HFIP-Promoted Substitution in the Ferrocene Series: Smooth Approach towards Original Catalysts**

Article abstract of DOI:10.1002/ejoc.202100824

Pseudo-benzylic substitution is an important reaction in the ferrocene series, especially to obtain ligands for catalysis. Herein, we described new reactions conditions, using fluorinated alcohols as both solvent and promoter, able to deliver iodoferrocen

Full text of DOI:10.1002/ejoc.202100824

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: HFIP-promoted substitution in the ferrocene series: smooth
approach towards original catalysts
Authors: William Erb, Victor Carré, and Thierry Roisnel
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100824
Link to VoR: https://doi.org/10.1002/ejoc.202100824
0
1/2020

European Journal of Organic Chemistry
10.1002/ejoc.202100824
FULL PAPER
HFIP-promoted substitution in the ferrocene series: smooth
approach towards original catalysts**
*
Dr. William Erb, Victor Carré, and Dr. Thierry Roisnel
Univ Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes) – UMR 6226, F-35000 Rennes, France.
william.erb@univ-rennes1.fr - https://iscr.univ-rennes1.fr/william-erb
*
* HFIP: Hexafluoroisopropanol
Supporting information for this article is given via a link at the end of the document.
Abstract: Pseudo-benzylic substitution is an important reaction in the
ferrocene series, especially to reach ligands for catalysis. Here, we
described new reactions conditions, using fluorinated alcohols as both
solvent and promoter, able to deliver iodoferrocene derivatives faster
than using classical solvents. Various N, O, P and C-nucleophiles
were found compatible with this transformation which occurs with full
retention of stereochemistry. Original P,N-ligands were finally
prepared by using iodine/lithium exchange-chlorophoshine trapping
sequences, and their properties were evaluated in Suzuki-Miyaura
and Buchwald-Hartwig coupling as well as in ketone α-arylation
reaction.
The synthetic value of this reaction was first demonstrated by
Dixneuf in 1969 from achiral ferrocenemethanol derivatives,
followed one year later by Ugi from chiral α-ferrocenylethylamine
derivatives.[10] The reaction was extended to other chiral
substrates and nucleophiles by Dixneuf[11] and Ugi[12] while the
use of ferrocenophane substrates was investigated with similar
success by Tainturier.[ Over the years, the reaction was studied
from a wide range of substrates, including ferrocenophanes,[14]
and various P-, N-, O-, S- and C-based nucleophiles,[15] in
homogeneous or biphasic systems as developed by Boev and
13]
Snegur,[ mainly to reach chiral ligands
16]
[17]
but also biologically
active products.[18] An important feature of this reaction is its high
level of stereoretention although partial inversion can occur on
specific substrates, either mono-[14c,19] or polysubstituted[20], which
Introduction
[21]
could be rationalized by following the work of Weissensteiner.
Although many reaction conditions have been reported, most of
them involved prolonged heating at high temperatures. Looking
for smoother alternatives, Šebesta reported in 2002 the
successful substitution of an acetate in aqueous media,
rationalized by the formation of hydrogen bonds able to facilitate
the leaving group departure.[22] Similarly, Cozzi reported in 2007
that ferrocenyl alcohols can react with nucleophiles in such
substitution “on water” at 80 °C for 24 h. Concerning alternative
solvents able to establish hydrogen bonds, fluorinated alcohols
emerged as promising candidates with their high hydrogen bond
Since its discovery in 1951,[1] ferrocene has gained a major place
in chemistry.[2] While it can be involved in many transformations,
three main reactions account for its large diversity of applications:
aromatic
electrophilic
substitution,
deprotometallation-
electrophilic trapping and pseudo-benzylic substitution. The latter
was first reported from achiral acetoxymethylferrocene by
Richards who proposed the formation of an iron-stabilized
pseudo-benzylic carbocation to explain the high reaction rate.[3]
Soon after, Bacskai and Richards found that the reaction occurs
with stereoretention from chiral cyclic and acyclic ferrocenes,
respectively.[ While the origin of the high stability of the
carbocation has remained a matter of debate for years,[5] Gleiter
and Seeger validated in 1971 the structure of a fulvene bent
towards the iron (Scheme 1) by using the extended Hückel
model.[ Additional evidence of such structures was obtained in
donating ability, increased acidity, low nucleophilicity and high
4]
[23]
dielectric constant.
Therefore, they proved ideal to generate
cations for both mechanistic studies[24] and methodology
development. Although fluorinated alcohols were recently used
[25]
[26]
to promote reactions involving carbocations, to the best of our
6]
knowledge, only two unoptimized examples have been reported
in the ferrocene series.[27] Therefore, we decided to study the use
of fluorinated alcohols to promote such pseudo-benzylic
substitution.
1
979 by Behrens who used X-ray diffraction analysis[7] while
detailed computational investigations were later described.[8]
Recently, Kronja revisited the early solvolysis studies, showing
that the positive charge of the cation was mainly shifted to the
organometallic core and that additional phenyl substituents have
a limited impact on the cation stability.[9]
Results and Discussion
The substrates (±)-1-3 were selected to study the substitution in
fluorinated alcohols (Scheme 2) as the presence of iodine would
allow further functionalization. These compounds can be obtained
from 2-iodo-N,N-diisopropylferrocenecarboxamide (see SI),
accessible in both racemic and enantioenriched form.[28] They
were
reacted
with
morpholine
in
an
excess
of
Scheme 1. Pseudo-benzylic substitution in the ferrocene series. LG: leaving
group, NuH: nucleophile.
hexafluoroisopropanol (HFIP) at 60 °C for 1 h. While moderate
conversions were observed with N,N-diisopropylamino ((±)-1) and
1
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202100824
FULL PAPER
hydroxyl ((±)-3) as leaving groups, complete conversion was
reached with the acetate (±)-2, and the title product (±)-4a was
isolated in a 91% yield.
Our optimal conditions in hand, we evaluated the ability of other
aliphatic amines to act as nucleophile in this HFIP-promoted
substitution from both (±)- and (S
have expected, no erosion of the enantiomeric ratio (er) was
observed in the reaction from (S )-2 (er 96:4) to (S )-4a. Acting as
p
)-2 (Scheme 3). As one could
p
p
a weakly acidic solvent, HFIP was found to tolerate tert-
butoxycarbonyl (Boc) protecting group with compound (±)-4b.
Piperazine led to both the monosubstituted product (±)-4c (68%
yield) and disubstituted product (±)-4h (24% yield). However,
moving to pyrrolidine resulted in a main drop of the yield in our
standard conditions (compound (±)-4d, 14% yield). This
unexpected result might result from the higher nucleophilicity of
pyrrolidine when compared with morpholine,[29] leading to the
formation of ammonium salts. However, further optimization using
an excess of amine resulted in moderate 36% yield. Similarly,
when the reaction was carried out in the presence of 2 equivalents
of diallylamine or dibenzylamine, expected to be as reactive,[
moderate yields were recorded for the compounds (±)-4e and f
Scheme 2. Evaluation of leaving groups.
29]
We found possible to reduce the amount of HFIP to 10
equivalents without detrimental effect (Table 1, entries 1-2) while
further reduction was accompanied by a major yield drop (entry
(
37 and 35%, respectively). Again, using 4 equivalents of
nucleophile restored high yields while benzylamine gave 56% of
3). The use of 1 to 4 equivalents of morpholine led to similar
compound (±)-4g in our standard conditions. Diamines can also
results (entries 2, 4-5); however, for reproducibility reasons, two
equivalents of nucleophile were preferred. Conducting the
reaction at lower temperature was detrimental to the yield (entries
be used, as shown with the compounds (±)-4h and (±)- or (S
i, obtained from piperazine and N,N’-dimethylethylenediamine
DMEDA), respectively. However, for bulky diamines, we found
better to react (±)-2 with 1.8 equivalent of both amine and HFIP,
as illustrated with the compounds 4j and (R,R,S )-4j. Pleasingly,
p p
,S )-
4
(
2, 6-7) while performing the reaction at 110 °C in a sealed tube
considerably fastened the reaction (entry 8). However, for safety
reasons, performing reactions in regular glassware at 60 °C was
p
it was possible to scale up the reaction to 5.0 mmol (2.3 g of
preferred. Other solvents were finally evaluated. With
4
compound (±)-4a isolated) with similar results.
equivalents of morpholine, similar results were obtained in
trifluoroethanol (TFE) and HFIP (entries 2 and 9). However, when
2
equivalents of morpholine were employed in TFE or isopropanol,
a major drop of the yield was observed (entries 10-11).
Table 1. Optimization of the reaction conditions.
Entry
Solvent
equiv)
Morpholine
(equiv)
T (°C)
Yield (%)
(
1
HFIP (30)
HFIP (10)
HFIP (5)
4
4
4
2
1
4
4
2
4
2
2
60
60
60
60
60
40
25
120
60
60
60
94
2
93
3
8
4
HFIP (10)
HFIP (10)
HFIP (10)
HFIP (10)
HFIP (10)
TFE (10)
TFE (10)
iPrOH (10)
88
5
92
6
72
7
72
8[a]
9
99
86
1
0
1
25
p
Scheme 3. Reaction between the substrates (±)- and (S )-2 and aliphatic
1
Traces
amines. a 4 Equiv of amine used. b Addition of (±)-2 onto a solution of pyrrolidine
in HFIP. c 0.5 Equiv of amine used. d 0.45 Equiv of amine used. e 1.8 Equiv of
amine and 1.8 equiv of HFIP used.
[
a] 10 min reaction time.
2
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202100824
FULL PAPER
We further engaged a few azoles in our optimized conditions
(
4
Scheme 4). While the use of pyrazole led to the compounds (±)-
k and (S )-4k in very good yields, only 50% of compound (±)-4l
p
was isolated when imidazole was used instead. A slightly
improved yield (up to 66%) was recorded when 4 equivalents of
imidazole were used. The compound (±)-4m was isolated in a
good 84% yield by using 1,2,4-triazole while 2-
mercaptobenzothiazole conducted to the isomeric products (±)-
4
n and (±)-4n’. As previously observed in a related reaction,[30] N-
alkylation predominates over S-alkylation. Finally, as observed in
other reaction conditions,[31] reacting indazole with (±)-2 afforded
both the N1- and N2-alkylated products (±)-4o and (±)-4o’ in close
yields (44 and 53%, respectively).
p
Scheme 5. Reaction between the substrates (±)- and (S )-2 and selected N-,
O-, P- and C-nucleophiles. a 30 Equiv of HFIP used. b 4 Equiv of phosphine
used.
Although a variety of nucleophiles were found to be compatible
with this HFIP-promoted substitution, these reaction conditions
were not suitable for some reagents such as anilines, aliphatic
and aromatic thiols, pyrrole, carbazole and phenothiazine. In all
these cases, various ill-defined products were formed from which
we could not identified any of the desired product.
We were intrigued by the formation of the ether (±)-4r as, with the
lowest Mayr’s nucleophilicity parameter (N = -1.93 for a 99:1
1
HFIP-water mixture), HFIP is not supposed to behave as a
nucleophile.[32] We were eager to verify if this reaction was specific
to the acetate (±)-2 and thus heated the amine (±)-1 in pure HFIP
(30 equivalents) for 14 h towards the same ether (±)-4r (Scheme
)-2 and azoles. a
4
Scheme 4. Reaction between the substrates (±)- and (S
Equiv of azole used.
p
6). Although we further found that similar yields could be obtained
by using only 10 equivalents of HFIP, stopping the reaction after
only 1 h led to a poor conversion (a (±)-1-(±)-4r mixture was
obtained in a 2.5:1 ratio).
Then, a few other N-, O-, P- and C-nucleophiles were selected to
establish the limitations of this methodology (Scheme 5). In our
classical conditions, tert-butylcarbamate was found reactive
enough to give the targeted compound (±)-4p while allylic alcohol
led to the ether (±)-4q and to the unexpected product (±)-4r (32
and 24% yield, respectively). To validate the structure of the later,
the substrates (±)- and (S
of any nucleophile. Full conversion was reached in only 10 min
and the compounds (±)- and (S )-4r were isolated in moderate
yields. The use of diphenylphosphine as nucleophile afforded the
corresponding phosphines (±)- and (S )-4s in 89 and 98% yield,
p
)-2 were heated in HFIP in the absence
p
p
Scheme 6. Reaction between the substrates (±)- and (S )-1 and HFIP.
p
respectively. Indole and N-methylindole both afforded the
expected C3-alkylated products (±)-4t and (±)-4u in similar yields
As we previously reported the synthesis of the 1,1’- and 1,3-
disubstituted compounds (±)-5 and 6,[33] we were interested to
evaluate the influence of the substitution pattern of ferrocene onto
the reaction outcome (Scheme 7). The reaction between the 1,3-
disubstituted ferrocene (±)-5 and either morpholine, pyrazole or
DMEDA led to the products (±)-7a-c in yields comparable to those
obtained from 1-iodo-2-(acetoxymethyl)ferrocene (±)-2. However,
the ether (±)-7d and the phosphine (±)-7e were obtained in slightly
(
81 and 80%, respectively). However, the yield dropped when
benzothiophene and benzofurane were evaluated. The only
products isolated were the C3-alkylated derivative (±)-4v by
starting from benzothiophene and the C2-alkylated product (±)-
4w by starting from benzofuran, in line with the usual reactivity of
these heterocycles.
3
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202100824
FULL PAPER
lower yields when compared with their 1,2-disubstituted isomers.
Finally, when the 1,1’-disubstituted ferrocene 6 was reacted with
morpholine, the product 8a was isolated in a 96% yield,
comparable to those obtained for the 1,2- and 1,3-disubstituted
isomers. Therefore, it seems that the substitution pattern of these
iodoferrocenes has a limited impact onto the substitution outcome.
p
was more reactive, affording the title product (R,S )-10 as a single
diastereoisomer in a 78% yield with full retention of the
stereochemistry, as confirmed by X-ray diffraction analysis (see
SI).
p p
Scheme 9. Reaction between substrates (R,S )-9a and (R,S )-9b with
morpholine.
Aromatic iodides can easily be functionalized by lithium/halogen
exchange, as demonstrated by Corey and Seebach[37] toward a
wide range of derivatives.[38] Therefore, we treated the
compounds (±)-4a and 8a with a two-fold excess of tert-
butyllithium
before
adding
chlorodiphenyl-
or
chlorodicyclohexylphosphine as electrophiles (Scheme 10). While
the phosphines (±)-11a and (±)-11b were isolated by column
chromatography in 43 and 75% yields, respectively, the
compound 11c required an intermediate protection as phosphine
borane, leading to a reduced 21% overall yield.
Scheme 7. Reaction between the substrates (±)-5 and
nucleophiles. 0.45 Equiv of amine used. 30 Equiv of HFIP used. 4 Equiv of
phosphine used.
6
and various
a
b
c
Since the ether (±)-4r can be formed in this HFIP-promoted
substitution, its role as a potential intermediate raised. Therefore,
the reaction between (±)-4r and morpholine (2 equiv) in HFIP was
attempted at 60 °C for 1 h (Scheme 8, bottom). However, the title
product (±)-4a was only isolated in a low 34% yield. Therefore,
considering the low 22% overall yield to reach (±)-4a through the
ether (±)-4r, its role as the main intermediate can be ruled out.
Scheme 10. Functionalization of the iodinated ferrocenes (±)-4a and 8a.
Finally, we were curious about the ligating abilities of the
ferrocene phosphines 11a-c which can behave as bidentate P,N
ligands.[39] Indeed, while related chiral ligands containing the
morpholino moiety have been used in Kumada coupling and
cyclobutanol opening,[40] they have never been evaluated in other
cross-couplings. As P,N ligands such as DavePhos,[
MorDalphos,[42] CataCXium[43] and an aminoferrocene
derivative[44] are efficient ligands in Suzuki-Miyaura, Buchwald-
Hartwig couplings or α-arylation of ketone, we selected these
reactions as benchmark tests. To evaluate the coordination ability
of (±)-11b, it was first reacted with PdCl (MeCN) in CH Cl at
Scheme 8. Evaluation of compound (±)-4r as intermediate in the synthesis of
41]
(±)-4a.
As the main application of the pseudo-benzylic substitution is to
get ferrocene derivatives with both stereogenic plane and centre,
derivatives of Ugi’s amine were also used as substrates.
2
2
2
2
Therefore, (R,S
p
)-9a (see SI)[34] was reacted with two equivalents
room temperature toward the complex (±)-12 (Scheme 11), as
demonstrated by NMR and high-resolution mass spectrometry
(see SI).
of morpholine in HFIP at 60 °C (Scheme 9). However, after 1 h
contact, we only recycled up to 95% of enantiopure substrate.
This lack of reactivity was predictable as, except for a few
azoles,[35] replacing an amine by another one usually requires
activation of the leaving group by treatment with either acetic
anhydride or methyl iodide.[15g, 36] However, the acetate (R,S
p
)-9b
4
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202100824
FULL PAPER
phosphine groups would facilitate the search of better ligands,
possibly enantioenriched by starting from (S )-2.
p
Some of the obtained solid-state structures obtained in the course
of this study deserve a few words. Indeed, we found that the
geometry of the three isomers (±)-4a, (±)-7a and 8a was not
influenced by the position of iodine as indicated by the good
overlay between (±)-4a and (±)-7a (RMS 0.0264 Å, Figure 1, left)
and between (±)-4a and 8a (RMS 0.0144 Å, Figure 1, right).
However, different intramolecular interactions were observed as
the 1,1’-substitution pattern of compound 8a allows the formation
of a homodimer linked by two I···O halogen bonds (Figure 2, top)
while the 1,3-substitution pattern of compound (±)-7a favours the
formations of strings of I···O halogen bonds (Figure 2, bottom).
Similar halogen bonds were recently identified in the ferrocene
series[45] and result from an interaction between the lone pair of
the oxygen and the σ-hole of the iodine atom.[46] Further
intermolecular interactions were also observed for the
Scheme 11. Formation of the complex (±)-12.
