% yield (entry 6, Table 2). Interest- tert-amyl alcohol and DCE under Pd-catalyzed reac-
ingly, use of sodium bicarbonate under similar reac- tion conditions.
tion conditions yielded monoethylferrocenecarbox-
Next, various monoalkyl-substituted ferrocenecar-
amide 5a in 45% yield (entry 12, Table 2).
boxamides 5a–5f were obtained using NaHCO3 in
As summarized in Scheme 3, various primary alkyl place of Cs2CO3 under optimized reaction conditions
iodides namely, methyl, n-propyl, n-butyl, n-hexyl, n- (entry 12, Table 2). The obtained yields of monoalkyl-
octyl, isopentyl and even benzyl iodides and iodoethyl substituted ferrocenecarboxamides 5a–5f were moder-
Table 2. Reaction conditions for the synthesis of bisalkyl- and monoalkylferrocenecarboxamides.[a]
Entry
Base
Additive
Solvent
Yield [%] of monoalkyl/dialkyl product[b]
1
2
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Na2CO3
Cs2CO3
K2HPO4
Na2HPO4
NaHCO3
NaHCO3
K2HPO4
NaHCO3
–
toluene
toluene
toluene
trace
0/20
0/35
0/45
0/35
0/66
40/5
35/15
15/15
40/8
15/5
45/0
AgOAc
3
(BnO)2POOH
(BnO)2POOH
(BnO)2POOH
(BnO)2POOH
(BnO)2POOH
(BnO)2POOH
(BnO)2POOH
Piv-OH
4[b]
5
t-amyl-OH:DCE
t-amyl-OH:DCE
t-amyl-OH:DCE
t-amyl-OH:DCE
t-amyl-OH:DCE
t-amyl-OH:DCE
t-amyl-OH:DCE
t-amyl-OH:DCE
t-amyl-OH:DCE
6
7
8
9[c]
10
11
12
Piv-OH
(BnO)2POOH
[a]
Reaction was carried out on a 0.1 mmol scale using 2.5 equiv. of iodoethane, 2.5 equiv. of base, 0.3 equiv. of additive, and
10 mol% of Pd(OAc)2 under argon, unless otherwise noted.
isolated yield.
t-Amyl-OH:DCE in a 1:1 ratio was used.
PdCl2(MeCN)2 was used.
[b]
[c]
[d]
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Palladium-Catalyzed C H Functionalization of Ferrocenecarboxylic Acid
Scheme 3. Selective monoalkylation and dialkylation. Isolated yields are given.
ate (32–46%) and the rest of the unreactive ferroce- to 3a in CH3CN at room temperature was unsuccess-
necarboxamide 1f was recovered from the reaction. ful. Treatment of 3a and 3f with BF3·OEt2 in CH3OH
We also attempted the synthesis of monoarylated fer- led to the smooth removal of 8-aminoquinoline, re-
rocenecarboxamides under optimized reaction condi- sulting in bis(aryl)ferrocenoylmethyl acetates 7a and
tions (entry 12, Table 2). Disappointingly, a mixture of 7b in 59 and 78% yields, respectively. Next, reaction
bis(arylated) and monoarylated ferrocenecarbox- of bis(aryl)ferrocenecarboxamide with Cp2Zr(H)Cl
amides (major and minor, respectively) was obtained reagent[20] provided bis(aryl)ferrocenecarboxalde-
and selective monoarylated ferrocenecarboxamides hydes, which are useful for late stage transformations.
5g–5i were isolated in poor yields.
Removal of the directing ligand was studied in the
end (Scheme 4). The addition of NaOH in CH3OH to Mechanism
the bis(aryl)ferrocenecarboxamide 3a under reflux
conditions failed to remove the 8-aminoquinoline The tentative mechanism for bis-arylation of ferroce-
ligand. Similarly, addition of ceric ammonium nitrate necarboxamide is depicted in Scheme 5.
The presence of a nitrogen atom seems important
for the coordination of metal with the substrate for
À
C H functionalization of the Cp ring as the substrates
1a–1c lacking a coordinating atom failed to yield the
arylated product. The coordination of Pd with the ni-
trogen atom followed by intramolecular OAc substi-
À
tution with N H group would form Pd(II) amidate in-
termediate I. Pd(II)-amidate I may undergo substitu-
À
tion with the C H bond, forming Pd-carbon bonded
intermediate II.[15b,16e] Next, oxidative addition of aryl
iodide would furnish Pd(IV) intermediate III. Reduc-
tive elimination would generate Pd(II) IV which fur-
À
ther led to substitution of OAc by C H forming V.
Oxidative addition of second molecule of aryl iodide
would afford Pd(IV) intermediate VI. Reductive
elimination would give VII and subsequent reaction
with AcOH would furnish bis(phenyl)ferrocenecar-
Scheme 4. Removal of the directing 8-aminoquinoline
ligand.
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Moh. Sattar et al.
Experimental Section
General Information
All NMR experiments were carried out on 400 MHz and
700 MHz spectrometers and NMR chemical shifts are re-
ported in ppm referenced to the solvent peaks of CDCl3,
1
(7.26 ppm for H and 77.16 (Æ0.06) ppm for 13C, respective-
ly), DMSO-d6 (3.31 ppm for H2O, 2.47 ppm for DMSO,
39.9 ppm for carbon). High resolution mass analysis was per-
formed on a quadruple-time of flight (Q-TOF) mass spec-
trometer equipped with an ESI source (+ve). Unless other-
wise noted, materials obtained from commercial suppliers
were used without further purification. Ferrocenecarboxylic
acid was prepared by following the reported method.[22] N-
Aryl-/alkylferrocenecarboxamides were synthesized from
the corresponding ferrocenoyl chloride and primary amines
(see experimental procedure). Iodoarenes, iodoalkanes, 8-
aminoquinoline, Pd(OAc)2, (BnO)2POOH, Cs2CO3, and
NaHCO3 were purchased from Sigma–Aldrich Company.
Silica gel (100–200 mesh size) was used for column chroma-
tography. TLC analysis of reaction mixtures was performed
using silica gel plates purchased from Merck.
Scheme 5. Proposed mechanism for the Pd-catalyzed bis-ar-
ylation of ferrocenecarboxamide.
Synthesis of N-Isopropylferrocenecarboxamide
(1a);[23] Typical Procedure
Oxalyl chloride (0.76 mL, 10 mmol) was added to stirred fer-
rocenecarboxylic acid (208 mg, 0.9 mmol) in a 25-mL round-
bottom flask at room temperature under nitrogen and after
complete addition, the resulting brown coloured suspension
was stirred for 30 min. After this, oxalyl chloride was re-
moved by distillation and the resulting ferrocenoyl chloride
was dried under high vacuum. The resultant viscous brown
solid was taken up in CH2Cl2 (5 mL) and added via syringe
to a stirred solution of isopropylamine (80 mL, 1.0 mmol)
and triethyamine (0.14 mL, 1.0 mmol) under nitrogen at 08C
and stirred for 1 h at this temperature. Water (50 mL) was
added to the reaction mixture and extracted with (20 mL”
3) CH2Cl2, dried over Na2SO4 and concentrated under
vacuum. The resulting crude amide was purified by column
chromatography on silica gel using hexane/ethyl acetate
(7:3) to afford an orange yellow solid; yield: 198 mg (81%);
Rf =0.5 (3:7 EtOAc:hexane). 1H NMR (400 MHz, CDCl3):
d=5.48 (s, 1H), 4.63 (s, 2H), 4.30 (s, 2H), 4.18 (s, 5H), 2.15
(s, 1H), 1.22 (d, J=6.5 Hz, 5H); 13C NMR (100 MHz,
CDCl3): d=169.2, 70.2, 69.7, 68.0, 41.2, 30.9, 23.0; GC-LR-
MS: m/z=271.0, calcd. for C14H17FeNO: 271.0.
boxamide 3a and concomitantly regeneration of
Pd(II) catalyst. A similar mechanism could be hy-
pothesized in the presence of Ni(II) catalysts.[14f]
Conclusions
Synthesis of bis(aryl)- and alkylferrocenecarboxa-
mides has been established from readily accessible
ferrocenecarboxylic acid in two steps using the 8-ami-
À
noquinoline directing ligand by Pd-catalyzed C H
functionalization. Aryl iodides containing various
functionalities such as NO2, I, CN, CO2Et, COMe and
NH showed amenability to the Pd-catalyzed reaction
conditions. The reaction could also be carried out
using a more economical Ni(II) catalyst. Moreover,
selective monoalkylation of ferrocenecarboxamide
was also achieved by using (BnO)2POOH and sodium
bicarbonate base under Pd-catalyzed reaction condi-
tions. Also bis(aryl)ferrocenecarboxaldehyde and
methyl ester, which could be easily manipulated
under mild reaction condition for later stage transfor-
mation, have been obtained by the removal of the di-
recting ligand 8-aminoquinoline. Because monoalkyla-
tion of ferrocenecarboxamide has been demonstrated,
it is possible to synthesize monosubstituted ferrocene-
carboxamides with planar chirality[8,21] and is under in-
vestigation in our laboratory.
