Breslow Intermediates from a Thiazolin-2-ylidene and Fluorinated Aldehydes: XRD and Solution-Phase NMR Spectroscopic Characterization

Article abstract of DOI:10.1002/anie.201904308

The first generation and X-ray diffraction (XRD) analysis of a crystalline Breslow intermediate (BI) derived from a thiazolin-2-ylidene, that is, the aromatic heterocycle present in vitamin B₁, is reported. Key to success was the combined use of pentafluorobenzaldehyde and a thiazolin-2-ylidene carrying an enol-stabilizing dispersion energy donor as N-substituent. A so-called primary intermediate (PI) could be isolated in protonated form (pPI) as well and analyzed by XRD. Furthermore, the first stable BI derived from an aromatic thiazolin-2-ylidene and an aliphatic aldehyde (trifluoroacetaldehyde) was prepared and characterized by NMR spectroscopy in solution. When switching to a saturated thiazolidin-2-ylidene, reaction with pentafluorobenzaldehyde afforded a new BI in solution (NMR spectroscopy). Attempts to crystallize the latter BI resulted in the isolation of a novel thiazolidin-2-ylidene dimer that had undergone rearrangement to a hexahydro[1,4]-thiazino[3,2-b]-1,4-thiazine.

Full text of DOI:10.1002/anie.201904308

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Accepted Article
Title: Breslow Intermediates from a Thiazolin-2-ylidene and Fluorinated
Aldehydes: First XRD Characterization, and Solution Phase NMR
Authors: Albrecht Berkessel, Mathias Paul, and Jörg M. Neudörfl
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Angewandte Chemie International Edition
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COMMUNICATION
Breslow Intermediates from a Thiazolin-2-ylidene and Fluorinated
Aldehydes: First XRD Characterization, and Solution Phase NMR
[
a]
[a,b]
[a]
Mathias Paul, Jörg-M. Neudörfl,
and Albrecht Berkessel*
Dedicated to the late Professor Ronald Breslow
Abstract: We report the first generation and X-ray diffraction (XRD)
analysis of a crystalline Breslow intermediate (BI) derived from a
thiazolin-2-ylidene, i.e. the aromatic heterocycle present in vitamin
the use of saturated imidazolidin-2-ylidenes, carrying dispersion
energy donor (DED) substituents on the heterocycle's N-atoms,
with SIPr (1a, DED = Dipp, i.e. 2,6-di(2-propyl)phenyl) being a
[
13,14]
B
1
. Key to success was the combined use of pentafluorobenz-
prominent example (Scheme 2).
aldehyde and a thiazolin-2-ylidene carrying an enol-stabilizing dis-
persion energy donor as N-substituent. A so-called primary inter-
mediate (PI) could be isolated in protonated form (pPI) as well, and
analyzed by XRD. Additionally, the first stable BI derived from an
aromatic thiazolin-2-ylidene and an aliphatic aldehyde (trifluoro-
acetaldehyde) was prepared and characterized by NMR in solution.
When switching to a saturated thiazolidin-2-ylidene, reaction with
pentafluorobenzaldehyde afforded a new BI in solution (NMR).
Attempts to crystallize the latter BI resulted in the isolation of a novel
thiazolidin-2-ylidene dimer that had undergone rearrangement to a
hexahydro[1,4]-thiazino[3,2-b]-1,4-thiazine.
