Fluorobissulfonylmethyl Iodides: An Efficient Scaffold for Halogen Bonding Catalysts with an sp3-Hybridized Carbon-Iodine Moiety

Article abstract of DOI:10.1021/acscatal.8b01330

The halogen-bond donors FBSM-I and FBDT-I, which contain an sp³-hybridized carbon-iodine (C_sp3-I) moiety, were designed and synthesized. The highly electron-withdrawing nature of the fluorobissulfonyl-methane scaffold leads to the ge

Full text of DOI:10.1021/acscatal.8b01330

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Letter
Fluorobissulfonylmethyl Iodides: An Efficient Scaffold for Halogen
Bonding Catalysts with an sp3-Hybridized Carbon-Iodine Moiety
Kohei Matsuzaki, Hiroto Uno, Etsuko Tokunaga, and Norio Shibata
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b01330 • Publication Date (Web): 12 Jun 2018
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Fluorobissulfonylmethyl Iodides: An Efficient Scaffold for Halogen
Bonding Catalysts with an sp3-Hybridized Carbon-Iodine Moiety
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Kohei Matsuzaki,† Hiroto Uno,† Etsuko Tokunaga,† and Norio Shibata†,‡,*
†Department of Nanopharmaceutical Sciences, and Department of Life Science and Applied Chemistry, Nagoya Institute of
Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan
‡Institute of Advanced Fluorine-Containing Materials, Zhejiang Normal University, 688 Yingbin Avenue, 321004 Jinhua,
China
ABSTRACT: The halogen-bond donors FBSM-I and FBDT-I, which contain an sp3-hybridized carbon-iodine (Csp3–I) moi-
ety, were designed and synthesized. The highly electron-withdrawing nature of the fluorobissulfonyl-methane scaffold leads
to the generation of σ-holes on the surface of the iodine atoms in FBSM-I and FBDT-I. Mukaiyama aldol reactions and hy-
drogen-transfer reductions are efficiently catalyzed by FBSM-I and FBDT-I under neutral and mild reaction conditions. The
driving force for these transformations should be the halogen bonding induced by FBSM-I and FBDT-I, which was confirmed
by DFT calculations, single-crystal X-ray diffraction analyses, and NMR titrations.
KEYWORDS: halogen bonding, fluorobissulfonyl methane, fluorine, iodine, organocatalysis
Halogen bonds refer to non-covalent interactions between an
electrophilic region associated with a halogen atom and a Lewis
basic moiety.1 While halogen bonding interactions have tradi-
tionally been investigated predominantly in the context of crys-
tal engineering, current research avenues encompass many ar-
eas with applications in liquid crystals, supramolecular assem-
blies, medicinal chemistry, and organic synthesis.1 Especially
the use of halogen bonding in organocatalysis has recently
gained substantial attention.2 Although much research efforts
have been devoted to this topic, most halogen-bond catalysts
(donors) are limited to those containing an sp2-hybridized car-
bon-iodine (Csp2–I) moiety, as in e.g. aryl iodides (Figure 1a)
and imidazolium iodides (Figure 1b).3 One example of a halo-
Figure 1. a-c) Structures of reported halogen-bond donors. d)
gen-bond catalyst that contains an sp-hybridized carbon-iodine
(Csp–I) moiety has also been reported (Figure 1c).4 However,
halogen-bond donors that contain an sp3-hybridized carbon-io-
dine (Csp3–I) moiety are extremely rare,5 despite the potential
structural variation including chiral structures that would arise
from tetra-substituted asymmetric carbon centers.
FBSM and FBDT as synthetic equivalents of monofluoromethide
species. e) Halogen-bond donors FBSM-I (1a) and FBDT-I (1b).
1-Fluoro-1,1-bis(phenylsulfonyl)methane (FBSM)6 and 2-
fluoro-1,3-benzodithiole-1,1,3,3-tetraoxide (FBDT)7 represent
synthetic equivalents of monofluoromethide species, and these
compounds have been employed in a wide range of nucleophilic
monofluoromethylation reactions that include asymmetric cat-
alytic reactions (Figure 1d).7,8 We speculated that iodinated an-
alogues of FBSM and FBDT, i.e., 1-fluoro-1-io-
dobis(phenylsulfonyl)methane (FBSM-I, 1a)9 and 2-fluoro-2-
iodo-1,3-benzodithiole-1,1,3,3-tetraoxide (FBDT-I, 1b) could
potentially be useful halogen-bond donors due to the poor elec-
tron density of the central sp3-hybridized carbon (Figure 1e).
We herein disclose fluorobissulfonylmethyl iodides such as
FBSM-I and FBDT-I as an efficient scaffold for halogen-bond-
ing catalysts with a Csp3–I moiety.