This procedure was followed for the synthesis of 1c, 1d,
1e, and 1f.
Synthesis of N-Methoxyferrocene-1-carboxamide (1b)
In a 25-mL round-bottom flask, O-methylhydroxylamine
salt (188 mg, 2.25 mmol) and potassium carbonate (415 mg,
3.0 mmol) were combined in a 2:1 mixture of EtOAc:H2O
(20 mL). The mixture was cooled in an ice bath. The ferro-
cenoyl chloride (372 mg, 1.5 mmol) was added dropwise and
the reaction was stirred at room temperature for 16 h. The
reaction mixture was washed with brine and extracted with
ethyl acetate. The organic layer was dried over Na2SO4. The
crude product was purified by column chromatography on
neutral alumina using CH2Cl2 to give pure amide 1b as
246
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Adv. Synth. Catal. 2016, 358, 240 – 253

À
FULL PAPERS
Palladium-Catalyzed C H Functionalization of Ferrocenecarboxylic Acid
a dark brown solid; yield: 495 mg (85%), Rf =0.9 (100%
CH2Cl2). H NMR (400 MHz, DMSO-d6): d=11.00 (s, 1H),
4.70 (s, 2H), 4.34 (s, 2H), 4.15 (s, 5H), 3.64 (s, 3H);
13C NMR (100 MHz, DMSO-d6): d=167.6, 74.1, 70.58, 69.9,
68.4, 63.7; HR-MS (ESI): m/z=282.0205, calcd. for
C12H13FeNO2 [M+Na]+: 282.0188.
4.68 (s, 2H), 4.63 (d, J=5.3 Hz, 2H), 4.27 (s, 5H); 13C NMR
(100 MHz, CDCl3): d=169.0, 156.2, 148.8, 137.1, 136.6,
128.6, 128.0, 126.7, 122.20, 122.14, 87.9, 83.0, 72.4, 68.4, 45.0;
HR-MS (ESI): m/z=473.1331, calcd. for C29H24FeN2O [M+
H]+ 473.1311.
1
2,5-Bisphenyl)-1-(N-quinolin-8-yl)ferrocene carboxamide
N-Phenylferrocene-1-carboxamide (c):[24] Yellow solid;
yield: 205 mg (74%); Rf =0.6 (100% CH2Cl2). 1H NMR
(400 MHz, CDCl3): d=7.60 (d, J=7.8 Hz, 1H), 7.48 (s, 1H),
7.34 (t, J=7.6 Hz, 1H), 7.11 (t, J=7.2 Hz, 1H), 4.81 (d, J=
23.4 Hz, 1H), 4.40 (s, 1H), 4.24 (s, 2H); 13C NMR
(100 MHz, CDCl3): d=168.6, 138.1, 129.1, 124.0, 119.8, 76.2,
70.9, 69.8, 68.2; GC-LR-MS: m/z=305.1, calcd. for
C17H15FeNO [M]+: 305.1.
1
(3a): Orange solid; yield: 46 mg (92%). H NMR (400 MHz,
CDCl3): d=10.77 (s, 1H), 8.85 (d, J=7.4 Hz, 1H), 8.56 (dd,
J=4.0, 1.3 Hz, 1H), 8.10 (d, J=8.2 Hz, 1H), 7.63 (d, J=
7.3 Hz, 4H), 7.54 (t, J=7.9 Hz, 1H), 7.48 (d, J=8.0 Hz,
1H), 7.34 (dd, J=8.2, 4.2 Hz, 1H), 7.23–7.15 (m, 4H), 7.13
(t, J=7.3 Hz, 2H), 4.76 (s, 2H), 4.41 (s, 5H); 13C NMR
(100 MHz, CDCl3): d=167.9, 147.8, 138.5, 136.8, 136.0,
134.7, 128.9, 128.0, 127.8, 127.4, 126.7, 121.41, 121.39, 116.1,
88.6, 82.2, 72.7, 69.3; HR-MS (ESI): m/z=508.1225, calcd.
for C32H24FeN2O [M]+: 508.1233.
N-(2-Pyridylmethyl)ferrocene-1-carboxamide
(1d):[25]
Blackish-green solid; yield: 243 mg (76%); Rf =0.4 (5:5,
EA:hexane). 1H NMR (400 MHz, CDCl3): d=8.54 (d, J=
3.7 Hz, 1H), 7.65 (t, J=7.4 Hz, 1H), 7.33 (d, J=7.6 Hz,
1H), 7.22–7.16 (m, 1H), 7.10 (s, 1H), 4.70 (d, J=18.6 Hz,
1H), 4.63 (d, J=4.3 Hz, 1H), 4.39–4.24 (m, 1H), 4.13 (s,
1H); 13C NMR (100 MHz, CDCl3): d=170.5, 156.9, 149.0,
136.8, 122.44, 122.43, 76.0, 70.4, 69.7, 68.2, 44.4; GC-LR-MS:
m/z=320.1, calcd. for C17H16FeN2O [M]+: 320.1.
2,5-Bis(4-methylphenyl)-1-N-(quinolin-8-yl)ferrocenecar-
boxamide (3d): Orange yellow solid; yield: 44 mg (82%).
1H NMR (400 MHz, CDCl3): d=10.77 (s, 1H), 8.85 (d, J=
7.4 Hz, 1H), 8.57 (d, J=2.8 Hz, 1H), 8.10 (d, J=8.1 Hz,
1H), 7.59–7.45 (m, 6H), 7.35 (dd, J=8.2, 4.1 Hz, 1H), 7.00
(d, J=7.8 Hz, 4H), 4.71 (s, 2H), 4.39 (s, 5H), 2.22 (s, 6H);
13C NMR (125 MHz, CDCl3): d=168.2, 147.8, 138.6, 136.47,
136.11, 134.9, 133.9, 128.84, 128.83, 127.92, 127.48, 121.48,
121.44, 116.2, 88.6, 82.2, 72.7, 69.1, 21.2; HR-MS (ESI): m/
z=537.1625, calcd. for C34H28FeN2O [M+H]+: 537.1624.
2,5-Bis(4-ethylphenyl)-1-(N-quinolin-8-yl)ferrocenecar-
N-(2-Methylthiophenyl)ferrocene-1-carboxamide
(1e):
Yellow solid; yield: 242 mg (69%); Rf =0.7 (1:9 EA:hex-
1
ane). H NMR (400 MHz, CDCl3): d=8.78 (s, 1H), 8.44 (dd,
J=8.2, 0.9 Hz, 1H), 7.51 (dd, J=7.8, 1.4 Hz, 1H), 7.38–7.28
(m, 1H), 7.06 (td, J=7.6, 1.2 Hz, 1H), 4.91–4.76 (m, 2H),
4.50–4.37 (m, 2H), 4.25 (d, J=8.8 Hz, 5H), 2.45 (s, 3H);
13C NMR (100 MHz, CDCl3): d=168.7, 138.8, 133.2, 129.2,
124.4, 123.8, 120.0, 76.3, 71.0, 69.9, 68.3, 19.1; HR-MS (ESI):
m/z=352.0448, calcd. for C18H17FeNOS [M+H]+: 352.0453.
N-(Quinolin-8-yl)ferrocene-1-carboxamide (1f):[26] Orange
crystalline solid; yield: 303 mg (85%); Rf =0.6 (100%
1
boxamide (3c): Orange solid; yield: 43 mg (76%); H NMR
(400 MHz, CDCl3): d=10.73 (s, 1H), 8.84 (dd, J=7.5,
0.9 Hz, 1H), 8.54 (dd, J=4.1, 1.5 Hz, 1H), 8.09 (dd, J=8.3,
1.4 Hz, 1H), 7.54 (m, 5H), 7.48 (dd, J=8.2, 0.9 Hz, 1H),
7.33 (dd, J=8.3, 4.2 Hz, 1H), 7.02 (d, J=8.1 Hz, 4H), 4.71
(s, 2H), 4.39 (s, 5H), 2.52 (q, J=7.6 Hz, 4H), 1.12 (t, J=
7.6 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=168.2, 147.7,
142.7, 138.5, 136.0, 134.9, 134.0, 128.9, 127.8, 127.5, 127.4,
121.3, 121.3, 116.1, 88.7, 81.9, 72.6, 69.2, 28.5, 15.3; HR-MS
(ESI): m/z=565.1931, calcd. for C36H32FeN2O [M+H]+:
565.1937.