Preliminary experiments were finally performed to evaluate the
ability of the phosphines 11a-c to act as ligands in the selected
reactions (Scheme 12). Furthermore, to establish whether the
morpholine
diphenylphosphino)ferrocene (13) was also tested. A Suzuki-
Miyaura cross-coupling between 4-chloroacetophenone (14) and
-methoxyphenylboronic acid in the presence of Pd(OAc) was
moiety
was
required,
the
simple
(
4
2
first attempted and, while all our new ligands gave better results
than 13, the best results were obtained with the bulky and
electron-rich phosphine (±)-11b. In the Buchwald-Hartwig
amination of 4-chlorobenzonitrile (16) with morpholine, as well as
in the α-arylation of acetone with 4-bromobenzonitrile (18), the
compounds (R,S
identified I···N interactions which form a zig zag bonding network
Figure 3, top) while halogen bonds[47] between iodine and the
p
)-10 and (±)-4n. Indeed, for the former, we
(
1,2-disubstituted phosphines (±)-11a,b were the most efficient
exocyclic sulfur atom were observed for the latter (Figure 3,
bottom).
ligands, the latter being slightly better.
Figure 1. Overlay of the compounds (±)-4a and (±)-7a (left) and (±)-4a and 8a
(right). Thermal ellipsoids shown at the 30% probability level.
Scheme 12. Preliminary investigation of the use of the ligands 11a-c and 13 in
palladium-catalysed transformations.
Figure 2. Halogen bond network observed for the compounds (±)-7a (top) and
a (bottom). Thermal ellipsoids shown at the 30% probability level. Selected
bond lengths and angles: I···O 3.294(2) Å and C-I···O 165.26(9) ° for (±)-7a,
I···O 3.1069(18) Å and C-I···O 176.41(7) ° for 8a.
8
From these unoptimized experiments, the compound (±)-11b
appears as the most promising of the three ligands prepared.
However, although none of our ligands can currently outperform
other reported P,N ligands, the rapid generation of many
derivatives allowed by the easy variation of the amine and
5
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202100824
FULL PAPER
F254). They were visualized by exposure to UV light. Melting points were
measured on a Kofler bench. IR spectra were taken on a Perkin-Elmer
Spectrum 100 spectrometer. H and 13C{1H} Nuclear Magnetic Resonance
1
(NMR) spectra were recorded either (a) on a Bruker Avance III
spectrometer at 300 MHz and 75.4 MHz, respectively, or (b) Bruker
Avance III HD at 400 MHz and 100 MHz, respectively, or (c) on a Bruker
1
Avance III HD at 500 MHz and 126 MHz, respectively. H chemical shifts
(
δ) are given in ppm relative to the solvent residual peak and 13C chemical
shifts are relative to the central peak of the solvent signal. Elemental
analyses were performed on a Thermo Fischer 1112 HT apparatus and
HRMS were recorded on a Thermo Fisher Q-Exactive mass spectrometer
at the Centre Régional de Mesures Physiques de l’Ouest. The numbering
used in this Experimental Section is defined in Supporting Information.
(
R,R)-(−)-Cyclohexane-1,2-diamine was prepared according to
Jacobsen.[
50]
(R,R)-N,N’-bis(1-naphthylmethyl)cyclohexane-1,2-diamine
was prepared according to Smith.[51]
Safety Considerations. Due to its high pyrophoric character, tBuLi need
to be used only under inert conditions (anhydrous, nitrogen or argon
atmosphere) and by people well-trained to the manipulation of reactive
organometallics.
p
Figure 3. Halogen bond network observed for the compounds (R,S )-10 (top)
and (±)-4n (bottom). Thermal ellipsoids shown at the 30% probability level.
Selected bond lengths and angles: I···N 3.225(3) Å and C-I···N 160.71(10) ° for
Crystallography. For (±)-4a, (±)-4n, (±)-4s, (±)-4v, (±)-4w, (±)-7b, 8a and
(
±)-11b, the X-ray diffraction data were collected using D8 VENTURE
Bruker AXS diffractometer equipped with a (CMOS) PHOTON 100
detector. For (±)-7a and (R,S )-10, the X-ray diffraction data were collected
(R,S
p
)-10, I···N 3.3584(8) Å, C-I···S and C-S···I 176.34(7) ° and 83.91(9) ° for
p
(±)-4n.
using APEXII Kappa-CCD (Bruker-AXS) diffractometer equipped with a
CCD plate detector. The samples were studied with monochromatized Mo-
Kα radiation (λ = 0.71073 Å) at the temperature given in the crystal data.
The structure was solved by dual-space algorithm using the SHELXT
program,[ and then refined with full-matrix least-square methods based
on F (SHELXL). All non-hydrogen atoms were refined with anisotropic
atomic displacement parameters. H atoms were finally included in their
calculated positions and treated as riding on their parent atom with
constrained thermal parameters. The molecular diagrams were generated
by MERCURY 2020.3.0.
Conclusion
52]
2
[53]
In conclusion, we have developed new reaction conditions, using
fluorinated alcohols, to promote a pseudo-benzylic substitution in
the ferrocene series. With smooth reaction conditions (moderate
temperature and short reaction time), it was possible to replace
an acetate by a variety of N, O, P, and C nucleophiles. The
reaction occurs with a high degree of stereochemical retention for
substrates having only a stereogenic plane or both stereogenic
plane and centre. Furthermore, an original ferrocene substituted
by a hexafluoropropyloxymethyl group was isolated, indicating
that from specific substrates and under the right reaction
conditions, HFIP can behave as a nucleophile, contrary to the
general thought. Three original phosphinoferrocene derivatives
were finally prepared and used as ligand in cross-couplings. From
this preliminary evaluation, one ligand emerged as promising for
this application. As pseudo-benzylic substitution is widely used in
the ferrocene series, it makes little doubt that combining these
easily set-up fast reaction conditions with further functionalization
will find applications, especially in the preparation of libraries of
ligands for applications in catalysis.
General procedure A: HFIP-promoted substitution. HFIP (10.0 equiv)
was added to a mixture of the required substrate (1.00 equiv) and required
nucleophile (2.00 equiv) and the reaction mixture was heated for 1 h at
6
0 °C in a pre-heated oil bath. The reaction was cooled to rt and was
poured onto a NEt -EtOAc mixture (1:1) and volatiles were removed under
vacuum to give the crude product. This was purified by column
chromatography over SiO , using PE-EtOAc (eluent given in product
description) to give the title product.
3
2
(±)-1-Iodo-2-(N-morpholinomethyl)ferrocene ((±)-4a): By following the
general procedure A from compound (±)-2 (115 mg, 0.30 mmol) and
morpholine (52.5 μL, 52.3 mg, 0.60 mmol) in HFIP (316 μL), (±)-4a was
obtained after column chromatography (PE-EtOAc, 40:60 with 1% of NEt
as an orange solid (115 mg, 93%). R (eluent: PE/EtOAc 40:60, 5 drops of
(film)/cm−1 2955, 2935, 2805, 1455, 1446,
NEt ) = 0.21. Mp 63-65 °C. ν
3
)
f
3
max
1
331, 1285, 1263, 1243, 1222, 1111, 999, 918, 859, 809. 1H NMR (300
MHz, CDCl ): δ (ppm) 4.43 (dd, J = 1.4, 2.0 Hz, 1H, FcCH, H5), 4.29 (dd,
J = 1.3, 2.2 Hz, 1H, FcCH, H3), 4.21 (t, J = 2.5 Hz, 1H, FcCH, H4), 4.11
s, 5H, Cp), 3.65 (t, J = 4.7 Hz, 4H, 2 x CH O), 3.47 (d, J = 13.3 Hz, 1H,
3
Experimental Section
(
2
CHH), 3.41 (d, J = 13.3 Hz, 1H, CHH), 2.57 (m, 2H, CH
2
N), 2.40 (m, 2H,
General Considerations. All nucleophilic substitutions promoted by HFIP
were performed under air. Unless otherwise stated, all the other reactions
were performed under an argon atmosphere with anhydrous solvents
using Schlenk technics. THF and dioxane were distilled over
sodium/benzophenone, acetone was dried by prolonged contact over
activated 3Å molecular sieve,[48] toluene and dichloromethane were
N). 13C{ H} NMR (75.4 MHz, CDCl
1
CH
2
3
): δ (ppm) 84.1 (FcC, C2), 75.0
O),
N), 46.5 (FcC, C1). Mass: 411 [M], 325 [M-
NO]. Anal. Calcd for C15 18FeINO: C, 43.83; H, 4.41; N, 3.41. Found:
C, 43.75; H, 4.36; N, 3.26. Crystal data for (±)-4a. C15 18FeINO, M =
11.05, T = 150 K; orthorhombic P b c a (I.T.#61), a = 11.233(2), b =
(FcCH, C5), 71.7 (Cp), 69.2 (FcCH, C4), 69.1 (FcCH, C3), 67.1 (2 x CH
2
58.1 (CH ), 53.3 (2 x CH
2
2
4
C H
8
H
H
4
9
=
1
2
distilled over CaH . Unless otherwise stated, all reagents were used
3
-3
.5399(17), c = 27.474(6) Å, V = 2944.2(10) Å . Z = 8, d = 1.855 g·cm , μ
3.113 mm . A final refinement on F with 3376 unique intensities and
72 parameters converged at ωR
without prior purification. All organolithium reagents were titrated before
use.[49] Column chromatography separations were achieved on silica gel
-1
2
2
F
F
= 0.0597 (R = 0.0252) for 3055
(
(
40-63 μm). PE refers to petroleum ether, rt refers to room temperature
25 °C). All Thin Layer Chromatographies (TLC) were performed on
observed reflections with I > 2σ(I). CCDC 2090455.
aluminium backed plates pre-coated with silica gel (Merck, Silica Gel 60
6
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202100824
FULL PAPER
(
S
p
)-1-Iodo-2-(N-morpholinomethyl)ferrocene ((S
p
)-4a): By following
as an orange oil (159 mg, 94%). R
f
(eluent: PE/EtOAc 95:5, 5 drops of
the general procedure A, starting from (S )-2a (115 mg, 0.30 mmol, 96:4
er) and morpholine (52.5 μL, 52.3 mg, 0.60 mmol) in HFIP (316 μL), the
p
NEt
3
) = 0.54. νmax (film)/cm−1 3075, 2918, 2800, 1675, 1641, 1445, 1416,
1
1372, 1350, 1254, 1105, 997, 975, 915, 820, 806, 749. H NMR (500 MHz,
title product was obtained as an orange solid (113 mg, 92%, 96:4 er).
3
CDCl ): δ (ppm) 5.87 (ddt, J = 6.2, 10.2, 17.1 Hz, 2H, 2 x CH=CHH, 5.20
Analytical data analogous to racemic compound. [α]
CHCl ). The enantiomeric ratio was determined on Chiralpak IA-3 column,
hexane with 0.1% of diethylamine/iPrOH: 95:5, 1.0 mL·min , 10 °C, λ =
54 nm, t (major) = 6.94 min, t (minor) = 7.33 min.
D
+13.3 (c 0.01 in
(d, J = 17.1 Hz, 2H, 2 x CH=CHH), 5.14 (d, J = 10.2 Hz, 2H, 2 x CH=CHH),
4.41 (s, 1H, FcCH, H5), 4.30 (s, 1H, FcCH, H3), 4.19 (s, 1H, FcCH, H4),
4.09 (s, 5H, Cp), 3.55 (d, J = 13.7 Hz, 1H, CHH), 3.42 (d, J = 13.7 Hz, 1H,
3
-
1
2
CHH), 3.11 (dd, J = 6.2, 14.0 Hz, 2H, 2 x CHH), 3.05 (dd, J = 6.2, 14.0 Hz,
2
1
H, 2 x CHH). 13C{ H} NMR (125 MHz, CDCl
1
3
): δ (ppm) 136.3 (CH=CHH),
17.4 (CH=CHH), 85.9 (FcC, C2), 74.8 (FcCH, C5), 71.7 (Cp), 69.1 (FcCH,
), 52.9 (CH ), 46.0 (FcC, C1). Anal.
20FeIN: C, 48.49; H, 4.79; N, 3.33. Found: C, 43.40; H, 4.73;
(
(
±)-1-Iodo-2-(N’-tert-butoxycarbonyl-N-piperazino)methylferrocene
(±)-4b): By following the general procedure A from compound (±)-2 (154
C3), 68.9 (FcCH, C4), 56.4 (2 x CH
2
2
Calcd for C17
H
mg, 0.40 mmol) and N-tert-butoxycarbonylpiperazine (149 mg, 0.80 mmol)
in HFIP (421 μL), (±)-4b was obtained after column chromatography (PE-
N, 3.25.
EtOAc, 80:20 to 60:40 with 1% of NEt
(eluent: PE/EtOAc 80:20, 5 drops of NEt
film)/cm−1 3008, 2967, 2929, 2808, 1683, 1454, 1420, 1364, 1296, 1269,
229, 1171, 1160, 1144, 1117, 1000, 947, 866, 822, 810, 764. 1H NMR
500 MHz, CDCl ): δ (ppm) 4.43 (s, 1H, FcCH, H5), 4.28 (s, 1H, FcCH,
3
) as an orange solid (180 mg, 88%).
R
(
1
(
f
3
) = 0.28. Mp 103-104 °C. νmax
(±)-1-Iodo-2-(N,N-dibenzylaminomethyl)ferrocene ((±)-4f): By following
the general procedure A from compound (±)-2 (154 mg, 0.40 mmol) and
dibenzylamine (307 µL, 316 mg, 1.60 mmol) in HFIP (421 μL), (±)-4f was
3
obtained after column chromatography (PE-EtOAc, 95:5 with 2% of NEt
as an orange oil (200 mg, 91%). R (eluent: PE/EtOAc 95:5, 5 drops of
NEt
) = 0.84. νmax (film)/cm−1 3024, 2791, 1493, 1451, 1368, 1229, 1105,
1027, 1000, 973, 957, 821, 806, 732, 695. 1H NMR (500 MHz, CDCl
): δ
3
)
H3), 4.22 (t, J = 2.1 Hz, 1H, FcCH, H4), 4.11 (s, 5H, Cp), 3.50 (d, J = 13.3
Hz, 1H, CHH), 3.44 (d, J = 13.3 Hz, 1H, CHH), 3.39-3.36 (m, 4H, 2 x
f
3
CH
2
NC(O)), 2.47-2.45 (m, 2H, CH
2
N), 2.35-2.33 (m, 2H, CH
): δ (ppm) 154.8 (C=O), 84.1
), 75.0 (FcCH, C5), 71.7 (Cp), 69.3 (FcCH, C4),
9.1 (FcCH, C3), 57.7 (CH2), 52.5 (2 x CH2N), 46.5 (FcC, C1), 44.0
CH NC(O)), 43.3 (CH NC(O)), 28.6 (C(CH ). Anal. Calcd for
27FeIN : C, 47.08; H, 5.33; N, 5.49. Found: C, 47.06; H, 5.20; N,
2
N), 1.43 (s,
3
1
9H, C(CH
3
)
3
). 13C{ H} NMR (125 MHz, CDCl
3
(ppm) 7.40 (d, J = 7.4 Hz, 4H, ArCH, 4 x H2’), 7.32 (t, J = 7.4 Hz, 4H, ArCH,
4 x H3’), 7.24 (t, J = 7.4 Hz, 2H, ArCH, 2 x H4’), 4.41 (dd, J = 1.4, 2.3 Hz,
1H, FcCH, H5), 4.36 (dd, J = 1.4, 2.3 Hz, 1H, FcCH, H3), 4.18 (t, J = 2.4
Hz, 1H, FcCH, H4), 3.60 (d, J = 13.7 Hz, 2H, 2 x CHHPh), 3.59 (d, J = 13.8
(
3 3
FcC, C2), 79.7 (C(CH )
6
(
2
2
3 3
)
C
20
H
O
2 2
Hz, 1H, CHH), 3.54 (d, J = 13.7 Hz, 2H, 2 x CHHPh), 3.45 (d, J = 13.8 Hz,
1H, CHH). 13C{ H} NMR (125 MHz, CDCl
1
5.22.
3
): δ (ppm) 139.9 (ArC, 2 x C1’),
1
(
5
28.9 (ArCH, 4 x C2’), 128.3 (ArCH, 4 x C3’), 126.9 (ArCH, 2 x C4’), 86.1
FcC, C2), 74.7 (FcCH, C5), 71.7 (Cp), 69.2 (FcCH, C3), 68.7 (FcCH, C4),
7.9 (2 x CH2Ph), 53.4 (CH2), 45.6 (FcC, C1). Anal. Calcd for C25 24FeIN:
C, 57.61; H, 4.64; N, 2.69. Found: C, 57.71; H, 4.60; N, 2.66.
(±)-1-Iodo-2-(N-piperazino)methylferrocene ((±)-4c): By following the
H
general procedure A from compound (±)-2 (154 mg, 0.40 mmol) and
piperazine (68.9 mg, 0.80 mmol) in HFIP (421 μL), (±)-4c was obtained
after column chromatography (PE-EtOAc, 90:10 with 2% of NEt
3
) as an
orange oil (112 mg, 68%). R
f
(eluent: EtOAc) = 0.15. νmax (film)/cm−1 3365,
(±)-1-Iodo-2-(N-benzylaminomethyl)ferrocene ((±)-4g): By following the
general procedure A from compound (±)-2 (154 mg, 0.40 mmol) and
benzylamine (87.4 µL, 85.7 mg, 0.80 mmol) in HFIP (421 μL), (±)-4g was
2
922, 2810, 1637, 1563, 1454, 1409, 1368, 1329, 1298, 1134, 1105, 998,
1
806. H NMR (500 MHz, CDCl
3
): δ (ppm) 4.74 (br s, 1H, NH), 4.40 (s, 1H,
FcCH, H5), 4.25 (s, 1H, FcCH, H3), 4.19 (s, 1H, FcCH, H4), 4.09 (s, 5H,
obtained after column chromatography (PE-EtOAc, 90:10 with 1% of NEt
as an orange solid (97 mg, 56%). R (eluent: PE/EtOAc 40:60, 5 drops of
NEt
) = 0.74. Mp 66-67 °C. νmax (film)/cm−1 3084, 3026, 2939, 2917, 2833,
3
)
Cp), 3.44 (s, 2H, CH
.46 (br s, 2H, CH
2
), 2.90 (br s, 4H, 2 x CH
2
NH), 2.56 (br s, 2H, CH
2
N),
f
2
2
N). 13C{ H} NMR (125 MHz, CDCl
1
3
): δ (ppm) 84.0 (FcC,
3
C2), 75.0 (FcCH, C5), 71.7 (Cp), 69.2 (FcCH, C4), 69.1 (FcCH, C3), 57.9
CH ), 52.5 (2 x CH N), 46.4 (FcC, C1), 45.2 (2 x CH NH). Anal. Calcd for
19FeIN : C, 43.93; H, 4.67; N, 6.83. Found: C, 43.82; H, 4.51; N, 6.76.
