Disubstituted Ferrocenyl Iodo- And Chalcogenoalkynes as Chiral Halogen and Chalcogen Bond Donors

Article abstract of DOI:10.1021/acs.organomet.0c00633

Asymmetric catalysis based on halogen and chalcogen bonds (XB and ChB) is in its infancy, and the search for new chiral XB and ChB donors represents a crucial step toward its development. In this context, we designed and prepared new motifs containing three key substructures: namely, regions of electron charge density depletion centered on iodine and chalcogen atoms, the ethynyl functionality, and the planar chiral ferrocenyl platform. Nine ferrocenyl iodoalkynes were prepared as pure enantiomers by asymmetric synthesis. The XB donor property of racemic ferrocenyl iodoalkynes was demonstrated in solution in two benchmark reactions: the Ritter reaction and the benzoxazole synthesis from thioamides. In contrast, the ferrocenyl chalcogenoalkynes were far less active in these reactions. The potential of racemic and enantiopure ferrocenyl iodoalkynes as XB donors was also confirmed by X-ray diffraction analysis, showing I···C contacts between the electropositive σ-hole of the iodine atom and electron-rich πclouds for all crystal structures studied in the solid state.

Full text of DOI:10.1021/acs.organomet.0c00633

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Disubstituted Ferrocenyl Iodo- and Chalcogenoalkynes as Chiral
Halogen and Chalcogen Bond Donors
Victor Mamane,* Paola Peluso,* Emmanuel Aubert, Robin Weiss, Emmanuel Wenger, Sergio Cossu,
and Patrick Pale
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ABSTRACT: Asymmetric catalysis based on halogen and chalcogen
bonds (XB and ChB) is in its infancy, and the search for new chiral XB
and ChB donors represents a crucial step toward its development. In
this context, we designed and prepared new motifs containing three key
substructures: namely, regions of electron charge density depletion
centered on iodine and chalcogen atoms, the ethynyl functionality, and
the planar chiral ferrocenyl platform. Nine ferrocenyl iodoalkynes were
prepared as pure enantiomers by asymmetric synthesis. The XB donor
property of racemic ferrocenyl iodoalkynes was demonstrated in solution in two benchmark reactions: the Ritter reaction and the
benzoxazole synthesis from thioamides. In contrast, the ferrocenyl chalcogenoalkynes were far less active in these reactions. The
potential of racemic and enantiopure ferrocenyl iodoalkynes as XB donors was also confirmed by X-ray diffraction analysis, showing
I···C contacts between the electropositive σ-hole of the iodine atom and electron-rich π clouds for all crystal structures studied in the
solid state.
asymmetric catalysis still remain huge challenges, as does the
design of appropriate XB or ChB chiral donor molecules.24
In general, electron-withdrawing residues increase the σ-
holes of X and Ch atoms. In this regard, perfluorinated and
cationic N-heterocyclic molecules are widely used for the
synthesis of strong XB and ChB donors, which have found
various applications to organocatalysis.7,8 A different approach
to increase σ-holes is to attach the halogen atom, in particular
iodine, to an acetylenic unit. Indeed, in these compounds,
iodine is directly attached to a Csp atom, where the
contribution of the s orbital is higher in comparison to sp2
and sp3 carbons. Remarkably, iodoalkynes are good building
blocks in crystal engineering25−27 but they have been far less
described in solution as XB donors. However, it has been
known for a long time that iodoalkynes can form strong XB
adducts in solution with Lewis bases, such adducts being
observed by UV−vis28 and by NMR.29 Two recent examples
highlighted the potential of these compounds in organic
synthesis, the iodoalkyne behaving either as a catalyst30 or as
an activator.31 The analogues thio- and selenoalkynes are
known to be stable useful synthons in organic synthesis,32−35
but the σ-hole donor properties of sulfur and selenium in these
INTRODUCTION
■
In the past few years, halogen and chalcogen bonds (XB and
ChB, respectively) have been recognized as important
noncovalent interactions and rationalized through the so-
called σ-hole, which characterizes a covalently bonded atom of
groups 13−18.1 These atoms (σ-hole donors) bear a region
with a positive electrostatic potential on unpopulated σ*
orbitals, allowing them to interact with a negative site (σ-hole
acceptor: anion, lone electron pair, π electrons).
Applications based on XB and ChB have grown rapidly
during the last 20 years, and important developments have
emerged in crystal engineering, in biology, in supramolecular
chemistry, and in catalysis.2−8 However, the involvement of XB
and ChB in stereoselective processes has remained unexplored
until recently. We described XB- and ChB-driven HPLC
enantioseparations of polyhalogenated 4,4′-bipyridines and
related recognition mechanisms.9−14 Beer’s group described
the enantioselective recognition of chiral anions of BINOL-
based XB donors15−18 and Kanger’s group developed chiral
triazole-based XB donors for the enantiodiscrimination of
neutral acceptors.19,20 In the field of catalysis, it is worth
mentioning the works of Arai and co-workers, who obtained
good enantiomeric excesses in asymmetric Mannich reactions
between malononitrile and N-Boc imines or N-Boc α-ketimino
esters using a quinidine-based chiral catalyst bearing a neutral
XB donor functionality.21,22 More recently, Huber and co-
workers described the first example of asymmetric catalysis
using a pure XB donor catalyst.23 Despite these achievements,
XB- and ChB-driven stereoselective processes and in particular
Received: September 22, 2020
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derivatives have never been considered. It is thus worth
exploring and possibly exploiting iodo- and more specifically
thio- and selenoalkynes as XB or ChB (chiral) donors.
With the aim of developing new chiral XB and ChB donor
molecules, we report herein the synthesis of chiral ferrocenyl
iodo- and chalcogenoalkynes by combining the σ-hole donor
properties of iodine, sulfur, and selenium when they are
bonded to an alkyne and the planar chirality of ferrocene.36 As
the ferrocene substitution pattern might influence iodine
polarization, both 1,2- and 1,3-disubstituted chiral ferrocene
derivatives were considered in this work. In comparison to 1,2-
disubstituted ferrocenes, whose applications are numerous,37,38
the 1,3-disubstituted ferrocenes have been much less described
in the literature. A few derivatives have been reported with
interesting activity in catalysis,39 medicinal chemistry,40 and
supramolecular chemistry, serving as hydrogen-bond41 or XB42
receptors.
be introduced by using a selective Sonogashira coupling with
the readily available iodoferrocenyl derivatives 1 and 2.
In the framework of a rational design approach, the V values
of iodo-, thio- and selenoethynylferrocenes 9a−c, 10b, 16a,
and 17a were computed on a 0.002 au molecular isosurface
(VS).
The VS values of pentafluorobenzenes 18−20, halobenzenes
21-23 and 25−30, and haloferrocenes 1b and 3a−b, as well as
nonsubstituted iodoethynylbenzene 24 and iodoethynylferro-
cene 31, were computed as benchmarks in order to evaluate
the effect of both the ferrocenyl and ethynyl substructures on
the local electron charge density of the σ-hole regions. For this
purpose, the VS maxima (VS,max) on the σ-holes centered on I
and Ch (S, Se) atoms were compared (Table 1) in order to
explore the effect of subtle structure modifications on the σ-
hole depth.
The geometry of all compounds given in Table 1 was
optimized using density functional theory with the B3LYP
functional (completed with D3 dispersion corrections) and the
Def2TZVPP basis set. The local maxima of the electrostatic
potential (VS,max) values were calculated on the 0.002 au
isodensity surface (see the Supporting Information for details).
As expected, these theoretical results confirmed the
beneficial effect of the alkyne moiety on the iodine σ-hole
depth (Table 1, entry 4 vs entry 12 and entry 7 vs entry 19).
The results also showed that the activation ability of the alkyne
function toward the iodine σ-hole is comparable to and even
slightly better than the effect of perfluorination (entry 10 vs
entry 1). This effect can be increased by an additional electron-
withdrawing halogen atom (entry 10 vs entries 11−13 and 16).
It is worth noting that the obtained VS,max values for the series
24−27 and 30 are in good agreement with the donor/acceptor
nature of substituents in other reports concerning similar
iodoalkyne-based structures.27,44−46 Interestingly, when the
chlorine was placed in the 3-position, the iodine σ-hole
increased (entry 12 vs entry 16). The beneficial effects on the
iodine σ-hole due to the additional halogen atom (entry 17 vs
entries 18−20) and its position (entry 19 vs entry 23) are also
observed in the ferrocenyl iodoalkyne series. However, lower
VS,max values are always obtained for the ferrocenyl derivatives
in comparison to the phenyl derivatives (entries 10−13 vs
entries 17−20 and entry 16 vs entry 23), confirming the
greater electron-donating ability of ferrocene in comparison to
phenyl. Nevertheless, the VS,max values of ferrocenyl com-
pounds 9a−c and 10b are still comparable to that of
iodopentafluorobenzene 18 (entry 1 vs entries18−20); there-
fore, interesting σ-hole-based properties can be expected with
these compounds.
The σ-hole donor property of the selected compounds was
investigated in solution by a preliminary evaluation of their
performance in the Ritter reaction43 and in the benzoxazole
synthesis from thioamides.30 The potential of racemic and
enantiopure ferrocenyl iodoalkynes as XB donors was also
evaluated in the solid state by X-ray diffraction (XRD) analysis.
RESULTS AND DISCUSSION
■
Design and Electrostatic Potential Analysis. The
design of the compounds reported here was based on 1,2- or
1,3-disubstituted ferrocenes, in which one of the substituents is
the iodo-, thio- and selenoethynyl moiety carrying σ-holes and
the other is an electron-withdrawing group in order to increase
the adjacent σ-hole depth. This design was also substantiated
by calculating the electrostatic potential (V) on focused
regions of these molecules, so that local electron charge
density, especially of σ-hole regions, could be anticipated.
A general strategy was thus designed for the synthesis of
various ferrocenyl-based iodoalkynes 9−13 and chalcogenoal-
kynes 16 and 17 starting from 1,2- or 1,3-disubstituted
ferrocenes 1 and 2 (Scheme 1). The σ-hole donor atom (I, S,
Scheme 1. General Strategy for the Synthesis of Ferrocenyl-
Based Iodoalkynes 9−13 and Chalcogenoalkynes 16 and 17
Regarding the chalcogen atoms, they possess two σ-holes,
one on the elongation of the CCF3−Ch bond and one on the
elongation of the CAr/Fc−Ch or Cethynyl−Ch bond. As a matter
of fact, in nonsymmetrical compounds such as 22, 23, 3a,b, 28,
29, 16a, and 17a, two conformations are observed depending
on the position of the CF3 group with respect to the chlorine
atom. Interestingly, in compounds 22, 23, and 3a−b (Table 1,
entries 5, 6, 8, and 9), the VS,max values along the CCF3−Ch
bond for the two conformers are completely different and in
three cases the σ-hole of one of the two conformers cannot be
observed (entries 5, 8, and 9). This effect is due to the
contribution of neighboring atoms to the analyzed molecular
surface. For example, in the second conformation of
compound 23, the expected selenium σ-hole opposite to the
CF3−Se bond is directly oriented toward the negative crown of
or Se) would be introduced in the late stage from silyl-
protected alkynes 4, 5, and 6−8 through a deprotection−
functionalization sequence that can be conducted in one or
two steps. With bromo-substituted ferrocenyl compounds 4a
and 5a (X = Br) as the starting materials, the introduction of
aryl and methyl groups can be carried out through Suzuki
coupling or bromine/lithium exchange followed by electro-
philic quenching. The alkyne function in derivatives 4−8 can
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calculations also confirmed the effect of shifting from sulfur to
selenium in all of the chalcogen series, for which the σ-hole
depth always increases.
Table 1. VS,max (kJ/mol) Values Calculated on I and Ch σ-
Holes (B3LYP-D3/Def2TZVPP)
a
On the basis of VS analysis, the alkyne substructure proved
to be a powerful tool to polarize both iodine and chalcogens,
generating σ-hole regions potentially able to promote the
catalytic activity of ferrocenyl derivatives 9−13, 16, and 17.