azolium salt, such as
vitamin B
1
(thiazolium, X = S)
R'
R''
N
X
H
R'''
H
R'
O
R''
O
δ+
R
N
R
H
R
α
X
benzoin OH
product
R'''
substrate
aldehyde
catalytically
active NHC
R'
R'
R'
R''
R
R''
R''
N
N
O
N
OH
H
R
OH
O
H
H
Both in enzymes and in organocatalytic Umpolung, catalysis by
X
X
R
X
R'''
R'''
R'''
primary
intermediate
PI)
protonated
primary
N-heterocyclic carbenes (NHCs) hinges on the formation of the
R
[
1,2]
so-called Breslow intermediates (BIs)
[chemically: (di)amino
(
intermediate
R'
R'
(pPI)
enols; BI, Scheme 1] in which the genuine polarity of e.g. an
O
δ+
R
R''
R''
N
OH
N
O
H
aldehyde substrate is inverted from electrophilic to nucleo-
α
δ
–
α
[
3,4]
[1,2]
substrate
aldehyde
X
X
H
R keto-
R
philic. Postulated in 1958,
diamino enols from aldehydes and carbenes, and their
the first successful generation of
R'''
R'''
tautomer (K)
The Breslow Intermediate (BI)
the "umpoled" (i.e. nucleophilic) aldehyde –
[
5,7]
–
characterization by in situ NMR was reported by us in 2012,
[
6,7]
and their first isolation and XRD-analysis in 2013.
importantly, we could show that 2,2-diamino enols BI (Scheme
Most
Scheme 1. Catalytic cycle of the benzoin condensation as proposed by
[
1,2]
[
5,7]
Breslow.
1
) indeed act as acyl anion equivalents.
Earlier attempts to
isolate intermediates resulted in the characterization of proton-
Refs. 5 – 7: First Breslow intermediates such as 3aa derived from saturated NHCs:
ated primary intermediates (pPI, Scheme 1), such as C2-
Dipp
N
Dipp
N
O
[
8]
Dipp:
H3C
H
OH
hydroxymethyl azolium salts by Teles et al., and hydroxybenzyl
+
[
9a]
CH3
CH3
azolium salts by O'Donoghue, Smith et al.,
Breslow intermediates and spiro-dioxolanes (i.e. 1:2 carbene-
the keto form of
N
N
Dipp
Dipp
3
H C
[
10]
aldehyde adducts) by ourselves,
aza-analogues of the
1a
2a
3aa (NMR, XRD)
[
11]
Breslow intermediate by Rovis et al., and O-methylated amino
[
12]
[5]
Ref. 16: First Breslow intermediate 3bb derived from an aromatic thiazolin-2-ylidene:
enols by Mayr et al. and ourselves.
O
CH3
CH3
H
F
F
H3C
H3C
H3C
H3C
CH3
CH3
C6F5
OH
Our initial preparations, in 2012 – 2015, of Breslow inter-
mediates (BIs) and our studies of their reactivity were based on
N
S
N
N
+
F
S
S
H3C
F
F
(1b)2
2b
3bb (NMR)
[
a]
Dr. M. Paul, Dr. J.-M. Neudörfl, Prof. Dr. A. Berkessel
Cologne University, Department of Chemistry
Greinstrasse 4, D-50939 Cologne (Germany)
Fax: (+49) 221-470-5102
This paper:
(i) First crystallization and XRD analysis of the Breslow intermediate 3cb derived from
an aromatic thiazolin-2-ylidene, and of the protonated primary intermediate 4cb';
E-mail: berkessel@uni-koeln.de
Homepage: www.berkessel.de
(ii) First Breslow intermediate 3cc derived from an aromatic thiazolin-2-ylidene and
an aliphatic aldehyde (trifluoroacetaldehyde):
Dipp
N
Dipp
N
Dipp
N
[
[
b]
X-Ray Crystallography
H3C
H3C
H C
H C
OH
3
OH
H
C F O
6
3
OH
**]
Support by the Deutsche Forschungsgemeinschaft (priority program
S
C6F5
S
S
CF3
3
H C
4
3
H C
1
807 "Control of London Dispersion Interactions in Molecular
3
cb (XRD, NMR)
4cb' (XRD, NMR)
3cc (NMR)
Chemistry", grant nos. BE 998/14-1,2), by the Fonds der
Chemischen Industrie and by BASF SE is gratefully acknowledged.
Supporting information for this article is given via a link at the end of
the document.
Scheme 2. Breslow intermediates derived from saturated and unsaturated/
aromatic NHCs.