Compound (±)-4h was also isolated as an orange solid (36 mg, 24%).
1493, 1452, 1407, 1365, 1105, 1064, 1052, 1026, 997, 972, 957, 824, 811,
1
(
C
2
2
2
800, 731. H NMR (500 MHz, CDCl
3
): δ (ppm) 7.36-7.32 (m, 4H, ArCH, 2
15
H
2
x H2’ and 2 x H3’), 7.27-7.25 (m, 1H, ArCH, H4’), 4.42 (s, 1H, FcCH, H5),
4.28 (s, 1H, FcCH, H3), 4.19 (s, 1H, FcCH, H4), 4.11 (s, 5H, Cp), 3.84 (d,
J = 13.3 Hz, 1H, CHHPh), 3.79 (d, J = 13.3 Hz, 1H, CHHPh), 3.70 (d, J =
3.4 Hz, 1H, CHHN), 3.53 (d, J = 13.4 Hz, 1H, CHHN). 13C{ H} NMR (125
1
1
(±)-1-Iodo-2-(N-pyrrolidinomethyl)ferrocene ((±)-4d): Compound (±)-2
MHz, CDCl
3
): δ (ppm) 140.4 (ArC, C1’), 128.5 (ArCH, 2 x C2’), 128.3
ArCH, 2 x C3’), 127.1 (ArCH, C4’), 87.5 (FcC, C2), 74.7 (FcCH, C5), 71.6
Cp), 68.7 (FcCH, C4), 68.1 (FcCH, C3), 53.3 (CH Ph), 48.7 (CH N); 44.8
FcC, C1). Anal. Calcd for C18 18FeIN: C, 50.15; H, 4.21; N, 3.25. Found:
(154 mg, 0.40 mmol, 1.00 equiv) was added in four portions to a solution
(
(
(
of pyrrolidine (133 µL, 114 mg, 1.6 mmol, 4.00 equiv) in HFIP (421 μL, 672
mg, 4.00 mmol, 10.0 equiv) at rt. After addition the reaction mixture was
heated for 1 h at 60 °C in a pre-heated oil bath. The reaction was cooled
2
2
H
C, 50.11; H, 4.37; N, 3.36.
to rt and was poured onto a NEt
were removed under vacuum to give the crude product. This was purified
by column chromatography over SiO , using PE-EtOAc (40:60 to 30:70
with 2% of NEt ) to give the title product as an orange oil (57 mg, 36%). R
eluent: PE/EtOAc 50:50, 5 drops of NEt
) = 0.55. νmax (film)/cm−1 3093,
3
-EtOAc mixture (1:1, 2 mL) and volatiles
2
N,N’-bis-(2-Iodoferrocenylmethyl)piperazine (4h): By following the
general procedure A from compound (±)-2 (154 mg, 0.40 mmol, 1.00
equiv) and piperazine (17.3 mg, 0.20 mmol, 0.50 equiv) in HFIP (421 μL),
(±)-4h was obtained after column chromatography (PE-EtOAc, 50:50 to
3
f
(
3
2
1
=
4
1
2
961, 2925, 2780, 1673, 1457, 1374, 1346, 1314, 1258, 1236, 1105, 1059,
1
028, 999, 875, 818, 804. H NMR (400 MHz, CDCl
3
): δ (ppm) 4.41 (dd, J
30:70 with 2% of NEt
PE/EtOAc 50:50, 5 drops of NEt
3
) as an orange solid (121 mg, 82%). R
f
(eluent:
1.5, 2.0 Hz, 1H, FcCH, H5), 4.32 (dd, J = 1.5, 2.3 Hz, 1H, FcCH, H3),
.20 (t, J = 2.5 Hz, 1H, FcCH, H4), 4.11 (s, 5H, Cp), 3.62 (d, J = 13.2 Hz,
3
) = 0.55. Mp < 50 °C. νmax (film)/cm−1 3092,
2929, 2805, 2767, 1645, 1453, 1368, 1328, 1285, 1151, 1132, 1105, 1001,
1
H, CHH), 3.47 (d, J = 13.2 Hz, 1H, CHH), 2.68-2.56 (m, 2H, CH
2
N), 2.52-
944, 806, 748. H NMR (400 MHz, CDCl
3
): δ (ppm) 4.39 (m, 2H, FcCH, 2
.45 (m, 2H, CH
2
N), 1.77-1.69 (m, 4H, 2 x CH
2
). 13C{ H} NMR (100 MHz,
1
x H5), 4.27 (m, 2H, FcCH, 2 x H3), 4.18 (m, 2H, FcCH, 2 x H4), 4.09 (s,
CDCl
C4), 68.7 (FcCH, C3), 54.8 (CH
2 x CH ). Anal. Calcd for C15 18FeIN: C, 45.60; H, 4.59; N, 3.55. Found:
C, 45.73; H, 4.70; N, 3.72.
3
): δ (ppm) 85.8 (FcC, C2), 74.7 (FcCH, C5), 71.7 (Cp), 69.1 (FcCH,
10H, 2 x Cp), 3.48 (d, J = 13.2 Hz, 2H, 2 x CHH), 3.39 (d, J = 13.2 Hz, 2H,
), 53.9 (2 x CH N), 46.1 (FcC, C1), 23.6
2
2 x CHH), 2.53 (br s, 4H, 2 x CH
NMR (100 MHz, CDCl
71.7 (2 x Cp), 69.2 (FcCH, 2 x C4), 69.1 (FcCH, 2 x C3), 57.5 (2 x CH
2
N), 2.42 (br m, 4H, 2 x CH
2
N). 13C{ H}
1
2
(
2
H
3
): δ (ppm) 84.4 (FcC, 2 x C2), 74.9 (FcCH, 2 x C5),
),
2 2 2 2
N), 46.6 (FcC, 2 x C1). Anal. Calcd for C26H28Fe I N : C,
2
52.6 (4 x CH
2.54; H, 3.85; N, 3.82. Found: C, 42.60; H, 3.82; N, 3.90.
4
(±)-1-Iodo-2-(N,N-diallylaminomethyl)ferrocene ((±)-4e): By following
the general procedure A from compound (±)-2 (154 mg, 0.40 mmol) and
diallylamine (198 µL, 155 mg, 1.60 mmol) in HFIP (421 μL), (±)-4e was
obtained after column chromatography (PE-EtOAc, 95:5 with 2% of NEt )
3
N,N’-Dimethyl-N,N’-bis-(2-iodoferrocenylmethyl)ethylenediamine
((±)-4i): By following the general procedure A from compound (±)-2 (169
7
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202100824
FULL PAPER
a 3
(dq, J = 2.1, 10.9 Hz, 1H, C ): δ
HH, H5). 13C{ H} NMR (126 MHz, CDCl
1
mg, 0.44 mmol, 2.20 equiv) and N,N’-dimethylethylenediamine (21.5 μL,
1
7.6 mg, 0.20 mmol, 1.00 equiv) in HFIP (210 μL), (±)-4i was obtained
after column chromatography (PE-EtOAc, 30:70 to 10:90 with 2% of NEt
as an orange oil (109 mg, 74%). R (eluent: PE/EtOAc 50:50, 5 drops of
NEt
) = 0.13. νmax (film)/cm−1 3093, 2939, 2778, 1452, 1411, 1371, 1233,
217, 1105, 1019, 1000, 821, 807, 747. 1H NMR (400 MHz, CDCl
): δ
ppm) 4.41 (s, 2H, FcCH, 2 x H5), 4.28 (s, 2H, FcCH, 2 x H3), 4.20 (s, 2H,
(ppm) 136.7 (ArC, C8), 135.6 (ArC, C19), 134.0 (ArC, C12), 133.5 (ArC,
C23), 132.6 (ArC, C28), 131.6 (ArC, C17), 128.5 (ArCH), 128.4 (ArCH),
128.1 (ArCH, C24), 127.8 (ArCH, C20), 126.6 (ArCH, C11), 126.0 (ArCH,
C26), 125.6 (3 x ArCH), 125.2 (ArCH), 125.1 (ArCH), 125.0 (ArCH, C27),
124.3 (ArCH, C9), 123.5 (ArCH), 86.6 (FcC, C30), 75.0 (FcCH, C32), 71.7
(Cp), 70.0 (FcCH, C34), 69.1 (FcCH, C33), 64.0 (CHN, C1), 58.5 (CHN,
3
)
f
3
1
(
3
FcCH, 2 x H4), 4.10 (s, 10H, 2 x Cp), 3.44 (m, 4H, 2 x CH
2
-Fc), 2.51 (s,
): δ
C6), 53.2 (CH
2
, C18), 49.5 (CH
2
, C29), 47.6 (CH
2
, C7), 45.4 (FcC, C31),
). 13C{ H} NMR (100 MHz, CDCl
1
32.1 (C , C5), 26.0 (C
H
a 2
2
4H, 2 x CH -N), 2.20 (s, 6H, 2 x CH
3
3
c 2
H , C3), 24.9 (C
d 2
H , C4), 22.8 (C H
b 2
, C2).
(ppm) 85.0 (FcC, 2 x C2), 74.9 (FcCH, 2 x C5), 71.7 (2 x Cp), 69.2 (FcCH,
Recovery of the remaining (R,R)-N,N’-bis(1-naphthylmethyl)cyclohexane-
2
5
x C4), 69.1 (FcCH, 2 x C3), 57.2 (CH
4.8 (CH -N), 46.7 (FcC, 2 x C1), 42.5 (2 x CH
: C, 45.91; H, 4.45; N, 4.12. Found: C, 46.04; H, 4.56; N, 4.20.
2
-Fc), 57.0 (CH
2
-Fc), 54.9 (CH
). Anal. Calcd for
2
-N),
1,2-diamine by column chromatography afforded 69.0 mg of pure product.
2
3
26 2 2
C H30FeI N
(±)-1-Iodo-2-(N-pyrazolinomethyl)ferrocene ((±)-4k): By following the
general procedure A from compound (±)-2 (23 mg, 0.06 mmol, 1.00 equiv)
and pyrazole (16.3 mg, 0.24 mmol, 4.00 equiv) in HFIP (63 μL), (±)-4k was
(
S
p
,S
iodoferrocenylmethyl)ethylenediamine ((S
general procedure A from compound (S )-2 (169 mg, 0.44 mmol, 2.20
equiv) and N,N’-dimethylethylenediamine (21.5 μL, 17.6 mg, 0.20 mmol,
.00 equiv) in HFIP (210 μL), S ,S )-4i was obtained after column
chromatography (PE-EtOAc, 30:70 to 10:90 with 2% of NEt ) as an orange
oil (100 mg, 68%, 94:6 er). Analytical data analogous to racemic
compound. [α] +33.3 (c 0.01 in CHCl ). The enantiomeric ratio was
determined on Chiralpak IA-3 column, hexane with 0.1% of
p
)-N,N’-Dimethyl-N,N’-bis-(2-
,S
p p
)-4i): By following the
obtained after column chromatography (PE-EtOAc, 80:20 with 1% of NEt
as an orange oil (23.2 mg, quant). R (eluent: PE/EtOAc 80:20, 5 drops of
NEt
) = 0.55. νmax (film)/cm−1 3095, 2923, 2851, 1718, 1510, 1408, 1390,
1369, 1273, 1106, 1086, 1045, 1000, 965, 824, 809, 745. 1H NMR (300
MHz, CDCl ): δ (ppm) 7.49 (d, J = 1.6 Hz, 1H, ArCH, H1’), 7.43 (d, J = 2.2
3
)
p
f
3
1
p
p
3
3
Hz, 1H, ArCH, H3’), 6.21 (t, J = 2.1 Hz, 1H, ArCH, H2’), 5.16 (d, J = 14.9
Hz, 1H, CHH), 5.11 (d, J = 14.9 Hz, 1H, CHH), 4.48 (dd, J = 1.3, 2.4 Hz,
D
3
1H, FcCH, H5), 4.39 (dd, J = 1.3, 2.6 Hz, 1H, FcCH, H3), 4.26 (t, J = 2.4
-
1
Hz, 1H, FcCH, H4), 4.17 (s, 5H, Cp). 13C{ H} NMR (75.4 MHz, CDCl
1
diethylamine/iPrOH: 97:3, 0.8 mL·min , 5 °C, λ = 254 nm, t (major) = 15.85
3
): δ
min, t (minor) = 14.31 min.
(ppm) 139.2 (ArCH, C1’), 128.9 (ArCH, C3’), 105.6 (ArCH, C2’), 84.4 (FcC,
C2), 75.3 (FcCH, C5), 71.9 (Cp), 69.8 (FcCH, C4), 68.6 (FcCH, C3), 51.9
2 3
(CH ), 44.7 (FcC, C1). Mass: 392 [M], 327 [Fc(I)CH + H], 265 [M-I]. Anal.
(
1R,2R)-N,N’-Bis(1-naphthylmethyl)-N-((±)-2-
Calcd for C14
H
13FeIN : C, 42.89; H, 3.34; N, 7.15. Found: C, 42.92; H,
2
iodoferrocenylmethyl)cyclohexane-1,2-diamine ((±)-4j): HFIP (42.0 μL,
3.39; N, 7.18.
67.2 mg, 0.40 mmol, 1.80 equiv) was added to a mixture of compound (±)-
2
(38.4 mg, 0.10 mmol, 1.00 equiv) and (R,R)-N,N’-bis(1-
naphthylmethyl)cyclohexane-1,2-diamine (158 mg, 0.40 mmol, 1.80 equiv)
in a dry tube under argon and the reaction mixture was heated overnight
at 60 °C (oil bath, external temperature). The reaction mixture was cooled
to rt and HFIP (42.0 μL, 67.2 mg, 0.40 mmol, 1.80 equiv) was added before
the reaction mixture was heated for 4 more hours at 60 °C. The reaction
mixture was cooled to rt, a buffered aqueous solution (5 mL, pH 7) was
added and the reaction mixture was extracted with EtOAc (3 x 5 mL). The
(S
p
)-1-Iodo-2-(N-pyrazolinomethyl)ferrocene ((S
)-2 (38.4 mg, 0.10 mmol, 1.00
equiv) and pyrazole (27.3 mg, 0.40 mmol, 4.00 equiv) in HFIP (63 μL),
(S )-4k was obtained after column chromatography (PE-EtOAc, 80:20 with
1% of NEt ) as an orange oil (36.0 mg, 92%, 94:6 er). Analytical data
analogous to racemic compound. [α] +10.9 (c 0.01 in CHCl ). The
enantiomeric ratio was determined on Chiralpak IC-3 column,
p
)-4k): By following the
general procedure A from compound (S
p
p
3
D
3
-
1
combined organic layers were dried over MgSO
and concentrated under vacuum using a rotary evaporator to give the
crude product. This was purified by column chromatography over SiO
using PE/EtOAc (10:1) with 2% of NEt to give the title product as an
4
, filtrated over cotton wool
hexane/iPrOH: 90:10, 0.8 mL·min , 20 °C, λ = 254 nm, t (major) = 11.86
min, t (minor) = 13.36 min.
2
,
3
(±)-1-Iodo-2-(N-imidazolinomethyl)ferrocene ((±)-4l): By following the
orange oil (51.0 mg, 71%). Analytical data in agreement with
enantioenriched compound.
general procedure A from compound (±)-2 (154 mg, 0.40 mmol, 1.00
equiv) and imidazole (109 mg, 1.60 mmol, 4.00 equiv) in HFIP (421 μL),
(
±)-4l was obtained after column chromatography (PE-EtOAc, 60:40 to
20:80 with 2% of NEt ) as an orange solid (104 mg, 66%). Mp 100-102 °C.
(eluent: PE/EtOAc 50:50, 5 drops of NEt
) = 0.41. νmax (film)/cm−1 3095,
1504, 1437, 1366, 1276, 1242, 1227, 1104, 1066, 1026, 999, 969, 906,
831, 817, 809, 768, 741. 1H NMR (500 MHz, CDCl
): δ (ppm) 7.56 (br s,
(
1R,2R)-N,N’-Bis(1-naphthylmethyl)-N-((S
iodoferrocenylmethyl)cyclohexane-1,2-diamine
following a similar protocol, starting from (S )-2 (38.4 mg, 0.10 mmol, 1.00
p
)-2-
3
((R,R,S
p
)-4j):
By
R
f
3
p
equiv, 96:4 er) and (R,R)-N,N’-bis(1-naphthylmethyl)cyclohexane-1,2-
diamine (158 mg, 0.40 mmol, 4.00 equiv), the title product was obtained
as an orange oil (40.0 mg, 55.5%). Attempts to determine the enantiomeric
3
1H, ArCH, H1’), 7.04 (br s, 1H, ArCH, H2’), 6.99 (br s, 1H, ArCH, H3’), 4.97
(d, J = 14.5 Hz, 1H, CHH), 4.89 (d, J = 14.5 Hz, 1H, CHH), 4.49 (s, 1H,
FcCH, H4 or H5), 4.25 (s, 3H, H3 and H4 or H5), 4.17 (s, 5H, Cp). 13C{ H}
1
ratio by chiral HPLC failed to provide any separation. [α]
D
-39.8 (c 0.01 in
) = 0.66. νmax
CHCl ). R (eluent: PE/EtOAc 80:20, 5 drops of NEt
3
f
3
NMR (125 MHz, CDCl
119.2 (ArCH, C3’), 84.4 (FcC, C2), 75.5 (FcCH, C4 or C5), 71.9 (Cp), 69.7
(FcCH, C4 or C5), 68.1 (FcCH, C3), 47.1 (CH ), 44.2 (FcC, C1). Anal.
: C, 42.89; H, 3.34; N, 7.15. Found: C, 42.80; H,
3
): δ (ppm) 137.2 (ArCH, C1’), 129.6 (ArCH, C2’),
−
1
(
7
film)/cm 2929, 2855, 1597, 1510, 1449, 1216, 1106, 1001, 791, 773,
1
54. H NMR (500 MHz, CDCl
3
): δ (ppm) 7.91 (d, J = 8.6 Hz, 1H, ArCH,
2
H27), 7.81 (d, J = 5.3 Hz, 1H, ArCH, H14 or H16 or H21), 7.80 (d, J = 7.1
Hz, 1H, ArCH, H14 or H16 or H21), 7.75-7.72 (m, 2H, 2 x ArCH, H24 and
H14 or H21), 7.64 (d, J = 8.2 Hz, 1H, ArCH, H11), 7.44-7.39 (m, 3H, 3 x
ArCH, H11 and H20 and H22), 7.37-7.31 (m, 2H, 2 x ArCH, H25 and H14
or H21), 7.22 (t, J = 7.5 Hz, 1H, ArCH, H10), 7.16 (dt, J = 1.0, 7.6 Hz, 1H,
ArCH, H26), 6.88 (br s, 1H, ArCH, H9), 4.33 (s, 1H, FcCH, H32), 4.27 (d,
J = 13.3 Hz, 1H, CHH, H18), 3.99 (s, 7H, Cp and FcCH, H35 and H33 and
H34), 3.96 (d, J = 13.1 Hz, 1H, CHH, H7), 3.88 (d, J = 13.3 Hz, 1H, CHH,
H18), 3.78 (d, J = 13.6 Hz, 1H, CHH, H29), 3.52 (d, J = 13.6 Hz, 1H, CHH,
H29), 3.48 (d, J = 13.1 Hz, 1H, CHH, H7), 2.85 (s, 1H, NH), 2.76 (t, J = 9.5
Calcd for C14H13FeIN
2
3.31; N, 7.05.