Figure 2. Optimized structures and mappings of the electrostatic
potential for a) 1a and b) 1b. All calculations were performed at
DFT/B3LYP/6-311+G(d,p) level of theory using Spartan14.
Treating FBSM and FBDT with iodine and cesium carbonate
in acetonitrile at room temperature resulted in the formation of
FBSM-I (1a) and FBDT-I (1b) as stable off-white solids in 95%
and 92% yield, respectively (Scheme S1). To evaluate the po-
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tential of 1a and 1b as halogen-bond donors, electronic poten-
Page 2 of 6
less basic 3,5-difluoropyridine (5f) did not affect the reaction.
These results strongly support the notion that 1b acts as a halo-
gen-bond donor (Scheme 2).
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tial maps were generated using DFT calculations at the
DFT/B3LYP/6-311+G(d,p) level of theory, which clearly re-
vealed the existence of σ-holes, i.e, electron-deficient areas, on
the surface of the iodine atoms (Figure 2).
Subsequently, we examined the substrate scope of the 1b-cata-
lyzed Mukaiyama aldol reaction with respect to various aromatic
aldehydes (2) (Table 1). Halogen (entries 1-3), alkyl (entries 4 and
5), phenyl (entry 6), and methoxy substituents (entries 7 and 8) on
the arylaldehydes 2 were tolerated under the applied conditions,
and the products (4) were obtained in high yield. Electron-with-
drawing cyano and trifluoromethyl groups on the aromatic ring of
2 decreased the yield (entries 9–11). The transformation of steri-
cally demanding naphthyl and heteroaryl aldehydes also proceeded
smoothly (entries 12-14), while n-octyl aldehyde 2n did not react
under these reaction conditions (entry 15).
Encouraged by the results of the DFT calculations, we next
attempted to use 1a and 1b as halogen-bond donors in a cata-
lytic Mukaiyama aldol reaction10 between aldehyde 2a and silyl
ketene acetal 3a to furnish 4a. As expected, aldol product 4a
was obtained in high yield when 10 mol% of 1a or 1b were
employed as catalysts. The cyclic fluorobissulfonylmethyl Io-
dide 1b afforded a slightly higher yield than acyclic fluorobis-
sulfonylmethyl Iodide 1a. When analogues of 1a that contain F
(1c), Cl (1d), Br (1e) or H (1f, FBSM) atoms instead of iodine
were employed as catalysts, the reaction did not proceed and
only 2a was recovered after 6 h. The presence of a fluorine atom
in 1a and 1b should be vital to obtain high yields, given that the
yield decreased dramatically using 1g. The replacement of the
sulfonyl group in 1a with fluorine (1h) resulted in a low product
yield, similar to when perfluoroalkyl iodides such as CF3I (1i)
and nC8F17I (1j) were used (Scheme 1).
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Table 1. Substrate Scope for the Mukaiyama Aldol Reaction
between 2 and 3 Catalyzed by 1ba
En-
try
1
2
3
4
5
6
7
Yield
(%)
87
94
80
89
87
97
98
99
59
73
49
98
87
98
-
Ar
R1
R2
2
3
4
4-F
3-Br
4-Br
4-Me
4-tBu
4-Ph
2-OMe
4-OMe
4-OAc
4-CN
4-CF3
-
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2l
2m
2n
3a 4a
3a 4b
3a 4c
3a 4d
3a 4e
3a 4f
3a 4g
3a 4h
8
9
3a
3a 4j
3a 4k
4i
10
11
12
13
14
15
2-naphthyl
2-naphthyl
2-thienyl
n-octyl
3a
4l
-
-
-
3b 4m
3a 4n
3a 4o
Scheme 1. Mukaiyama Aldol Reaction between 2a and 3a in
the Presence of Catalytic Amounts of Halogen-bond Donors
1 or Related Compoundsa
Me
Me
aThe reaction between aldehyde 2 (0.20 mmol) and silyl ketene ac-
etal 3 (0.30 mmol) was carried out in the presence of 1b (0.020
mmol) in CH2Cl2 (0.2 mL) at room temperature for 6 h. The yields
refer to isolated yields.
aThe reaction between 2a (0.20 mmol) and 3a (0.30 mmol) was
carried out in the presence of 1 (0.020 mmol) in CH2Cl2 (0.2 mL)
at room temperature. Yields were calculated based on the 19
F
NMR data of the crude reaction mixture using PhCF3 as an inter-
nal standard. bAn excess of CF3I was used.
Table 2. Reduction of Quinolones 6 with a Hantzsch Ester Cat-
alyzed by 1ba
Scheme 2. Effect of Additives (5) on the Mukaiyama Aldol
Reaction between 2a and 3a Catalyzed by 1b.
aReduction of quinolones 6 (0.20 mmol) by a Hantzsch ester (0.44
mmol) in the presence of 1b (0.010 mmol) in CH2Cl2 (2.8 mL) at
room temperature. Yields refer to isolated yields.
