A Dendralenic C-H Acid

Article abstract of DOI:10.1055/s-0037-1612246

The design and synthesis of a strong, dendralenic C-H acid is described. Crystal structure analyses confirm the proposed structure. Despite the moderate stability of our motif, an application to Bronsted acid catalysis has been explored.

Full text of DOI:10.1055/s-0037-1612246

SYNLETT
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Georg Thieme Verlag Stuttgart · New York
2019, 30, A–D
letter
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Synlett
D. Höfler et al.
Letter
A Dendralenic C–H Acid
Denis Höfler
Richard Goddard
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Nils Nöthling
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i) H2CTf2 (6.0 equiv)
Ac2O (16 equiv)
MeC(OMe)3 (4.0 equiv)
CH2Cl2, –78 °C to RT
ii) TMP (6.0 equiv)
Benjamin List*
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Tf
O
O
H
H
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz
, 45470, Mülheim an der Ruhr, Germany
Tf
Tf
Tf
1
H
O
list@kofo.mpg.de
iii) H2SO4 (work-up)
Tf
Tf
Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue
HTBT
Received: 16.01.2019
Accepted after revision: 01.02.2019
Published online: 14.02.2019
EWG
EWG
H
N
EWG
DOI: 10.1055/s-0037-1612246; Art ID: st-2018-r0028-l
EWG OH
EWG
EWG
License terms:
EWG
EWG
EWG
Abstract The design and synthesis of a strong, dendralenic C–H acid is
described. Crystal structure analyses confirm the proposed structure.
Despite the moderate stability of our motif, an application to Brønsted
acid catalysis has been explored.
trivinylmethane-derived
C–H acid
EWG
EWG
EWG
EWG
EWG
EWG
EWG
EWG
Key words dendralenic C–H acids, cross-conjugated acids, triflyl
groups, strong acids, non-coordinating anions, Brønsted acids
EWG
EWG
Acidity trend:
Tf
Tf
EWG
Tf
H
>
>
>
In contrast to N–H- and O–H-based Brønsted acids, C–H
acids enable the incorporation of a greater number of elec-
tron-withdrawing groups (EWGs) by virtue of carbon’s
N
TfOH
Tf
Tf
EWG
dendralene-derived
C–H acid
EWG
Tf
Tf
Tf
Tf
TTP
1
2
3
higher valency. Experimental and estimated pK values of
Scheme 1 Lead structures for the design of trivinylmethane-derived
and highly conjugated dendralene-derived C–H acids
a
the simple trifluoromethanesulfonyl (triflyl, Tf) containing
O–H, N–H, and C–H acids suggest that their acidity directly
correlates with the number of electron-withdrawing
groups (Scheme 1). Accordingly, tris(triflyl)methane (1)
should be the strongest acid in the series, and indeed it
shows a high reactivity in Brønsted and Lewis acid cataly-
These considerations led to the design of tris(bis(tri-
4
flyl)vinyl)methane (HTBT). Irrespective of the location of
the acidic proton on HTBT, only one anion should be ob-
tained (TBT, after deprotonation) with a highly delocalized
1
sis. Still more electron-withdrawing groups can be intro-
negative charge and a possible C -symmetry (Scheme 2).
3
duced by choosing allylic C–H acid frameworks. This notion
led to the design of 1,1,3,3-tetratriflylpropene (TTP), which
showed a remarkable acidity and catalytic activity.1 In the
search for still stronger acids, we sought to further increase
the number of EWGs, which led to our interest in triene-
Furthermore, the peripheral location of the triflyl groups
may enable a planar structure of the anion. As a result of
this enhanced planarization and the greater number of
electron-withdrawing groups, the acidity of HTBT was
expected to be significantly higher in comparison to the re-
lated allylic C–H acid TTP. Synthetic access to HTBT was
envisaged from triformylmethane and bis(triflyl)methane,
as Yanai and coworkers have already demonstrated that
bis(triflyl)methane reacts with a variety of aldehydes in a
self-promoted Knoevenagel-type condensation reaction.
d
2
derived C–H acids. Purely hydrocarbon-based C–H acid
scaffolds on the basis of fluorene and dibenzofluorene have
5
already been realized by Kuhn and the latter showed a
3
remarkable pK value of 5.9 (in water). Depending on the
a
location of the acidic proton, either trivinylmethane or
dendralene-derived C–H acids are possible.