(±)-1-Iodo-2-(N-1,2,4-triazolinomethyl)ferrocene ((±)-4m): By following
the general procedure A from compound (±)-2 (115 mg, 0.30 mmol, 1.00
equiv) and 1,2,4-triazole (41.5 mg, 0.60 mmol, 2.00 equiv) in HFIP (316
μL), (±)-4m was obtained after column chromatography (PE-EtOAc, 80:20
with 2% of NEt
(
3
) as an orange solid (99 mg, 84%). Mp 115-117 °C. R
) = 0.29. νmax (film)/cm−1 3113,
eluent: PE/EtOAc 70:30, 5 drops of NEt
f
3
2
9
8
990, 1503, 1429, 1371, 1347, 1279, 1239, 1201, 1133, 1105, 1019, 1000,
57, 869, 843, 825, 808, 778, 711. 1H NMR (500 MHz, CDCl
): δ (ppm)
.08 (s, 1H, ArCH, H2’), 7.91 (s, 1H, ArCH, H1’), 5.20 (d, J = 14.7 Hz, 1H,
Hz, 1H, CHN, H1), 2.55 (s, 1H, CHN, H6), 2.18 (d, J = 11.9 Hz, 1H, C
H5), 2.09 (d, J = 12.2 Hz, 1H, C HH, H2), 1.91 (dd, J = 2.9, 6.4 Hz, 1H,
HH, H3), 1.73 (dd, J = 2.1, 5.9 Hz, 1H, C HH, H4), 1.62 (dq, J = 3.2,
2.0 Hz, 1H, C HH, H2), 1.33-1.25 (m, 2H, C HH, C HH, H3 and H4), 1.04
a
HH,
3
b
C
c
d
CHH), 5.14 (d, J = 14.7 Hz, 1H, CHH), 4.51 (dd, J = 1.3, 2.3 Hz, 1H, FcCH,
H5), 4.41 (dd, J = 1.3, 2.3 Hz, 1H, H3), 4.30 (t, J = 2.6 Hz, 1H, FcCH, H4),
1
b
c
d
8
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202100824
FULL PAPER
.18 (s, 5H, Cp). 13C{ H} NMR (125 MHz, CDCl
1
MHz, CDCl
4
3
): δ (ppm) 151.9 (ArCH,
3
): δ (ppm) 148.7 (ArC, C7’), 125.9 (ArCH, C5’), 122.3 (ArCH,
C1’), 142.8 (ArCH, C2’), 82.5 (FcC, C2), 75.6 (FcCH, C5), 72.0 (Cp), 70.1
FcCH, C4), 68.7 (FcCH, C3), 49.9 (CH ), 44.4 (FcC, C1). Anal. Calcd for
12FeIN : C, 39.73; H, 3.08; N, 10.69. Found: C, 40.17; H, 2.94; N,
0.37.
C1’), 121.9 (ArC, C2’), 121.7 (ArCH, C4’), 120.3 (ArCH, C3’), 117.6 (ArCH,
C6’), 84.4 (FcC, C2), 75.5 (FcCH, C5), 72.0 (Cp), 70.1 (FcCH, C4), 68.9
(
C
1
2
13
H
3
2 2
(FcCH, C3), 53.5 (CH ), 44.9 (FcC, C1). Anal. Calcd for C18H15FeIN : C,
48.90; H, 3.42; N, 6.34. Found: C, 48.81; H, 3.35; N, 6.21.
(
±)-1-Iodo-2-(N-2-thionobenzothiazolomethyl)ferrocene ((±)-4n): By
(±)-1-Iodo-2-(tert-butoxycarbonylaminomethyl)ferrocene ((±)-4p): By
following the general procedure A from compound (±)-2 (154 mg, 0.40
mmol, 1.00 equiv) and tert-butylcarbamate (93.7 mg, 0.80 mmol, 2.00
equiv) in HFIP (421 μL), (±)-4p was obtained after column chromatography
following the general procedure A from compound (±)-2 (115 mg, 0.30
mmol, 1.00 equiv) and 2-mercaptobenzothiazole (52.3 mg, 0.60 mmol,
2
.00 equiv) in HFIP (316 μL), (±)-4n was obtained after column
chromatography (PE-EtOAc, 80:20 with 1% of NEt ) as an orange solid
(eluent: PE/EtOAc 90:10) = 0.48. νmax
3
(PE-EtOAc, 90:10) as an orange oil (79 mg, 45%). R
f
(eluent: PE/EtOAc
(
113 mg, 76%). Mp 159-160 °C. R
f
95:5) = 0.77. νmax (film)/cm−1 3090, 2931, 1461, 1369, 1316, 1292, 1202,
film)/cm−1 3089, 2930, 1461, 1431, 1386, 1369, 1316, 1292, 1237, 1202,
1141, 1129, 1052, 969, 822, 804, 757. H NMR (500 MHz, DMSO-d ): δ
(ppm) 7.14 (t, J = 6.6 Hz, 1H, NH), 4.42 (s, 1H, FcCH, H5), 4.29 (s, 1H,
FcCH, H3), 4.21 (s, 1H, FcCH, H4), 4.14 (s, 5H, Cp), 4.03 (dd, J = 6.6,
15.0 Hz, 1H, CHH), 3.76 (dd, J = 6.6, 15.0 Hz, 1H, CHH), 1.14 (s, 9H,
1
6
(
1
1
7
141, 1129, 1053, 969, 822, 804, 757. H NMR (300 MHz, CDCl
3
): δ (ppm)
.44 (d, J = 7.7 Hz, 1H, ArCH, H5’), 7.33-7.26 (m, 2H, 2 x ArCH, H2’ and
H3’), 7.24 (m, 1H, ArCH, H4’), 6.34 (d, J = 15.3 Hz, 1H, CHH), 4.82 (d, J =
1
5
3 3
)
). 13C{ H} NMR (125 MHz, DMSO-d ): δ (ppm) 155.5 (C=O), 87.8
1
6
5.3 Hz, 1H, CHH), 4.44 (s, 1H, FcH, H5), 4.43 (s, 1H, FcCH, H3), 4.25 (s,
C(CH
(FcC, C2), 77.7 (Cq), 73.6 (FcCH, C5), 71.2 (Cp), 68.2 (FcCH, C4), 67.2
(FcCH, C3), 43.0 (FcC, C1), 39.7 (CH ), 28.3 C(CH ). Anal. Calcd for
20FeINO : C, 43.57; H, 4.57; N, 3.18. Found: C, 43.70; H, 4.71; N,
3.29.
H, Cp), 4.15 (t, J = 2.6 Hz, 1H, FcH, H4). 13C{ H} NMR (75.4 MHz, CDCl
1
3
):
δ (ppm) 189.9 (C=S), 141.3 (ArC, C1’), 127.5 (ArC, C6’), 127.0 (ArCH, C3’),
2
3 3
)
1
7
4
24.9 (ArCH, C4’), 121.3 (ArCH, C5’), 113.7 (ArCH, C2’), 83.6 (FcC, C2),
4.2 (FcCH, C5), 72.6 (Cp), 69.5 (FcCH, C4), 68.3 (FcCH, C3), 46.2 (CH ),
3.9 (FcC, C1). Anal. Calcd for C18 14FeINS : C, 44.01; H, 2.87; N, 2.85;
16
C H
2
2
H
2
S, 13.06. Found: C, 43.77; H, 2.91; N, 2.35; S, 12.58. Crystal data for (±)-
(
±)-1-Iodo-2-(allyloxymethyl)ferrocene ((±)-4q): By following the general
4
1
3
n. C18
H
14FeINS
2
, M = 491.17, T = 150 K; monoclinic C 2/c (I.T.#15), a =
procedure A from compound (±)-2 (154 mg, 0.40 mmol, 1.00 equiv) and
allyl alcohol (54.5 µL, 46.5 mg, 0.80 mmol, 2.00 equiv) in HFIP (421 μL),
8.761(2), b = 14.6448(15), c = 12.5847(14) Å, β = 95.803(4) °, V =
3
-3
-1
440.0(6) Å . Z = 8, d = 1.897 g·cm , μ = 2.911 mm . A final refinement
(
±)-4q was obtained after column chromatography (PE-EtOAc, 95:5) as an
orange oil (49 mg, 32%). R (eluent: PE/EtOAc 95:5) = 0.63. νmax
film)/cm−1 3090, 2850, 1645, 1446, 1410, 1368, 1287, 1252, 1230, 1191,
2
2
on F with 3908 unique intensities and 209 parameters converged at ωR
F
f
=
2
4
9
9
0.0533 (R
F
= 0.0245) for 3581 observed reflections with I > 2σ(I). CCDC
(
090456. (±)-1-Iodo-2-(S-2-thionobenzothiazolomethyl)ferrocene ((±)-
’n) was also isolated as an orange oil (9 mg, 6%). R (eluent: PE/EtOAc
f
0:10) = 0.66. νmax (film)/cm−1 2918, 1455, 1424, 1308, 1237, 1105, 1075,
105, 1077, 1055, 1000, 921, 819, 745. 1H NMR (500 MHz, CDCl
1
3
): δ
), 5.32 (dq, J = 1.5, 17.2 Hz, 1H, HC=CHH),
.20 (dq, J = 1.3, 10.4 Hz, 1H, HC=CHH), 4.45 (dd, J = 1.4, 2.1 Hz, 1H,
and FcH, CH -Fc and H3), 4.23 (t, J =
.4 Hz, 1H, FcCH, H4), 4.14 (s, 5H, Cp), 4.03 (m, 2H, CH
(ppm) 5.94 (m, 1H, HC=CH
2
5
1
90, 956, 821, 806, 752, 724. H NMR (500 MHz, CDCl
3
): δ (ppm) 7.93 (d,
FcCH, H5), 4.37-4.32 (m, 3H, CH
2
NMR (125 MHz, CDCl
2
2
J = 8.2 Hz, 1H, ArCH, H2’), 7.76 (d, J = 8.0 Hz, 1H, ArCH, H5’), 7.43 (dt, J
-CH). 13C{ H}
), 117.1 (HC=CH ), 85.0
-CH), 69.4 (FcCH, C4),
-Fc), 45.0 (FcC, C1). Anal. Calcd for
15FeIO: C, 44.02; H, 3.96. Found: C, 44.05; H, 4.00.
1
2
=
4
4
4
0.9, 8.2 Hz, 1H, ArCH, H3’), 7.30 (dt, J = 0.9, 8.0 Hz, 1H, ArCH, H4’),
.64 (d, J = 13.1 Hz, 1H, CHH), 4.47 (dd, J = 1.2, 2.1 Hz, 1H, FcCH, H5),
3
): δ (ppm) 135.1 (HC=CH
2
2
(FcC, C2), 75.3 (FcCH, C5), 71.6 (Cp), 71.3 (CH
2
.45 (dd, J = 1.4, 2.4 Hz, 1H, FcCH, H3), 4.34 (d, J = 13.3 Hz, 1H, CHH),
6
C
8.8 (FcCF, C3), 68.4 (CH
2
.21 (s, 6H, Cp and FcCH, Cp and H4). 13C{ H} NMR (125 MHz, CDCl
1
3
):
14
H
δ (ppm) 166.5 (C=N), 153.4 (ArC, C1’), 135.6 (ArC, C6’), 126.2 (ArCH,
C3’), 124.4 (ArCH, C4’), 121.6 (ArCH, C2’), 121.2 (ArCH, C5’), 84.7 (FcC,
C2), 75.0 (FcCH, C5), 72.0 (Cp), 69.3 (FcCH, C4), 68.4 (FcCH, C3), 45.2
(
4
(
±)-1-Iodo-2-(1,1,1,3,3,3-hexafluoro-2-propoxymethyl)ferrocene ((±)-
r): A solution of compound (±)-2 (50.0 mg, 0.13 mmol, 1.00 equiv) in HFIP
410 μL, 665 mg, 3.90 mmol, 30.0 equiv) was heated at 60 °C for 1 h in a
pre-heated oil bath. The reaction mixture was cooled to rt and was poured
onto 2 mL of EtOAc and 1 mL of NEt . Volatiles were removed under
vacuum using a rotary evaporator to give the crude product. This was
purified by column chromatography over SiO , using PE/EtOAc (14:1 to
0:1) with 1% of NEt to give the title product ((±)-4r as an orange solid
41.0 mg, 64%). Alternatively, (±)-4r can also be prepared from (±)-1: A
(
FcC, C1), 34.5 (CH
2
).
(±)-1-Iodo-2-(N-indazolomethyl)ferrocene ((±)-4o): By following the
3
general procedure A from compound (±)-2 (154 mg, 0.40 mmol, 1.00
equiv) and indazole (94.5 mg, 0.80 mmol, 2.00 equiv) in HFIP (421 μL),
2
(
7
±)-4o was obtained after column chromatography (PE-EtOAc, 90:10 to
0:30 with 2% of NEt ) as an orange oil (79 mg, 44%). R (eluent:
PE/EtOAc 90:10, 5 drops of NEt
) = 0.48. νmax (film)/cm−1 3093, 1614, 1498,
1
(
3
3
f
3
solution of compound (±)-1 (55.0 mg, 0.13 mmol, 1.00 equiv) in HFIP (410
μL, 665 mg, 3.90 mmol, 30.0 equiv) was heated at 60 °C for 1 h in a pre-
heated oil bath. The reaction mixture was cooled to rt and was poured onto
1
463, 1417, 1368, 1252, 1168, 1105, 1059, 1028, 1001, 904, 823, 762,
1
737. H NMR (300 MHz, CDCl
3
): δ (ppm) 8.03 (s, 1H, ArCH, H1’), 7.73 (d,
J = 8.1 Hz, 1H, ArCH, H3’), 7.60 (d, J = 8.6 Hz, 1H, ArCH, H6’), 7.38 (t, J
2
mL of EtOAc and 1 mL of NEt
using a rotary evaporator to give the crude product. This was purified by
column chromatography over SiO , using PE/EtOAc (12:1 to 10:1) with 1%
of NEt to give the title product as an orange solid (59.0 mg, 92%). R
3
. Volatiles were removed under vacuum
=
8.2 Hz, 1H, ArCH, H5’), 7.14 (t, J = 7.6 Hz, 1H, ArCH, H4’), 5.44 (d, J =
15.3 Hz, 1H, CHH), 5.34 (d, J = 15.3 Hz, 1H, CHH), 4.45 (dd, J = 1.4, 2.1
2
Hz, 1H, FcCH, H3), 4.32 (dd, J = 1.4, 2.3 Hz, 1H, FcCH, H5), 4.19 (t, J =
3
f
1
2
.5 Hz, 1H, FcCH, H4), 4.14 (s, 5H, Cp). 13C{ H} NMR (75.4 MHz, CDCl
3
):
(
(
3
eluent: PE/EtOAc 14:1, 5 drops of NEt ) = 0.69. Mp 53-55 °C. νmax
δ (ppm) 139.4 (ArC, C7’), 133.3 (ArCH, C1’), 126.3 (ArCH, C6’), 124.1
film)/cm−1 3097, 2932, 1455, 1371, 1284, 1262, 1216, 1185, 1099, 1000,
(ArC, C2’), 121.1 (ArCH, C3’), 120.6 (ArCH, C4’), 109.8 (ArCH, C5’), 85.5
1
971, 895, 870, 825. H NMR (500 MHz, CDCl
3
): δ (ppm) 4.74 (d, J = 11.7
(FcC, C2), 74.8 (FcCH, C5), 71.9 (Cp), 69.4 (FcCH, C4), 68.2 (FcCH, C3),
Hz, 1H, CHH), 4.72 (d, J = 11.7 Hz, 1H, CHH), 4.53 (dd, J = 1.4, 2.2 Hz,
H, FcCH, H5), 4.37 (dd, J = 1.3, 2.3 Hz, 1H, FcCH, H3), 4.32 (t, J = 2.5
Hz, 1H, FcCH, H4), 4.21 (sept, J = 6.0 Hz, 1H, CH), 4.17 (s, 5H, Cp).
2 2
49.1 (CH ), 44.1 (FcC, C1). Anal. Calcd for C18H15FeIN : C, 48.90; H, 3.42;
1
N, 6.34. Found: C, 48.95; H, 3.49; N, 6.37. (±)-1-Iodo-2-(N’-
indazolomethyl)ferrocene ((±)-4o’) was also isolated as an orange solid
13
1
C{ H} NMR (125 MHz, CDCl
CF ), 82.1 (s, FcC, C2), 76.0 (s, FcCH, C5), 74.2 (sept, J = 32.7 Hz, CH),
2.4 (s, CH ), 71.8 (Cp), 70.3 (s, FcCH, C2), 69.2 (s, FcCH, C3), 44.6 (s,
3
): δ (ppm) 121.7 (dq, J = 30.6, 284 Hz, 2 x
(
94 mg, 53%). Mp 111-113 °C. R
NEt
) = 0.34. νmax (film)/cm−1 3095, 1624, 1512, 1465, 1434, 1423, 1375,
333, 1294, 1145, 1129, 1105, 1002, 821, 810, 785, 755. 1H NMR (300
MHz, CDCl ): δ (ppm) 7.92 (s, 1H, ArCH, H1’), 7.71 (d, J = 8.7 Hz, 1H,
ArCH, H6’), 7.61 (d, J = 8.6 Hz, 1H, ArCH, H3’), 7.27 (t, J = 7.4 Hz, 1H,
ArCH, H5’), 7.05 (t, J = 7.4 Hz, 1H, ArCH, H4’), 5.44 (s, 2H, CH ), 4.51 (dd,
f
(eluent: PE/EtOAc 90:10, 5 drops of
3
3
7
2
1
19
1
FcC, C1). F{ H} NMR (283 MHz, CDCl
3
): δ (ppm) -73.6 (m, 2 x CF
IO: C, 34.18; H, 2.25. Found: C,
4.53; H, 2.41. Crystal data for (±)-4r. C14 FeIO, M = 491.98, T =
50 K; monoclinic C 2/c (I.T.#15), a = 42.045(8), b = 7.5013(14), c =
3
).