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COMMUNICATION
According to our recent computational assessment, the stability
of BIs such as 3aa-Dipp, prepared from SIPr (1a-Dipp) and
benzaldehyde (2a, Scheme 2) hinged on both the saturation of
the carbene moiety, as well as the dispersive stabilization of the
diaminoenol effected by the N-DED-substituents such as Dipp
4,5-Dimethyl-3-[2,6-(2-propyl)phenyl]thiazol-2-ylidene
(1c,
[
17]
Scheme 3) was first reported by Arduengo et al. in 1997. For
our purposes, we prepared this N-heterocyclic carbene by
deprotonation of the azolium perchlorate 1c•HClO
4
with KOtBu
in THF (Scheme 3). After removal of the KClO precipitation by
4
[
15]
13
13
[
2,6-di(2-propyl)phenyl] or Mes (2,4,6-trimethylphenyl).
To
filtration, C-CHO labeled pentafluorobenzaldehyde (2b CHO,
1
3
achieve optimal catalytic power, Nature's umpolung catalyst
thiamine is, in contrast, based on an aromatic heterocycle (i.e.,
thiazole). As the next step, we have recently been able to
generate and characterize the much more delicate BI 3bb
1 equiv) was added, for convenient reaction monitoring by
C
[
18]
13
NMR.
We were delighted to see that the BI 3cb COH was
1
3
formed instantaneously, as evidenced by its C resonance at δ
1
= 106 ppm and the typical enolic H NMR resonance at δ = 5.26
(
Scheme 2), exploiting the enol-stabilizing effect of the electron-
ppm (see Figures S2.2 – S2.5 in the Supporting Information).
Evaporation of the solvent at r.t., and under rigorous exclusion of
oxygen (glovebox), furnished yellow crystals of the BI 3cb (from
non-labeled aldehyde 2b), suitable for X-ray crystallography.
The result is shown in Scheme 3. Characteristic structural
features are the planar aminothioenol unit (dihedral angles O-C-
[
15b,16]
withdrawing C
6
F
5
-substituent on the aldehyde moiety.
In
the latter study, we also attempted to generate and characterize,
in solution, the BI 3cb (Scheme 2) which carries a Dipp group on
the thiazolin-2-ylidene portion for additional dispersive enol
stabilization. Unfortunately, NMR-monitoring of these preliminary
experiments showed that the combination of in situ-formed 4,5-
dimethyl-3-[2,6-(2-propyl)phenyl]thiazol-2-ylidene (1c, Scheme
C
1
-S = −179.7°, O-C-C
1
-N = 1.2°), while the length of the enolic
C=C double bond [d = 1.374 (3) Å] falls well within the range of
[
6,16]
3
) with pentafluorobenzaldehyde (2b) resulted in an intractable
Breslow intermediates characterized by us earlier.
The
[
16]
product mixture.
shortening of this exocyclic C-C bond relative to the one
1
3
observed in compound 4cb' COH (see below) allows for the
We now present – based on the pre-formation of the NHC 1c in
solution, and subsequent reaction with pentafluorobenzaldehyde
clear distinction of the delocalized thioaminoenol BI structure in
3
cb as opposed to a more localized carbanion intermediate. In
(
(
2b) – the successful generation, isolation and characterization
NMR, XRD) of the BI 3cb. The same holds for the protonated
the crystal, the aminothioenol 3cb forms dimers by OH···OH
hydrogen bonding (see Figure S2.8 in the Supporting Infor-
primary intermediate (pPI) 4cb' (NMR, XRD; Scheme 2). Note
that the aminothioenol 3cb is the first thiazole-derived BI
characterized by XRD, while the pPI 4cb' constitutes the first
isolated and characterized example of its kind, based on an
aromatic 2-thiazolium core carrying a N-DED substituent.
13
mation). It shall finally be mentioned that C NMR monitoring of
the reaction between the thiazolin-2-ylidene 1c and the aldehyde
13
2
b CHO revealed the formation of decafluorobenzoin, as
13
evidenced by its characteristic C NMR resonance at δ = 123.5
ppm (enediol form, see Figure S2.3 in the Supporting Inform-
[
16]
ation). Benzoin formation thus proves the acyl anion character
1
3
of the Breslow intermediate 3cb CHO.