1
CH2Cl2). H NMR (400 MHz, CDCl3): d=10.28 (s, 1H), 8.87
(dd, J=4.2, 1.6 Hz, 1H), 8.79 (dd, J=7.6, 1.2 Hz, 1H), 8.17
(dd, J=8.3, 1.5 Hz, 1H), 7.56 (t, J=7.9 Hz, 1H), 7.52–7.43
(m, 2H), 4.95 (s, 2H), 4.45 (s, 2H), 4.27 (s, 5H); 13C NMR
(100 MHz, CDCl3): d=169.1, 148.2, 138.5, 136.4, 134.8,
128.0, 127.5, 121.6, 121.0, 116.1, 76.9, 70.9, 69.9, 68.5; HR-
MS (ESI): m/z=357.0676, calcd. for C20H16FeN2O [M+H]+:
357.0685.
2,5-Bis(4-tert-butylphenyl)-1-N-(quinolin-8-yl)ferrocene-
carboxamide (3d): Light yellow solid; yield: 48 mg (77%);
1H NMR (400 MHz, CDCl3): d=10.73 (s, 1H), 8.91–8.86 (m,
1H), 8.55 (dd, J=4.2, 1.6 Hz, 1H), 8.12 (dd, J=8.3, 1.6 Hz,
1H), 7.58 (d, J=8.3 Hz, 5H), 7.51 (dd, J=8.3, 1.2 Hz, 1H),
7.36 (dd, J=8.3, 4.2 Hz, 1H), 7.23 (d, J=8.4 Hz, 4H), 4.76
(s, 2H), 4.43 (s, 5H), 1.24 (s, 18H); 13C NMR (100 MHz,
CDCl3): d=168.3, 149.5, 147.7, 138.5, 137.1, 135.9, 134.9,
133.7, 128.7, 127.94–127.31 (m), 124.8, 121.2, 121.2, 116.0,
88.7, 81.5, 72.6, 69.3, 34.4, 31.2; HR-MS (ESI): m/z=
621.2590, calcd. for C40H40FeN2O [M+H]+: 621.2563.
2,5-Bis(4-trifluoromethylphenyl)-1-N-(quinolin-8-yl)ferro-
cenecarboxamide (3e): Light yellow solid; yield: 45 mg
General Procedure for Bis-arylation of N-(Quinolin-
8-yl)ferrocene-1-carboxamide
One equiv. of N-(quinolin-8-yl)ferrocene-1-carboxamide
(35.6 mg, 0.1 mmol), Pd(OAc)2 (2.24 mg, 10 mol%), Cs2CO3
(43 mg, 2.1 equiv.), and aryl iodide (3 equiv.) were added
into dry toluene (2 mL) in a dried sealed tube having a mag-
netic bead purged with argon to evacuate air in dry toluene
(2 mL). The reaction mixture was heated at 1208C for 8–
24 h. The reaction mixture was then cooled and filtered
through celite and the organic layer was extracted with ethyl
acetate (10 mL x 3) and washed with water. The organic
layer passed through Na2SO4 and concentrated under
vacuum. The crude product was purified by column chroma-
tography.
1
(70%); H NMR (400 MHz, CDCl3): d=10.71 (s, 1H), 8.84
(dd, J=7.3, 1.4 Hz, 1H), 8.51 (dd, J=4.2, 1.5 Hz, 1H), 8.12
(dd, J=8.3, 1.5 Hz, 1H), 7.74 (d, J=8.1 Hz, 4H), 7.60–7.50
(m, 2H), 7.47 (d, J=8.2 Hz, 4H), 7.35 (dt, J=10.6, 5.3 Hz,
1H), 4.86 (s, 2H), 4.43 (s, 5H); 13C NMR (100 MHz,
CDCl3): d=167.20, 147.99, 141.05, 141.03, 138.39, 136.26,
134.33, 129.09, 127.95, 127.35, 125.56, 122.86, 121.99, 121.59,
116.30, 87.32, 82.46, 73.12, 70.12; HR-MS (ESI): m/z=
645.1074, calcd. for C34H22F6FeN2O [M+H]+: 645.1059.
2,5-Bis(4-methoxyphenyl)-1-N-(quinolin-8-yl)ferrocene-
carboxamide (3f): Red brown solid; yield: 42 mg (74%).
2,5-Bisphenyl(2-pyridylmethylamino)ferrocene-1-carbox-
amide (2a): Yellow brown solid; yield: 26 mg (54%).
1H NMR (400 MHz, CDCl3): d= 8.42 (d, J=4.6 Hz, 1H),
7.68–7.52 (m, 6H), 7.29–7.25 (m, 3H), 7.23–7.13 (m, 5H),
Adv. Synth. Catal. 2016, 358, 240 – 253
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247

FULL PAPERS
Moh. Sattar et al.
1H NMR (400 MHz, CDCl3): d=10.75 (s, 1H), 8.85 (dd, J=
7.5, 1.2 Hz, 1H), 8.58 (dd, J=4.2, 1.6 Hz, 1H), 8.10 (dd, J=
8.3, 1.5 Hz, 1H), 7.57–7.52 (m, 5H), 7.48 (dd, J=8.3, 1.2 Hz,
1H), 7.35 (dd, J=8.3, 4.2 Hz, 1H), 6.74 (d, J=8.8 Hz, 4H),
4.67 (s, 2H), 4.38 (s, 5H), 3.70 (s, 6H); 13C NMR (100 MHz,
CDCl3): d=168.2, 158.5, 147.8, 138.5, 136.0, 134.8, 129.9,
128.9, 127.89, 127.43, 121.40, 121.34, 116.1, 113.5, 88.4, 81.5,
77.36, 77.04, 76.7, 72.4, 68.8, 55.1; HR-MS (ESI): m/z=
568.1469, calcd. for C34H28FeN2O3 [M]+: 568.1444.
2,5-Bis(4-N,N-dimethylphenyl)-1-N-(quinolin-8-yl)ferro-
cenecarboxamide (3g): Light red solid; yield: 45 mg (76%).
1H NMR (400 MHz, CDCl3): d=10.82 (s, 1H), 8.88 (d, J=
6.9 Hz, 1H), 8.58 (dd, J=4.1, 1.4 Hz, 1H), 8.09 (dd, J=8.2,
1.3 Hz, 1H), 7.60–7.43 (m, 6H), 7.34 (dd, J=8.2, 4.2 Hz,
1H), 6.57 (d, J=8.7 Hz, 4H), 4.64 (s, 2H), 4.38 (s, 5H), 2.84
(s, 12H); 13C NMR (100 MHz, CDCl3): d=168.7, 149.4,
147.7, 138.7, 135.9, 135.1, 129.5, 127.8, 127.4, 124.6, 121.2,
121.1, 116.1, 112.2, 88.9, 81.3, 72.2, 68.2, 40.5; HR-MS (ESI):
m/z=595.2157, calcd for C36H34FeN4O [M+H]+: 595.2155.
2,5-Bis(4-chlorophenyl)-1-N-(quinolin-8-yl)ferrocenecar-
boxamide (3h): Light yellow solid; yield: 33 mg (57%).
1H NMR (400 MHz, CDCl3): d=10.70 (s, 1H), 8.81 (dd, J=
7.2, 1.5 Hz, 1H), 8.57 (dd, J=4.1, 1.5 Hz, 1H), 8.13 (dd, J=
8.3, 1.5 Hz, 1H), 7.57–7.50 (m, 6H), 7.38 (dd, J=8.3, 4.2 Hz,
1H), 7.16 (d, J=8.5 Hz, 4H), 4.74 (s, 2H), 4.38 (s, 5H);
13C NMR (100 MHz, CDCl3): d=167.4, 147.9, 138.4, 136.2,
135.4, 134.4, 132.6, 130.0, 128.2, 127.9, 127.3, 121.7, 121.5,
116.2, 87.5, 82.0, 72.8, 69.4; HR-MS (ESI): m/z=576.0490,
calcd. for C32H22Cl2FeN2O [M]+: 576.0454.
2,5-Bis(4-iodophenyl)-1-N-(quinolin-8-yl)ferrocenecarbox-
amide (3i): Yellow solid; yield: 49 mg (64%); 1H NMR
(400 MHz, CDCl3): d=10.70 (d, J=16.8 Hz, 1H), 8.79 (dd,
J=7.1, 1.6 Hz, 1H), 8.57 (dd, J=4.1, 1.4 Hz, 1H), 8.13 (dd,
J=8.3, 1.4 Hz, 1H), 7.57–7.47 (m, 6H), 7.40 (dd, J=8.2,
4.2 Hz, 1H), 7.34 (d, J=8.4 Hz, 4H), 4.73 (s, 2H), 4.37 (s,
5H); 13C NMR (100 MHz, CDCl3): d=167.4, 148.0, 138.4,
137.1, 136.5, 136.2, 134.4, 130.6, 127.9, 127.3, 121.8, 121.6,
116.2, 92.3, 87.6, 82.0, 72.8, 69.4; HR-MS (ESI): m/z=
759.9137, calcd. for C32H22FeI2N2O [M]+: 759.9166.
2,5-Bis(4-cyanophenyl)-1-N-(quinolin-8-yl)ferrocenecar-
boxamide (3j): Yellow brown solid; yield: 33 mg (59%).