Racemic synthesis. The starting substituted iodoferro-
cenes 1a−d and 2a−c have been described in the literature and
were prepared accordingly (Scheme 2).47−49
Scheme 2. Starting Substituted Iodoferrocenes
The ethynyl moiety was then introduced on 1,2- and 1,3-
iodoferrocenes 1 and 2 by Sonogashira coupling with
trimethylsilylacetylene. Classical conditions, based on Pd-
(PPh3)4 and CuI as catalysts and on diisopropylamine as
base and solvent,50 provided variable results depending on the
X substituent nature (Scheme 3, conditions A).
a
VS,max (kJ/mol)
Ch
Ch
Ch
b
b
b
entry compound
I
(CAr/Fc−Ch)
(Cethynyl−Ch)
(CCF3−Ch)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
18
19
20
21
22
23
1b
3a
3b
24
25
26
27
28
29
30
31
9c
181
100
136
140
158
Scheme 3. Sonagashira Coupling of Iodoferrocenes 1 and 2
122
119
c
c
54/56
87/87
94/-
113/33
c
c
47/51
81/86
-/81
-/101
183
187
188
189
c
c
95/95
97/106
124/131
138/135
194
176
182
182
182
9b
9a
16a
17a
10b
An optimization study performed on 1-bromo-2-iodoferro-
cene (1a) revealed that 3 equiv of trimethylsilylacetylene was
necessary to achieve complete conversion. The expected
compound 4a was thus isolated with 98% yield. However,
the yield dropped significantly as the electron-withdrawing
ability of the atom adjacent to iodine increased and when the
substituent was placed in the 3-position to iodine. Along with
the expected compounds 4b,c or 5a−c, a substantial amount of
the deiodinated starting material was isolated. In the case of
4d, the so-formed cyanoferrocene could not be removed by
chromatography (see Scheme S1 in the Supporting Informa-
tion for more details).
The hydrodehalogenation reaction could be completely
suppressed by using Pd(Pt-Bu3)2, previously described as a
highly active catalyst in the Sonogashira reaction of 1,1′-
diiodoferrocene.51 Except for 4c, yields were significantly
improved and compound 4d could be obtained in pure form
after the unreacted starting material was removed (Scheme 3,
conditions B).
c
c
78/83
91/84
115/110
119/124
185
a
Calculations were performed by using the Gaussian09 Version D.01
program (see the Supporting Information for details). Corresponds
to the hole along the Cl−Ch axis. Two conformations were observed
b
c
for these compounds.
the adjacent chlorine atom, leading to a VS value smaller than
that in the first conformation, where the same σ-hole points
toward the exterior of the molecule. In the case of 3b this effect
is even more pronounced, since the expected σ-hole points
toward a hydrogen atom of the neighboring cyclopentadienyl
ring and appears buried inside the chosen molecular envelope
and is thus not revealed on this surface (see Figure S26 in the
Supporting Information).
From the results, it can also be noted that the alkyne
function also polarizes sulfur and selenium atoms, increasing
the σ-hole depth in both the phenyl (Table 1; for S, entry 5 vs
entry 14 and for Se, entry 6 vs entry 15) and ferrocenyl (for S,
entry 8 vs entry 21, and for Se, entry 9 vs entry 22) series. The
To compare with the effect of the halogeno or cyano
substituents, neutral non-electron-withdrawing groups were
also introduced on the ferrocenyl unit. The simple methyl
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group was selected, as well as two aryl groups, phenyl and the
larger 2-naphthyl (Scheme 4). The introduction of the latter
was readily achieved through a Suzuki reaction.
Scheme 5. Preparation of Ferrocenyliodoalkynes 9-13
through Deprotection−Iodination of Compounds 4−8
a
Scheme 4. Arylation and Methylation of
Bromoferrocenylacetylenes 4a and 5a
Coupling phenyl- and 2-naphthylboronic acids with bromo-
substituted ferrocenylalkynes 4a and 5a was efficiently
performed by using 2-dicyclohexylphosphino-2′,6′-dimethox-
ybiphenyl (SPhos) as a ligand and potassium phosphate as a
base in toluene at 100 °C.52 Indeed, good yields ranging from
80% to 98% were obtained for derivatives 6 and 7. The methyl
group was introduced by addition of n-BuLi on compound 4a
followed by quenching the lithiated ferrocenyl species.
Derivative 8 was thus obtained with a good yield of 70%
(Scheme 4).
For the synthesis of ferrocenyl iodoalkynes 9−13, we
explored the possibility to perform in one step the
trimethylsilyl (TMS) group removal and the iodination of
compounds 4−8.
a
Conditions: (a) 1.05 equiv of AgF, 1.05 equiv of NIS, CH3CN, rt, 15
h; (b) 2.5 equiv of KOH, MeOH, rt, 2 h; (c) 2.5 equiv of KOH, 1.5
equiv of NIS, MeOH, rt, 2 h; (d) (1) 5 equiv of KOH, MeOH, rt, 2 h,
(2) 1.5 equiv of NIS, rt, 2 h.
chloroalkene 18.59 Therefore, the 17b/18 mixture was treated
with an excess of LiOH in DMSO60 to deliver the pure
compound 17b with a moderate overall yield (Scheme 6).
Scheme 6. Synthesis of Ferrocenyl-Based Thioalkynes 16a,b
and Selenoalkynes 17a,b
The combination of silver(I) fluoride and N-iodosuccini-
mide (NIS) has already been described for this purpose with a
variety of TMS-protected alkynes.53 Although the expected
iodoalkynes were obtained in all cases, the yields were
generally low to moderate (Scheme 5, conditions a). This
could be due to oxidation of the ferrocene moiety by the silver
salts present in the reaction mixture.54,55
With the aim of avoiding silver salts and of increasing the
yields, a two-step procedure was tested. TMS-alkynes 4b and
5b were first deprotected with KOH in methanol at room
temperature to give alkynes 14 and 15 with good yields
(Scheme 5, conditions b). These alkynes were then treated
again with KOH before addition of NIS56 to give iodoalkynes
9b and 10b with good yields (Scheme 5, conditions c). Since
KOH is used in the two steps, a one-pot procedure was
employed with 4b and 5b, directly furnishing iodoalkynes 9b
and 10b with yields superior to those of the two-step
procedure. This protocol was therefore applied to TMS-
alkynes 4a,c,d and 5c, greatly increasing the yields of the
corresponding iodoalkynes 9a,c,d and 10c (Scheme 5, d).
For the synthesis of chalcogenoalkynes 16 and 17, 2- and 3-
chloroferrocenyl acetylenes 14 and 15 were functionalized
through lithiation and electrophilic quenching with donors of
SCF3 and SeCF3 groups. Alkyne deprotonation of 14 and 15
was performed with n-BuLi, and the resulting lithioalkynes
were trapped with N-methyl-N-(trifluoromethylsulfanyl)-
aniline57 to give thioalkynes 16a,b and with the in situ
Evaluation of Ferrocenyl Iodo- or Chalcogenoal-
kynes: C−Br and Thioamide Activation. In order to
evaluate the σ-hole donor properties in solution of the new
ferrocene-based iodo- and chalcogenoalkynes, we have
considered two benchmark reactions: the Ritter reaction,61
allowing the transformation of benzhydryl bromide 32 to
acetamide 33, and the synthesis of benzoxazole 35 from
thioamide 3462 (Scheme 7). In order to study the influence of
the substituent in both reactions, five compounds of the 2-
58
generated ClSeCF3 to furnish selenoalkynes 17a,b. Un-
expectedly, 17b was obtained as an inseparable mixture with
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analogue 9b, despite the stronger electron-withdrawing
character of the latter.
Scheme 7. XB or ChB Activation of C−Br and Thioamide
These results revealed that the iodine σ-hole is well activated
by the alkyne function and that the substituent on the
ferrocene moiety only has a moderate influence on reactivity,
except for the strongly electron withdrawing fluorine. In
contrast, the nature of the σ-hole donor has a strong influence
on the reaction efficiency. Indeed, with the seleno derivative
17a, the reaction proved to be slower, giving only 35%
conversion after 10 h and 60% conversion after 24 h.
Benzoxazoles are important compounds due to their various
biological activities and their roles in fluorescent and/or
electroluminescent materials.67 In 2016, Matsuzawa and co-
workers have shown that iodoalkynes are able to catalyze the
synthesis of benzoxazole from thioamides and 2-aminophenol
on the basis of an iodine−sulfur interaction.30 This reaction is
thus worthy of comparison (Table 2). Interestingly, all of the
ferrocenyl iodoalkynes were able to act as a catalyst and gave
the expected benzoxazole 35. High yields were obtained with
the 2-chlorinated and 2-fluorinated compounds 9b,c, whereas a
lower yield was obtained with the 2-brominated analogue 9a.
In contrast to the Ritter results, the 3-chloro catalyst 10b
proved to be less effective, as the yield significantly dropped
(64 vs 86%). As for the Ritter reaction, the aryl-substituted
ferrocenyl iodoalkynes 11a,b were very efficient, giving high to
quantitative yields of benzoxazole 35. The selenium derivative
17a proved again to be less efficient than the iodinated
derivatives, since almost no benzoxazole was formed during the
reaction.
In summary, with regard to the results of Table 2, the effects
of nature and position of the halogen substituent on the
activity of the iodoalkynes as activators or catalysts in the
considered reactions are very difficult to analyze. It is clear,
however, that the aryl-substituted compounds 11a,b are very
active in both reactions, which opens up the possibility to use
them or other analogous substituents in asymmetric catalysis.
Asymmetric Synthesis of Ferrocenyl Iodoalkynes.
Considering the above results, we decided to focus only on
the synthesis of enantiopure ferrocenyl iodoalkynes. As shown
through the racemic synthesis, compounds 4a and 5a are key
intermediates for the synthesis of ferrocenyl iodoalkynes
bearing substituents of different natures. For the 1,2-
disubstituted series, we considered the preparation of
enantiopure (SFc)-1a as described in the literature,68 but the
yields and the enantiomeric excess that we obtained were
unsatisfactory. Another useful enantiopure 1,2-substituted
ferrocenyl synthon, the (Ss,SFc)-sulfinylferrocenylboronic acid,
attracted our attention, but it is suitable only for the
preparation of aryl-substituted ferrocenes.69
substituted ferrocenyl iodoalkyne family (9a−c and 11a,b)
were tested. Moreover, the effects of the substituent position
and the nature of the donor atom were also evaluated by using
compounds 10b and 17a (Table 2).
Table 2. Results of Ritter Reaction and Benzoxazole
Synthesis
yield (%)
a
c
XB/ChB donor
X/Ch
R
33
35
9a
9b
10b
9c
I
I
I
I
2-Br
2-Cl
3-Cl
2-F
100
91
94
72
86
64
35
86
11a
11b
17a
I
I
Se
2-Ph
2-Naph
2-Cl
100
100
35
97
83
<5%
b
a
1H NMR conversions obtained by integration of peaks at 6.44 ppm
(starting material) and at 5.77 ppm (product) in CD3CN.31 60%
b
c
conversion after 24 h. 1H NMR yields by using DMF as an internal
standard.30
Ritter-type reactions63 involve the nucleophilic substitution
of an alcohol, sulfate, or halide group by acetonitrile or related
nitriles, usually used as the solvent. The resulting nitrilium is
then hydrolyzed to the corresponding amide by added water.
Depending on the leaving group nature, electrophilic assistance
could facilitate the reaction and catalysis could be established.