3
Mass: 492 [M]. Anal. Calcd for C14 11FeF
H
6
3
1
1
11 6
H F
2
J = 1.1, 2.0 Hz, 1H, FcCH, H5), 4.49 (dd, J = 1.5, 2.6 Hz, 1H, FcCH, H3),
3
-3
0.080(2) Å, β = 102.947(7) °, V = 3098.3(11) Å . Z = 8, d = 2.109 g·cm ,
1
4
.29 (t, J = 2.6 Hz, 1H, FcCH, H4), 4.20 (s, 5H, Cp). 13C{ H} NMR (75.4
9
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202100824
FULL PAPER
-
1
2
μ = 3.029 mm . A final refinement on F with 3540 unique intensities and
1
(±)-1-Iodo-2-(N-methyl-3-indolylmethyl)ferrocene ((±)-4u): By following
the general procedure A from compound (±)-2 (154 mg, 0.40 mmol, 1.00
equiv) and N-methylindole (105 mg, 0.80 mmol, 2.00 equiv) in HFIP (421
μL), (±)-4u was obtained after column chromatography (PE-EtOAc, 95:5
2
84 parameters converged at ωR(F ) = 0.0688 (R(F) = 0.0304) for 3074
observed reflections with I > 2σ(I). CCDC 1898629.
with 2% of NEt
3
) and trituration in pentane as an orange solid (146 mg,
(
(
(
S
(S
p
)-1-Iodo-2-(1,1,1,3,3,3-hexafluoro-2-propoxymethyl)ferrocene
)-4r): By following a similar protocol, starting from compound (S
50.0 mg, 0.13 mmol, 1.00 equiv, er 96:4), the title product was obtained
80%). It can also be prepared on a larger scale by following the general
p
p
)-2
procedure A from compound (±)-2 (499 mg, 1.30 mmol, 1.00 equiv) and
N-methylindole (341 mg, 2.60 mmol, 2.00 equiv) in HFIP (1.40 mL).
as an orange solid (27.0 mg, 42%, er 96:4). Analytical data analogous to
racemic compound. [α] -18.5 (c 0.01 in CHCl ). The enantiomeric ratio
was determined on Chiralpak IA-3 column, hexane/iPrOH: 99:1, 0.5
mL/min, 5 °C, λ = 254 nm, t (major) = 11.64 min, t (minor) = 10.84 min).
Alternatively, (S
Compound (±)-4u was obtained as an orange solid (499 mg, 84%). R
f
D
3
(
eluent: PE/EtOAc 95:5) = 0.53. Mp 136-137 °C. νmax (film)/cm−1 3093,
2
929, 1614, 1472, 1432, 1368, 1328, 1231, 1204, 1156, 1102, 1030, 997,
1
961, 807, 742. H NMR (500 MHz, CDCl
3
): δ (ppm) 7.66 (d, J = 8.0 Hz, 1H,
p
p
)-4r can also be prepared from (S )-1: By following a
ArCH, H4’), 7.28 (d, J = 8.1 Hz, 1H, ArCH, H7’), 7.22 (dt, J = 0.8, 7.2 Hz,
H, ArCH, H6’), 7.12 (dt, J = 1.0, 7.0 Hz, 1H, ArCH, H5’), 6.76 (s, 1H, ArCH,
H1’), 4.42 (dd, J = 1.3, 2.3 Hz, 1H, FcCH, H5), 4.23 (dd, J = 1.3, 2.3 Hz,
H, FcCH, H3), 4.16 (s, 5H, Cp), 4.14 (t, J = 2.3 Hz, 1H, FcCH, C4), 3.90
similar protocol, starting from compound (S
p
)-1 (55.0 mg, 0.13 mmol, 1.00
1
equiv), the title product was obtained as an orange solid (56.0 mg, 87.5%,
er 95:5). Analytical data analogous to racemic compound. The
enantiomeric ratio was determined on Chiralpak IA-3 column,
1
-
1
(d, J = 16.7 Hz, 1H, CHH), 3.86 (d, J = 16.7 Hz, 1H, CHH), 3.72 (s, 3H,
hexane/iPrOH: 99:1, 0.5 mL·min , 5 °C, λ = 254 nm, t (major) = 11.72 min,
1
CH
3
). 13C{ H} NMR (125 MHz, CDCl
3
): δ (ppm) 137.0 (ArC, C8’), 127.7
t (minor) = 10.97 min.
(
(
(
ArC, C3’), 127.0 (ArCH, C1’), 121.6 (ArCH, C6’), 119.2 (ArCH, C4’), 118.8
ArCH, C5’), 114.3 (ArC, C2’), 109.3 (ArCH, C7’), 89.7 (FcC, C2), 74.2
FcCH, C5), 71.8 (Cp), 68.3 (FcCH, C4), 67.9 (FcCH, C3), 45.7 (FcC, C1),
(
±)-1-Iodo-2-(diphenylphosphinomethyl)ferrocene
((±)-4s):
By
following the general procedure A from compound (±)-2 (57.6 mg, 0.15
mmol, 1.00 equiv) and diphenylphosphine (104 µL, 112 mg, 0.60 mmol,
4
3
3
C
2.8 (CH
.08. Found: C, 52.90; H, 4.01; N, 3.15. Crystal data for (±)-4u.
18FeIN, M = 455.10, T = 150 K; monoclinic P 2 /c (I.T.#14), a =
12.3344(7), b = 11.2470(6), c = 12.5667(7) Å, β = 95.672(2) °, V =
3 2
), 26.3 (CH ). Anal. Calcd for C20H18FeIN: C, 52.78; H, 3.99; N,
.00 equiv) in HFIP (160 μL), (±)-4s was obtained after column
20
H
1
chromatography (PE-EtOAc, 50:1) as an orange oil (68 mg, 89%). R
f
eluent: PE/EtOAc 20:1) = 0.67. νmax (film)/cm−1 3069, 2921, 2245, 1952,
(
3
-3
-1
1
734.78(17) Å . Z = 4, d = 1.743 g·cm , μ = 2.647 mm . A final refinement
1
8
4
1
885, 1724, 1585, 1479, 1432, 1408, 1365, 1105, 1026, 999, 950, 908,
2
1
on F with 3895 unique intensities and 209 parameters converged at
ωR(F ) = 0.0774 (R(F) = 0.0355) for 3384 observed reflections with I >
2
18, 737, 693. H NMR (500 MHz, CDCl
3
): δ (ppm) 7.47-7.39 (m, 4H, ArCH,
2
x H2’), 7.36-7.31 (m, 6H, ArCH, 4 x H3’ and 2 x H4’), 4.37 (dd, J = 2.2,
.4 Hz, 1H, FcCH, H5), 4.09 (s, 5H, Cp), 4.05 (t, J = 2.5 Hz, 1H, FcCH,
σ(I). CCDC 2090457.
H4), 3.82 (s, 1H, FcCH, H3), 3.22 (d, J = 14.4 Hz, 1H, CHH), 3.19 (d, J =
4.4 Hz, 1H, CHH). 1 C{ H} NMR (125 MHz, CDCl
3
1
(±)-1-Iodo-2-(3-benzothiophenylmethyl)ferrocene ((±)-4v): By following
the general procedure A from compound (±)-2 (154 mg, 0.40 mmol, 1.00
equiv) and benzothiophene (107 mg, 0.80 mmol, 2.00 equiv) in HFIP (421
μL), (±)-4v was obtained after column chromatography (PE-EtOAc, 15:1)
1
3
): δ (ppm) 138.8 (d, J =
15.3 Hz, ArC, C1’), 138.2 (d, J = 15.3 Hz, ArC, C1’), 133.7 (d, J = 19.8 Hz,
ArCH, 2 x C2’), 132.5 (d, J = 17.9 Hz, ArCH, 2 x C2’), 129.1 (s, ArCH, 2 x
C4’), 128.5 (d, J = 4.5 Hz, ArCH, 4 x C3’), 86.1 (d, J = 15.4 Hz, FcC, C2),
as an orange solid (45 mg, 24%). R
33-135 °C. νmax (film)/cm−1 3088, 1456, 1426, 1406, 1281, 1252, 1133,
1104, 1018, 998, 958, 861, 825, 807, 758, 742, 727. 1H NMR (500 MHz,
CDCl ): δ (ppm) 7.85 (d, J = 7.5 Hz, 1H, ArCH, H7’), 7.84 (d, J = 7.5 Hz,
H, ArCH, H4’), 7.41 (t, J = 7.5 Hz, 1H, H6’), 7.35 (t, J = 7.5 Hz, 1H, ArCH,
f
(eluent: PE/EtOAc 90:10) = 0.80. Mp
7
4.1 (s, FcCH, C5), 71.9 (s, Cp), 68.3 (s, FcCH, C4), 67.9 (d, J = 5.7 Hz,
1
FcCH, C3), 48.7 (d, J = 3.3 Hz, FcC, C1), 30.6 (d, J = 15.6 Hz, CH ).
2
31
1
3
P{ H} NMR (121 MHz, CDCl ): δ (ppm) -13.8.
3
1
(
S
p
)-1-Iodo-2-(diphenylphosphinomethyl)ferrocene
following the general procedure A from compound (S
mmol, 1.00 equiv) and diphenylphosphine (69.6 µL, 74.5 mg, 0.40 mmol,
.00 equiv) in HFIP (106 μL), (S )-4s was obtained after column
chromatography (PE-EtOAc, 50:1) as an orange oil (50.0 mg, 98%, 95:5
er). Analytical data analogous to racemic compound. [α] +3.54 (c 0.01 in
CHCl ). The enantiomeric ratio was determined on Chiralpak IA-3 column,
((S
p
)-4s):
By
H5’), 6.96 (s, 1H, ArCH, H1’), 4.46 (s, 1H, FcCH, H5), 4.19 (s, 1H, FcCH,
p
)-2 (38.4 mg, 0.1
1
H3), 4.18 (s, 1H, H5), 4.16 (s, 5H, Cp), 3.96 (s, 2H, CH
125 MHz, CDCl
C2’), 124.3 (ArCH, C5’), 124.0 (ArCH, C6’), 123.0 (ArCH, C7’), 122.9
2
). 13C{ H} NMR
(
3
): δ (ppm) 140.6 (ArC, C8’), 138.8 (ArC, C3’), 135.5 (ArC,
4
p
(
(
ArCH, C1’), 121.9 (ArCH, C4’), 87.9 (FcC, C2), 74.6 (FcCH, C5), 71.9
Cp), 68.6 and 68.1 (FcCH, C3 and C4), 45.7 (FcC, C1), 29.7 (CH ). Anal.
15FeIS: C, 49.81; H, 3.30; S, 7.00. Found: C, 49.96; H, 3.28;
N, 6.82. Crystal data for (±)-4v. C19 15FeIS, M = 458.12, T = 150 K;
D
2
3
-
1
Calcd for C19H
hexane/iPrOH: 99:1, 0.8 mL·min , 20 °C, λ = 254 nm, t (major) = 6.21 min,
t (minor) = 6.80 min.
H
monoclinic P 2
1
/c (I.T.#14),
a
=
10.3379(9),
b
=
11.6871(9),
c
=
3
-
1
,
3.8680(12) Å, β = 101.121(3) °, V = 1644.1(2) Å . Z = 4, d = 1.851 g·cm
μ = 2.915 mm . A final refinement on F with 3730 unique intensities and
(±)-1-Iodo-2-(3-(N-indolyl)methyl)ferrocene ((±)-4t): By following the
3
-1
2
general procedure A from compound (±)-2 (154 mg, 0.40 mmol, 1.00
equiv) and indole (94.0 mg, 0.80 mmol, 2.00 equiv) in HFIP (421 μL), (±)-
2
169 parameters converged at ωR(F ) = 0.1460 (R(F) = 0.0628) for 3196
observed reflections with I > 2σ(I). CCDC 2090458.
4
t was obtained after column chromatography (PE-EtOAc, 95:5 with 2%
of NEt ) as an orange solid (143 mg, 81%). R (eluent: PE/EtOAc 95:5) =
.32. Mp 170-171 °C. νmax (film)/cm−1 3411, 3089, 3053, 2892, 1615, 1455,
3
f
(±)-1-Iodo-2-(2-benzofuranylmethyl)ferrocene ((±)-4w): By following the
general procedure A from compound (±)-2 (154 mg, 0.40 mmol, 1.00
equiv) and benzofurane (94.5 mg, 0.80 mmol, 2.00 equiv) in HFIP (421
μL), (±)-4w was obtained after column chromatography (PE-EtOAc, 20:1)
0
1
418, 1403, 1354, 1335, 1221, 1102, 1088, 1011, 996, 958, 829, 804, 752.
1
3
H NMR (500 MHz, CDCl ): δ (ppm) 7.89 (br s, 1H, NH), 7.67 (d, J = 7.7
Hz, 1H, ArCH, H4’), 7.34 (d, J = 8.1 Hz, 1H, ArCH, H7’), 7.20 (dt, J = 1.1,
as an orange oil (65 mg, 36%). R
f
(eluent: PE/EtOAc 90:10) = 0.82. νmax
8
1
2
.1 Hz, 1H, ArCH, H6’), 7.13 (dt, J = 0.9, 7.7 Hz, 1H, ArCH, H5’), 6.92 (m,
H, ArCH, H1’), 4.42 (dd, J = 1.4, 2.3 Hz, 1H, FcCH, H5), 4.22 (dd, J = 1.4,
.3 Hz, 1H, FcCH, H3), 4.15 (s, 5H, Cp), 4.13 (t, J = 2.3 Hz, 1H, FcCH,
(
film)/cm−1 3087, 1599, 1586, 1453, 1418, 1252, 1167, 1105, 1000, 950,
1
3
907, 823, 801, 729. H NMR (500 MHz, CDCl ): δ (ppm) 7.49 (d, J = 7.3
Hz, 1H, ArCH, H4’), 7.45 (d, J = 8.0 Hz, 1H, ArCH, H7’), 7.23 (dt, J = 1.2,
). 13C{ H} NMR (125 MHz, CDCl
1
H4), 3.89 (s, 2H, CH
2
3
): δ (ppm) 136.3
8
1
1
.0 Hz, 1H, ArCH, H6’), 7.19 (t, J = 0.8, 7.3 Hz, 1H, ArCH, H5’), 6.39 (s,
H, ArCH, H2’), 4.45 (dd, J = 1.2, 1.9 Hz, 1H, FcCH, H5), 4.28 (dd, J = 1.2,
(
(
(
ArC, C8’), 127.4 (ArC, C3’), 122.3 (ArCH, C1’), 122.1 (ArCH, C6’), 119.5
ArCH, C5’), 115.8 (ArC; C2’), 111.2 (ArCH, C7’), 89.5 (FcC, C2), 74.2
FcCH, C5), 71.8 (Cp), 68.3 (FcCH, C4), 67.9 (FcCH, C3), 45.7 (FcC, C1),
.9 Hz, 1H, FcCH, H3), 4.19 (t, J = 2.4 Hz, 1H, FcCH, H4), 4.15 (s, 5H,
1
Cp), 3.89 (s, 2H, CH
2
). 13C{ H} NMR (125 MHz, CDCl
3
): δ (ppm) 157.1
26.3 (CH
2
). Anal. Calcd for C19H16FeIN: C, 51.74; H, 3.66; N, 3.18. Found:
(
(
(
ArC, C1’), 154.8 (ArC, C8’), 128.9 (ArC, C3’), 123.5 (ArCH, C6’), 122.7
ArCH, C5’), 120.6 (ArCH, C4’), 111.0 (ArCH, C7’), 103.2 (ArCH, C2’), 85.9
FcC, C2), 74.5 (FcCH, C5), 71.9 (Cp), 68.6 (FcCH, C4), 67.9 (FcCH, C3),
C, 51.54; H, 3.53; N, 2.98.
1
0
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202100824
FULL PAPER
2
45.2 (FcC, C1), 29.9 (CH ). Anal. Calcd for C19H15FeIO: C, 51.62; H, 3.42.
h in a pre-heated oil bath. The reaction mixture was cooled to rt and was
Found: C, 51.89; H, 3.37.
poured onto 2 mL of EtOAc and 1 mL of NEt
under vacuum using a rotary evaporator to give the crude product. This
was purified by column chromatography over SiO , using PE/EtOAc (20:1)
with 2% of NEt to give the title product as an orange solid (26.1 mg, 53%).
(eluent: PE/EtOAc 10:1) = 0.69. Mp 124-126 °C. νmax (film)/cm−1 2924,
3
. Volatiles were removed
2
(±)-1-Iodo-3-(N-morpholinomethyl)ferrocene ((±)-7a): By following the
3
general procedure A from compound (±)-5 (115 mg, 0.30 mmol) and
morpholine (52.5 μL, 52.3 mg, 0.60 mmol) in HFIP (316 μL), (±)-7a was
obtained after column chromatography (PE-EtOAc, 80:20 to 20:80 with 1%
R
f
1
462, 1399, 1367, 1288, 1206, 1195, 1117, 1093, 1031, 1000, 963, 895,
1
873, 827, 758, 737, 683. H NMR (400 MHz, CDCl
3
): δ (ppm) 4.62 (d, J =
of NEt
drops of NEt
3
) as an orange solid (111 mg, 90%). R
f
(eluent: PE/EtOAc 80:20, 5
) = 0.22. Mp 99-100 °C. νmax (film)/cm−1 2928, 2861, 1799,
11.2 Hz, 1H, CHH), 4.58 (d, J = 11.2 Hz, 1H, CHH), 4.55 (m, 1H, FcCH,
3
H2), 4.51 (m, 1H, FcCH, H5), 4.29 (s, FcCH, H4), 4.22 (s, 5H, Cp), 4.14
2
8
1
751, 1449, 1349, 1330, 1284, 123, 1155, 1104, 1070, 1029, 997, 907,
(sept, 6.0 Hz, 1H, CH). 13C{ H} NMR (100 MHz, CDCl
1
1
3
): δ (ppm) 121.7 (d,
71, 861, 851, 819, 800. H NMR (500 MHz, CDCl
3
): δ (ppm) 4.44 (t, J =
3
J = 284.0 Hz, 2 x CF ), 81.6 (s, FcC, C3), 75.8 and 75.7 (s, 2 x FcH, C2
.2 Hz, 1H, FcCH, H2), 4.38 (dd, J = 1.2, 1.9 Hz, 1H, FcCH, H5); 4.17 (dd,
and C5), 74.4 (sept, J = 32.5 Hz, CH), 72.0 (s, CH
2
), 71.9 (s, Cp), 70.2 (s,
): δ (ppm) -
FeIO: C, 34.18;
J = 1.2, 1.9 Hz, 1H, FcCH, H4), 4.14 (s, 5H, Cp), 3.65 (t, J = 4.7 Hz, 4H, 2
x CH O), 3.30 (d, J = 12.9 Hz, 1H, CHH), 3.24 (d, J = 12.9 Hz, 1H, CHH),
FcCH, C4), 39.6 (s, FcC, C1). 19F{ H} NMR (376 MHz, CDCl
1
3
2
N). 13C{ H} NMR (125 MHz, CDCl
1
3
73.7 (m, 2 x CF ). Mass: 492 [M]. Anal. Calcd for C14
H F
11 6
2
8
.38 (t, J = 4.7 Hz, 4H, 2 x CH
3.6 (FcC, C3), 76.6 (FcCH, C2), 74.7 (FcCH, C5), 71.8 (Cp), 71.0 (FcCH,
O), 58.5 (CH ), 53.3 (2 x CH N), 39.7 (FcC, C1). Anal.