1H NMR (400 MHz, CDCl3): d=10.67 (s, 1H), 8.78 (dd, J=
6.6, 2.2 Hz, 1H), 8.54 (dd, J=4.1, 1.5 Hz, 1H), 8.15 (dd, J=
8.3, 1.5 Hz, 1H), 7.69 (d, J=8.4 Hz, 4H), 7.61–7.54 (m, 2H),
7.48 (d, J=8.4 Hz, 4H), 7.41 (dd, J=8.3, 4.2 Hz, 1H), 4.88
(s, 2H), 4.40 (s, 5H); 13C NMR (100 MHz, CDCl3): d=
166.7, 148.0, 142.4, 138.3, 136.4, 134.0, 131.8, 129.2, 127.9,
127.4, 122.2, 121.7, 118.8, 116.3, 110.4, 86.8, 82.8, 73.2, 70.3;
HR-MS (ESI): m/z=581.1058, calcd. for C34H22FeN4O [M+
Na]+: 581.1036.
2,5-Bis(4-acylphenyl)-1-N-(quinolin-8-yl)ferrocenecarbox-
amide (3l): Reddish brown solid; yield: 41 mg (69%);
1H NMR (400 MHz, CDCl3): d=10.80 (s, 1H), 8.84 (dd, J=
7.4, 1.3 Hz, 1H), 8.53 (dd, J=4.2, 1.5 Hz, 1H), 8.11 (dd, J=
8.3, 1.5 Hz, 1H), 7.78 (d, J=8.4 Hz, 4H), 7.69 (d, J=8.4 Hz,
4H), 7.61–7.44 (m, 2H), 7.35 (dd, J=8.3, 4.2 Hz, 1H), 4.89
(s, 2H), 4.41 (s, 5H), 2.48 (s, 6H); 13C NMR (100 MHz,
CDCl3): d=197.6, 167.3, 147.9, 142.5, 138.4, 136.2, 135.4,
134.4, 128.7, 128.2, 127.9, 127.4, 121.9, 121.5, 116.3, 87.2,
83.1, 73.1, 70.1, 26.5; HR-MS(ESI): m/z=593.1512, calcd.
for C36H28FeN2O3 [M+H]+: 593.1523.
2,5-Bis(3-methylphenyl)-1-N-(quinolin-8-yl)ferrocenecar-
boxamide (3m): Orange red solid; yield: 53.6 mg (69%).
1H NMR (400 MHz, CDCl3): d=10.77 (s, 1H), 8.84 (dd, J=
7.5, 0.9 Hz, 1H), 8.57 (dd, J=4.1, 1.5 Hz, 1H), 8.10 (dd, J=
8.3, 1.5 Hz, 1H), 7.55 (t, J=7.9 Hz, 1H), 7.48 (dd, J=10.7,
3.9 Hz, 3H), 7.40 (s, 2H), 7.35 (dd, J=8.3, 4.2 Hz, 1H), 7.09
(t, J=7.6 Hz, 2H), 6.93 (d, J=7.5 Hz, 2H), 4.74 (s, 2H),
4.42 (s, 5H), 2.20 (s, 6H); 13C NMR (125 MHz, CDCl3): d=
?168.2, 147.8, 138.5, 137.4, 136.84, 136.11, 134.9, 129.6, 127.9,
127.9, 121.6, 127.4, 126.2, 121.4, 116.1, 88.7, 82.4, 72.7, 69.3,
21.4; HR-MS (ESI): m/z=536.1544, calcd. for C34H28FeN2O
[M]+: 536.1546.
2,5-Bis(3-methoxyphenyl)-1-N-(quinolin-8-yl)ferrocene-
1
carboxamide (3n): Red solid; yield: 41 mg (72%). H NMR
(400 MHz, CDCl3): d=10.90 (s, 1H), 8.88 (d, J=7.4 Hz,
1H), 8.59 (dd, J=4.0, 1.3 Hz, 1H), 8.15–8.03 (m, 1H), 7.54
(t, J=7.9 Hz, 1H), 7.47 (dd, J=14.9, 7.3 Hz, 1H), 7.35 (dd,
J=8.2, 4.2 Hz, 1H), 7.25 (dd, J=16.9, 9.2 Hz, 4H), 7.12 (t,
J=7.9 Hz, 2H), 6.69 (dd, J=8.1, 2.0 Hz, 2H), 4.77 (s, 2H),
4.44 (s, 5H), 3.65 (s, 6H); 13C NMR (100 MHz, CDCl3): d=
167.9, 159.1, 147.9, 138.54, 138.40, 136.1, 134.8, 129.0, 127.9,
127.4, 121.57, 121.49, 121.44, 116.1, 114.1, 112.7, 88.3, 82.9,
72.7, 69.2, 55.0; HR-MS (ESI): m/z=569.1520, calcd. for
C34H28FeN2O3 [M+H]+: 569.1523.
2,5-Bis(3-nitrophenyl)-1-N-(quinolin-8-yl)ferrocenecar-
boxamide (3o): Red solid; yield: 39 mg (65%). 1H NMR
(400 MHz, CDCl3): d=10.67 (s, 1H), 8.77 (dd, J=7.3,
1.5 Hz, 1H), 8.52 (t, J=1.8 Hz, 2H), 8.50 (dd, J=4.2,
1.6 Hz, 1H), 8.12 (dd, J=8.3, 1.5 Hz, 1H), 8.00 (dd, J=8.2,
1.3 Hz, 2H), 7.92 (d, J=7.9 Hz, 2H), 7.53 (dd, J=8.3,
4.4 Hz, 2H), 7.39–7.31 (m, 3H), 4.93 (s, 2H), 4.46 (s, 5H);
13C NMR (100 MHz, CDCl3): d=166.6, 148.1, 148.0, 138.9,
138.3, 136.3, 134.8, 134.0, 129.0, 127.9, 127.4, 123.7, 122.0,
121.8, 121.6, 116.4, 86.8, 82.2, 73.1, 70.3; HR-MS (ESI): m/
z=599.1006, calcd. for C32H22FeN4O5 [M+H]+: 599.1013.
2,5-Bis(3-methylbenzoate)-1-N-(quinolin-8-yl)ferrocene-
carboxamide (3p): Dark brown solid; yield: 44 mg (70%).
1H NMR (400 MHz, CDCl3): d=10.74 (s, 1H), 8.81 (d, J=
7.2 Hz, 1H), 8.51 (d, J=2.9 Hz, 1H), 8.31 (s, 2H), 8.10 (d,
J=7.8 Hz, 1H), 7.81 (d, J=3.2 Hz, 4H), 7.58–7.45 (m, 2H),
7.35 (dd, J=8.2, 4.1 Hz, 1H), 7.24 (t, J=7.7 Hz, 3H), 4.86
(s, 2H), 4.42 (s, 5H), 3.81 (s, 6H); 13C NMR (175 MHz,
CDCl3): d=167.5, 166.9, 147.9, 138.4, 137.3, 136.2, 134.5,
133.2, 129.9, 129.8, 128.2, 128.0, 127.8, 127.4, 121.7, 121.6,
116.3, 87.6, 82.1, 72.9, 69.9, 52.2; HR-MS (ESI): m/z=
647.1269, calcd. for C36H28FeN2O5 [M+Na]+: 647.1240.
2,5-Bis(3-cyanophenyl)-1-N-(quinolin-8-yl)ferrocenecar-
boxamide (3q): Yellow brown solid; yield: 27 mg (48%).
1H NMR (400 MHz, CDCl3): d=10.59 (s, 1H), 8.76 (dd, J=
7.2, 1.5 Hz, 1H), 8.56 (dd, J=4.1, 1.5 Hz, 1H), 8.13 (dd, J=
8.3, 1.4 Hz, 1H), 7.92 (s, 2H), 7.81 (d, J=8.0 Hz, 2H), 7.60–
2,5-Bis(4-nitrophenyl)-1-N-(quinolin-8-yl)ferrocenecar-
boxamide (3k): Dark red solid; yield: 45 mg (75%).
1H NMR (400 MHz, CDCl3): d=10.74 (s, 1H), 8.80 (dd, J=
6.9, 1.9 Hz, 1H), 8.53 (dd, J=4.2, 1.5 Hz, 1H), 8.13 (dd, J=
8.3, 1.5 Hz, 1H), 8.05 (d, J=8.8 Hz, 4H), 7.75 (d, J=8.8 Hz,
4H), 7.56 (q, J=6.7 Hz, 2H), 7.37 (dd, J=8.3, 4.2 Hz, 1H),
4.96 (s, 2H), 4.44 (s, 5H); 13C NMR (100 MHz, CDCl3): d=
166.6, 148.0, 146.5, 144.7, 138.3, 136.5, 134.0, 129.2, 128.0,
127.4, 123.4, 122.3, 121.7, 116.4, 86.4, 83.4, 77.3, 77.0, 76.7,
73.4, 70.6; HR-MS (ESI): m/z=597.0838, calcd. for
C32H22FeN4O5 [MÀH]À: 597.0856.