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

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D. Höfler et al.
Letter
O
CF3
CF3
O
O
O
S
Tf
H
Tf
O
2 2
i) H CTf (6.0 equiv)
Ac2O (16 equiv)
N
H2
F3C
S
S
Tf
Tf
Tf
Tf
Tf
Tf
MeC(OMe)3 (4.0 equiv)
CH2Cl2, –78 °C to RT
ii) TMP (6.0 equiv)
–
H
Tf
H
O
O
O
O
H
H
F3C
O
Tf
Tf
S
Tf
Tf
Tf
H
O
O
O
Tf
Tf
S
S
O
Tf
TBT–
O
CF3 CF3
tris(bis(triflyl)vinyl)methane (HTBT)
Tf
HTMP⋅TBT
60 mg, 5.8% yield)
Negative charge delocalized
over six triflyl groups
increased distance between
sulfonyl groups
(
O
H
Tf
Tf
3
+
H
O
potentially planar
a more acidic conjugate acid?
Shorter distance of HTMP cation to
solvent water (N···O distance 2.780 Å)
than to TBT anion (N···O distance
O
H
2
.971 Å)
Scheme 2 Design and retrosynthesis of the tris(bistriflylvinyl)methane
Anion is not planar
Short contacts between sulfonyl
oxygens and vinylic hydrogens
(
HTBT) and its anion TBT. The synthesis of triformylmethane has been
6
previously described
While our first attempts at the synthesis of HTBT led to
2
the formation of a purely organic tricarbanion salt, we
7
found that by condensing triformylmethane with bis(tri-
flyl)methane followed by treatment with 2,2,6,6-tetra-
Scheme 3 Synthesis of HTMP·TBT. HTMP = 2,2,6,6-tetramethylpiperi-
dinium
methylpiperidine (TMP), the desired HTMP salt of TBT
8
(
HTMP·TBT) was obtained in poor yield (Scheme 3). Inter-
estingly, crystal structure analysis of this ion pair revealed
…
that the HTMP cation formed a slightly shorter N–H O
…
hydrogen bond to solvent water (N O, 2.780(4) Å), which
N
H
was introduced during the crystallization, than to the nega-
2
…
Tf
Tf
tively charged TBT anion (N O, 2.971(3) Å). Despite the in-
creased distance between the triflyl groups, the TBT anion
adopts a slightly non-planar chiral conformation. We
assume that this may be due to the short contacts between
the vinylic hydrogen atoms and the sulfonyl oxygen atoms.
Tf
Tf
Tf
conc. H SO
Tf
Tf
Tf
2
4
Tf
Tf
(work-up)
Tf
Tf
HTMP⋅TBT
HTBT
While we observe a local C -symmetry around the central
3
carbon atom with similar bond lengths and torsion angles
(
see the Supporting Information), no global C -symmetry
3
was observed in the TBT anion.
A work-up with concentrated H SO finally delivered
2
4
9
HTBT as the free acid (Scheme 4). NMR spectroscopic in-
vestigations and single-crystal structure analysis of HTBT
confirmed the location of the acidic proton not on the cen-
tral carbon atom, as in the crystal of bullvalene, but be-
tween two triflyl groups. As a result, HTBT can be consid-
ered a cross-conjugated, dendralenic C–H acid. Due to the
low stability of HTBT at room temperature and at –25 °C no
satisfactory yield could be determined. We would expect
the stability of such acids to be increased in a non-coordi-
nating and non-polar solvent, as a degradation pathway via
a nucleophilic attack can be prevented. However, we are yet
to identify such a solvent system that is also capable of sol-
ubilizing HTBT.
Acidic proton is not on central
carbon (in accordance with
1H NMR spectra)
Dendralene-derived C–H acid
Scheme 4 Synthesis of HTBT. Due to the low stability of HTBT no
yields could be determined
Despite the inherent low stability of HTBT, we attempt-
ed to directly employ freshly prepared HTBT for a bench-
mark Brønsted acid catalyzed Friedel–Crafts acylation reac-
tion of weakly reactive chlorobenzene with p-fluorobenzo-
yl chloride (Scheme 5).1
d,10
While TTP provided higher
yields, HTBT was also able to catalyze this transformation.