18FeINO: C, 43.83; H, 4.41; N, 3.41. Found: C, 43.82; H,
.34; N, 3.31. Crystal data for (±)-7a. C15 18FeINO, M = 411.05, T = 150
K; monoclinic P 2 /n (I.T.#14), a = 6.8814(4), b = 26.8918(16), c =
.9563(5) Å, β = 94.774(2) °, V = 1467.23(15) Å . Z = 4, d = 1.861 g·cm ,
2
3
): δ (ppm)
H, 2.25. Found: C, 34.22; H, 2.31.
C4), 67.0 (2 x CH
Calcd for C15
4
2
2
2
H
(±)-1-Iodo-3-(diphenylphosphinomethyl)ferrocene
((±)-7e):
By
H
following the general procedure A from compound (±)-2 (57.6 mg, 0.15
mmol, 1.00 equiv) and diphenylphosphine (104 µL, 112 mg, 0.60 mmol,
4.00 equiv) in HFIP (160 μL), (±)-7e was obtained after column
chromatography (PE-EtOAc, 50:1) as an orange oil (60 mg, 78%). R
f
(eluent: PE/EtOAc 20:1) = 0.79. νmax (film)/cm−1 3070, 3051, 2923, 1584,
1
3
-3
7
-
1
2
μ = 3.123 mm . A final refinement on F with 3326 unique intensities and
2
172 parameters converged at ωR(F ) = 0.0603 (R(F) = 0.0309) for 3018
observed reflections with I > 2σ(I). CCDC 2090459.
1480, 1460, 1432, 1409, 1376, 1105, 1067, 1025, 999, 933, 870, 738, 721.
1H NMR (500 MHz, CDCl
3
): δ (ppm) 7.38-7.34 (m, 4H, ArCH), 7.32-7.30
(m, 6H, ArCH), 4.22 (dd, J = 1.2, 2.2 Hz, 1H, FcCH, H5), 4.16 (s, 1H, FcCH,
(±)-1-Iodo-3-(N-pyrazolinomethyl)ferrocene ((±)-7b): By following the
H2), 4.10 (s, 5H, Cp), 3.87 (t, J = 1.7 Hz, 1H, FcCH, H4), 3.07 (d, J = 14.2
Hz, 1H, CHH), 3.03 (d, J = 14.2 Hz, 1H, CHH). 13C{ H} NMR (126 MHz,
general procedure A from compound (±)-5 (38.4 mg, 0.10 mmol) and
pyrazole (13.7 mg, 0.20 mmol) in HFIP (106 μL), (±)-7b was obtained after
1
3
CDCl ): δ (ppm) 138.6 (d, J = 11.4 Hz, ArC, C1’), 138.5 (d, J = 11.3 Hz,
column chromatography (PE-EtOAc, 75:25 with 1% of NEt
3
) as an orange
ArC, C1’), 133.1 (d, J = 19.5 Hz, ArCH, 2 x C2’), 132.9 (d, J = 19.0 Hz,
ArCH, 2 x C2’), 129.0 (d, J = 5.2 Hz, ArCH, 2 x C4’), 128.6 (d, J = 6.6 Hz,
ArCH, 4 x C3’), 85.6 (d, J = 15.6 Hz, FcC, C3), 75.7 (d, J = 4.2 Hz, FcCH,
solid (39.1 mg, quant). R (eluent: PE/EtOAc 80:20, 5 drops of NEt ) = 0.38.
f 3
Mp 92-94 °C. νmax (film)/cm−1 2923, 1511, 1444, 1395, 1353, 1272, 1237,
1
1
216, 1105, 1085, 1049, 998, 968, 871, 826, 764, 706. H NMR (500 MHz,
C2), 73.9 (s, FcCH, C5), 72.1 (s, Cp), 69.9 (d, J = 4.4 Hz, FcCH, C4), 39.8
CDCl
3
): δ (ppm) 7.48 (d, J = 1.1 Hz, 1H, ArCH, H1’), 7.32 (d, J = 2.0 Hz,
H, ArCH, H3’), 6.21 (t, J = 2.0 Hz, 1H, ArCH, H2’), 4.98 (d, J = 14.7 Hz,
H, CHH), 4.94 (d, J = 14.7 Hz, 1H, CHH), 4.49 (s, 1H, FcCH, H2), 4.40
1
(
s, FcC, C1), 30.1 (d, J = 15.3 Hz, CH
2
). 31P{ H} NMR (121 MHz, CDCl
3
):
1
1
δ (ppm) -12.6.
(
4
dd, J = 1.1, 2.0 Hz, 1H, FcCH, H5), 4.24 (t, J = 1.7 Hz, 1H, FcCH, H4),
.15 (s, 5H, Cp). 13C{ H} NMR (125 MHz, CDCl
1
1-Iodo-1’-(N-morpholinomethyl)ferrocene (8a): By following the general
procedure A from compound 6 (768 mg, 2.00 mmol) and morpholine (350
μL, 349 mg, 4.00 mmol) in HFIP (2.10 mL), 8a was obtained after column
3
): δ (ppm) 139.3 (ArCH,
H1’), 128.6 (ArCH, C3’), 105.8 (ArCH, C2’), 84.4 (FcC, C3), 75.2 and 75.1
FcCH, C2 and C5), 72.1 (Cp), 69.6 (FcCH, C4), 51.2 (CH ), 39.6 (FcC,
C1). Mass: 392 [M], 265 [M-I]. Anal. Calcd for C14 13FeIN : C, 42.89; H,
.34; N, 7.15. Found: C, 42.95; H, 3.48; N, 7.18. Crystal data for (±)-7b.
13FeIN , M = 392.01, T = 150 K; monoclinic P 2 /c (I.T.#14), a =
7.842(3), b = 7.5959(11), c = 9.9836(19) Å, β = 92.201(8) °, V = 1352.0(4)
(
2
H
2
chromatography (PE-EtOAc, 50:50 to 30:70 with 1% of NEt
3
) as an orange
3
C
1
solid (787 mg, 96%). R (eluent: PE/EtOAc 50:50, 5 drops of NEt ) = 0.38.
f
3
14
H
2
1
Mp 73-74 °C. νmax (film)/cm−1 2922, 2864, 2793, 1446, 1392, 1344, 1326,
1283, 1265, 1126, 1107, 1071, 1002, 859, 819, 801. 1H NMR (500 MHz,
3
-3
-1
2
Å . Z = 4, d = 1.926 g·cm , μ = 3.381 mm . A final refinement on F with
3
CDCl ): δ (ppm) 4.33 (t, J = 1.7 Hz, 2H, FcCH, H2 and H5), 4.16 (t, J = 1.8
Hz, 2H, FcCH, H3’ and H4’), 4.13 (t, J = 1.8 Hz, 2H, FcCH, H2’ and H5’),
2
3
091 unique intensities and 139 parameters converged at ωR(F ) = 0.0984
(
1
R(F) = 0.0395) for 2694 observed reflections with I > 2σ(I). CCDC
898630.
4.11 (t, J = 1.7 Hz, 2H, FcCH, H3 and H4), 3.66 (t, J = 4.6 Hz, 4H, 2 x
N). 13C{ H} NMR
1
CH
(
(
6
2
O), 3.38 (s, 2H, CH
125 MHz, CDCl
FcCH, C2’ and C5’), 71.4 (FcCH, C3’ and C4’), 69.5 (FcCH, C3 and C4),
7.0 (2 x CH O), 58.1 (CH2), 53.3 (2 x CH2N), 40.4 (FcC, C1). Anal. Calcd
for C15 18FeINO: C, 43.83; H, 4.41; N, 3.41. Found: C, 43.67; H, 4.06; N,
.52. Crystal data for 8a. C15 18FeINO, M = 411.05, T = 150 K;
monoclinic P 2 /n (I.T.#14), a = 6.2155(5), b = 9.6683(6), c = 24.5900(18)
Å, β = 94.916(2) °, V = 1472.26(18) Å . Z = 4, d = 1.854 g·cm , μ = 3.112
2
), 2.41 (t, J = 4.6 Hz, 4H, 2 x CH
3
): δ (ppm) 83.9 (FcC, C1’), 75.3 (FcCH, C2 and C5), 73.5
2
N,N’-Dimethyl-N,N’-(3-iodoferrocenylmethyl)ethylenediamine
7
0
mg, 0.10 mmol, 0.45 equiv) in HFIP (210 μL), (±)-7c was obtained after
column chromatography (PE-EtOAc, 50:50 to 0:100 with 2% of NEt ) as
f 3
an orange oil (52 mg, 70%). R (eluent: PE/EtOAc 20:80, 5 drops of NEt )
=
1
((±)-
c): By following the general procedure A from compound (±)-5 (84.5 mg,
.22 mmol, 1.00 equiv) and N,N’-dimethylethylenediamine (11.0 μL, 8.81
2
H
3
H
1
3
3
-3
-
1
2
0.18. νmax (film)/cm−1 2775, 1454, 1410, 1358, 1344, 1318, 1270, 1237,
mm . A final refinement on F with 3357 unique intensities and 172
2
1
parameters converged at ωR(F ) = 0.0550 (R(F) = 0.0228) for 3183
157, 1118, 1103, 1029, 1013, 868, 834, 821. H NMR (400 MHz, CDCl
3
):
observed reflections with I > 2σ(I). CCDC 2090460.
δ (ppm) 4.39 (m, 2H, FcCH, 2 x H2), 4.35 (m, 2H, FcCH, 2 x H5), 4.11 (s,
12H, Cp and FcCH, 2 x Cp and 2 x H4), 3.31 (d, J = 13.3 Hz, 2H, 2 x CHH),
3
x CH
.24 (d, J = 13.3 Hz, 2H, 2 x CHH), 2.33 (s, 4H, 2 x CH
2
N), 2.12 (s, 6H, 2
(R,S
the general procedure A from compound (R,S
and morpholine (52.5 μL, 52.3 mg, 2.00 mmol) in HFIP (316 μL), ((R,S
10 was obtained after column chromatography (PE-EtOAc, 90:10 to 70:30
with 2% of NEt ) as an orange solid (100 mg, 78%). R (eluent: PE/EtOAc
80:20, 5 drops of NEt ) = 0.62. Mp 115-116 °C. [α] -32.4 (c 0.01 in CHCl ).
max (film)/cm−1 2945, 2884, 2844, 2826, 1438, 1378, 1283, 1253, 1229,
p
)-1-Iodo-2-(N-morpholinoethyl)ferrocene ((R,S
)-9b (119 mg, 0.30 mmol)
)-
p
)-10): By following
). 13C{ H} NMR (100 MHz, CDCl
1
3
3
): δ (ppm) 84.0 (FcCH, 2 x C3), 76.7
p
(FcCH, 2 x C2), 74.6 (FcCH, 2 x C5), 71.8 (2 x Cp), 71.0 (2 x FcCH, C4),
p
5
7.2 (CH
), 39.8 (FcC, 2 x C1). Anal. Calcd for C26
N, 3.81. Found: C, 42.50; H, 4.21; N, 3.87.
2 2 2 2
-Fc), 57.1 (CH -Fc), 54.0 (CH N), 53.9 (CH N), 42.4 (CH
3
), 42.3
(CH
3
H30Fe
2
I
2 2
N : C, 42.43; H, 4.11;
3
f
3
D
3
ν
1
1
128, 1116, 1029, 1002, 958, +20, 854, 819, 762, 725. H NMR (500 MHz,
): δ (ppm) 4.47 (s, 1H, FcCH, H5), 4.23 (s, 1H, FcCH, H4), 4.13 (s,
H, FcCH, H3), 4.12 (s, 5H, Cp), 3.67 (q, J = 6.8 Hz, 1H, CH), 3.60 (t, J =
(
7
±)-1-Iodo-3-(((1,1,1,3,3,3-hexafluoro-2-propoxymethyl)ferrocene ((±)-
d): A solution of compound (±)-5 (38.4 mg, 0.10 mmol, 1.00 equiv) in
HFIP (315 μL, 504 mg, 3.00 mmol, 30.0 equiv) was heated at 60 °C for 1
CDCl
3
1
1
1
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202100824
FULL PAPER
3
4
.3 Hz, 4H, 2 x CH
2
O), 2.49-2.45 and 2.39-2.36 (m, 2H, 2 x CH
2
N), 1.51
= 91.501(4), β = 94.190(3), γ = 101.417(3) °, V = 1225.3(2) Å . Z = 2, d =
). 13C{ H} NMR (125 MHz, CDCl
1
): δ (ppm) 89.7
O),
N), 45.6 (FcC, C1), 15.6 (CH ).
20FeINO: C, 45.21; H, 4.74; N, 3.29. Found: C, 45.29;
)-10. C16 20FeINO, M = 425.08, T
(I.T.#19), a = 7.3714(5), b = 11.6599(6),
1.305 g·cm , μ = 0.700 mm . A final refinement on F with 5543 unique
intensities and 280 parameters converged at ωR(F ) = 0.1025 (R(F) =
0.0406) for 4968 observed reflections with I > 2σ(I). CCDC 2090462.
-3
-1
2
(d, J = 6.8 Hz, 3H, CH
3
3
2
(FcC, C2), 74.7 (FcCH, C5), 71.8 (Cp), 68.3 (FcCH, C4), 67.5 (2 x CH
2
66.0 (FcCH, C3), 58.2 (CH), 49.3 (2 x CH
2
3
Anal. Calcd for C16
H
H, 4.79; N, 3.33. Crystal data for (R,S
150 K; orthorhombic P 2
c = 18.1493(12) Å, V = 1559.93(17) Å . Z = 4, d = 1.810 g·cm , μ = 2.941
p
H
1
-Diphenylphosphino-1’-(N-morpholinomethyl)ferrocene (11c): By
following the general procedure B from compound 8 (308 mg, 0.75 mmol,
.00 equiv) and diphenylchlorophosphine (166 µL, 199 mg, 0.9 mmol), the
crude product was obtained after column chromatography (PE/EtOAc,
0:40 to 40:60 with 2% of NEt ). This was dissolved in THF (9 mL) at rt
and BH ·THF complex (1M in THF, 4.5 mL, 4.5 mmol, 6.00 equiv) was
=
1 1 1
2 2
3
-3
1
-
1
2
mm . A final refinement on F with 3564 unique intensities and 182
parameters converged at ωR 2
= 0.0446 (R = 0.0202) for 3456 observed
reflections with I > 2σ(I). CCDC 2090461.
F
F
6
3
3
added and the reaction mixture was stirred at rt for 2 h. Water was added
to the reaction mixture which was extracted with EtOAc. The combined
organic layers were dried over MgSO , filtrated over cotton wool and
4
concentrated under vacuum using a rotary evaporator to give the crude
product. This was purified by column chromatography, using PE-EtOAc
(90:10 to 70:30) to give the phosphine-borane adduct (125 mg). This was
dissolved in diethylamine (7.30 mL) at rt and the reaction mixture was
stirred for 16 h. Volatiles were removed under vacuum to give the crude
product. This was purified by column chromatography, eluting with PE-
General procedure B: Li/I exchange-trapping sequence. tBuLi (1.6M,
.00 equiv) was added dropwise to a solution of the required substrate
1.00 equiv) in THF (10 mL per mmol) at -80 °C. The reaction mixture was
stirred at the same temperature for 10 min before the required electrophile
was added. After addition, the reaction mixture was stirred at the same
temperature for 10 min before being warmed to rt. Methanol was added
and volatiles were removed under vacuum to give the crude product. This
2
(
was purified by column chromatography over SiO
product description) to give the title product.