248
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Palladium-Catalyzed C H Functionalization of Ferrocenecarboxylic Acid
7.50 (m, 2H), 7.45–7.36 (m, 3H), 7.27 (t, J=7.9 Hz, 2H),
4.82 (s, 2H), 4.42 (s, 5H); 13C NMR (100 MHz, CDCl3): d=
166.6, 148.0, 138.5, 138.3, 136.3, 134.0, 133.3, 132.2, 130.5,
128.9, 127.9, 127.4, 122.0, 121.6, 118.7, 116.3, 112.3, 86.9,
81.9, 73.1, 70.0; HR-MS (ESI): m/z=581.1026, calcd. for
C34H22FeN4O [M+Na]+: 581.1036.
2,5-Bis(3,4-dimethylphenyl)-1-N-(quinolin-8-yl)ferrocene-
carboxamide (3r): Orange yellow solid; yield: 48 mg (85%).
1H NMR (400 MHz, CDCl3): d=10.80 (s, 1H), 8.86 (dd, J=
7.5, 1.3 Hz, 1H), 8.60 (dd, J=4.2, 1.6 Hz, 1H), 8.14 (dd, J=
8.3, 1.6 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.52 (dd, J=8.2,
1.2 Hz, 1H), 7.40 (dd, J=12.0, 7.9 Hz, 5H), 6.99 (d, J=
7.8 Hz, 2H), 4.74 (s, 2H), 4.44 (d, J=1.2 Hz, 5H), 2.15 (d,
J=9.7 Hz, 12H); 13C NMR (100 MHz, CDCl3): d=168.3,
147.7, 138.6, 136.0, 136.9, 135.0, 135.0, 134.2, 130.1, 129.3,
127.8, 127.4, 126.5, 121.3, 121.2, 116.1, 88.7, 82.2, 72.5, 69.0,
19.7, 19.4; HR-MS (ESI): m/z=565.1949, calcd. for
C36H32FeN2O [M+H]+: 565.1937.
102.6, 90.2, 82.0, 72.4, 69.1; HR-MS (ESI): m/z=587.1567,
calcd. for C36H26FeN4O [M+H]+: 587.1529.
2,5-Bis(2-thiophene)-1-N-(quinolin-8-yl)ferrocenecarbox-
amide (3w): Red solid; yield: 29 mg (56%); 1H NMR
(400 MHz, CDCl3): d=11.16 (s, 1H), 8.98 (d, J=7.3 Hz,
1H), 8.68 (d, J=2.2 Hz, 1H), 8.12 (d, J=8.1 Hz, 1H), 7.59
(t, J=7.8 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.43–7.33 (m,
1H), 7.23 (s, 2H), 7.13 (d, J=4.7 Hz, 2H), 6.88–6.73 (m,
2H), 4.79 (s, 2H), 4.51 (s, 5H); 13C NMR (100 MHz,
CDCl3): d=166.9, 148.0, 139.7, 138.6, 136.2, 134.7, 128.0,
127.52, 127.28, 125.9, 124.6, 121.80, 121.63, 116.4, 82.8, 81.1,
73.3, 69.4; HR.MS (ESI): m/z=521.0447, calcd. for
C28H20FeN2OS2 [M+H]+: 521.0440.
General Procedure for Bis-alkylation of N-(Quinolin-
8-yl)ferrocene-1-carboxamide
N-(Quinolin-8-yl)ferrocene-1-carboxamide
(0.1 mmol,
2,5-Bis(3,5-dimethyphenyl)-1-N-(quinolin-8-yl)ferrocene-
carboxamide (3s): Orange solid; yield: 44 mg (78%).
1H NMR (400 MHz, CDCl3): d=10.74 (s, 1H), 8.80 (dd, J=
7.5, 1.0 Hz, 1H), 8.58 (dd, J=4.1, 1.5 Hz, 1H), 8.11 (dd, J=
8.3, 1.5 Hz, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.48 (dd, J=8.2,
1.0 Hz, 1H), 7.36 (dd, J=8.3, 4.2 Hz, 1H), 7.22 (s, 4H), 6.74
(s, 2H), 4.70 (s, 2H), 4.41 (s, 5H), 2.15 (s, 12H); 13C NMR
(100 MHz, CDCl3): d=168.1, 147.7, 138.6, 137.2, 136.6,
136.0, 135.0, 128.5, 127.8, 127.4, 126.9, 121.3, 121.2, 116.0,
88.8, 82.4, 72.6, 69.1, 21.2; HR-MS (ESI): m/z=564.1882,
calcd. for C36H32FeN2O [M]+: 564.1859.
35.6 mg), Pd(OAc)2 (2.24 mg, 10 mol%), Cs2CO3 (65.2 mg,
2.0 equiv.), and alkyl iodide (3 equiv.) were added into a mix-
ture of DCE and tert-amyl alcohol (0.75 mL + 0.75 mL) in
a sealed tube containing a magnetic bead and purged with
argon. The reaction mixture was heated at 1208C for 8–24 h.
The reaction mixture was cooled and filtered through celite
and the organic layer was extracted with ethyl acetate
(10 mL”3) and washed with water (50 mL). The organic
layer passed through Na2SO4 and concentrated under
vacuum. The crude product was purified by column chroma-
tography.
2,5-Bisethyl-1-N-(quinolin-8-yl)ferrocenecarboxamide
(4a): Yellow viscous liquid; yield: 27 mg (66%). 1H NMR
(400 MHz, CDCl3): d=10.73 (s, 1H), 8.86 (dd, J=4.8,
2.8 Hz, 2H), 8.18 (dd, J=8.3, 1.5 Hz, 1H), 7.57 (t, J=
7.9 Hz, 1H), 7.51 (dd, J=8.2, 1.3 Hz, 1H), 7.46 (dd, J=8.3,
4.2 Hz, 1H), 4.28 (s, 5H), 4.19 (s, 2H), 2.77–2.58 (m, 4H),
1.33–1.14 (m, 10H); 13C NMR (100 MHz, CDCl3): d=169.7,
148.2, 138.6, 136.3, 135.0, 128.1, 127.60, 121.62, 121.10, 116.1,
91.0, 79.2, 70.7, 67.4, 21.8, 15.2; HR-MS (ESI): m/z=
412.1262, calcd. for C24H24FeN2O [M]+: 412.1233.
2,5-Bis(2-methylphenyl)-1-N-(quinolin-8-yl)ferrocenecar-
1
boxamide (3t): Yellow solid; yield: 24 mg (45%). H NMR
(400 MHz, CDCl3): d=10.10 (s, 1H), 8.63–8.56 (m, 1H),
8.52 (dd, J=4.1, 1.5 Hz, 1H), 8.07–8.00 (m, 3H), 7.38–7.29
(m, 3H), 7.24 (t, J=7.27 Hz, 2H), 7.20–7.12 (m, 2H), 7.09
(d, J=7.4 Hz, 2H), 4.58 (s, 5H), 4.53 (s, 2H), 2.16 (s, 6H);
13C NMR (100 MHz, CDCl3): d=167.8, 147.4, 138.4, 138.3,
135.8, 135.2, 134.9, 132.1, 129.6, 127.7, 127.3, 125.3, 121.1,
120.6, 115.8, 90.9, 78.5, 72.1, 71.5, 20.5; HR-MS (ESI): m/z=
536.1532, calcd. for C34H28FeN2O [M]+: 536.1546.
2,5-Bis(1-methyl-indol-5-yl)-1-N-(quinolin-8-yl)ferrocene-
carboxamide (3u): Light yellow solid; yield: 42 mg (68%).
1H NMR (400 MHz, CDCl3): d=10.82 (s, 1H), 8.87 (dd, J=
7.6, 0.9 Hz, 1H), 8.41–8.31 (m, 1H), 8.00 (dd, J=8.3, 1.5 Hz,
1H), 7.93 (t, J=9.2 Hz, 2H), 7.55 (dt, J=5.3, 2.6 Hz, 2H),
7.51 (t, J=8.0 Hz, 1H), 7.41 (dd, J=8.2, 0.9 Hz, 1H), 7.21
(dd, J=12.2, 8.0 Hz, 1H), 7.11 (d, J=8.5 Hz, 2H), 6.94 (d,
J=3.0 Hz, 2H), 6.39 (d, J=2.8 Hz, 2H), 4.77 (s, 2H), 4.46
(s, 5H), 3.66 (s, 6H); 13C NMR (100 MHz, CDCl3): d=
168.7, 147.6, 138.6, 135.97, 135.81, 135.12, 128.92, 128.34,
127.79, 127.73, 127.39, 123.4, 121.14, 121.10, 121.03, 116.2,
108.6, 101.0, 90.2, 82.4, 72.4, 68.9, 32.7; HR-MS (ESI): m/z=
614.1746, calcd. for C38H30FeN4O [M]+: 614.1764.