Lewis acids could act as such, and some could catalyze such
reactions.64 With σ-hole-based organocatalysts and halogen-
ated substrates, the Ritter reaction is not catalytic due to its
mechanism, close to an SN1 process. In this reaction, the σ-
hole donor interacts with the bromine of the substrate
(compound 32 here; Scheme 7) to abstract it and the
nucleophilic acetonitrile solvent replaces it. Nevertheless, the
Ritter reaction allows a reliable evaluation of the σ-hole donor
ability in solution.31,43,65,66 All of the ferrocenyl derivatives
examined were able to efficiently promote the expected
transformation, except for the fluoro derivative (Table 2).
In the 2-haloferrocenyl iodoalkyne series 9a−c, high
conversions were obtained with the 2-bromo and 2-chloro
derivatives 9a,b, whereas a low conversion of 34% was
observed with the 2-fluoro derivative 9c. This difference in
reactivity was unexpected with regard to the calculated VS,max
values (Table 1, entries 18−20). A comparison of the 2- and 3-
chloro derivatives 9b/10b showed that the position of the
halogen on the ferrocene moiety has very little effect on the
reactivity but is in agreement with their slightly different VS,max
values (Table 1, entry 23 vs entry 19). Surprisingly, the 2-
arylferrocenyl iodoalkynes 11a,b were as effective as the 2-
bromo derivative 9a but were more effective than the 2-chloro
We finally turned our attention to Kagan’s method, which
delivers enantiopure 2-substituted ferrocenecarboxaldehydes.70
In particular, 2-bromoferrocenecarboxaldehyde ((SFc)-36) was
prepared71 and transformed to the alkyne (SFc)-37 through a
Seyferth−Gilbert homologation with Ohira−Bestmann reagent
38.72 A TMS group was then introduced on the alkyne to give
the key compound (SFc)-4a. With regard to the 1,3-
disubstituted series, enantiopure compound 5a was not
available but the iodinated analogue (SFc)-39 has been
described in the literature.73 It was then transformed to the
key compound (SFc)-41 through alkyne (SFc)-40 (Scheme 8).
On one hand, when the experimental conditions set up for
the Suzuki coupling of related compounds were applied (see
Scheme 4), compounds (SFc)-4a and (SFc)-41 were very
E
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Scheme 8. Synthesis of Enantiopure Key Compounds (SFc)-
4a and (SFc)-41
Scheme 10. Synthesis of Enantiopure
Ferrocenyliodoalkynes
efficiently transformed to (SFc)-6a,b and (SFc)-7a,b, respec-
tively (Scheme 9, left). On the other hand, halogen−lithium
The enantiomeric purity of compounds (SFc)-9a,c,d, (SFc)-
10a, (SFc)-11a,b, (SFc)-12a,b, and (RFc)-13 was determined
through high-performance liquid chromatography (HPLC) on
polysaccharide-based chiral columns. For compounds 9a,d,
10a, 11b, 12a,b, and 13, the proper combination of column
and mobile phase was optimized, allowing us to obtain baseline
enantioseparations. For compounds 9c and 11a only partial
separation was achievable. For all compounds, enantiomeric
excesses of ≥92.8% were measured (Scheme 10; see see Table
S1 and Figure S1−S9 in the Supporting Information for
details).
Scheme 9. Functionalization of (SFc)-4a and (SFc)-41
Solid-State Analysis. With these racemic and chiral
ferrocenyl iodoethynes in hand, their σ-hole donor properties
in the solid state were investigated by X-ray diffraction analysis
(XRD) when possible. Crystal structures were determined by
single-crystal XRD for a selected number of compounds.
Hirshfeld molecular surfaces were computed for these
structures (except for 9c, which presents a disorder linked to
symmetry), and actual surface contacts were compared to
equiprobable contacts in order to derive the enrichment ratios
(E).74 As seen in Table S2 in the Supporting Information, Fe
atoms in these ferrocenyl compounds are almost fully buried
between the cyclopentadienyl rings, offering a very small
contribution to the total molecular surface; thus, variations of
this small surface between actual and equiprobable contacts are
meaningless and will not be discussed. An enrichment ratio E
larger (respectively smaller) than 1 means that the considered
contact is enriched (respectively impoverished) in the actual
crystal structure in comparison to the situation of equiprobable
contacts. It can be noted (Tables S3−S10) that, despite the
richness of aromatic groups in the studied compounds, no π···π
interaction is observed, carbon···carbon contacts being clearly
under-represented (E(C···C) = 0.7−0.8), except for (SFc)-12a,
in which the phenyl groups stack in somewhat long π···π
contacts (E(C···C) = 1.06; intercentroid distance of 4.187 Å;
tilt angle of 23.96°). Whereas H···H contacts are under-
represented as well, contacts of hydrogen atoms with carbon
and iodine atoms are over-represented (except in 13 with
E(H···I) = 0.97).
exchange followed by electrophilic quenching afforded differ-
ently substituted derivatives. With (SFc)-4a as the starting
material, quenching the lithiated species with MeI, N-
fluorobenzenesulfonimide (NFSI), or p-toluenesulfonyl cya-
nide (TsCN) delivered compounds (RFc)-8, (SFc)-4c, and
(SFc)-4d, respectively. Addition of α,α′-dibromoxylene to the
lithiated intermediate obtained from (SFc)-41 furnished (SFc)-
5a, which contained small amounts of inseparable impurities
(Scheme 9, right).
Finally, the deprotection−iodination methods (see Scheme
5) were applied to all enantiopure/enantioenriched ferrocenyl
trimethylsilylethynes. This sequence furnished diversely
substituted ferrocene iodoethynes: i.e., (SFc)-9a,c,d, (SFc)-
10a, (SFc)-11a,b, (SFc)-12a,b, and (RFc)-13 (Scheme 10).
In all obtained crystal structures, I···C XBs are observed
between the electropositive σ-hole of the iodine atom and
F
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electron-rich π clouds (Tables S3−S10 and Table S11).
Interestingly, the XB acceptors vary and can be the alkyne
carbon atoms75 ((SFc)-12a, (RFc)-13, (SFc)-9a), the cyclo-
pentadienyl rings bearing the alkyne group (13, (SFc)-11a,
(SFc)-11b), the unsubstituted cyclopentadienyl rings76 (9c,
(SFc)-9c), or the naphthyl group (11b). The negatively
charged belts usually found around polarized heavy halogen
atoms (see the Supporting Information) are not involved as σ-
hole acceptors in these structures; thus, no halogen···halogen
bonds are evidenced for these compounds. Indeed, as can be
seen for example in Figure S29 (compound 9b) the ethynyl
group offers a more negative VS value in comparison to the
bonded iodine atom itself.
two structures can be deduced from the other by a translation
of half the b unit cell parameter. The larger difference in c unit
cell parameters arises from the fact that the aromatic rings are
oriented along the [001] direction (Figure S18).
(SFc)-11a and (SFc)-12a are isomers, differing in the position
of the phenyl group on the substituted cyclopentadienyl ring.
Although these two structures display similar in-plane areas per
molecule (Table S11), their molecular planes containing the
I···C motif differ in the orientations of the molecules within
them (Figures S10 and S13) and in somewhat different plane
thicknesses (Table S11), making these two structures less
superimposable than are (SFc)-11a and (SFc)-11b (phenyl/
naphthyl substitution).
These halogen interactions form infinite corrugated
molecular chains in most of the structures (9c, 11b, (RFc)-
13, (SFc)-9a, (SFc)-9c, (SFc)-11a, (SFc)-11b, (SFc)-12a) (Figure
1 and Figures S10−S15). These chains stack to form planes
(SFc)-9c and 9c crystallize in the P212121 and Pnma space
groups, respectively. Their crystal structures only differ in the
ordering of the fluorine position in enantiopure (SFc)-9c with
respect to the F/H site position disorder observed for the
racemic 9c.
(SFc)-11b and its racemic counterpart 11b have also similar
crystal packings to some extent. Although the molecular
orientations differ, leading to different plane thicknesses (Table
S11), the more pronounced interplane penetration found in
(SFc)-11b leads finally to a similar packing when the barycenter
of ferrocenyl groups is considered (Figure S20).
In addition to these eight crystal structures sharing similar
molecular plane packings, the methyl-substituted derivative 13
exhibits an interesting further level of sophistication in its
structure. Indeed, the halogen I···C interactions form inter-
penetrated helices of reversed chirality parallel to the [010]
direction (Figure 2).
Figure 1. Planes containing the stacking of chains made of I···C
halogen bonds (highlighted in cyan) in (SFc)-9a (left, (101) plane)
and in (SFc)-9c (right, (010) plane).
which then interact through numerous H···C contacts to form
3D structures. Further H···F and π···π contacts can be noticed,
respectively, in (SFc)-9c and 9c, and in (SFc)-12a (see the
Supporting Information).
One can distinguish two types of such planes among the
structures, which can be grouped into two families. In the first
family the infinite chains are relatively separated ((SFc)-9a,
(RFc)-13, associated with a relatively large in-plane area per
molecule), but in the second family these chains are more
intimately nested and these structures have a relative small in-
plane area per molecule ((SFc)-11a, (SFc)-11b, 11b, (SFc)-12a,
(SFc)-9c, 9c) (Table S11).
The thickness of the planes depends on the R substituent
adjacent to the iodoalkyne functionality (Figure S16), and the
thinner is obtained for the smallest R group (9c and (SFc)-9c
where R = F). The thickness also depends on the molecular
orientation relative to the plane, with for example (SFc)-11b
and 11b where R = naphthyl exhibiting ∼30% plane width
difference (Table S11).
The two members of the first family are isostructural ((RFc)-
13 and (SFc)-9a), differing only in Me/Br substitution. In the
second family, the structures offer different levels of
similarities. (SFc)-11a and (SFc)-11b both crystallize in
P212121 space group with similar a and b unit cell parameters;
these two structures are not strictly isostructural but never-
theless share common packing characteristics, both having very
similar (001) molecular packing planes (Figures S10, S11, and
S17) formed by the stacking of the infinite I···C XB chains
(Table S11). The main difference between the crystal
structures of these two compounds is then the packing of
their (001) planes along the [001] direction, where one of the
Figure 2. Views along [010] (left) and [001]* (right) of the infinite
chains made of I···C halogen bonds (shown in dashed cyan) forming
interpenetrating helices (highlighted in blue and green) in 13.
CONCLUSION
■
Two series of chiral σ-hole bond donors based on the
ferrocenyl ethynyl scaffold were prepared and studied. In these
systems, the direct attachment of the donor atoms (I, S, Se) to
the alkyne function allows increasing their σ-hole depth.
Representative compounds of each series of these new chiral σ-
hole bond donors were used in solution for the activation of
either a C−Br bond in a Ritter reaction or a thioamide for the
synthesis of benzoxazole. Whereas the Se-based compound
furnished low or no conversion, the ferrocenyl iodoalkyne
derivatives generally showed a very good activity in both
reactions. Therefore, in view of the develpoment of
enantiopure XB-based organocatalysts, the asymmetric syn-
thesis of 1,2- and 1,3-disubstituted ferrocenyl iodoalkynes was
performed with functional group introduction in 2- or 3-
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15 h. After the mixture was cooled to room temperature, it was
filtered over Celite and washed with dichloromethane. The filtrate was
washed with water, and the organic phase was collected and dried
over Na2SO4. After filtration and concentration, the crude product
was purified by chromatography on silica gel (pentane or pentane/
Et2O 98/2) to give the expected product.
Conditions B. In a flask containing iodoferrocene 1 or 2 (1 equiv),
Pd(-Pt-Bu3)2 (3 mol %), and CuI (3 mol %) were placed a degassed
THF/iPr2NH 3/1 mixture (1.5 mL/mmol) and finally trimethylsily-
lacetylene (2 equiv). After it was stirred at room temperature for 20 h,
the mixture was filtered over Celite and washed with dichloro-
methane. After concentration, the crude product was purified by
chromatography on silica gel (pentane or pentane/Et2O 98/2) to give
the expected product.
positions of different natures. The crystal structures of some
derivatives in racemic or enantiopure forms were analyzed,
confirming their good σ-hole bond donor property also in the
solid state. Indeed, several intermolecular contacts between the
electropositive σ-hole of the iodine atom and electron-rich π
clouds were noticed, such as the C−C triple bond and the Cp
ring. The search for asymmetric reactions catalyzed by
appropriately decorated enantiopure ferrocenyl iodoalkynes is
currently underway in our laboratory.