2
(eluant given in the
EtOAc (73:30 to 50:50, with 1% NEt
3
) to give the title product as a yellow
solid after trituration in pentane (2 mL) (72 mg, 21% over three steps). R
f
(
(
1
eluent: PE/EtOAc 70:30, 5 drops of NEt
film)/cm−1 2965, 2924, 2859, 2805, 1478, 1452, 1433, 1329, 1287, 1270,
116, 1071, 1027, 1005, 909, 866, 825, 811, 745. 1H NMR (500 MHz,
CDCl ): δ (ppm) 7.38-7.35 (m, 4H, ArCH, 4 x H2”), 7.31-7.30 (m, 6H, ArCH,
3
) = 0.43. Mp 119-120 °C. νmax
(
±)-1-Diphenylphosphino-2-(N-morpholinomethyl)ferrocene ((±)-11a):
By following the general procedure B from compound (±)-4a (205 mg, 0.50
mmol, 1.00 equiv) and diphenylchlorophosphine (111 µL, 132 mg, 0.6
mmol), (±)-11a was obtained after column chromatography (PE/EtOAc,
3
4
=
x H3” and 2 x H4”), 4.33 (t, J = 1.5 Hz, 2H, FcCH, H3 and H4), 4.10 (t, J
1.4 Hz, 2H, FcCH, H2’ and H5’), 4.05 (q, J = 1.5 Hz, 2H, FcCH, H2 and
7
0:30 to 50:50 with 1% of NEt
3
) as an orange solid (101 mg, 43%). R
f
(
(
eluent: PE/EtOAc 50:50, 5 drops of NEt
3
) = 0.66. Mp 140-142 °C. νmax
film)/cm−1 2956, 2928, 2861, 2796, 1475, 1431, 1348, 1327, 1289, 1132,
H5), 4.03 (t, J = 1.4 Hz, 2H, FcCH, H3’ and H4’), 3.64 (t, J = 4.5 Hz, 4H, 2
N). 13C{ H} NMR (125
1
1
x CH
MHz, CDCl
9.6 Hz, ArCH, 4 x C2”), 128.7 (s, ArCH, 2 x C4”), 128.3 (d, J = 6.8 Hz,
ArCH, 4 x C3”), 8.1 (s, FcC, C1’), 76.3 (d, J = 6.4 Hz, FcC, C1), 73.6 (d, J
14.9 Hz, FcCH, C2 and C5), 71.6 (d, J = 2.5 Hz, FcCH, C3 and C4), 71.5
2 2
O), 3.07 (s, 2H, CH ), 2.32 (s, 4H, 2 x CH
2
1
7
7
110, 1004, 861, 809, 751, 698. H NMR (500 MHz, CDCl
.55 (m, 2H, ArCH, 2 x H2’), 7.38-7.36 (m, 3H, ArCH, 2 x H3’ and H4’),
.25-7.20 (m, 5H, ArCH, 2 x H2’ and 2 x H3’ and H4’), 4.39 (s, 1H, FcCH,
3
): δ (ppm) 7.58-
3
): δ (ppm) 139.3 (d, J = 9.7 Hz, ArC, 2 x C1”), 133.4 (d, J =
1
H3), 4.25 (t, J = 2.1 Hz, 1H, FcCH, H4), 3.99 (s, 5H, Cp), 3.87 (dd, J = 12.6,
=
2
2.0 Hz, 1H, CHH), 3.81 (s, 1H, FcCH, H5), 3.25-3.22 (m, 2H, CH O), 3.11-
N). 1 C{ H} NMR
3
1
(s, FcCH, C2’ and C5’), 69.5 (s, FcCH, C3’ and C4’), 66.9 (s, 2 x CH
2
O),
): δ (ppm)
3
.09 (m, 3H, CHH + CH
): δ (ppm) 140.3 (d, J = 8.4 Hz, ArC, C1’), 137.9 (d, J =
O), 2.23-2.15 (m, 4H, 2 x CH
2 2
58.3 (s, CH
2
), 53.2 (s, 2 x CH
2
N). 31P{ H} NMR (202 MHz, CDCl
1
3
(125 MHz, CDCl
3
-
16.9.
8.5 Hz, 1H, ArC, C1’), 135.1 (d, J = 21.1 Hz, ArCH, 2 x C2’), 132.8 (d, J =
19.0 Hz, ArCH, 2 x C2’), 129.1 (s, ArCH, C4’), 128.1 (d, J = 7.6 Hz, ArCH,
2 x C3’), 127.9 (d, J = 5.6 Hz, ArCH, 2 x C3’), 127.8 (s, ArCH, C4’), 89.5
(±)-1-Dicyclohexylphosphino-2-(N-morpholinomethyl)ferrocene
palladium dichloride complex ((±)-12): Compound (±)-11b (48.1 mg,
1.00 mmol, 1.00 equiv) and PdCl .MeCN (25.9 Mg, 1.00 mmol, 1.00
2 2
equiv) were charged in a Schlenk tube which was subjected to three cycles
of vacuum/argon. Anhydrous CH2Cl2 (1 mL) was added and the reaction
mixture was stirred at 30 °C for 16 h. Volatiles were removed under
vacuum and the resulting solids were triturated with pentane (2 x 2 mL) to
afford the title product (±)-12 as a red solid (55.1 mg, 84%). Mp 130-131 °C
(
3
d, J = 24.9 Hz, FcC, C2), 77.3 (multiplicity hidden, FcC, C1), 73.3 (d, J =
.6 Hz, FcCH, C3), 72.1 (d, J = 4.3 Hz, FcCH, C5), 69.8 (s, Cp), 69.1 (s,
FcCH, C4), 66.8 (s, 2 x CH O), 57.7 (d, J = 7.6 Hz, CH ), 53.1 (s, 2 x CH N).
P{ H} NMR (121 MHz, CDCl ): δ (ppm) -23.9.
2
2
2
3
1
1
3
(±)-1-Dicyclohexylphosphino-2-(N-morpholinomethyl)ferrocene ((±)-
1
1b): By following the general procedure B from compound (±)-4a (411
(
1
decomp). νmax (film)/cm−1 2923, 2851, 1446, 1248, 1214, 1163, 1110,
mg, 1.00 mmol, 1.00 equiv) and dicyclohexylchlorophosphine (265 µL, 279
mg, 1.20 mmol), (±)-11b was obtained after column chromatography
1
003, 909, 849, 820, 725. H NMR (500 MHz, CDCl
3
): δ (ppm) 5.56 (dt, J
=
3.7, 12.9 Hz, 1H), 4.65 (s, 1H), 4.60 (s, 1H), 4.57 (s, 1H), 4.36 (s, 5H,
(PE/EtOAc, 95:5 to 90:10 with 1% of NEt ) as an orange solid (360 mg,
3
Cp), 4.22 (dd, J = 6.1, 13.3 Hz, 1H), 4.09 (t, J = 12.1 Hz, 1H), 3.95 (dt, J =
2.6, 13.2 Hz, 1H), 3.85 (d, J = 13.2 Hz, 1H), 3.72-3.67 (m, 2H), 3.40 (d, J
= 11.8 Hz, 1H), 2.89 (d, J = 13.2 Hz, 1H), 2.69-2.62 (m, 1H), 2.45-2.43 (m,
7
ν
5%). R (eluent: PE/EtOAc 95:5, 5 drops of NEt ) = 0.25. Mp 145-147 °C.
f 3
max (film)/cm−1 2919, 2848, 2794, 1442, 1348, 1327, 1286, 1264, 1115,
1
1069, 1030, 1005, 988, 852, 825, 803. H NMR (500 MHz, CDCl
3
): δ (ppm)
1
2
1
(
6
H), 2.36-2.32 (m, 1H), 2.28 (d, J = 13.2 Hz, 1H), 2.22-2.19 (m, 1H), 2.09-
.05 (m, 3H), 1.98-1.96 (m, 2H), 1.89-1.75 (m, 4H), 1.67-1.65 (m, 1H),
4
.26 (s, 1H, FcCH, H3), 4.23 (t, J = 2.2 Hz, 1H, FcCH, H4), 4.08 (s, 1H,
FcCH, H5), 4.06 (s, 5H, Cp), 3.80 (dd, J = 2.3, 12.5 Hz, 1H, CHH), 3.66-
.58 (m, 4H, 2 x CH O), 3.01 (d, J = 12.5 Hz, 1H, CHH), 2.49-2.47 (m, 2H,
CH N), 2.38-2.33 (m, 3H, CH N and CH), 2.07-2.03 (m, 1H, CH), 2.03-
3
1
1
.45-1.39 (m, 4H), 1.27-1.16 (m, 4H). P{ H} NMR (202 MHz, CDCl
3
): δ
P56Fe106Pd
92.03028; Found 692.0304. HRMS (ESI+) m/z: [M-Cl]+ Calcd for
40NO35ClP56Fe106Pd 622.09147; Found 622.0915.
3
2
ppm) 28.2. HRMS (ESI ) m/z: [M+Cl] Calcd for C27H
40NO35Cl
3
-
-
2
2
1.97 (m, 1H), 1.90-1.85 (m, 3H), 1.74 (d, J = 11.3 Hz, 1H), 1.68-1.65 (m,
27
C H
3
(
H), 1.62-1.58 (m, 2H), 1.45-1.35 (m, 4H), 1.32-1.25 (m, 2H), 1.22-1.04
m, 4H). 13C{ H} NMR (126 MHz, CDCl
1
3
): δ (ppm) 87.5 (d, J = 20.6 Hz,
FcC, C1), 79.7 (d, J = 16.7 Hz, FcC, C2), 72.6 (d, J = 2.4 Hz, FcCH, C3),
0.6 (d, J = 2.0 Hz, FcCH, C5), 69.9 (s, Cp), 68.2 (FcCH, C4), 67.1 (s, 2 x
CH O), 57.9 (d, J = 9.0 Hz, CH ), 53.5 (s, 2 x CH N), 36.5 (d, J = 12.6 Hz,
CH), 34.0 (d, J = 10.2 Hz, 1H, CH), 32.9 (d, J = 19.0 Hz, CH ), 31.8 (d, J
14.6 Hz, CH ), 30.7 (d, J = 8.9 Hz, CH ), 29.2 (d, J = 9.0 Hz, CH ), 28.2
d, J = 11.8 Hz, CH ), 27.9 (d, J = 4.7 Hz, CH ), 27.8 (s, CH ), 27.5 (d, J =
). 31P{ H} NMR (202 MHz, CDCl
): δ (ppm) -
2.3. Crystal data for (±)-11b. C27 40FeNOP, M = 481.42, T = 150 K;
4-(4-Methoxyphenyl)acetophenone (15): 4-Methoxyphenylboronic acid
(114 mg, 0.75 mmol, 1.50 equiv), Pd(OAc) (2.24 mg, 0.010 mmol, 0.020
7
2
2
2
2
equiv), ligand (±)-11b (9.63 mg, 0.020 mmol, 0.040 equiv) and CsF (228
mg, 1.50 mmol, 3.00 equiv) were charged in a Schlenk tube which was
subjected to three cycles of vacuum/argon. 4-Chloroacetophenone (65.0
μL, 77.3 mg, 0.50 mmol, 1.00 equiv) and dioxane (2.5 mL) were added
and the reaction mixture was heated at 100 °C overnight (oil bath, external
temperature). The reaction mixture was cooled to rt, water (4 mL) and
EtOAc (2 mL) were added and the layers were separated. The aqueous
2
=
(
2
2
2
2
2
2
1
8.0 Hz, CH
2
), 26.6 (s, 2 x CH
2
3
1
H
triclinic P -1 (I.T.#2), a = 8.1886(9), b = 11.7712(11), c = 13.0146(13) Å, α
1
2
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202100824
FULL PAPER
layer was extracted with EtOAc (2 x 2 mL), the combined organic layers
This work was supported by the Université de Rennes 1 and
CNRS. We gratefully acknowledge the Fonds Européen de
Développement Régional (FEDER; D8 VENTURE Bruker AXS
diffractometer), Rennes Métropole and Thermofisher (generous
gift of (R)-(-)-N,N-dimethyl-1-ferrocenyl-ethylamine (L)-tartrate).
W.E. would like to thank Prof. F. Mongin for support, critically
reviewing this document and making valuable suggestions.
were dried over MgSO
vacuum using a rotary evaporator to give the crude product. This was
purified by column chromatography over SiO , using PE/EtOAc (90:10) to
4
, filtrated over cotton wool and concentrated under
2
give the title product as a white solid (109 mg, 96%). Analytical data
analogous to those reported previously.[54]
f
R (eluent: PE/EtOAc 10:1) =
0
1
8
7
.21. Mp 156-158 °C. νmax (film)/cm−1 2958, 2841, 1673, 1597, 1578, 1527,
495, 1400, 1359, 1291, 1269, 1252, 1197, 1184, 1031, 1010, 998, 957,
1
14. H NMR (300 MHz, CDCl
3
): δ (ppm) 8.01 (d, J = 8.4 Hz, 2H, 2 x ArCH),
.65 (d, J = 8.4 Hz, 2H, 2 x ArCH), 7.58 (d, J = 8.7 Hz, 2H, 2 x ArCH), 7.00
Keywords: Cross-coupling • Ferrocene • Fluorinated solvent •
Ligand design • Substitution
1
(d, J = 8.7 Hz, 2H, 2 x ArCH), 3.87 (s, 3H, CH
3
O), 2.63 (s, 3H, CH
3
). 13C{ H}
3
NMR (75.4 MHz, CDCl ): δ (ppm) 197.8 (C=O), 160.1 (ArCO), 145.5 (ArC),
1
(
[
35.5 (ArC-CO), 132.4 (ArC), 129.1 (2 x ArCH), 128.6 (2 x ArCH), 126.8
2 x ArCH), 114.6 (2 x ArCH), 55.5 (CH O), 26.8 (CH ). Mass: 226 [M], 211
M-CH ].
3
3
[1]
a) T. J. Kealy, P. L. Pauson, Nature 1951, 168, 1039-
040; b) S. A. Miller, J. A. Tebboth, J. F. Tremaine, J.
1
3
Chem. Soc. 1952, 632-635.
[
2]
a) Ferrocenes: Homogeneous Catalysis, Organic
Synthesis, Materials Science (Eds.; A. Togni, T. Hayashi),
Wiley-VCH, Weinheim, 1995; b) Ferrocenes: Ligands,
Materials and Biomolecules (Ed.: P. Štěpnička), Wiley-
Chichester, 2008; c) Chiral Ferrocenes in Asymmetric
Catalysis (Eds.; L.-X. Dai, X.-L. Hou), Wiley-VCH,
Weinheim, 2010.
4
-Morpholinobenzonitrile (17): 4-Chlorobenzonitrile (68.8 mg, 0.50
(5.75 mg, 0.010 mmol, 0.020 equiv), ligand
±)-11b (9.60 mg, 0.020 mmol, 0.040 equiv) and tBuOK (78.5 mg, 0.70
mmol, 1.00 equiv), Pd(dba)
(
mmol, 1.40 equiv) were charged in a Schlenk tube which was subjected to
three cycles of vacuum/argon. Morpholine (52.5 μL, 52.3 mg, 0.60 mmol,
2
1.20 equiv) and toluene (1.0 mL) were added and the reaction mixture was
heated at 100 °C overnight (oil bath, external temperature). The reaction
mixture was cooled to rt, water (4 mL) and EtOAc (2 mL) were added and
the layers were separated. The aqueous layer was extracted with EtOAc
[3]
J. H. Richards, E. A. Hill, J. Am. Chem. Soc. 1959, 81,
3484-3485.
[
4]
a) D. S. Trifan, R. Bacskai, Tetrahedron Lett. 1960, 1, 1-8;
b) E. A. Hill, J. H. Richards, J. Am. Chem. Soc. 1961, 83,
(
2 x 2 mL), the combined organic layers were dried over MgSO
over cotton wool and concentrated under vacuum using
evaporator to give the crude product. This was purified by column
chromatography over SiO , using PE/EtOAc (70:30, with 1% of NEt ) to
give the title product as a light yellow solid (43 mg, 45%). Analytical data
analogous to those reported previously.[55]
(eluent: PE/EtOAc 70:30) =
.32. Mp 74-76 °C. νmax (film)/cm−1 2831, 2216, 1604, 1515, 1453, 1383,
266, 1244, 1180, 1113, 927, 833, 815. 1H NMR (300 MHz, CDCl
): δ
4
, filtrated
3840-3846; c) E. A. Hill, J. H. Richards, J. Am. Chem.
a
rotary
Soc. 1961, 83, 4216-4221.
a) J. C. Ware, T. G. Traylor, Tetrahedron Lett. 1965, 6,
[
[
5]
6]
2
3
1295-1302; b) M. Cais, Organometal. Chem. Revi. 1966,
4, 435.
R
f
R. Gleiter, R. Seeger, Helv. Chim. Acta 1971, 54, 1217-
1220.
0
1
3
[7]
[8]
U. Behrens, J. Organomet. Chem. 1979, 182, 89-98.
a) R. Gleiter, C. Bleiholder, F. Rominger, Organometallics
2007, 26, 4850-4859; b) C. Bleiholder, F. Rominger, R.
Gleiter, Organometallics 2009, 28, 1014-1017; c) H.
Goodman, L. Mei, T. L. Gianetti, Frontiers in Chemistry
(ppm) 7.51 (d, J = 9.0 Hz, 2H, 2 x ArCH), 6.86 (d, J = 9.0 Hz, 2H, 2 x ArCH),
3
.84 (t, J = 5.0 Hz, 4H, 2 x CH
2
N), 3.27 (t, J = 5.0 Hz, 4H, 2 x CH
): δ (ppm) 153.6 (ArCN), 133.6 (2 x ArCH),
O), 47.4 (2 x
2
O).
13
1
C{ H} NMR (75.4 MHz, CDCl
3
120.0 (CN), 114.2 (2 x ArCH), 101.1 (ArCCN), 66.6 (2 x CH
2
2019, 7.
CH
2
N). Mass: 188 [M], 130, 102 [M-C NO].
4 8
H
[
[
9]
M. Marijan, S. Jurić, Z. Mihalić, O. Kronja, Eur. J. Org.
Chem. 2019, 2019, 537-546.
α-(4-Cyanophenyl)acetone (19): 4-Bromobenzonitrile (91.0 mg, 0.50
mmol, 1.00 equiv), [Pd(allyl)Cl] (2.70 mg, 7.50 μmol, 1.5 mol%), ligand
±)-11b (9.60 mg, 30.0 μmol, 6.0 mol%) and Cs CO (329 mg, 1.00 mmol,
.00 equiv) were charged in a Schlenk tube which was subjected to three
10]
a) P. Dixneuf, C. R. Acad. Sci. paris, Ser. C 1969, 269,
424-426; b) G. Gokel, P. Hoffmann, H. Klusacek, D.
Marquarding, E. Ruch, I. Ugi, Angew. Chem. Int. Ed. Engl.
1970, 9, 64-65; c) D. Marquarding, H. Klusacek, G. Gokel,
P. Hoffmann, I. Ugi, J. Am. Chem. Soc. 1970, 92, 5389-
2
(
2
3
2
cycles of vacuum/argon. Acetone (367 μL, 290 mg, 5.00 mmol, 10.0 equiv)
and dioxane (1.00 mL) were added and the reaction mixture was heated
at 90 °C overnight (oil bath, external temperature). The reaction mixture
was cooled to rt, water (4 mL) and EtOAc (2 mL) were added and the layers
were separated. The aqueous layer was extracted with EtOAc (2 x 2 mL),
5393.
[
[
[
11]
12]
13]
a) P. Dixneuf, Tetrahedron Lett. 1971, 12, 1561-1563; b)
P. Dixneuf, R. Dabard, Bull. Soc. Chim. Fr. 1972, 7, 2847-
2
854.
a) G. W. Gokel, I. K. Ugi, Angew. Chem. Int. Ed. Engl.