The addition of catalytic amounts (20 mol%) of halogen-
bond acceptors such as 3,5-lutidine (5a), 2,6-lutidine (5b), tet-
rabutylammonium chloride ([nBu4N]Cl, 5c) and tetrabu-
tylammonium bromide ([nBu4N]Br, 5d) significantly sup-
pressed the 1b-catalyzed Mukaiyama aldol reaction. On the
other hand, sterically demanding 2,6-di-t-butylpyridine (5e) and
To investigate the further versatility of 1b as a halogen-bond
donor, we carried out the catalytic hydrogen-transfer reduction
of quinolone derivatives 6 with a Hantzsch ester3b, 5 in CH2Cl2
using 5 mol% of 1b (Table 2). The targeted C2-alkylated or -
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arylated tetrahydroquinolines (7) were obtained in good to ex-
whereby difluorinated 1c was used as a control (Figure 5). After
the titration, the 19F NMR signals were significantly up-field
shifted (> −9 ppm) in the case of 1a and 1b. On the other hand,
the titration of 1c revealed only a small shift (< 0.4 ppm) of its
19F NMR peak under identical conditions. This result indicates
that the iodine atoms in 1a and 1b interact with the chloride
anion (Cl-) in [nBu4N]Cl, while the fluorine atoms in 1a-c do
not engage in any significant interactions with the chloride. The
shapes of the peaks of 1a and 1b changed from sharp to broad
and sharp again with increasing amount of [nBu4N]Cl during
the titration, which suggests an equilibrium between mono-
meric 1a,b and halogen-bonding complexes 1a,b/Cl- in solution.
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cellent yield independent of the substitution at the aromatic ring
with electron-donating or -withdrawing groups.
In order to ascertain the effect of halogen bonding on these
reactions, single-crystal X-ray diffraction analyses of 1a and 1b
were examined. Interestingly, the crystal structures of 1a and
1b clearly show intermolecular halogen-bonding interactions
between the iodine atoms and the oxygen atoms of one sulfonyl
group (Figure 3). The I-O bond distances are unequivocally
shorter than the corresponding sum of van der Waals radii, and
the C1–I1–O1 angles are close to 180°, which represent ideal
conditions for halogen-bonding interactions.11
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Figure 3. X-ray crystallographic structures of a) 1a (CCDC
1834149) and b) 1b (CCDC 1834152), which show halogen bond-
ing between I1–O1 (1a: 2.93 Å; 1b: 2.97 Å); thermal ellipsoids set
to 50% probability and hydrogen atoms omitted for clarity.
Figure 5. 19F NMR titration of 1a-c with [nBu4N]Cl in CDCl3.
Considering that the 1b-catalyzed Mukaiyama aldol reaction
was inhibited by the addition of by halogen-bond acceptors such
as 3,5-lutidine (5a) (Scheme 2), we then attempted to examine
complexation between 1a or 1b and 5a. Recrystallization of 1:1
mixtures of 1a or 1b and 5a from CH2Cl2/n-hexane resulted in
the formation of 1/1 complexes of 1a/5a or 1b/5a. Single-crys-
tal X-ray diffraction analyses these complexes clearly revealed
halogen-bonding interactions (Figure 4), wherein 5a indeed
serves as a halogen-bond acceptor. Both I1-N1 bonds (1a/5a:
2.64 Å; 1b/5a: 2.62 Å) are shorter than the corresponding I1-O1
bonds (1a: 2.93 Å; 1b: 2.97 Å) shown in Figure 3, which sug-
gests that the aromatic nitrogen moiety in 5a is a stronger halo-
gen-bond acceptor than the sulfonyl group in 1a/b. The C1-I1
bonds in 1/5a are elongated compared to those in 1 (1a: 2.13 Å;
1b: 2.11 Å; 1a/5a: 2.18 Å; 1b/5a: 2.15 Å), which strongly sup-
ports halogen bonding between I1 and N1.
Peak shifts in the 13C NMR spectra of 1b were also observed,
whereby the carbon atom at the α-position relative to the iodine
atom showed the largest shift (+1.58 ppm) after the addition of
1.0 equiv of [nBu4N]Cl (Figure 6). This result is consistent with
previous reports on halogen-bond donors.12 Slight peak shifts of
the other peaks might be due to the effects of the sulfonyl group
in 1b to act as a Lewis base or halogen-bond acceptor.
Figure 6. 13C NMR titration of 1b with [nBu4N]Cl in CDCl3.