2,5-Bis(1H-indol-5-yl)-1-N-(quinolin-8-yl)ferrocenecar-
boxamide (3v): Light yellow solid; yield: 20 mg (34%).
1H NMR (400 MHz, CDCl3): d=10.80 (s, 1H), 8.85 (d, J=
6.8 Hz, 1H), 8.34 (dd, J=4.1, 1.5 Hz, 1H), 8.07 (s, 2H), 8.01
(dd, J=8.2, 1.4 Hz, 1H), 7.91 (s, 2H), 7.49 (dd, J=13.0,
4.8 Hz, 3H), 7.42 (d, J=7.4 Hz, 1H), 7.24–7.20 (m, 1H),
7.14 (d, J=8.5 Hz, 2H), 7.11–7.05 (m, 2H), 6.44 (s, 2H),
4.75 (s, 2H), 4.43 (s, 5H); 13C NMR (100 MHz, CDCl3): d=
168.8, 147.6, 138.6, 135.8, 135.05, 135.03, 128.1, 127.78,
127.76, 127.3, 124.3, 123.9, 121.1, 121.0, 120.9, 116.1, 110.4,
2,5-Bismethyl-1-N-(quinolin-8-yl)ferrocenecarboxamide
(4b): Light yellow viscous liquid; yield: 26 mg (68%).
1H NMR (400 MHz, CDCl3): d=10.67 (s, 1H), 8.92–8.79 (m,
2H), 8.18 (dd, J=8.3, 1.5 Hz, 1H), 7.57 (t, J=7.9 Hz, 1H),
7.51 (dd, J=8.2, 1.1 Hz, 1H), 7.46 (dd, J=8.3, 4.2 Hz, 1H),
4.25 (s, 5H), 4.17 (s, 2H), 2.29 (s, 6H); 13C NMR (100 MHz,
CDCl3): d=169.8, 148.2, 138.6, 136.3, 135.0, 128.1, 127.5,
121.61, 121.08, 116.1, 84.2, 79.3, 71.0, 69.7, 14.7 HR-MS
(APCI): m/z=383.0841, calcd. for C22H20FeN2O [MÀH]À:
383.0842.
2,5-Bis(n-propyl)-1-N-(quinolin-5-yl)ferrocenamide (4c):
Yellow viscous liquid; yield: 20 mg (45.4%). 1H NMR
(400 MHz, CDCl3): d=10.74 (s, 1H), 8.91–8.86 (m, 2H),
8.22 (d, J=8.2 Hz, 1H), 7.61 (t, J=7.9 Hz, 1H), 7.55 (d, J=
8.1 Hz, 1H), 7.50 (dd, J=8.2, 4.2 Hz, 1H), 4.30 (s, 5H), 4.22
(s, 2H), 2.83–2.74 (m, 2H), 2.59–2.50 (m, 2H), 1.74–1.61 (m,
4H), 0.96 (t, J=7.3 Hz, 6H); 13C NMR (100 MHz, CDCl3):
d=169.7, 148.1, 138.7, 136.3, 135.0, 128.1, 127.6, 121.6, 121.0,
116.1, 89.3, 70.8, 69.7, 68.3, 31.1, 24.4, 14.2; HR-MS (ESI):
m/z=440.1527, calcd. for C26H28FeN2O [M]+: 440.1546.
2,5-Bis(n-butyl)-1-N-(quinolin-8-yl)ferrocenecarboxamide
(4d): Yellow orange viscous liquid; yield: 25 mg (53%).
1H NMR (400 MHz, CDCl3): d=10.71 (s, 1H), 8.88–8.80 (m,
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Moh. Sattar et al.
2H), 8.18 (dd, J=8.3, 1.5 Hz, 1H), 7.57 (t, J=7.9 Hz, 1H),
7.53–7.49 (m, 1H), 7.46 (dd, J=8.3, 4.2 Hz, 1H), 4.26 (s,
5H), 4.18 (s, 2H), 2.81–2.70 (m, 2H), 2.60–2.49 (m, 2H),
1.67–1.54 (m, 4H), 1.33 (dd, J=14.8, 7.4 Hz, 4H), 0.86 (t,
J=7.3 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=164.44,
142.80, 133.38, 131.04, 129.74, 122.81, 122.30, 116.29, 115.71,
110.80, 84.29, 73.81, 65.49, 62.92, 28.07, 23.34, 17.46, 8.69;
HR-MS (ESI): m/z=468.1888, calcd. for C28H32FeN2O [M]+:
468.1859.
(dd, J=8.2, 4.2 Hz, 1H), 5.21 (s, 1H), 4.47–4.42 (m, 2H),
4.36 (s, 5H), 4.23 (dtd, J=10.6, 7.1, 3.5 Hz, 2H), 4.14–4.07
(m, 2H), 4.00 (d, J=16.3 Hz, 1H), 3.68 (d, J=16.3 Hz, 1H),
1.26 (d, J=7.1 Hz, 3H), 1.18–1.07 (m, 4H); HR-MS (ESI):
m/z=527.1284, calcd. for C28H28FeN2O5 [M]+: 527.1264.
General Procedure for Monoalkylation of N-
(Quinolin-8-yl)ferrocene-1-carboxamide
2,5-Bis(isopentyl)-1-N-(quinolin-8-yl)ferrocenecarboxa-
mide (4e): Yellow viscous liquid; yield: 24 mg (48%).
1H NMR (400 MHz, CDCl3): d=10.68 (s, 1H), 8.85 (dd, J=
6.2, 2.4 Hz, 2H), 8.18 (dd, J=8.3, 1.4 Hz, 1H), 7.57 (t, J=
7.9 Hz, 1H), 7.53–7.49 (m, 1H), 7.46 (dd, J=8.3, 4.2 Hz,
1H), 4.25 (s, 5H), 4.17 (s, 2H), 2.73 (ddd, J=15.5, 10.3,
5.4 Hz, 2H), 2.62–2.52 (m, 2H), 1.56–1.42 (m, 6H), 0.86 (t,
J=6.4 Hz, 12H), 13C NMR (125 MHz, CDCl3): d=169.7,
148.1, 138.6, 136.3, 135.0, 128.1, 127.6, 121.61, 121.01, 116.0,
89.8, 79.0, 70.8, 67.9, 40.2, 28.1, 26.6, 22.64, 22.52; HR-MS
(ESI): m/z=496.2172, calcd. for C30H36FeN2O [M]+:
496.2172.
N-(Quinolin-8-yl)ferrocene-1-carboxamide
(0.1 mmol,
35.6 mg), Pd(OAc)2 (2.24 mg, 10 mol%), NaHCO3 (21 mg,
2.5 equiv.), (BnO)2POOH (8.4 mg, 0.3 equiv.), and alkyl
iodide (3 equiv.) were transferred to a sealed tube contain-
ing a 1:1 mixture of DCE and tert-amyl alcohol (1.5 mL).
The reaction mixture was heated at 1208C for 8–24 h. The
reaction mixture was cooled and filtered through celite and
the organic layer was extracted with ethyl acetate (10 mL”
3) and the organic layer dried over Na2SO4 and concentrat-
ed under vacuum. The crude product was purified by
column chromatography using silica gel with 5% ethyl ace-
tate and hexane as eluent.
2,5-Bis(n-hexyl)-1-N-(quinolin-8-yl)ferrocenecarboxamide
(4f): Yellow viscous liquid; yield: 23 mg (44%). 1H NMR
(400 MHz, CDCl3): d=10.71 (s, 1H), 8.90–8.82 (m, 2H),
8.21–8.16 (m, 1H), 7.57 (t, J=7.9 Hz, 1H), 7.51 (d, J=
7.4 Hz, 1H), 7.46 (dd, J=8.2, 4.2 Hz, 1H), 4.26 (s, 5H), 4.17
(s, 2H), 2.80–2.70 (m, 2H), 2.57–2.48 (m, 2H), 1.61 (dd, J=
20.2, 7.3 Hz, 4H), 1.37–1.26 (m, 8H), 1.22 (s, 4H), 0.79 (t,
J=6.6 Hz, 6H); 13C NMR (125 MHz, CDCl3): d=169.7,
148.1, 138.7, 136.3, 135.0, 128.1, 127.6, 121.59, 121.01, 116.1,
89.6, 70.8, 69.7, 68.2, 31.68, 31.13, 29.4, 28.9, 22.6, 14.0; HR-
MS (ESI): m/z=524.2489, calcd. for C32H40FeN2O [M]+:
524.2485.