EXPERIMENTAL SECTION
■
General Information. Proton (1H NMR) and carbon (13C
NMR) nuclear magnetic resonance spectra were recorded on a 300,
400, or 500 MHz instrument. The chemical shifts are given in parts
per million (ppm) on the δ scale. The solvent peak was used as a
((2-Bromoferrocenyl)ethynyl)trimethylsilane (4a). Conditions A:
4a (3.04 g, 98%) obtained from 1a (8.57 mmol, 3.35 g). Conditions
B: 4a (115 mg, 89%) obtained from 1a (0.358 mmol, 140 mg). Red
1
reference value: for H NMR, CDCl3 at 7.26 ppm; for 13C NMR,
1
solid. Mp: 38−40 °C. H NMR (500 MHz, CDCl3): δ 4.47 (s, 1H),
CDCl3 at 77.16 ppm. Data are presented as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint =
quintet, m = multiplet, b = broad), integration, and coupling
constants (J/Hz). High-resolution mass spectra (HRMS) data were
recorded on a micrOTOF spectrometer equipped with an orthogonal
electrospray interface (ESI). [α]D values were measured at the sodium
D line on a JASCO J-815 CD spectropolarimeter, in CHCl3 in a
quartz cuvette (1 cm) at 20 °C. Melting points were obtained in open
capillary tubes and are uncorrected. Analytical thin-layer chromatog-
raphy (TLC) was carried out on silica gel 60 F254 plates with
visualization by ultraviolet light. Reagents and solvents were purified
using standard means. Tetrahydrofuran (THF) was distilled from
sodium metal/benzophenone and used fresh. Anhydrous toluene,
acetonitrile, and MeOH were obtained by passing through activated
alumina under a positive pressure of argon using GlassTechnology
GTS100 devices. Diisopropylamine was distilled over CaH2 and
stored over KOH, under an argon atmosphere. Anhydrous reactions
were carried out in flame-dried glassware and under an argon
atmosphere. All other chemicals were used as received.
Computational Details. The 3D structures of selected
compounds (see Table 1) were optimized at the DFT level of theory
using the B3LYP functional (completed with D3 dispersion
corrections) and the Def2TZVPP basis set. Conformations were
searched by scanning the corresponding degrees of freedom, and
frequency calculations were performed in order to check that true
energy minima were obtained. The computations of the electrostatic
potential mapped on 0.002 au electron density isosurfaces and
searches for extrema VS,max were performed with the AIMAll77 and
MultiWfn programs.78,79
HPLC on Chiral Stationary Phase. An Agilent Technologies
(Waldbronn, Germany) 1100 Series HPLC system (high-pressure
binary gradient system equipped with a diode-array detector operating
at multiple wavelengths (220, 254, 280 nm), a programmable
autosampler with a 20 μL loop, and a thermostated column
compartment) was employed for analytical enantioseparations. Data
acquisition and analyses were carried out with Agilent Technologies
ChemStation Version B.04.03 chromatographic data software. The
UV absorbance is reported as milliabsorbance units (mAU). Lux
Cellulose-1 (coated cellulose tris(3,5-dimethylphenylcarbamate)), i-
Cellulose-5 (immobilized tris(3,5-dichlorophenylcarbamate)), and i-
Amylose-3 (immobilized amylose tris(3-chloro-5-methylphenylcarba-
mate)) (Phenomenex Inc., Torrance, CA, USA) were used as chiral
columns (250 × 4.6 mm; 5 μm). i-Cellulose-5 and i-Amylose-3 were
kindly provided by Prof. Bezhan Chankvetdze, University of Tbilisi
(Tbilisi, Georgia). HPLC-grade n-heptane, n-hexane, methanol, and
2-propanol were purchased and used as received. Analyses were
performed at a flow rate of 0.8 mL/min and 22 °C.
4.41 (s, 1H), 4.23 (s, 5H), 4.14 (s, 1H), 0.26 (s, 9H). 13C NMR (126
MHz, CDCl3): δ 101.7, 94.5, 81.0, 72.9, 70.8, 70.2, 67.3, 67.0, 0.3.
HRMS (ESI-TOF): m/z [M]+ calcd for C15H17BrFeSi 359.9627;
found 359.9613.
((2-Chloroferrocenyl)ethynyl)trimethylsilane (4b). Conditions A:
4b (540 mg, 62%) obtained from 1b (2.77 mmol, 960 mg).
Conditions B: 4b (82 mg, 94%) obtained from 1b (0.277 mmol, 96
mg). Red solid. Mp: 45−47 °C. 1H NMR (500 MHz, CDCl3): δ 4.45
(m, 1H), 4.37 (m, 1H), 4.24 (s, 5H), 4.08 (m, 1H), 0.27 (s, 9H). 13C
NMR (126 MHz, CDCl3): δ 100.9, 94.7, 94.5, 72.5, 69.5, 68.4, 66.0,
65.1, 0.3. HRMS (ESI-TOF): m/z [M]+ calcd for C15H17ClFeSi
316.0132; found 316.0143.
((2-Fluoroferrocenyl)ethynyl)trimethylsilane (4c). Conditions A:
4c (127 mg, 42%) obtained from 1c (1 mmol, 330 mg). Conditions
B: 4c (49 mg, 46%) obtained from 1c (0.352 mmol, 116 mg) (50 mg
1
of starting material was recovered). Red oil. H NMR (500 MHz,
CDCl3): δ 4.35 (s, 1H), 4.28 (s, 5H), 4.11 (s, 1H), 3.82 (s, 1H), 0.25
(s, 9H). 13C NMR (126 MHz, CDCl3): δ 135.4 (d, J = 274.9 Hz),
99.5 (d, J = 3.8 Hz), 94.4, 71.6, 65.3 (d, J = 2.5 Hz), 60.9 (d, J = 3.8
Hz), 56.5 (d, J = 13.9 Hz), 54.6 (d, J = 12.6 Hz), 0.3. 19F NMR (75
MHz, CDCl3): δ −186.7. HRMS (ESI-TOF): m/z [M]+ calcd for
C15H17FFeSi 300.0427; found 300.0424.
2-((Trimethylsilyl)ethynyl)cyanoferrocene (4d). Conditions A: 4d
obtained from 1d (0.816 mmol, 275 mg) as a 3:2 mixture with
cyanoferrocene (180 mg). Conditions B: 4d (20 mg, 55%) obtained
from 1d (0.118 mmol, 39.6 mg). Red oil. 1H NMR (500 MHz,
CDCl3): δ 4.66 (bs, 1H), 4.63 (bs, 1H), 4.39 (t, J = 2.5 Hz, 1H), 4.36
(s, 5H), 0.25 (s, 9H). 13C NMR (126 MHz, CDCl3): δ 118.8, 99.3,
96.2, 73.8, 72.9, 72.1, 70.8, 69.4, 55.8, 0.2. HRMS (ESI-TOF): m/z
[M]+ calcd for C16H17FeNSi 307.0474; found 307.0455.
((3-Bromoferrocenyl)ethynyl)trimethylsilane (5a). Conditions A:
5a (176 mg, 48%) obtained from 2a (1.023 mmol, 400 mg).
Conditions B: 5a (118 mg, 91%) obtained from 2a (0.358 mmol, 140
mg). Red solid. Mp: 58−60 °C. 1H NMR (500 MHz, CDCl3): δ 4.69
(m, 1H), 4.43 (m, 1H), 4.37 (m, 1H), 4.26 (s, 5H), 0.21 (s, 9H). 13C
NMR (126 MHz, CDCl3): δ 102.5, 92.1, 77.2, 73.5, 72.8, 71.0, 70.8,
64.6, 0.3. HRMS (ESI-TOF): m/z [M]+ calcd for C15H17BrFeSi
359.9627; found 359.9619.
((3-Chloroferrocenyl)ethynyl)trimethylsilane (5b). Conditions A:
5b (55 mg, 38%) obtained from 2b (0.462 mmol, 160 mg).
Conditions B: 5b (134 mg, 92%) obtained from 2b (0.462 mmol, 160
mg). Red oil. 1H NMR (500 MHz, CDCl3): δ 4.67 (s, 1H), 4.40 (m,
1H), 4.33 (s, 1H), 4.27 (s, 5H), 0.21 (s, 9H). 13C NMR (126 MHz,
CDCl3): δ 102.6, 92.2, 91.8, 72.5, 71.3, 69.8, 68.7, 63.5, 0.3. HRMS
(ESI-TOF): m/z [M]+ calcd for C15H17ClFeSi 316.0132; found
316.0140.
((3-Fluoroferrocenyl)ethynyl)trimethylsilane (5c). Conditions A:
5c (46 mg, 31%) obtained from 2c (0.5 mmol, 165 mg). Conditions
B: 5c (111 mg, 74%) obtained from 2c (0.5 mmol, 165 mg). Red oil.
1H NMR (500 MHz, CDCl3): δ 4.60 (s, 1H), 4.34 (s, 1H), 4.30 (s,
5H), 4.11 (s, 1H), 0.21 (s, 9H). 13C NMR (126 MHz, CDCl3): δ
134.6 (d, J = 270.9 Hz), 103.2, 91.1, 71.7, 65.0, 59.6 (d, J = 15.1 Hz),
General Procedures for the Sonogashira Reaction. Con-
ditions A. To the substituted iodoferrocene 1 or 2 (1 equiv) under
argon were successively added degassed diisopropylamine (5 mL/
mmol), Pd(PPh3)4 (5 mol %), and CuI (10 mol %). After the mixture
was stirred at room temperature for 5 min, trimethylsilylacetylene (3
equiv) was added and the mixture was heated at 60 °C and stirred for
H
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58.5 (d, J = 5.0 Hz), 57.0 (d, J = 15.1 Hz), 0.3. 19F NMR (75 MHz,
CDCl3): δ −186.1. HRMS (ESI-TOF): m/z [M]+ calcd for
C15H17FFeSi 300.0427; found 300.0435.
Trimethyl((2-(naphthalen-2-yl)ferrocenyl)ethynyl)silane (6b).
Red oil (572 mg, 93%) obtained from 4a (1.5 mmol, 542 mg). H
1
NMR (500 MHz, CDCl3): δ 8.33 (s, 1H), 8.00 (dd, J = 8.5, 1.5 Hz,
1H), 7.83 (m, 3H), 7.47 (m, 2H), 4.74 (m, 1H), 4.65 (m, 1H), 4.38
(t, J = 3.0 Hz, 1H), 4.13 (s, 5H), 0.29 (s, 9H). 13C NMR (126 MHz,
CDCl3): δ 135.6, 133.5, 132.4, 127.85, 127.8, 127.4, 126.7, 126.3,
125.8, 125.6, 104.7, 93.9, 87.5, 73.4, 71.9, 68.85, 68.8, 63.9, 0.3.
HRMS (ESI-TOF): m/z [M]+ calcd for C25H24FeSi 408.0991; found
408.0997.
General Procedure for Aldehyde Homologation. Ferrocene-
carboxaldehyde (SFc)-36 or (SFc)-39 (1 equiv) was dissolved in THF
(3 mL/mmol), and the temperature was lowered to 0 °C. A solution
of diazophosphonate 38 (1.2 equiv) in MeOH (2.5 mL/mmol) was
added, followed by K2CO3 (2.2 equiv). The temperature was raised to
room temperature, and the mixture was stirred for 15 h. After
concentration, the crude product was extracted with Et2O and the
extract washed with water and brine. The organic phases were
collected, dried over Na2SO4, and concentrated. The crude product
was purified by chromatography on silica gel (pentane/Et2O 4/1) to
give the expected product.