Figure 4. X-ray crystallographic structures for the 1/1 halogen-
bonding complexes of a) 1a/5a (CCDC 1834147) and b) 1b/5a
(CCDC 1834148); I1-N1 bonds (1a/5a: 2.64 Å; 1b/5a: 2.62 Å);
thermal ellipsoids at 50% probability and hydrogen atoms omitted
for clarity.
Based on the results obtained from solid-state and solution ex-
periments, a plausible reaction pathway is shown in Scheme 3. In-
itially, 1b should act as a Lewis acid to activate the carbonyl group
in aldehydes 2 or the nitrogen atom in quinolines 6 to form a halo-
gen-bonding complex (I/II). Then, the nucleophile (3) or hydride
could attack the substrates (2/6) in I or II to form the desired prod-
uct (4/7) (Scheme 3a, b). Although we failed to obtain evidence for
the activation of aldehydes (2) by halogen bonding induced by 1b,
the formation of 1/1 halogen bonding complex II of 1b with 6h
(1b/6h) was confirmed by single-crystal X-ray diffraction analysis,
which revealed strong halogen bonding between the iodine atom of
1b and the nitrogen atom of quinoline 6h (Scheme 3c).
Encouraged by this clear evidence for the presence of halo-
gen bonding induced by 1a,b in the solid state, we subsequently
attempted to observe halogen bonding in solution. Based on the
fact that [nBu4N]Cl (5c) inhibited the aldol reaction catalyzed
by 1b (Scheme 2), NMR titration experiments on 1a, 1b, and
1c in CDCl3 in the presence of [nBu4N]Cl were carried out,
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The manuscript was written through contributions of all authors. /
All authors have given approval to the final version of the manu-
script.
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ACKNOWLEDGMENT
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This research was partially supported by the Society of Iodine Sci-
ence (SIS) and the Asahi Glass Foundation.
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Scheme 3. (a) Plausible Reaction Intermediates I or II for
the Mukaiyama Aldol Reactions and (b) Hydrogen Transfer
Reactions, Using a Catalytic Amount of 1b. (c) X-ray Crys-
tallographic Structure of 1/1 Halogen Bonding Complex
1b/6h (CCDC 1834151); Thermal Ellipsoids at 50% Proba-
bility and Hydrogen Atoms Omitted for Clarity.
In conclusion, we have disclosed the new halogen-bond do-
nors FBSM-I and FBDT-I, which contain sp3-hybridized car-
bon-iodine bonds (Csp3–I). Both FBSM-I and FBDT-I effi-
ciently catalyze the Mukaiyama aldol reaction of aldehydes
with silyl enol ethers and the hydrogen-transfer reduction of
quinolines with a Hantzsch ester to furnish the corresponding
products in high yield. The highly electron-withdrawing nature
of the fluorobissulfonyl-methane scaffold results in the for-
mation of σ-holes on the surface of the iodine atoms in FBSM-
I and FBDT-I, and these were examined by DFT calculations.
Halogen-bonding interactions induced by FBSM-I and FBDT-I
were confirmed in the solid state using single-crystal X-ray dif-
fraction analyses, and in solution using 19F and 13C NMR titra-
tion experiments.13 Considering that the structural variation of
previously reported halogen-bond donors are essentially limited
to iodo-compounds with a sp2-hybridized carbon-iodine bond
(Csp2–I), our fluorobissulfonylmethyl iodide scaffold for halo-
gen-bond donors should present an attractive alternative for the
design of new halogen-bond catalysts that contain a tetra-sub-
stituted chiral carbon center. Further applications of this con-
cept for the design of novel chiral halogen-bond donors for en-
antioselective reactions are currently under investigation. Be-
sides, 1a is used for radical addition of terminal alkenes under
reaction conditions,9 it might be possible to show a unique us-
age of 1 as both a catalyst and a reactant in a tandem process
using a stoichiometric amount of 1, i.e., 1-catalyzed aldol reac-
tions of substrates with a terminal alkene followed by the radi-
cal addition of 1 to the terminal alkene moiety of the substrates.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: .
Experimental details, analytical data (HRMS), and copies of
1H, 13C and 19F NMR spectra.
AUTHOR INFORMATION
Corresponding Author
*E-mail: nozshiba@nitech.ac.jp
Author Contributions
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FBSM-I as a radical monofluoromethylating reagent for alkenes, but
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(13) We observed that < 30% of 1b (FBDT-I) was lost after the com-
pletion of Mukaiyama Aldol reaction and detected FBDT and α-io-
dinated ester by 19F NMR and GC. The results indicate that 1b acts not
only as a catalyst but also as an electrophilic iodinating reagent for silyl
ketene acetal 3. We also confirmed the by-product, α-iodinated ester
(10mol%), cannot catalyze the Mukaiyama Aldol reaction.
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