2,5-Bis(n-octyl)-1-N-(quinolin-8-yl)ferrocenecarboxamide
(4g): Yellow viscous liquid; yield: 32 mg (55%). 1H NMR
(400 MHz, CDCl3): d=10.70 (s, 1H), 8.92–8.80 (m, 2H),
8.18 (dd, J=8.3, 1.4 Hz, 1H), 7.57 (t, J=7.9 Hz, 1H), 7.53–
7.49 (m, 1H), 7.46 (dd, J=8.3, 4.2 Hz, 1H), 4.26 (s, 5H),
4.17 (s, 2H), 2.78–2.71 (m, 2H), 2.58–2.46 (m, 2H), 1.69–
1.57 (m, 4H), 1.29 (m, 6H), 1.20 (m, 14H), 0.82 (t, J=
6.9 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=169.7, 148.1,
138.6, 136.3, 135.0, 128.1, 127.6, 121.5, 121.0, 116.1, 89.6,
79.1, 70.7, 68.2, 31.8, 31.1, 29.7, 29.4, 29.2, 28.9, 22.6, 14.1;
HR-MS (ESI): m/z=580.3112, calcd. for C36H48FeN2O [M]+:
580.3111.
2,5-Bisbenzyl-1-N-(quinolin-8-yl)ferrocenecarboxamide
(4h): Yellow viscous liquid; yield: 26 mg (49%). 1H NMR
(400 MHz, CDCl3): d=10.78 (s, 1H), 8.85 (dd, J=7.4,
1.3 Hz, 1H), 8.81 (dd, J=4.2, 1.5 Hz, 1H), 8.19 (dd, J=8.3,
1.5 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.53 (dd, J=8.2,
1.2 Hz, 1H), 7.47 (dd, J=8.3, 4.2 Hz, 1H), 7.29–7.23 (m,
8H), 7.17 (ddd, J=8.4, 5.4, 2.6 Hz, 2H), 4.29 (d, J=7.1 Hz,
5H), 4.17 (s, 1H), 4.14 (s, 1H), 4.09 (s, 2H), 3.97 (s, 1H),
3.92 (s, 1H); 13C NMR (100 MHz, CDCl3): d=169.1, 148.2,
140.9, 138.6, 136.4, 134.8, 128.89, 128.30, 128.13, 127.6, 126.0,
121.65, 121.28, 116.3, 88.6, 79.2, 71.2, 69.3, 34.9; HR-MS
(ESI): m/z=536.1563, calcd. for C34H28FeN2O [M]+:
536.1546.
2-Ethyl-1-N-(quinolin-8-yl)ferrocenecarboxamide
(5a):
1
Yellow orange viscous liquid; yield: 17 mg (45%). H NMR
(400 MHz, CDCl3): d=10.40 (s, 1H), 8.86 (dd, J=4.2,
1.6 Hz, 1H), 8.79 (dd, J=7.5, 1.2 Hz, 1H), 8.17 (dd, J=8.3,
1.5 Hz, 1H), 7.56 (t, J=7.9 Hz, 1H), 7.51–7.45 (m, 2H), 4.82
(s, 1H), 4.37 (s, 1H), 4.30 (s, 1H), 4.26 (s, 5H), 2.97–2.87
(m, 1H), 2.80–2.71(m, 1H), 1.30–1.25 (m, 3H); 13C NMR
(100 MHz, CDCl3): d=170.0, 148.2, 138.6, 136.3, 135.0,
128.1, 127.5, 121.6, 120.9, 116.1, 92.4, 75.3, 71.0, 70.3, 68.78,
68.11, 22.0, 15.2; HR-MS (ESI): m/z=384.0922, calcd. for
C22H20FeN2O [M]+: 384.0920.
2-n-Propyl-1-N-(quinolin-8-yl)ferrocenecarboxamide (5b):
Yellow viscous liquid; yield: 15 mg (38%). 1H NMR
(400 MHz, CDCl3): d=10.43 (s, 1H), 8.90 (dd, J=4.1,
1.5 Hz, 1H), 8.84 (d, J=7.5 Hz, 1H), 8.21 (dd, J=8.3,
1.4 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 7.55–7.48 (m, 2H), 4.86
(s, 1H), 4.39 (s, 1H), 4.34 (t, J=2.4 Hz, 1H), 4.26 (s, 5H),
3.04 (ddd, J=14.9, 9.8, 5.4 Hz, 1H), 2.68–2.59 (m, 1H),
1.81–1.73 (m, 1H), 1.70–1.62 (m, 1H), 1.03 (t, J=7.3 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=170.0, 148.1, 138.6,
136.3, 135.0, 128.1, 127.5, 121.5, 120.8, 116.1, 90.7, 75.3, 71.8,
70.4, 68.7, 68.2, 31.1, 24.5, 14.2; HR-MS (ESI): m/z=
398.1076, calcd. for C23H22FeN2O [M]+: 398.1076.
2-n-Butyl-1-N-(quinolin-8-yl)ferrocenecarboxamide (5c):
Yellow orange viscous liquid; yield: 19 mg (46%). H NMR
1
(400 MHz, CDCl3): d=10.40 (s, 1H), 8.86 (dd, J=4.1,
1.5 Hz, 1H), 8.80 (dd, J=7.5, 1.1 Hz, 1H), 8.17 (dd, J=8.3,
1.5 Hz, 1H), 7.55 (t, J=7.9 Hz, 1H), 7.53–7.43 (m, 2H), 4.82
(s, 1H), 4.35 (s, 1H), 4.29 (t, J=2.5 Hz, 1H), 4.25 (s, 5H),
3.03–2.95 (m, 1H), 2.70–2.59 (m, 1H), 1.75–1.64 (m, 1H),
1.42 (dq, J=14.8, 7.4 Hz, 2H), 1.27 (dd, J=13.7, 5.9 Hz,
1H), 0.99–0.89 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=170.0, 148.1, 138.6, 136.3, 135.0, 128.1, 127.5,
121.5, 120.8, 116.1, 90.9, 75.3, 71.7, 70.4, 68.78, 68.19, 33.4,
28.8, 22.8, 14.0; HR-MS (ESI): m/z=435.1160, calcd. for
C24H24FeN2O [M+Na]+: 435.1130.
2-n-Hexyl-1-N-(quinolin-8-yl)ferrocenecarboxamide (5d):
Yellow orange viscous liquid; yield: 14 mg (32%). H NMR
(400 MHz, CDCl3): d=10.39 (s, 1H), 8.86 (d, J=3.2 Hz,
1H), 8.79 (d, J=7.4 Hz, 1H), 8.17 (d, J=8.1 Hz, 1H), 7.55
(t, J=7.9 Hz, 1H), 7.51–7.44 (m, 2H), 4.81 (s, 1H), 4.35 (s,
1
2,5-Bis(ethyl acetate)-1-N-(quinolin-8-yl)ferrocenecarbox-
amide (4i): Yellow viscous liquid; yield: 19 mg (36%).
1H NMR (400 MHz, CDCl3): d=10.57 (s, 1H), 8.85–8.72 (m,
2H), 8.19 (dd, J=8.3, 1.2 Hz, 1H), 7.59–7.52 (m, 2H), 7.47
250
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Palladium-Catalyzed C H Functionalization of Ferrocenecarboxylic Acid
1H), 4.29 (s, 1H), 4.23 (s, 5H), 3.03–2.94 (m, 1H), 2.67–2.59
(m, 1H), 1.73–1.64 (m, 2H), 1.42–1.36 (m, 2H), 1.32–1.27
(m, 4H), 0.86 (t, J=6.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d=170.0, 148.1, 138.6, 136.3, 135.0, 128.1, 127.5,
121.6, 120.8, 116.1, 90.9, 75.3, 71.7, 70.4, 68.78, 68.19, 31.7,
29.46, 29.07, 22.7, 19.1, 14.1; HR-MS (ESI): m/z=440.1554,
calcd. for C26H28FeN2O [M]+: 440.1546.
General Procedure for the Removal of the 8-
Aminoquinoline Directing Ligand
Bis-arylferrocenecarboxamide 3a (53.6 mg. 0.1 mmol) was
dissolved in dry THF (2 mL) under argon. This solution was
then added to Cp2Zr(H)Cl (51.6 mg, 0.2 mmol), at room
temperature under argon. After 30 min, the reaction mix-
ture was concentrated under vacuum. The resulting crude
solid was purified by column chromatography using silica
gel with 5% ethyl acetate in hexane as eluent.
2,5-Bisphenylferrocene-1-carbaldehyde (6a): Yellow vis-
cous liquid; yield: 27 mg (75%). 1H NMR (400 MHz,
CDCl3): d=10.30 (d, J=12.2 Hz, 1H), 7.65–7.59 (m, 4H),
7.38–7.27 (m, 6H), 4.92 (s, 2H), 4.23 (s, 5H); 13C NMR
(100 MHz, CDCl3): d=192.75, 135.98, 130.16, 127.96, 127.37,
92.90, 74.27, 72.68; HR-MS (ESI): m/z=389.0628, calcd. for
C23H18FeO [M+Na]+: 389.0599..