(SFc)-Trimethyl((2-(naphthalen-2-yl)ferrocenyl)ethynyl)silane
((SFc)-6b). Red oil (200 mg, 98%) obtained from (SFc)-4a (0.5 mmol,
20
180 mg). [α]D = +107 (c = 0.5, CHCl3). HRMS (ESI-TOF): m/z
[M]+ calcd for C25H24FeSi 408.0991; found 408.0971.
Trimethyl((3-phenylferrocenyl)ethynyl)silane (7a). Red solid (60
mg, 82%) obtained from 5a (0.208 mmol, 75 mg). Mp: 120−122 °C.
1H NMR (500 MHz, CDCl3): δ 7.45 (d, J = 7.0 Hz, 2H), 7.30 (t, J =
7.0 Hz, 2H), 7.21 (t, J = 7.0 Hz, 1H), 4.93 (m, 1H), 4.66 (m, 1H),
4.58 (m, 1H), 4.09 (s, 5H), 0.25 (s, 9H). 13C NMR (126 MHz,
CDCl3): δ 138.3, 128.6, 126.5, 126.3, 104.0, 91.2, 86.3, 72.6, 71.8,
70.1, 67.3, 65.8, 0.4. HRMS (ESI-TOF): m/z [M]+ calcd for calcd for
C21H22FeSi 358.0835; found 358.0843.
(SFc)-1-Bromo-2-ethynylferrocene ((SFc)-37). Red oil (1.59 g, 89%)
1
obtained from (SFc)-36 (6.14 mmol, 1.8 g). H NMR (500 MHz,
CDCl3): δ 4.50 (bs, 1H), 4.45 (bs, 1H), 4.26 (s, 5H), 4.17 (t, J = 2.5
Hz, 1H), 2.94 (s, 1H). 13C NMR (126 MHz, CDCl3): δ 80.8, 80.5,
20
76.8, 72.8, 70.9, 70.5, 67.4, 66.0. [α]D = +21 (c = 0.7, CHCl3).
HRMS (ESI-TOF): m/z [M]+ calcd for C12H9BrFe 287.9232; found
287.9228.
(SFc)-Trimethyl((3-phenylferrocenyl)ethynyl)silane ((SFc)-7a). Red
(SFc)-1-Ethynyl-3-iodoferrocene ((SFc)-40). Red oil (460 mg, 86%)
1
solid (130 mg, 84%) obtained from (SFc)-41 (0.43 mmol, 175 mg).
obtained from (SFc)-39 (1.59 mmol, 540 mg). H NMR (500 MHz,
20
Mp: 142−144 °C. [α]D = +65 (c = 0.5, CHCl3). HRMS (ESI-
CDCl3): δ 4.72 (bs, 1H), 4.453 (s, 1H), 4.451 (s, 1H), 4.25 (s, 5H),
TOF): m/z [M]+ calcd for C21H22FeSi 358.0835; found 358.0837.
Trimethyl((3-(naphthalen-2-yl)ferrocenyl)ethynyl)silane (7b).
Red solid (46 mg, 80%) obtained from 5a (0.141 mmol, 51 mg).
2.77 (s, 1H); 13C NMR (126 MHz, CDCl3): δ 81.0, 77.8, 75.4, 75.1,
20
73.1, 72.6, 65.3, 38.9. [α]D = +125 (c = 0.5, CHCl3). HRMS (ESI-
TOF): m/z [M]+ calcd for C12H9FeI 335.9093; found 335.9083.
General Procedure for TMS Protection. To a solution of
ethynylferrocene (SFc)-37 or (SFc)-40 (1 equiv) at −78 °C was added
a freshly prepared solution of LiHMDS (1 M in THF, 1.5 equiv), and
the mixture was stirred for 30 min at −78 °C. TMSCl (1.5 equiv) was
added, and stirring was continued for 30 min at −78 °C before the
temperature was raised to ambient. A saturated solution of NH4Cl
was added, and the mixture was extracted with Et2O and the extract
washed with water. After drying the organic phase over Na2SO4, it was
filtered and concentrated. The crude was purified by chromatography
on silica gel (pentane/Et2O 8/1) to give the expected product.
1
Mp: 85−87 °C. H NMR (500 MHz, CDCl3): δ 7.86 (s, 1H), 7.79
(m, 3H), 7.61 (dd, J = 8.5, 1.5 Hz, 1H), 7.46 (m, 2H), 5.07 (m, 1H),
4.79 (m, 1H), 4.65 (t, J = 3.0 Hz, 1H), 4.10 (s, 5H), 0.26 (s, 9H). 13C
NMR (126 MHz, CDCl3): δ 135.8, 133.7, 132.4, 128.1, 127.9, 127.7,
126.5, 125.6, 125.2, 124.0, 103.9, 91.3, 86.1, 72.8, 71.9, 70.3, 67.4,
66.1, 0.4. HRMS (ESI-TOF): m/z [M]+ calcd for C25H24FeSi
408.0991; found 408.0994.
(SFc)-Trimethyl((3-(naphthalen-2-yl)ferrocenyl)ethynyl)silane
((SFc)-7b). Red solid (150 mg, 85%) obtained from (SFc)-41 (0.43
20
mmol, 175 mg). Mp: 95−97 °C. [α]D = +131 (c = 0.7, CHCl3).
HRMS (ESI-TOF): m/z [M]+ calcd for C25H24FeSi 408.0991; found
408.0991.
(SFc)-((2-Bromoferrocenyl)ethynyl)trimethylsilane ((SFc)-4a). Red
20
oil (1.75 g, 99%) obtained from (SFc)-37 (4.84 mmol, 1.4 g). [α]D
=
General Procedure for the Lithiation/Electrophilic Trap-
ping. To a solution of 4a or (SFc)-4a (1 equiv) in THF (5 mL/
mmol) at −78 °C was slowly added n-BuLi (1.4 M in hexanes, 1.2
equiv), and the mixture was stirred at −78 °C for 1 h. An electrophile
(1.2 equiv) was added, and stirring was continued at −78 °C for 1 h.
The temperature was raised to 0 °C before the mixture was quenched
with a saturated solution of NH4Cl. The mixture was extracted with
ethyl acetate and the extract washed with water and brine. After
drying over Na2SO4, filtration, and concentration, the crude product
was purified by chromatography on silica gel (pentane/Et2O 98/2) to
give the expected product.
−16 (c = 0.7, CHCl3). HRMS (ESI-TOF): m/z [M]+ calcd for
C15H17BrFeSi 359.9627; found 359.9637.
(SFc)-((3-Iodoferrocenyl)ethynyl)trimethylsilane ((SFc)-41). Red
solid (540 mg, 99%) obtained from (SFc)-40 (1.335 mmol, 450
1
mg). Mp: 50−52 °C. H NMR (500 MHz, CDCl3): δ 4.69 (s, 1H),
4.43 (s, 1H), 4.41 (s, 1H), 4.22 (s, 5H), 0.22 (s, 9H). 13C NMR (126
MHz, CDCl3): δ 102.4, 92.3, 77.8, 75.3, 73.2, 72.5, 66.3, 39.1, 0.3.
[α]D20 = +126 (c = 0.6, CHCl3). HRMS (ESI-TOF): m/z [M]+ calcd
for C15H17FeISi 407.9488; found 407.9486.
General Procedure for the Suzuki Reaction. Haloferrocene 4a,
5a, or (SFc)-41 (1 equiv), Pd2dba3 (2 mol %), SPhos (4 mol %),
boronic acid (1.5 equiv), and crushed K3PO4 (3 equiv) were placed in
a Schlenk tube under argon. Degassed toluene (3 mL/mmol) was
added, and the mixture was heated at 100 °C and stirred for 15 h.
After it was cooled to room temperature, the mixture was filtered over
Celite and washed with ethyl acetate. The filtrate was concentrated
and purified by chromatography on silica gel (pentane or pentane/
Et2O 98/2) to give the expected product.
Trimethyl((2-methylferrocenyl)ethynyl)silane (8). Red oil (208
mg, 70%) obtained by using 1 mmol of 4a and 1.2 mmol of MeI
1
(neat) as the electrophile. H NMR (500 MHz, CDCl3): δ 4.34 (m,
1H), 4.14 (m, 1H), 4.09 (s, 5H), 4.04 (t, J = 2.5 Hz, 1H), 2.08 (s,
3H), 0.24 (s, 9H). 13C NMR (126 MHz, CDCl3): δ 104.0, 92.5, 87.0,
70.9, 70.6, 69.7, 67.1, 65.8, 13.7, 0.5. HRMS (ESI-TOF): m/z [M]+
calcd for C16H20FeSi 296.0678; found 296.0671.
(RFc)-Trimethyl((2-methylferrocenyl)ethynyl)silane ((RFc)-8). Red
Trimethyl((2-phenylferrocenyl)ethynyl)silane (6a). Red solid
(1.05 g, 98%) obtained from 4a (3 mmol, 1.08 g). Mp: 46−48 °C.
1H NMR (500 MHz, CDCl3): δ 7.87 (d, J = 7.0 Hz, 2H), 7.35 (t, J =
7.0 Hz, 2H), 7.27 (t, J = 7.0 Hz, 1H), 4.63 (m, 1H), 4.61 (m, 1H),
4.33 (t, J = 3.0 Hz, 1H), 4.13 (s, 5H), 0.27 (s, 9H). 13C NMR (126
MHz, CDCl3): δ 138.0, 128.0, 127.9, 126.6, 104.7, 93.8, 87.9, 73.0,
71.9, 68.6, 68.5, 63.9, 0.2. HRMS (ESI-TOF): m/z [M]+ calcd for
C21H22FeSi 358.0835; found 358.0823.
solid (120 mg, 73%) obtained by using by using 0.55 mmol of 4a and
20
0.66 mmol of MeI (neat) as the electrophile. Mp: 33−35 °C. [α]D
=
−49 (c = 0.3, CHCl3). HRMS (ESI-TOF): m/z [M]+ calcd for
C16H20FeSi 296.0678; found 296.0662.
(SFc)-((2-Fluoroferrocenyl)ethynyl)trimethylsilane ((SFc)-4c). Red
oil (118 mg, 71%) obtained by using 0.55 mmol of 4a and 0.66 mmol
20
of NFSI (solid) as the electrophile. [α]D = −4 (c = 1.4, CHCl3).
HRMS (ESI-TOF): m/z [M]+ calcd for C15H17FFeSi 300.0427;
found 300.0431.
(SFc)-Trimethyl((2-phenylferrocenyl)ethynyl)silane ((SFc)-6a). Red
oil (160 mg, 89%) obtained from (SFc)-4a (0.5 mmol, 180 mg).
(SFc)-2-((Trimethylsilyl)ethynyl)cyanoferrocene ((SFc)-4d). Red oil
20
[α]D = −16 (c = 0.5, CHCl3). HRMS (ESI-TOF): m/z [M]+ calcd
(70 mg, 41%) obtained by using 0.55 mmol of 4a and 0.66 mmol of
20
for C21H22FeSi 358.0835; found 358.0829.
TsCN (in THF) as the electrophile. [α]D = −37 (c = 0.2, CHCl3).
I
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1
HRMS (ESI-TOF): m/z [M]+ calcd for C16H17FeNSi 307.0474;
found 307.0465.
70−72 °C. H NMR (500 MHz, CDCl3): δ 4.48 (m, 1H), 4.43 (m,
1H), 4.27 (s, 5H), 4.15 (t, J = 2.5 Hz, 1H). 13C NMR (126 MHz,
CDCl3): δ 89.9, 80.9, 72.7, 70.7, 70.5, 67.7, 67.3, 3.5. HRMS (ESI-
TOF): m/z [M]+ calcd for C12H8BrFeI 413.8198; found 413.8202.
(SFc)-1-Bromo-2-(iodoethynyl)ferrocene ((SFc)-9a). Conditions a:
(61 mg, 53%) obtained from (SFc)-4a (0.277 mmol, 100 mg).