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

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Synlett
D. Höfler et al.
Letter
Cl
structural comparison with related BArF etherates indicates
that the TBT anion may be classified as a C–H-acid-based
weakly coordinating anion.
O
O
(
3.0 equiv)
catalyst (5 mol%)
Cl
neat, reflux, 11 h
F
F
Cl
Acknowledgment
HTBT: 27% yield (o:p = 1:14)
catalyst decomposition observed)
TTP: 59% yield (o:p = 1:10)
Generous support by the Max-Planck-Society, the Deutsche Forschungs-
gemeinschaft (Leibniz Award to B.L. and Cluster of Excellence RESOLV,
EXC 1069), and the European Research Council (Advanced Grant ‘C–H
Acids for Organic Synthesis, CHAOS’) is gratefully acknowledged. We
also thank Jennifer Arlt for her technical support and the members of
our analytical departments for their excellent service. We acknowl-
edge DESY (Hamburg, Germany), a member of the Helmholtz Associa-
tion HGF, for the provision of experimental facilities. Parts of this
research were carried out at PETRA III and we would like to thank
Anja Burkhardt, Eva Crosas, and Sebastian Günther for assistance in
using the P11 beamline.
(
Scheme 5 Application of HTBT to the Friedel–Crafts acylation reaction
of chlorobenzene with p-fluorobenzoyl chloride and a comparison with
TTP
The acidity of HTBT is sufficient to protonate ethers
thus allowing its transformation into an etherate salt when
11
an excess of Et O was added (Scheme 6). Single-crystal
2
structure analysis revealed that the TBT anion neither
adopts an idealized C -symmetry nor a planar conforma-
3
tion, which is in accordance with our previous findings.
Interestingly, the oxonium proton prefers to coordinate to
the oxygen atom of a second ether molecule rather than to
one of the negatively charged triflyl oxygen atoms on the
TBT carbanion. We were intrigued to find that the distances
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1612246.
S
u
p
p
orit
n
g Inform ati
o
n
S
u
p
p
orit
n
g Inform ati
o
n
between the oxygen atoms of both Et O molecules are
2
References and Notes
almost identical to those found in BArF etherates with the
−
+ 12
molecular formula [B(C F ) ] [H(OEt ) ] . Consequently, a
(1) (a) Kütt, A.; Rodima, T.; Saame, J.; Raamat, E.; Mäemets, V.;
Kaljurand, I.; Koppel, I. A.; Garlyauskayte, R. Yu.; Yagupolskii, Y.
L.; Yagupolskii, L. M.; Bernhardt, E.; Willner, H.; Leito, I. J. Org.
Chem. 2011, 76, 391. (b) Koppel, I. A.; Taft, R. W.; Anvia, F.; Zhu,
S.-Z.; Hu, L.-Q.; Sung, K.-S.; DesMarteau, D. D.; Yagupolskii, L.
M.; Yagupolskii, Y. L. J. Am. Chem. Soc. 1994, 116, 3047.
6
5
4
2 2
similar anion coordination can be assumed, thus classifying
the TBT anion as a weakly coordinating anion.
Tf
Tf
Tf
Tf
Tf
Et2O (excess)
Tf
Tf
Tf
(c) Turowsky, L.; Seppelt, K. Inorg. Chem. 1988, 27, 2135.
[H(Et2O)2]
(d) Höfler, D.; van Gemmeren, M.; Wedemann, P.; Kaupmees,
Tf
Tf
K.; Leito, I.; Leutzsch, M.; Lingnau, J. B.; List, B. Angew. Chem. Int.
Ed. 2017, 56, 1411. (e) Ishihara, K.; Hiraiwa, Y.; Yamamoto, H.
Synlett 2000, 80. (f) For a description of pentacarboxycyclopen-
tadiene-derived acids, see: Gheewala, C. D.; Radtke, M. A.; Hui,
J.; Hon, A. B.; Lambert, T. H. Org. Lett. 2017, 19, 4227; and refer-
ences cited therein.