Prolonged NMR monitoring revealed a gradual change of the
1
3
signature of the Breslow intermediate 3cb COH to a new set of
1
3
resonances. After ca. 24 h at r.t., a C NMR signal at δ = 72.3
1
ppm and a H NMR resonance at δ = 4.32 ppm (see Figures
S2.2 – S2.5 in the Supporting Information) became clearly
1
visible. Besides the chemical shift values, the characteristic JCH
1
coupling of 163.4 Hz observed for the H NMR resonance at δ =
4
.32 ppm pointed to the secondary alcohol structure typical for a
[
8,9]
primary intermediate (PI, or pPI, Scheme 1).
When the
solvent was evaporated after ca. 24 h, almost colorless air and
moisture stable crystals were obtained, and subjected to X-ray
crystallography. The result is shown in Scheme 3 (bottom). The
1
3
newly formed compound 4cb' COH is in fact an O-protonated
[
9,19]
primary intermediate (pPI).
moiety has been replaced by a phenolate oxygen atom,
The para-fluorine atom of the
6 5
C F
[
20]
potentially due to reaction with adventitious water.
The
tetrahedral geometry around the former aldehydic carbon atom
is clearly visible. The length of the exocyclic C-C single bond is
1
.523 (5) Å, and the four atoms O-C-C-S are arranged in an
almost planar fashion (dihedral angle O-C-C
1
-S = 4.8°, O-C-C
1
-
N = −171.4°). Within the thiazolium ring, the S-C
1
and N-C
1
1
3
bonds are shorter relative to the BI 3cb: dS-C1 (4cb' COH) =
1
3
1
.691 (3) Å vs. dS-C1 (3cb) = 1.748 (2) Å; dN-C1 (4cb' COH) =
1.342 (5) Å vs. dN-C1 (3cb) = 1.386 (3) Å. In the crystal, individual
1
3
Scheme 3. Top: generation of the Breslow intermediate (BI) 3cb COH,
together with its X-ray crystal structure (3cb); bottom: molecular and crystal
1
3
molecules of 4cb' COH form strong OH···O (phenolate)
1
3
structure of the protonated primary intermediate (pPI) 4cb' COH.
hydrogen bonds with one another (see Figure S2.10 in the
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COMMUNICATION
Supporting Information). It is currently not clear whether the
hydrolytic defluorination occurs on free pentafluorobenzaldehyde
Exposure of the carbene 1c to a dilute solution of 2d in
[D
8
]THF did not result in a clean transformation. We were
1
3
13
(
2b CHO), or on one of its bound forms (such as BI 3cb COH),
and whether or not this process is catalyzed by the carbene 1c.
A related adventitious exchange of a C para-fluorine atom for
a hydroxy group has been reported by Rovis et al. for an N-C
delighted to see, however, that the reaction of the polymer poly-
2d with the carbene 1c in [D ]THF at 10 °C cleanly furnished the
8
6
F
5
Breslow intermediate 3cd (see Section S2.4 of the Supporting
Information for the preparation/characterization of mono- and
polymeric trifluoroacetaldehyde 2d/poly-2d, and Figures S2.23
6
F
5
[
20a]
triazolium salt.
–
S2.26 for the NMR-spectra of the BI 3cd). The assignment of
We also examined the reaction of the thiazolin-2-ylidene 1c
with benzaldehyde (2a, Figure 1). NMR monitoring (see Figures
the E-configuration shown for 3cd in Scheme 4 rests on the pro-
1
1
nounced H, H-NOE observed between the enol's OH and the
Dipp substituent's CH -groups. In summary, the generation of
S2.11 – S2.17 in the Supporting Information) in [D
solvent revealed the rapid formation of the Breslow intermediate
ca, followed by the appearance of its keto tautomer 5ca.
8
]THF as
3
the enol 3cd represents the first successful access to a Breslow
intermediate combining a thiazolin-2-ylidene and an aliphatic
aldehyde.