Conditions d: 9a (36 mg, 87%) obtained from (SFc)-4a (0.1 mmol, 36
(SFc)-((3-Bromoferrocenyl)ethynyl)trimethylsilane ((SFc)-5a).
(SFc)-41 (0.452 mmol, 185 mg) was dissolved in THF (3 mL), and
the solution was cooled to −78 °C. t-BuLi (1.7 M in pentane, 0.95
mmol, 0.56 mL) was slowly added, and the mixture was stirred at −78
°C for 30 min. A solution of α,α′-dibromoxylene (0.54 mmol, 140
mg) in THF (2 mL) was added, and stirring was continued for 30
min. The temperature was raised to ambient temperature, and water
(0.5 mL) was slowly added. After filtration on Celite (Et2O), the
organic phase was separated and dried over Na2SO4. After filtration
and concentration, the crude product was purified by chromatography
20
mg). Red solid. Mp: 99−101 °C. [α]D = +12 (c = 0.6, CHCl3).
HRMS (ESI-TOF): m/z [M]+ calcd for C12H8BrFeIi 413.8198; found
413.8102.
1-Chloro-2-(iodoethynyl)ferrocene (9b). Conditions a: 9b (124
mg, 48%) obtained from 4b (0.695 mmol, 220 mg). Conditions c: 9b
(25 mg, 72%) obtained from 14 (0.094 mmol, 23 mg). Conditions d:
9b (37 mg, 77%) obtained from 4b (0.13 mmol, 41 mg). Red solid.
1
on silica gel (pentane) to give a red solid (150 mg) with a H NMR
spectrum similar to that of racemic 5a. However, it contained some
inseparable impurities and was used without further purification in the
next step.
1
Mp: 80−82 °C. H NMR (500 MHz, CDCl3): δ 4.45 (m, 1H), 4.38
(m, 1H), 4.28 (s, 5H), 4.09 (t, J = 2.5 Hz, 1H). 13C NMR (126 MHz,
CDCl3): δ 94.7, 89.2, 72.4, 69.7, 68.4, 66.0, 65.8, 3.7. HRMS (ESI-
TOF): m/z [M]+ calcd for C12H8ClFeI 369.8703; found 369.8705.
1-Fluoro-2-(iodoethynyl)ferrocene (9c). Conditions a: 9c (25 mg,
42%) obtained from 4c (0.167 mmol, 50 mg). Conditions d: 9c (54
mg, 93%) obtained from 4c (0.163 mmol, 49 mg). Red solid. Mp:
General Procedures for the Deprotection−Iodination.
Conditions a. The ferrocenyl ethynyltrimethylsilane (1 equiv) was
dissolved in acetonitrile (10 mL/mmol) and placed in the dark at
room temperature. AgF (1.1 equiv) and NIS (1.1 equiv) were
successively added, and the mixture was stirred for 15 h. After
filtration over Celite (Et2O) and concentration, the crude product was
purified by chromatography on silica gel (pentane or pentane/Et2O
98/2) to give the expected product.
Conditions b. The ferrocenyl ethynyltrimethylsilane (1 equiv) was
dissolved in methanol (15 mL/mmol) and the solution was cooled to
0 °C. Crushed KOH (2.5 equiv) was added, and the mixture was
stirred at 0 °C for 5 min and at room temperature for 2 h. Diethyl
ether was added, and the mixture was washed with water and then
with brine. The organic phase was extracted, dried over Na2SO4,
filtered, and concentrated. The crude product was purified by
chromatography on silica gel (pentane/Et2O 99/1) to give the free
alkynes.
1
63−65 °C. H NMR (500 MHz, CDCl3): δ 4.36 (m, 1H), 4.31 (s,
5H), 4.12 (m, 1H), 3.84 (m, 1H). 13C NMR (126 MHz, CDCl3): δ
135.8 (d, J = 275.9 Hz), 87.8 (d, J = 3.8 Hz), 71.4, 65.2 (d, J = 1.3
Hz), 60.9 (d, J = 4.0 Hz), 56.4 (d, J = 13.9 Hz), 55.3 (d, J = 12.6 Hz),
3.5. 19F NMR (75 MHz, CDCl3): δ −186.7. HRMS (ESI-TOF): m/z
[M]+ calcd for C12H8FFeI 353.8999; found 353.9000.
(SFc)-1-Fluoro-2-(iodoethynyl)ferrocene ((SFc)-9c). Conditions a:
(SFc)-9c (59 mg, 51%) obtained from (SFc)-4c (0.327 mmol, 98 mg).
Red solid. Mp: 107−109 °C. [α]D20 = −10 (c = 0.44, CHCl3). HRMS
(ESI-TOF): m/z [M]+ calcd for C12H8FFeI 353.8999; found
353.8983.
2-(Iodoethynyl)cyanoferrocene (9d). Conditions d: 9d (20 mg,
1-Chloro-2-ethynylferrocene (14). Compound 14 (red oil, 25 mg,
79%) obtained from 4b (0.13 mmol, 41 mg) and KOH (0.325 mmol,
18.2 mg) in MeOH (2 mL). 1H NMR (500 MHz, CDCl3): δ 4.47 (br
s, 1H), 4.40 (br s, 1H), 4.27 (s, 5H), 4.11 (t, J = 2.5 Hz, 1H), 2.95 (s,
1H). 13C NMR (126 MHz, CDCl3): δ 94.5, 79.7, 72.5, 69.7, 68.5,
66.1, 64.1. HRMS (ESI-TOF): m/z [M]+ calcd for C12H9ClFe
243.9737; found 243.9750.
85%) obtained from 4d (20 mg, 0.065 mmol). Light-sensitive red
1
solid. Mp: 119−121 °C. H NMR (500 MHz, CDCl3): δ 4.67 (m,
1H), 4.65 (m, 1H), 4.41 (m, 1H), 4.40 (s, 5H). 13C NMR (126 MHz,
CDCl3): δ 118.8, 87.8, 74.1, 72.1, 70.8, 70.0, 55.8, 6.6. HRMS (ESI-
TOF): m/z [M]+ calcd for C13H8FeIN 360.9045; found 360.9037.
(SFc)-2-(Iodoethynyl)cyanoferrocene ((SFc)-9d). Conditions a:
(SFc)-9d (60 mg, 77%) obtained from (SFc)-4d (0.217 mmol, 67
20
1-Chloro-3-ethynylferrocene (15). Compound 15 (red oil, 46 mg,
mg). Light-sensitive red solid. Mp: 150−152 °C. [α]D = +65 (c =
0.5, CHCl3). HRMS (ESI-TOF): m/z [M]+ calcd for C13H8FeIN
360.9045; found 360.9042.
87%) obtained from compound 5b (0.212 mmol, 67 mg) and KOH
1
(0.529 mmol, 29.6 mg) in MeOH (3.2 mL). H NMR (500 MHz,
CDCl3): δ 4.69 (br s, 1H), 4.43 (br s, 1H), 4.36 (br s, 1H), 4.29 (s,
5H), 2.71 (s, 1H). 13C NMR (126 MHz, CDCl3): δ 92.2, 81.3, 74.6,
72.4, 71.3, 69.8, 68.7. HRMS (ESI-TOF): m/z [M]+ calcd for
C12H9ClFe 243.9737; found 243.9756.
Conditions c. The free alkynylferrocene (1 equiv) was dissolved in
methanol (15 mL/mmol), and the solution was cooled to 0 °C.
Crushed KOH (2.5 equiv) was added, and the mixture was stirred at 0
°C for 15 min. NIS (1.5 equiv) was added, and the mixture was stirred
for 5 min at 0 °C and then for 2 h at room temperature. Diethyl ether
was added, and the mixture was washed with water and then with
brine. The organic phase was extracted, dried over Na2SO4, filtered,
and concentrated. The crude product was purified by chromatography
on silica gel (pentane/Et2O 99/1) to give the iodoalkynes.
Conditions d (One Pot). The ferrocenyl ethynyltrimethylsilane (1
equiv) was dissolved in methanol (15 mL/mmol), and the solution
was cooled to 0 °C. Crushed KOH (5 equiv) was added, and the
mixture was stirred at 0 °C for 5 min and at room temperature for 2 h.
After the mixture was cooled to 0 °C, NIS (1.5 equiv) was added and
the mixture was stirred for 5 min at 0 °C and then for 2 h at room
temperature. Diethyl ether was added, and the mixture was washed
with water and then with brine. The organic phase was extracted,
dried over Na2SO4, filtered, and concentrated. The crude product was
purified by chromatography on silica gel (pentane/Et2O 99/1) to give
the iodoalkynes.
1-Bromo-3-(iodoethynyl)ferrocene (10a). Conditions a: 10a (24
mg, 84%) obtained from 5a (0.069 mmol, 25 mg). Red oil. 1H NMR
(500 MHz, CDCl3): δ 4.69 (br s, 1H), 4.44 (br s, 1H), 4.38 (br s,
1H), 4.29 (s, 5H). 13C NMR (126 MHz, CDCl3): δ 90.5, 77.0, 73.5,
72.7, 70.9, 65.3, 1.4. HRMS (ESI-TOF): m/z [M]+ calcd for
C12H8BrFeI 413.8200; found 413.8190.
(SFc)-1-Bromo-3-(iodoethynyl)ferrocene ((SFc)-10a). Conditions a:
(SFc)-10a (72 mg, 38% for 2 steps) obtained from (SFc)-41. Red oil.
HRMS (ESI-TOF): m/z [M]+ calcd for C12H8BrFeI 413.8200; found
413.8188.
1-Chloro-3-(iodoethynyl)ferrocene (10b). Conditions a: 10b (29
mg, 50%) obtained from 5b (0.158 mmol, 50 mg). Conditions c: 10b
(54 mg, 78%) obtained from 15 (0.188 mmol, 46 mg). Conditions d:
9b (63 mg, 80%) obtained from 5b (0.212 mmol, 67 mg). Red oil. 1H
NMR (500 MHz, CDCl3): δ 4.67 (m, 1H), 4.41 (m, 1H), 4.34 (m,
1H), 4.30 (s, 5H); 13C NMR (126 MHz, CDCl3): δ 92.0, 90.7, 72.4,
71.2, 69.9, 68.6, 64.1, 1.1; HRMS (ESI-TOF): m/z [M]+ calcd for
C12H8ClFe 369.8703; found 369.8689.
1-Fluoro-3-(iodoethynyl)ferrocene (10c). Conditions a: 10c (17
mg, 36%) obtained from 4c (0.133 mmol, 40 mg). Conditions d: 10c
1
(105 mg, 80%) obtained from 4c (0.37 mmol, 111 mg). Red oil. H
NMR (500 MHz, CDCl3): δ 4.60 (m, 1H), 4.34 (m, 1H), 4.32 (s,
5H), 4.12 (m, 1H). 13C NMR (126 MHz, CDCl3): δ 134.2 (d, J =
270.9 Hz), 91.1, 94.4, 71.5, 65.1 (d, J = 2.4 Hz), 59.6 (d, J = 15.0 Hz),
59.2 (d, J = 5.2 Hz), 57.0 (d, J = 14.7 Hz), 0.2. 19F NMR (75 MHz,
CDCl3): δ −185.8. HRMS (ESI-TOF): m/z [M]+ calcd for C12H8FFe
353.8999; found 353.8986.
1-Bromo-2-(iodoethynyl)ferrocene (9a). Conditions a: 9a (82 mg,
56%) obtained from 4a (0.354 mmol, 128 mg). Conditions d: 9a (49
mg, 71%) obtained from 4a (0.166 mmol, 60 mg). Red solid. Mp:
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1-(Iodoethynyl)-2-phenylferrocene (11a). Conditions a: 11a (74
mg, 72%) obtained from 6a (0.25 mmol, 90 mg). Red oil. H NMR
cooled to −78 °C. n-BuLi (1.6 M, 1 equiv) was added, and stirring
was continued for 1 h. A solution of N-methyl-N-[(trifluoromethyl)-
sulfanyl]aniline (1 equiv) in THF (0.5 mL/mmol) was added, and the
mixture was stirred at −78 °C for 3 h. HCl (6 M) was added, and the
mixture was extracted with pentane and the extract washed with HCl
(6 M) and water and dried over Na2SO4. After filtration and
concentration, the crude product was purified by chromatography on
silica gel (pentane) to give the expected product.