Tf
Tf
HTBT
Anion is not planar
Avg. distance between oxygen
atoms in etherate cation: 2.444 Å
(2) Höfler, D.; Goddard, R.; Lingnau, J. B.; Nöthling, N.; List, B.
Angew. Chem. Int. Ed. 2018, 57, 8326.
(3) Kuhn, R.; Rewicki, D. Angew. Chem. 1967, 79, 648.
–
+
For [B(C6F5)4] [H(OEt2)2] = BArF
etherates: 2.445 Å
(
4) (a) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165.
b) Hendrickson, J. B.; Giga, A.; Wareing, J. J. Am. Chem. Soc.
974, 96, 2275.
5) (a) Yanai, H.; Egawa, S.; Taguchi, T. Tetrahedron Lett. 2013, 54,
160. (b) Yanai, H.; Egawa, S.; Yamada, K.; Ono, J.; Aoki, M.;
Matsumoto, T.; Taguchi, T. Asian J. Org. Chem. 2014, 3, 556.
A C–H acid-based weakly
coordinating anion
(
1
(
2
Scheme 6 Conversion of HTBT into the diethyl ether–diethyloxonium
salt TBT·H(OEt ) and structural comparison with related BArF ether-
2
2
(6) (a) Arnold, Z.; Budesinsky, M. J. Org. Chem. 1988, 53, 5352.
(b) Krasnaya, Z. A.; Smirnova, Y. V.; Krystal, G. V.; Bogdanov, V.
S. Mendeleev Commun. 1996, 6, 17. (c) Buděšínský, M.; Fiedler,
P.; Arnold, Z. Synthesis 1989, 858.
ates12
In summary, we have designed and developed a synthe-
sis of the cross-conjugated dendralenic C–H acid HTBT. Sev-
eral crystal structures confirmed our design and revealed
that the TBT anion adopts a non-planar and chiral confor-
mation. Despite its low stability, HTBT was found to cata-
lyze a Friedel–Crafts acylation reaction of chlorobenzene. A
(
7) Triformylmethane was prepared in two steps from commer-
cially available bromoacetic acid following our recently
reported procedure, see Ref. 2.
(8) HTMP·TBT
A Schlenk flask was charged with bis(triflyl)methane (1.7 g, 6.0
mmol, 6.0 equiv) and dry CH Cl (1 mL) was added under argon.
2
2
The colorless, clear solution so obtained was cooled to –78 °C in
an acetone/dry ice bath. Triformylmethane (0.10 g, 1.0 mmol)
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

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Synlett
D. Höfler et al.
Letter
was added and a slurry was obtained. Trimethyl orthoacetate
0.47 g, 3.9 mmol, 0.50 mL, 3.9 equiv) and acetic anhydride (1.6
(9) Synthesis of HTBT as the Free Acid
(
HTMP·TBT (17 mg, 0.017 mmol) was dissolved in CH Cl2 (10
2
g, 16 mmol, 1.5 mL, 16 equiv) were added and the reaction
mixture was allowed to reach RT overnight. A dark red solution
was obtained. All volatiles were removed under reduced pres-
sure and the solid mixture so obtained was dissolved in CH Cl
mL) and conc. H SO (10 mL) was added. The mixture was
stirred at RT for 30 min and the sulfuric acid phase was
2
4
removed using a Pasteur pipet. BaCl (dry) was added and after
2
stirring for 30 min, the solution was filtered and all volatiles
were removed under reduced pressure. A yellowish solid was
2
2
(5 mL). 2,2,6,6-Tetramethylpiperidine (0.85 g, 6.0 mmol, 1.0 mL,
1
19
6.0 equiv) was added and the reaction mixture was subse-
obtained. NMR spectra ( H and F) in CDCl3 were acquired.