971, 10, 191-191; b) G. W. Gokel, D. Marquarding, I. K.
the combined organic layers were dried over MgSO
wool and concentrated under vacuum using a rotary evaporator to give the
crude product. This was purified by preparative TLC over SiO , using
PE/EtOAc (80:20 to 70:30) to give the title product as a white solid (39 mg,
9%). R (eluent: PE/EtOAc 80:20) = 0.18. Analytical data analogous to
those reported previously.
4
, filtrated over cotton
1
Ugi, J. Org. Chem. 1972, 37, 3052-3058.
2
a) G. Tainturier, K. C. Y. Sok, B. Gautheron, C. R. Acad.
Sci. paris, Ser. C 1973, 277, 1269-1270; b) K. C. Y. Sok,
G. Tainturier, B. Gautheron, C. R. Acad. Sci. paris, Ser. C
1974, 278, 1347-1348; c) K. C. Y Sok, G. Tainturier, B.
Gautheron, J. Organomet. Chem. 1977, 132, 173-189.
a) M. Hillman, J. D. Austin, Organometallics 1987, 6,
4
f
[
56]
Mp 80-82 °C. νmax (film)/cm−1 3405, 3072,
2
1
955, 2893, 2225, 1706, 1608, 1513, 1504, 1419, 1407, 1355, 1333, 1313,
213, 1153, 1019, 979, 959, 911, 855, 789, 734. 1H NMR (300 MHz,
[14]
1
737-1743; b) I. Yamaguchi, T. Sakano, H. Ishii, K.
Osakada, T. Yamamoto, J. Organomet. Chem. 1999, 584,
13-216; c) N. Fleury-Brégeot, A. Panossian, A. Chiaroni,
3
CDCl ): δ (ppm) 7.62 (d, J = 8.3 Hz, 2H, 2 x ArCH), 7.30 (d, J = 8.3 Hz, 2H,
). 1 C{ H} NMR (75.4 MHz,
3
1
2
x ArCH), 3.79 (s, 2H, CH
2
), 2.21 (s, 3H, CH
): δ (ppm) 204.4 (C=O), 139.5 (ArC), 132.5 (2 x ArCH), 130.5 (2 x
), 29.9 (CH ). Mass: 159
3
2
CDCl
3
A. Marinetti, Eur. J. Inorg. Chem. 2007, 2007, 3853-3862;
d) A. Voituriez, A. Panossian, N. Fleury-Brégeot, P.
Retailleau, A. Marinetti, J. Am. Chem. Soc. 2008, 130,
ArCH), 118.8 (CN), 111.2 (ArC-CN), 50.5 (CH
2
3
[
M], 117 [NC-C -CH ].
6
H
4
3
14030-14031; e) A. Voituriez, A. Panossian, N. Fleury-
CCDC deposition numbers. 2090455 (for 4a), 2090456 (for 4n),
Brégeot, P. Retailleau, A. Marinetti, Adv. Synth. Catal.
2009, 351, 1968-1976; f) E. M. Barreiro, D. F. D. Broggini,
L. A. Adrio, A. J. P. White, R. Schwenk, A. Togni, K. K. Hii,
Organometallics 2012, 31, 3745-3754; g) G. Kutschera, C.
Kratky, W. Weissensteiner, M. Widhalm, J. Organomet.
Chem. 1996, 508, 195-208; h) D. P. Huber, G. Kehr, K.
Bergander, R. Fröhlich, G. Erker, S. Tanino, Y. Ohki, K.
1
1
898629 (for 4r), 2090457 (for 4u), 2090458 (for 4v), 2090459 (for 7a),
898630 (for 7b), 2090460 (for 8a), 2090461 (for 10), 2090462 (for 11b).
Acknowledgements
1
3
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202100824
FULL PAPER
Tatsumi, Organometallics 2008, 27, 5279-5284; i) P.
Štěpnička, K. Škoch, I. Císařová, Organometallics 2013,
2, 623-635.
[26]
a) P. Trillo, A. Baeza, C. Nájera, J. Org. Chem. 2012, 77,
7344-7354; b) J. Xiao, K. Zhao, T.-P. Loh, Chem.
Commun. 2012, 48, 3548-3550; c) F.-Z. Zhang, Y. Tian,
G.-X. Li, J. Qu, J. Org. Chem. 2015, 80, 1107-1115; d) X.-
D. An, J. Xiao, The Chemical Record 2020, 20, 142-161.
a) S. U. Shisodia, S. Auricchio, A. Citterio, M. Grassi, R.
Sebastiano, Tetrahedron Lett. 2014, 55, 869-872; b) P. G.
Cozzi, L. Zoli, Angew. Chem. Int. Ed. 2008, 47, 4162-
4166.
a) M. Tsukazaki, M. Tinkl, A. Roglans, B. J. Chapell, N. J.
Taylor, V. Snieckus, J. Am. Chem. Soc. 1996, 118, 685-
686; b) W. Erb, T. Roisnel, V. Dorcet, Synthesis 2019, 51,
3205-3213; c) M. Hedidi, G. Dayaker, Y. Kitazawa, Y.
Tatsuya, M. Kimura, W. Erb, G. Bentabed-Ababsa, F.
Chevallier, M. Uchiyama, P. C. Gros, F. Mongin, New J.
Chem. 2019, 43, 14898-14907.
T. Kanzian, T. A. Nigst, A. Maier, S. Pichl, H. Mayr, Eur. J.
Org. Chem. 2009, 2009, 6379-6385.
A. N. Rodionov, K. Y. Zherebker, L. V. Snegur, A. A.
Korlyukov, D. E. Arhipov, A. S. Peregudov, M. M. Ilyin, M.
M. Ilyin, O. M. Nikitin, N. B. Morozova, A. A. Simenel, J.
Organomet. Chem. 2015, 783, 83-91.
V. V. Gumenyuk, Z. A. Starikova, Y. S. Nekrasov, V. N.
Babin, Russ. Chem. Bull. 2002, 51, 1894-1899.
a) S. Minegishi, S. Kobayashi, H. Mayr, J. Am. Chem.
Soc. 2004, 126, 5174-5181; b) J. Ammer, H. Mayr, J.
Phys. Org. Chem. 2013, 26, 59-63.
a) W. Erb, L. Kadari, K. Al-Mekhlafi, T. Roisnel, V. Dorcet,
P. Radha Krishna, F. Mongin, Adv. Synth. Catal. 2020,
362, 832-850; b) L. Kadari, T. Roisnel, W. Erb, P. R.
Krishna, F. Mongin, Synthesis 2020, 52, 3153-3161.
H. V. Nguyen, A. Sallustrau, J. Balzarini, M. R. Bedford, J.
C. Eden, N. Georgousi, N. J. Hodges, J. Kedge, Y.
Mehellou, C. Tselepis, J. H. R. Tucker, J. Med. Chem.
2014, 57, 5817-5822.
a) U. Burckhardt, L. Hintermann, A. Schnyder, A. Togni,
Organometallics 1995, 14, 5415-5425; b) D.-Y. Wang, X.-
P. Hu, C.-J. Hou, J. Deng, S.-B. Yu, Z.-C. Duan, J.-D.
Huang, Z. Zheng, Org. Lett. 2009, 11, 3226-3229.
M. Spescha, N. W. Duffy, B. H. Robinson, J. Simpson,
Organometallics 1994, 13, 4895-4904.
a) E. J. Corey, D. J. Beames, J. Am. Chem. Soc. 1972,
94, 7210-7211; b) D. Seebach, H. Neumann, Chem. Ber.
1974, 107, 847-853.
a) Organolithiums: Selectivity for Synthesis, J. Clayden,
Ed. Pergamon: 2001; b) M. Schlosser, Angew. Chem. Int.
Ed. 2005, 44, 376-393.
a) Privileged Chiral Ligands and Catalysts, Q.-L. Zhou, Ed.
Wiley-VCH: Weinheim, 2011; b) P. J. Guiry, C. P.
Saunders, Adv. Synth. Catal. 2004, 346, 497-537; c) T.
Noël, J. Van der Eycken, in Green Processing and
Synthesis, Vol. 2, 2013, p. 297; d) M. P. Carroll, P. J.
Guiry, Chem. Soc. Rev. 2014, 43, 819-833.
3
[
15]
a) H. Tamio, M. Takaya, F. Motoo, K. Masahiro, N. Nobuo,
H. Yuji, M. Akira, K. Sota, K. Mitsuo, Y. Keiji, K. Makoto,
Bull. Chem. Soc. Jpn. 1980, 53, 1138-1151; b) A. Togni,
C. Breutel, A. Schnyder, F. Spindler, H. Landert, A. Tijani,
J. Am. Chem. Soc. 1994, 116, 4062-4066; c) M. Lotz, T.
Ireland, K. Tappe, P. Knochel, Chirality 2000, 12, 389-395;
d) R. J. Kloetzing, M. Lotz, P. Knochel, Tetrahedron:
Asymmetry 2003, 14, 255-264; e) P. Vicennati, P. G.
Cozzi, Eur. J. Org. Chem. 2007, 2007, 2248-2253; f) J. F.
Buergler, A. Togni, Organometallics 2011, 30, 4742-4750;
g) R. Schuecker, A. Zirakzadeh, K. Mereiter, F. Spindler,
W. Weissensteiner, Organometallics 2011, 30, 4711-4719;
h) R. Mazzoni, M. Salmi, S. Zacchini, V. Zanotti, Eur. J.
Inorg. Chem. 2013, 2013, 3710-3718; i) L. A. Oparina, A.
V. Artem'ev, O. V. Vysotskaya, O. A. Tarasova, V. A.
Shagun, I. Y. Bagryanskaya, B. A. Trofimov, Tetrahedron
[27]
[28]
[29]
[30]
2016, 72, 4414-4422; j) E. V. Shevaldina, K. A.
Opredelennova, O. A. Chichvarina, Y. Y. Spiridonov, A. F.
Smol'yakov, P. V. Dorovatovskii, S. K. Moiseev, Appl.
Organomet. Chem. 2019, 33, e5228; k) M. Zábranský, I.
Císařová, P. Štěpnička, Dalton Trans. 2015, 44, 14494-
[31]
[32]
14506; l) L. V. Snegur, A. A. Simenel, A. N. Rodionov, V. I.
Boev, Russ. Chem. Bull. 2014, 63, 26-36.
V. I. Boev, L. V. Snegur, V. N. Babin, Y. S. Nekrasov,
Russian Chemical Reviews 1997, 66, 613-636.
a) R. C. J. Atkinson, V. C. Gibson, N. J. Long, Chem. Soc.
Rev. 2004, 33, 313-328; b) P. Barbaro, C. Bianchini, G.
Giambastiani, S. L. Parisel, Coord. Chem. Rev. 2004, 248,
[
[
16]
17]
[33]
[34]
[35]
2131-2150; c) R. Gómez Arrayás, J. Adrio, J. C.
Carretero, Angew. Chem. Int. Ed. 2006, 45, 7674-7715; d)
L. Cunningham, A. Benson, P. J. Guiry, Org. Biomol.
Chem 2020, 18, 9329-9370.
a) M. Patra, K. Ingram, V. Pierroz, S. Ferrari, B. Spingler,
J. Keiser, G. Gasser, J. Med. Chem. 2012, 55, 8790-8798;
b) N. Wambang, N. Schifano-Faux, A. Aillerie, B.
Baldeyrou, C. Jacquet, C. Bal-Mahieu, T. Bousquet, S.
Pellegrini, P. T. Ndifon, S. Meignan, J.-F. Goossens, A.
Lansiaux, L. Pélinski, Biorg. Med. Chem. 2016, 24, 651-
[
18]
[36]
[37]
660; c) J. Hess, G. Panic, M. Patra, L. Mastrobuoni, B.
Spingler, S. Roy, J. Keiser, G. Gasser, ACS Infectious
Diseases 2017, 3, 645-652; d) S. Pedotti, M. Ussia, A.
Patti, N. Musso, V. Barresi, D. F. Condorelli, J.
Organomet. Chem. 2017, 830, 56-61; e) V. Raičević, N.
Radulović, L. Jovanović, M. Rodić, I. Kuzminac, D.
Jakimov, T. Wrodnigg, T.-O. Knedel, C. Janiak, M. Sakač,
Appl. Organomet. Chem. 2020, 34, e5889.
a) H. Seo, B. Y. Kim, J. H. Lee, H.-J. Park, S. U. Son, Y.
K. Chung, Organometallics 2003, 22, 4783-4791; b) Z.-Y.
Tang, Y. Lu, Q.-S. Hu, Org. Lett. 2003, 5, 297-300.
a) N. Taniguchi, M. Uemura, Tetrahedron Lett. 1998, 39,
[38]
[39]
[
[
19]
20]
5
385-5388; b) S.-i. Fukuzawa, T. Suzuki, Eur. J. Org.
[40]
a) T. Hayashi, M. Konishi, M. Fukushima, T. Mise, M.
Kagotani, M. Tajika, M. Kumada, J. Am. Chem. Soc. 1982,
104, 180-186; b) T. Nishimura, S. Matsumura, Y. Maeda,
S. Uemura, Tetrahedron Lett. 2002, 43, 3037-3039; c) T.
Nishimura, S. Matsumura, Y. Maeda, S. Uemura, Chem.
Commun. 2002, 50-51; d) S. Matsumura, Y. Maeda, T.
Nishimura, S. Uemura, J. Am. Chem. Soc. 2003, 125,
8862-8869.
Chem. 2006, 2006, 1012-1016; c) S.-i. Fukuzawa, M.
Yamamoto, S. Kikuchi, J. Org. Chem. 2007, 72, 1514-
1517; d) T. Takahashi, T. Konno, K. Ogata, S.-i.
Fukuzawa, J. Org. Chem. 2012, 77, 6638-6642; e) W. Erb,
T. Roisnel, Chem. Commun. 2019, 55, 9132-9135.
R. Schuecker, W. Weissensteiner, K. Mereiter, M. Lotz, F.
Spindler, Organometallics 2010, 29, 6443-6458.
[
[
[
21]
22]
23]
R. Šebesta, Š. Toma, M. Sališová, Eur. J. Org. Chem.
[41]
[42]
D. W. Old, J. P. Wolfe, S. L. Buchwald, J. Am. Chem. Soc.
1998, 120, 9722-9723.
2
002, 2002, 692-695.
a) J.-P. Bégué, D. Bonnet-Delpon, B. Crousse, Synlett
004, 2004, 18-29; b) I. Colomer, A. E. R. Chamberlain,
M. B. Haughey, T. J. Donohoe, Nat. Rev. Chem. 2017, 1,
088; c) V. Pozhydaiev, M. Power, V. Gandon, J. Moran,
a) R. J. Lundgren, B. D. Peters, P. G. Alsabeh, M.
Stradiotto, Angew. Chem. Int. Ed. 2010, 49, 4071-4074; b)
R. J. Lundgren, A. Sappong-Kumankumah, M. Stradiotto,
Chem. Eur. J. 2010, 16, 1983-1991; c) K. D. Hesp, R. J.
Lundgren, M. Stradiotto, J. Am. Chem. Soc. 2011, 133,
5194-5197; d) B. J. Tardiff, R. McDonald, M. J. Ferguson,
M. Stradiotto, J. Org. Chem. 2012, 77, 1056-1071.
a) F. Rataboul, A. Zapf, R. Jackstell, S. Harkal, T.
Riermeier, A. Monsees, U. Dingerdissen, M. Beller, Chem.
Eur. J. 2004, 10, 2983-2990; b) A. Zapf, R. Jackstell, F.
Rataboul, T. Riermeier, A. Monsees, C. Fuhrmann, N.
2
0
D. Lebœuf, Chem. Commun. 2020, 56, 11548-11564.
a) R. A. McClelland, Tetrahedron 1996, 52, 6823-6858; b)
H. Mayr, S. Minegishi, Angew. Chem. Int. Ed. 2002, 41,
[
[
24]
25]
4
493-4495.
a) I. A. Shuklov, N. V. Dubrovina, A. Börner, Synthesis
007, 2007, 2925-2943; b) S. K. Sinha, T. Bhattacharya,
D. Maiti, Reaction Chemistry & Engineering 2019, 4, 244-
53.
[43]
2
2
1
4
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202100824
FULL PAPER
Shaikh, U. Dingerdissen, M. Beller, Chem. Commun.
004, 38-39.
C. Metallinos, J. Zaifman, L. Dodge, Org. Lett. 2008, 10,
527-3530.
a) V. Mamane, P. Peluso, E. Aubert, R. Weiss, E. Wenger,
S. Cossu, P. Pale, Organometallics 2020, 39, 3936-3950;
b) M. Wen, W. Erb, F. Mongin, Y. S. Halauko, O. A.
Ivashkevich, V. E. Matulis, T. Roisnel, V. Dorcet,
Organometallics 2021, 40, 1129-1147.
2
[
[
44]
45]
3
[
46]
G. Cavallo, P. Metrangolo, R. Milani, T. Pilati, A. Priimagi,
G. Resnati, G. Terraneo, Chem. Rev. 2016, 116, 2478-
2601.
[
[
[
[
[
47]
48]
49]
50]
51]
E. Bartashevich, S. Mukhitdinova, I. Yushina, V. Tsirelson,
Acta Crystallographica Section B 2019, 75, 117-126.
D. B. G. Williams, M. Lawton, J. Org. Chem. 2010, 75,
8351-8354.
A. F. Burchat, J. M. Chong, N. Nielsen, J. Organomet.
Chem. 1997, 542, 281-283.
J. F. Larrow, E. N. Jacobsen, Y. Gao, Y. Hong, X. Nie, C.
M. Zepp, J. Org. Chem. 1994, 59, 1939-1942.
N. Duguet, A. Donaldson, S. M. Leckie, J. Douglas, P.
Shapland, T. B. Brown, G. Churchill, A. M. Z. Slawin, A. D.
Smith, Tetrahedron: Asymmetry 2010, 21, 582-600.
G. Sheldrick, Acta Crystallogr. Sect. A 2015, 71, 3-8.
G. Sheldrick, Acta Crystallogr. C 2015, 71, 3-8.
S. Bernhardt, G. Manolikakes, T. Kunz, P. Knochel,
Angew. Chem. Int. Ed. 2011, 50, 9205-9209.
[
[
[
52]
53]
54]
[
[
55]
56]
J. P. Wolfe, S. L. Buchwald, J. Am. Chem. Soc. 1997, 119,
6054-6058.
S. Inaba, R. D. Rieke, J. Org. Chem. 1985, 50, 1373-1381.
1
5
This article is protected by copyright. All rights reserved.