1
(500 MHz, CDCl3): δ 7.78 (dd, J = 8.0, 1.5 Hz, 2H), 7.36 (t, J = 8.0
Hz, 2H), 7.28 (dt, J = 7.5, 1.5 Hz, 1H), 4.61 (m, 2H), 4.32 (t, J = 3.0
Hz, 1H), 4.15 (s, 5H). 13C NMR (126 MHz, CDCl3): δ 137.7, 128.2,
127.9, 126.7, 92.1, 88.3, 73.3, 71.7, 68.6, 68.5, 64.7, 2.1. HRMS (ESI-
TOF): m/z [M]+ calcd for C18H13FeI 411.9406; found 411.9404.
(SFc)-1-(Iodoethynyl)-2-phenylferrocene ((SFc)-11a). Conditions a:
(SFc)-11a (81 mg, 59%) obtained from (SFc)-6a (0.335 mmol, 120
((2-Chloroferrocenyl)ethynyl)(trifluoromethyl)sulfane (16a). Red
20
1
mg). Red solid. Mp: 92−94 °C. [α]D = +42 (c = 0.4, CHCl3).
oil (47 mg, 68%) obtained from 14 (0.2 mmol, 49 mg). H NMR
HRMS (ESI-TOF): m/z [M]+ calcd for C18H13FeI 411.9406; found
411.9387.
(500 MHz, CDCl3): δ 4.56 (dd, J = 2.5, 1.5 Hz, 1H), 4.47 (dd, J =
2.5, 1.5 Hz, 1H), 4.29 (s, 5H), 4.20 (t, J = 2.5 Hz, 1H). 13C NMR
(126 MHz, CDCl3): δ 127.8 (q, J = 313.7 Hz), 99.4, 95.5, 72.6, 70.6,
69.6, 67.2, 66.2 (d, J = 4.2 Hz), 62.6. 19F NMR (75 MHz, CDCl3): δ
−44.4. HRMS (ESI-TOF): m/z [M]+ calcd for C13H8ClF3FeS
343.9331; found 343.9352.
1-(Iodoethynyl)-2-(naphthalen-2-yl)ferrocene (11b). Conditions
a: 11b (73 mg, 63%) obtained from 6b (0.25 mmol, 102 mg). Red
1
solid. Mp: 114−116 °C. H NMR (500 MHz, CDCl3): δ 8.21 (s,
1H), 7.93 (d, J = 8.5 Hz, 1H), 7.84 (m, 3H), 7.47 (m, 2H), 4.73 (br s,
1H), 4.66 (br s, 1H), 4.38 (m, 1H), 4.16 (s, 5H). 13C NMR (126
MHz, CDCl3): δ 135.3, 133.5, 132.5, 128.0, 127.8, 127.6, 126.6,
126.3, 125.9, 125.8, 92.3, 88.1, 73.5, 71.7, 68.8, 68.7, 64.8, 2.3. Mp:
126−128 °C. HRMS (ESI-TOF): m/z [M]+ calcd for C22H15FeI
461.9562; found 461.9547.
((3-Chloroferrocenyl)ethynyl)(trifluoromethyl)sulfane (16b). Red
1
oil (22 mg, 52%) obtained from 15 (0.123 mmol, 30 mg). H NMR
(500 MHz, CDCl3): δ 4.76 (br s, 1H), 4.52 (br s, 1H), 4.44 (br s,
1H), 4.31 (s, 5H). 13C NMR (126 MHz, CDCl3): δ 127.8 (q, J =
313.4 Hz), 101.0, 92.8, 72.5, 72.0, 71.0, 69.9, 63.6 (d, J = 4.3 Hz),
60.8. 19F NMR (75 MHz, CDCl3): δ −44.4. HRMS (ESI-TOF): m/z
[M]+ calcd for C13H8ClF3FeS 343.9331; found 343.9332.
(SFc)-1-(Iodoethynyl)-2-(naphthalene-2-yl)ferrocene ((SFc)-11b).
Conditions a: (SFc)-11b (137 mg, 67%) obtained from (SFc)-6b
(0.44 mmol, 180 mg). Red solid. Mp: 127−129 °C. [α]D20 = +90 (c =
0.4, CHCl3). HRMS (ESI-TOF): m/z [M]+ calcd for C22H15FeI
461.9562; found 461.9541.
General Procedure for the Alkyne Selenation. In one flask
under argon were added benzyl(trifluoromethyl)selane (1 equiv) and
THF (1 mL/mmol). Sulfuryl chloride (1 equiv) was added at room
temperature, and the mixture was stirred for 15 min and then cooled
to −78 °C. In a second flask, the alkyne (1.5 equiv) was dissolved in
THF (2 mL/mmol) and the solution was cooled to −78 °C. n-BuLi
(1.4 M in hexanes, 1.4 equiv) was added, and the mixture was stirred
for 1 h. The alkynyllithium solution was cannulated to the first flask at
−78 °C. After the mixture was stirred for 10 min, the temperature was
raised to ambient temperature. Water was added, and the mixture was
extracted with Et2O and the extract dried over Na2SO4. After filtration
and concentration, the crude product was purified by chromatography
on silica gel (pentane) to give the expected product.
1-(Iodoethynyl)-3-phenylferrocene (12a). Conditions a: 12a (10
mg, 45%) obtained from 7a (0.053 mmol, 19 mg). Red solid. Mp:
1
120−122 °C. H NMR (500 MHz, CDCl3): δ 7.42 (dd, J = 8.0, 1.5
Hz, 2H), 7.27 (t, J = 8.0 Hz, 2H), 7.19 (dt, J = 7.5, 1.5 Hz, 1H), 4.90
(t, J = 1.5 Hz, 1H), 4.64 (dd, J = 2.5, 1.5 Hz, 1H), 4.57 (dd, J = 2.5,
1.5 Hz, 1H), 4.09 (s, 5H). 13C NMR (126 MHz, CDCl3): δ 138.0,
128.6, 126.6, 126.3, 91.9, 86.3, 72.6, 71.7, 70.1, 67.2, 66.5, 0.0. HRMS
(ESI-TOF): m/z [M]+ calcd for C18H13FeI 411.9406; found
411.9391.
(SFc)-1-(Iodoethynyl)-3-phenylferrocene ((SFc)-12a). Conditions a:
(SFc)-12a (65 mg, 56%) obtained from (SFc)-7a (0.28 mmol, 100
((2-Chloroferrocenyl)ethynyl)(trifluoromethyl)selane (17a). Red
oil (104 mg, 71% based on benzyl(trifluoromethyl)selane) obtained
from 14 (0.558 mmol, 136 mg), benzyl(trifluoromethyl)selane (0.372
20
mg). Red solid. Mp: 132−134 °C. [α]D = +33 (c = 0.5, CHCl3).
HRMS (ESI-TOF): m/z [M]+ calcd for C18H13FeI 411.9406; found
411.9400.
1
mmol, 88 mg), and sulfuryl chloride (0.372 mmol, 30 μL). H NMR
1-(Iodoethynyl)-3-(naphthalene-2-yl)ferrocene (12b). Conditions
(500 MHz, CDCl3): δ 4.55 (br s, 1H), 4.46 (br s, 1H), 4.29 (s, 5H),
4.19 (t, J = 2.5 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 120.3 (q, J
= 337.4 Hz), 104.7, 95.3, 72.5, 70.3, 69.3, 67.0, 63.3, 61.3 (d, J = 3.2
Hz). 19F NMR (75 MHz, CDCl3): δ −36.9. HRMS (ESI-TOF): m/z
[M]+ calcd for C13H8ClF3FeSe 391.8776; found 391.8793.
a: 12b (8 mg, 44%) obtained from 7b (0.039 mmol, 16 mg). Red
1
solid. Mp: 66−68 °C. H NMR (500 MHz, CDCl3): δ 7.84 (s, 1H),
7.79 (t, J = 8.0 Hz, 3H), 7.60 (dd, J = 8.5, 1.5 Hz, 1H), 7.46 (m, 2H),
5.05 (br s, 1H), 4.79 (m, 1H), 4.65 (m, 1H), 4.13 (s, 5H). 13C NMR
(126 MHz, CDCl3): δ 135.6, 133.7, 132.4, 128.1, 127.9, 127.7, 126.5,
125.7, 125.1, 124.6, 91.9, 86.1, 72.9, 71.7, 70.2, 67.2, 66.8, 0.2. HRMS
(ESI-TOF): m/z [M]+ calcd for C22H15FeI 461.9562; found
461.9554.
((3-Chloroferrocenyl)ethynyl)(trifluoromethyl)selane (17b). The
general procedure was performed on 15 (0.131 mmol, 32 mg),
benzyl(trifluoromethyl)selane (0.087 mmol, 21 mg), and sulfuryl
chloride (0.087 mmol, 5.7 μL). After purification, the mixture (27
mg) was dissolved in DMSO (2 mL) and LiOH·H2O (0.66 mmol, 28
mg) was added. After it was stirred for 4 h, the mixture was poured on
ice and extracted with Et2O. After drying over Na2SO4, filtration, and
concentration, the crude product was purified by chromatography on
silica gel (pentane) to give 17b (15 mg, 44% based on benzyl-
(trifluoromethyl)selane) as a red solid. Mp: 36−38 °C. 1H NMR (500
MHz, CDCl3): δ 4.75 (br s, 1H), 4.51 (br s, 1H), 4.43 (br s, 1H),
4.31 (s, 5H). 13C NMR (126 MHz, CDCl3): δ 120.3 (q, J = 337.3
Hz), 106.4, 92.7, 72.5, 71.8, 70.7, 69.7, 61.5, 61.3 (d, J = 5.0 Hz). 19F
NMR (75 MHz, CDCl3): δ −36.9. HRMS (ESI-TOF): m/z [M]+
calcd for C13H8ClF3FeSe 391.8776; found 391.8771.
General Procedure for the Ritter Reaction. Benzhydryl
bromide 32 (0.04 mmol, 9.9 mg) was placed in a flask under
argon. A 2 mL portion of a stock solution (prepared by mixing 30 mL
of CH3CN and 14.4 μL of H2O) was added, followed by a solution of
iodoalkyne activator (0.04 mmol) in 1 mL of the same stock solution
(note: iodoalkyne 11b was not soluble in CH3CN and was added as a
solid). After it was stirred for 10 h at room temperature, the mixture
was filtered on Celite and evaporated. The residue was analyzed by 1H
NMR in CD3CN (see spectra in the Supporting Information).
(SFc)-1-(Iodoethynyl)-3-(naphthalen-2-yl)ferrocene ((SFc)-12b).
Conditions a: (SFc)-12b (55 mg, 49%) obtained from (SFc)-7b
(0.28 mmol, 100 mg). Conditions d: (SFc)-12b (14 mg, 62%)
obtained from (SFc)-7b (0.049 mmol, 20 mg). Red solid. Mp: 68−70
20
°C. [α]D = +60 (c = 0.3, CHCl3). HRMS (ESI-TOF): m/z [M]+
calcd for C22H15FeI 461.9562; found 461.9559.
1-(Iodoethynyl)-2-methylferrocene (13). Conditions a: 13 (47 mg,
50%) obtained from 8 (0.27 mmol, 80 mg). Red solid. Mp: 93−95
1
°C. H NMR (500 MHz, CDCl3): δ 4.35 (dd, J = 2.5, 1.5 Hz, 1H),
4.14 (m, 1H), 4.13 (s, 5H), 4.04 (t, J = 2.5 Hz, 1H), 2.09 (s, 3H). 13C
NMR (126 MHz, CDCl3): δ 91.8, 87.2, 70.8, 70.7, 69.6, 67.0, 66.5,
13.8, 0.3. HRMS (ESI-TOF): m/z [M]+ calcd for C13H11FeI
349.9249; found 349.9236.