1
19
quently concentrated under reduced pressure. Almost complete
After 3 d, H and F NMR spectra were acquired once again, but
removal of all volatiles was achieved by dissolving in CHCl and
evaporation to dryness. The solid mixture was transferred to a
after this time period, all product signals had vanished due to
3
1
deprotonation and decomposition. H NMR (501 MHz, CDCl ):
3
separation funnel with CHCl (20 mL) and washed with sat. aq
 = 8.80 (t, J = 1.7 Hz, 1 H), 8.59 (t, J = 1.7 Hz, 1 H), 6.52 (d,
3
13
NaHCO (20 mL). Both phases were separated and the aq phase
J = 10.9 Hz, 1 H), 5.36 (d, J = 10.9 Hz, 1 H); C NMR (126 MHz,
CD Cl ):  = 162.66, 158.32, 136.73, 123.98, 119.52 (q, J = 331
3
was washed with CHCl (20 mL), acidified with aq HCl (conc.) to
3
2
2
a pH of 1, and extracted with CH Cl (20 mL). The pooled CH Cl
Hz), 76.06. (Due to the fast decomposition of the desired
2
2
2
2
13
19
phases were concentrated under reduced pressure to give the
TMP salt of the title compound as an orange solid (0.35 g). As
this compound still contained significant amounts of bis(tri-
product and the observed C to F coupling, not all signals in
13
19
the C NMR spectrum were obtained.) F NMR (471 MHz,
CDCl ):  = –71.48, –72.25, –72.52, –72.87, –73.00. The
3
flyl)methane, the solid mixture was dissolved in CHCl , washed
HTMP·TBT salt (0.017 g, 0.017 mmol) was dissolved in CH Cl2
3
2
with aq HCl (conc.), dried over MgSO , filtered, and concen-
(10 mL) and conc. H SO (10 mL) was added. The mixture was
4
2
4
trated under reduced pressure. The red solid so obtained was
dissolved in CHCl3 and all volatiles were removed under
reduced pressure. This procedure was repeated once more with
CHCl3 and then with 1,2-dichloroethane. A red solid was
stirred at RT for 30 min and the sulfuric acid phase was
removed. Treatment with BaCl2 was omitted. After three
months, single crystals of the title compound were obtained
which were suitable for structure analysis.
obtained, which was triturated with CHCl to give the TMP salt
(10) Höfler, D. Ph.D. thesis. Universität zu Köln: Germany 2018.
(11) Conversion of HTBT into the Etherate Salt
3
of the title compound as a yellow solid (60 mg, 0.058 mmol,
1
5
.8% yield). H NMR (500 MHz, CDCl ):  = 8.31 (s, 3 H), 5.61 (s, 2
HTMP·TBT (43 mg, 0.042 mmol) was dissolved in CH Cl2 (10
3
2
14
H), 1.86–1.81 (m, 2 H), 1.75–1.72 (m, 4 H), 1.49 (s, 12 H). (
couplings can be observed in the H NMR spectrum. However,
N
mL) and conc. H SO (10 mL) was added. The mixture was
2
4
1
stirred at RT for 30 min and the sulfuric acid phase was
removed. All volatiles were removed under reduced pressure
the signals of NH group was not sharp enough for an accurate
2
1
13
determination of J1H14N.) C NMR (126 MHz, CDCl ):  = 165.51,
and a colorless solid was obtained. Et O was added, which
3
2
1
1
1
19.82 (q, JCF = 328 Hz), 114.79, 108.53, 59.94, 35.23, 27.87,
5.95; F NMR (471 MHz, CDCl ):  = –73.96; HRMS (ESIneg):
afforded a clear, yellow solution. All volatiles were removed
under reduced pressure and a yellow solid was obtained. CH Cl2
(10 mL) was added and the formation of a biphasic mixture was
noticed. Slow evaporation over 14 d led to the formation of
single crystals of the etherate salt, which were suitable for
structure analysis.
19
3
2
+
–
m/z [M
–
H ] calcd for C13H O12F18S6
:
884.7667; found:
3
8
84.7667. Single crystals suitable for structural analysis were
obtained after dissolving the initially obtained orange solid
containing bis(triflyl)methane impurities] in CHCl3 or 1,2-
dichloroethane and slowly evaporating the solvent.
[
(12) Jutzi, P.; Müller, C.; Stammler, A.; Stammler, H.-G. Organometal-
lics 2000, 19, 1442.
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D