2-Octyl-1-N-(quinolin-8-yl)ferrocenecarboxamide
(5e):
1
Yellow orange viscous liquid; yield: 19 mg (41%); H NMR
(400 MHz, CDCl3): d=10.35 (s, 1H), 8.86 (dd, J=4.1,
1.5 Hz, 1H), 8.79 (dd, J=7.5, 1.1 Hz, 1H), 8.17 (dd, J=8.3,
1.5 Hz, 1H), 7.56 (t, J=7.9 Hz, 1H), 7.51–7.43 (m, 2H), 4.81
(s, 1H), 4.35 (s, 1H), 4.29 (t, J=2.5 Hz, 1H), 4.22 (s, 5H),
3.04–2.92 (m, 1H), 2.68–2.57 (m, 1H), 1.79–1.61 (m, 2H),
1.38 (dd, J=12.8, 5.6 Hz, 2H), 1.28 (m, 8H), 0.84 (m, 3H);
13C NMR (125 MHz, CDCl3): d=170.0, 148.1, 138.6, 136.3,
135.0, 128.1, 127.5, 121.6, 120.8, 116.1, 90.9, 75.3, 71.7, 70.4,
68.77, 68.19, 31.93, 31.29, 29.80, 29.55, 29.36, 29.07, 22.6,
14.1; HR-MS (ESI): m/z=468.1862, calcd. for C28H32FeN2O
[M]+: 468.1859.
2,5-Bis(4-trifluoromethylphenyl)ferrocene-1-carbaldehyde
(6b): The synthesis of compound 6b follows the same proce-
dure as 6a to afford a yellow viscous liquid; yield: 22 mg
1
(44%). H NMR (400 MHz, CDCl3): d=10.26 (s, 1H), 7.72
2-Isopentyl-1-N-(quinolin-8-yl)ferrocenecarboxamide (5f):
(d, J=8.1 Hz, 4H), 7.61 (d, J=8.2 Hz, 4H), 5.01 (s, 2H),
4.26 (s, 5H); 13C NMR (100 MHz, CDCl3): d=191.76,
139.98, 130.30, 129.68, 125.50, 125.04–124.93(q, CF3), 91.5,
75.0, 73.2, 72.6; HR-MS (ESI): m/z=525.0335, calcd. for
C25H16F6FeO [M+Na]+: 525.0347.
1
Yellow orange viscous liquid; yield: 17 mg (40%). H NMR
(400 MHz, CDCl3): d=10.40 (s, 1H), 8.86 (dd, J=4.1,
1.5 Hz, 1H), 8.80 (dd, J=7.5, 1.0 Hz, 1H), 8.17 (dd, J=8.2,
1.4 Hz, 1H), 7.58–7.45 (m, 3H), 4.82 (s, 1H), 4.35 (s, 1H),
4.30 (d, J=2.4 Hz, 1H), 4.23 (s, Hz, 5H), 2.95 (ddd, J=15.4,
10.8, 4.9 Hz, 1H), 2.73–2.64 (m, 1H), 1.69–1.59 (m, 2H),
0.96 (dd, J=10.6, 6.2 Hz, 7H); 13C NMR (100 MHz, CDCl3):
d=170.0, 148.1, 138.6, 136.3, 135.0, 130.9, 127.5, 121.5, 120.8,
116.1, 91.1, 75.3, 71.4, 70.4, 68.8, 68.1, 40.2, 28.1, 27.7, 26.8,
19.1; HR-MS (ESI): m/z=426.1393, calcd. for C25H26FeN2O
[M]+: 426.1389.
General Procedure for the Removal of 8-
Aminoquinolone Directing Group; Transformation
into Ester
A mixture of bis-arylferrocenecarboxamide 3a (53.6 mg,
0.1 mmol,) and BF3·OEt2 (123 mL, 1.0 mmol) in one mL of
MeOH was refluxed for 24 h under a nitrogen atmosphere.
After this the reaction mixture was bought to room temper-
ature, then quenched with Et3N (139 mL, 1.0 mmol) and con-
centrated under vacuum. The resulting crude solid was puri-
fied by column chromatography using silica gel and hexane
and ethyl acetate as eluents.
2,5-Bisphenylferrocene-1-methyl carboxylate (7a): Yellow
viscous liquid; yield: 23.4 mg (59%). 1H NMR (400 MHz,
CDCl3): d=7.56–7.51 (m, 4H), 7.31 (t, J=7.2 Hz, 4H),
7.29–7.25 (m, 2H), 4.66 (s, 2H), 4.18 (s, 5H), 3.67 (s, 3H);
HR-MS (ESI): m/z=396.0827, calcd. for C24H20FeO2 [M]+:
396.0807..
2,5-Bis(4-methoxyphenyl)ferrocene-1-methyl carboxylate
(7b): The synthesis of 7b follows the same procedure as 7a
to afford a yellow solid; yield: 35.6 mg (78%); 1H NMR
(400 MHz, CDCl3): d=7.46 (d, J=8.7 Hz, 4H), 6.86 (d, J=
8.7 Hz, 4H), 4.58 (s, 2H), 4.16 (s, 5H), 3.82 (s, 6H), 3.67 (s,
3H); 13C NMR (100 MHz, CDCl3): d=171.4, 158.5, 130.2,
129.4, 113.2, 89.5, 74.5, 72.5, 69.5, 55.2, 51.8; HR-MS (ESI):
m/z=456.1040, calcd. for C26H24FeO4 [M]+: 456.1019.
2-Methoxyphenyl-1-N-(quinolin-8-yl)ferrocenecarboxam-
1
ide (5g): Yellow orange solid; yield: 10 mg (13%). H NMR
(400 MHz, CDCl3): d=10.16 (s, 1H), 8.78 (dd, J=7.6,
1.0 Hz, 1H), 8.43 (dd, J=4.1, 1.6 Hz, 1H), 8.06 (dd, J=8.3,
1.5 Hz, 1H), 7.93 (dd, J=7.5, 1.7 Hz, 1H), 7.50 (t, J=
8.1 Hz, 1H), 7.41 (dd, J=8.2, 1.0 Hz, 1H), 7.32 (dd, J=8.3,
4.2 Hz, 1H), 7.21 (td, J=8.2, 1.7 Hz, 1H), 7.06 (td, J=7.5,
0.8 Hz, 1H), 6.61 (t, J=8.2 Hz, 1H), 5.03 (q, J=2.54,
1.6 Hz, 1H), 4.54–4.50 (m, 1H), 4.48 (t, J=2.5 Hz, 1H), 4.32
(s, 5H), 3.47 (s, 3H); HR-MS (ESI): m/z=485.0945, calcd.
for C27H22FeN2O2 [M+Na]+: 485.0923.
3-Cyanophenyl-1-N-(quinolin-8-yl)ferrocenecarboxamide
(5h): Yellow orange solid; yield: 3.2 mg (4%). 1H NMR
(400 MHz, CDCl3): d=10.29 (s, 1H), 8.75 (dd, J=7.4,
1.3 Hz, 1H), 8.63 (dd, J=4.2, 1.6 Hz, 1H), 8.15 (dd, J=8.3,
1.5 Hz, 1H), 8.00 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.57–7.48
(m, 3H), 7.42 (dd, J=8.3, 4.2 Hz, 1H), 7.34 (t, J=7.8 Hz,
1H), 5.06–5.05 (m, 1H), 4.67–4.62 (m, 1H), 4.56 (t, J=
2.6 Hz, 1H), 4.35 (s, 5H); HR-MS (ESI): m/z=487.0785,
calcd. for C27H19FeN3O [M+Na]+: 487.0770.
4-Cyanophenyl-1-N-(quinolin-8-yl)ferrocenecarboxamide
(5i): Yellow orange solid; yield: 3.2 mg (4%). 1H NMR
(400 MHz, CDCl3): d=10.33 (s, 1H), 8.76 (dd, J=7.4,
1.4 Hz, 1H), 8.62 (dd, J=4.2, 1.5 Hz, 1H), 8.15 (dd, J=8.3,
1.5 Hz, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.58–7.50 (m, 4H),
7.43 (dt, J=6.6, 3.3 Hz, 1H), 5.07–5.06 (m, 1H), 4.72–4.65
(m, 1H), 4.59 (t, J=2.4 Hz, 1H), 4.36 (s, 5H); HR-MS
(ESI): m/z=457.0898, calcd. for C27H19FeN3O [M]+:
457.0872.
Supporting Information
1H, 13C NMR and HR-mass spectra of the synthesized ferro-
cenecarboxamides 1a–1f and bisaryl-, alkyl-, monoaryl-, al-
kylferrocenecarboxamides 2a, 3a–3w, 4a–4i, 5a–5i, 6a, 6b, 7a,
and 7b and crystal structure data of 3a, 3i, 3o, and 3w[19] are
given in the Supporting Information.
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asc.wiley-vch.de
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Acknowledgements
We thank Mr. Shailendra Agarwal for helping in the synthesis
of ferrocenecarboxylic acid. SK thanks IISER Bhopal and
DRDO New Delhi for generous funding. MS, P, and CDP
acknowledge CSIR New Delhi, DST, and CSIR-UGC, re-
spectively, for fellowships.
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