(RFc)-1-(Iodoethynyl)-2-methylferrocene ((RFc)-13). Conditions a:
(RFc)-13 (46 mg, 39%) obtained from (RFc)-8 (0.338 mmol, 100 mg).
Conditions d: (RFc)-13 (12 mg, 73%) obtained from (RFc)-8 (0.047
20
mmol, 14 mg). Red solid. Mp: 153−155 °C. [α]D = −9 (c = 0.47,
CHCl3). HRMS (ESI-TOF): m/z [M]+ calcd for C13H11FeI
349.9249; found 349.9233.
General Procedure for the Alkyne Sulfanylation. The alkyne
(1 equiv) was dissolved in THF (2 mL/mmol), and the solution was
K
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General Procedure for Benzoxazole Synthesis. Thioaceta-
mide 34 (0.2 mmol, 15 mg), 2-aminophenol (0.4 mmol, 43.6 mg),
and the catalyst (0.02 mmol) were placed in a resealable tube under
argon. Degassed toluene (0.4 mL) was added, and the mixture was
stirred for 15 h at 90 °C. After it was cooled to room temperature, the
crude product was filtered on Celite, washed with diethyl ether, and
concentrated with a rotavap at 20 °C (the use of high vacuum must be
avoided). A 1 mL portion of a 0.2 M solution of DMF in
dichloromethane was added. Dichloromethane was removed with a
rotavap at 20 °C, and the residue was analyzed by H NMR (see
spectra in the Supporting Information).
X-ray Structure Determination. X-ray crystallographic data
were collected at low temperature on a CCD or CMOS diffractometer
using Mo Kα radiation.
Crystal Data for (SFc)-9a: C12H8BrFeI, Mr 414.84, monoclinic, a =
8.0567(7) Å, b = 9.2384(8) Å, c = 8.9782(7) Å, β = 115.956(3)°, V =
600.85(9) Å3, T = 100(2) K, space group P21, Z = 2, μ(Mo Kα) =
7.111 mm−1, 30382 reflections measured, 5746 independent
reflections (Rint = 0.0394). Flack parameter = 0.007(9). The final
R1 values were 0.0224 (I > 2σ(I)) and 0.0241 (all data). The final
wR(F2) values were 0.0533 (I > 2σ(I)) and 0.0540 (all data). The
goodness of fit on F2 was 1.041. CCDC no. 1995956.
Crystal Data for (RFc)-13: C13H11FeI. Mr 349.97, monoclinic, a =
8.1541(11) Å, b = 8.9666(12) Å, c = 9.0907(12) Å, β = 116.395(4) °,
V = 595.37(14) Å3, T = 100(2) K, space group P21, Z = 2, μ(Mo Kα)
= 3.822 mm−1, 61869 reflections measured, 5702 independent
reflections (Rint = 0.0333). Flack parameter = 0.007(12). The final
R1 values were 0.0118 (I > 2σ(I)) and 0.0121 (all data). The final
wR(F2) values were 0.0318 (I > 2σ(I)) and 0.0319 (all data). The
goodness of fit on F2 was 1.043. CCDC no. 1995953.
Crystal Data for 13: C13H11FeI. Mr 349.97, monoclinic, a =
13.14030(10) Å, b = 12.99390(10) Å, c = 14.08200(10) Å, β =
103.6150(10) °, V = 2336.85(3) Å3, T = 100(2) K, space group P21/c,
Z = 8, μ(Mo Kα) = 3.895 mm−1, 87060 reflections measured, 11589
independent reflections (Rint = 0.0341). The final R1 values were
0.0209 (I > 2σ(I)) and 0.0285 (all data). The final wR(F2) values
were 0.0471 (I > 2σ(I)) and 0.0493 (all data). The goodness of fit on
F2 was 1.046. CCDC no. 1995955.
1
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
Crystal Data for (SFc)-9c: C12H8FFeI. Mr 353.93, orthorhombic, a
= 16.4655(16) Å, b = 8.9985(8) Å, c = 7.3936(7) Å, V = 1095.47(18)
Å3, T = 100(2) K, space group P212121, Z = 4, μ(Mo Kα) = 4.168
mm−1, 32379 reflections measured, 5244 independent reflections (Rint
= 0.0331). Flack parameter = 0.00(2). The final R1 values were
0.0176 (I > 2σ(I)) and 0.0184 (all data). The final wR(F2) values
were 0.0441 (I > 2σ(I)) and 0.0444 (all data). The goodness of fit on
F2 was 1.090. CCDC no. 1995957.
Crystal Data for 9c: C12H8FFeI. Mr 353.93, orthorhombic, a =
16.43910(10) Å, b = 8.99930(10) Å, c = 7.41700(10) Å, V =
1097.27(2) Å3, T = 100(2) K, space group Pnma, Z = 4, μ(Mo Kα) =
4.161 mm−1, 79465 reflections measured, 2761 independent
reflections (Rint = 0.0482). The final R1 values were 0.0183 (I >
2σ(I)) and 0.0198 (all data). The final wR(F2) values were 0.0483 (I
> 2σ(I)) and 0.0490 (all data). The goodness of fit on F2 was 1.090.
CCDC no. 1995952.
https://pubs.acs.org/doi/10.1021/acs.organomet.0c00633.
1H and 13C NMR spectra of all new compounds, HPLC
and computational details, and XRD details for the
structures of (SFc)-9a, (SFc)-9c, 9c, (SFc)-11a, (SFc)-11b,
11b, (SFc)-12a, (RFc)-13, and 13 (PDF)
Accession Codes
CCDC 1995952−1995960 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Crystal Data for (SFc)-11a: C18H13FeI. Mr 412.03, orthorhombic, a
= 8.8955(9) Å, b = 10.9653(11) Å, c = 15.3106(17) Å, V = 1493.4(3)
Å3, T = 100(2) K, space group P212121, Z = 4, μ(Mo Kα) = 3.063
mm−1, 190633 reflections measured, 8528 independent reflections
(Rint = 0.0328). Flack parameter = −0.017(14). The final R1 values
were 0.0208 (I > 2σ(I)) and 0.0245 (all data). The final wR(F2)
values were 0.0462 (I > 2σ(I)) and 0.0473 (all data). The goodness of
fit on F2 was 1.072. CCDC no. 1995958.
AUTHOR INFORMATION
■
Corresponding Authors
Victor Mamane − Institut de Chimie de Strasbourg, UMR
CNRS 7177, Equipe LASYROC, 67008 Strasbourg Cedex,
France; orcid.org/0000-0001-8996-7880;
Email: vmamane@unistra.fr
Crystal Data for (SFc)-11b: C22H15FeI. Mr 462.09, orthorhombic, a
= 8.4360(6) Å, b = 10.9150(7) Å, c = 19.1274(13) Å, V = 1761.2(2)
Å3, T = 100(2) K, space group P212121, Z = 4, μ(Mo Kα) = 2.608
mm−1, 28923 reflections measured, 8376 independent reflections (Rint
= 0.0342). Flack parameter = −0.01(2). The final R1 values were
0.0381 (I > 2σ(I)) and 0.0609 (all data). The final wR(F2) values
were 0.0730 (I > 2σ(I)) and 0.0802 (all data). The goodness of fit on
F2 was 1.033. CCDC no. 1995959.
Crystal Data for 11b: C22H15FeI. Mr 462.09, monoclinic, a =
8.1177(2) Å, b = 11.1905(2) Å, c = 18.9284(5) Å, β = 90.164(2) °, V
= 1719.47(7) Å3, T = 100(2) K, space group P21/n, Z = 4, μ(Mo Kα)
= 2.671 mm−1, 31600 reflections measured, 5160 independent
reflections (Rint = 0.0445). The final R1 values were 0.0412 (I >
2σ(I)) and 0.0505 (all data). The final wR(F2) values were 0.0887 (I
> 2σ(I)) and 0.0925 (all data). The goodness of fit on F2 was 1.064.
CCDC no. 1995954.
Crystal Data for (SFc)-12a: C18H13FeI. Mr 412.03, monoclinic, a =
9.7598(10) Å, b = 7.8063(8) Å, c = 10.0468(11) Å, β = 105.676(4) °,
V = 736.97(13) Å3, T = 100(2) K, space group P21, Z = 2, μ(Mo Kα)
= 3.103 mm−1, 43287 reflections measured, 7044 independent
reflections (Rint = 0.0478). Flack parameter = −0.01(2). The final
R1 values were 0.0330 (I > 2σ(I)) and 0.0461 (all data). The final
wR(F2) values were 0.0588 (I > 2σ(I)) and 0.0620 (all data). The
goodness of fit on F2 was 1.067. CCDC no. 1995960.
Paola Peluso − Istituto di Chimica Biomolecolare ICB, CNR,
Sede secondaria di Sassari, 07100 Li Punti, Sassari, Italy;
Email: paola.peluso@cnr.it
Authors
́
Emmanuel Aubert − Universite de Lorraine, CNRS, CRM2, F-
54000 Nancy, France
Robin Weiss − Institut de Chimie de Strasbourg, UMR CNRS
7177, Equipe LASYROC, 67008 Strasbourg Cedex, France
́
Emmanuel Wenger − Universite de Lorraine, CNRS, CRM2, F-
54000 Nancy, France
Sergio Cossu − Dipartimento di Scienze Molecolari e
̀
Nanosistemi DSMN, Universita Ca’ Foscari Venezia, 30172
Mestre Venezia, Italy
Patrick Pale − Institut de Chimie de Strasbourg, UMR CNRS
7177, Equipe LASYROC, 67008 Strasbourg Cedex, France
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.organomet.0c00633
Notes
The authors declare no competing financial interest.
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Foldamers as Tetradentate Halogen Bonding Anion Receptors. Chem.
Commun. 2017, 53, 2483−2486.
ACKNOWLEDGMENTS
■
This work was supported by the CNRS and University of
Strasbourg. P.Peluso and S.C. are grateful to Universita Ca’
́
(17) Lim, J. Y. C.; Marques, I.; Felix, V.; Beer, P. D. Enantioselective
̀
Anion Recognition by Chiral Halogen-Bonding [2]Rotaxanes. J. Am.
Chem. Soc. 2017, 139, 12228−12239.
Foscari Venezia, Italy (Dipartimento di Scienze Molecolari e
Nanosistemi, DSMN ADIR funds). We thank the PMD2X X-
́
(18) Lim, J. Y. C.; Marques, I.; Felix, V.; Beer, P. D. A Chiral
́
Halogen-Bonding [3]Rotaxane for the Recognition and Sensing of
Biologically Relevant Dicarboxylate Anions. Angew. Chem., Int. Ed.
2018, 57, 584−588.
ray diffraction facility of the Institut Jean Barriol, Universite de
Lorraine, for X-ray diffraction measurements, data processing,
and analysis and for providing reports for publication (http://
crm2.univ-lorraine.fr/lab/fr/services/pmd2x). The EXPLOR
mesocentre is thanked for providing access to their computing
facility (project 2019CPMXX0984/wbg13). We thank J. N.
Abergel for his help in the preparation of the starting
dihaloferrocenes.
̈
(19) Kaasik, M.; Kaabel, S.; Kriis, K.; Jarving, I.; Aav, R.; Rissanen,
K.; Kanger, T. Synthesis and Characterisation of Chiral Triazole-
Based Halogen-Bond Donors: Halogen Bonds in the Solid State and
in Solution. Chem. - Eur. J. 2017, 23, 7337−7344.
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Kanger, T. Tunable Chiral Triazole-Based Halogen Bond Donors:
Assessment of Donor Strength in Solution with Nitrogen-Containing
Acceptors. RSC Adv. 2019, 9, 11718−11721.
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