3
Unfortunately, attempts to crystallize the enol 3ca from this
solution met with frustration. In contrast, running the same reac-
tion (i.e. 1c plus 2a) in benzene resulted in the crystallization of
the keto tautomer 5ca, the X-ray crystal structure of which is
displayed in Figure 1. In earlier experiments involving SIPr (1a)
as the carbene component, we had found that the keto/enol
tautomerization involving bis-Dipp BIs such as 3aa (Scheme 2)
To further support the above NMR assignments, and based
on our earlier experience with the saturated NHC SIPr (1a) as
the carbene component, we decided to also generate the
Breslow intermediate 3db from the saturated azolium salt 1d•HI
(Scheme 5; see section S3 of the Supporting Information for the
[
15b]
[24]
is kinetically inhibited.
In contrast, the enol/keto transforma-
preparation of 1d•HI and the characterization of the BI 3db).
tion observed for the mono-Dipp thiazolin-2-ylidene pair 3ca/5ca
makes it a functional model for keto/enol tautomerization that
has been postulated for thiamine-dependent enzymes such as
As it turned out, the formation of the enol 3db could be observed
by NMR within minutes at r.t. upon adding KOtBu to mixtures of
8
the azolium salt 1d•HI with excess aldehyde 2b in [D ]THF. The
[
21]
13
pyruvate oxidase (bottom Scheme 1, BI vs. K).
C NMR resonances observed for the enol 3db are shown in
Scheme 5, and they compare well with those observed before
[
5]
for diamino enols derived from the saturated NHC SIPr (1a),
and with those determined for the thiazolin-2-ylidene-derived
Breslow intermediate 3cb (Scheme 3). Attempts to isolate the
BIs 3db for XRD analysis were not successful. Upon evapora-
tion of the solvent(s), invariably the rearranged carbene dimer 6
crystallized (Scheme 5), while the "regular" carbene dimer (1d)
2
was not observed. The hexahydro[1,4]thiazino-[3,2-b]-1,4-thi-
azine 6 appears to be the first representative of a hitherto
unknown class of compounds. For its formation, we assume that
the first step in the dimerization of NHC 1d proceeds according
Figure 1. Left and middle: Breslow intermediate 3ca and its keto tautomer
5
ca; right: X-ray crystal structure of the ketone 5ca.
As the next step, we intended to extend the generation and
to the Alder-mechanism for carbene dimerization (Scheme 5,
characterization of Breslow intermediates to those derived from
[25–27]
bottom).
2
Instead of direct deprotonation to the dimer (1d) ,
the thiazolin-2-ylidene 1c and aliphatic aldehydes. We had ob-
the intermediate 7 undergoes twofold 1,2-sulfur migration, po-
tentially via episulfonium ion intermediates. Deprotonation of the
resulting iminium ion 8 then affords the rearranged dimer 6.
[
16a]
served earlier
that the reaction of carbene 1c with acetalde-
hyde (2c) yields exclusively the ketone (5cc), in line with the
[
15b]
calculated energetic preference for this tautomer.
We expect-
ed that access to the first Breslow intermediate derived from a
thazolin-2-ylidene (such as 1c) and an aliphatic aldehyde may
become possible by switching to trifluoroacetaldehyde (2d) as
the carbene's reaction partner (Scheme 4). The latter aldehyde,
a gas under standard conditions, is typically liberated from its
ethyl hemiacetal by treatment with conc. sulfuric acid and
[
22]
collected in a cold trap.
trifluoroacetaldehyde (2d) tends to polymerize, affording poly-2d
In the presence of acids or bases,
[
23]
as a waxy solid.
Dipp
Dipp
N
13C-NMR ([D
8
]THF):
38.4 ppm
108.2 ppm
H
3
C
C
H
3
3
C
C
N
O
H
OH
1
+
HO
[
D
1
8
]THF,
0 °C
S
CF3
S
CF3
H
3
n
H
2
CF
( J = 36.6 Hz)
1
c
poly-2d
3cd
Scheme 5. Top: Generation of the Breslow intermediate 3db from the
thiazolinium salt 1d•HI, and of the rearranged carbene dimer 6; bottom:
mechanistic proposal for the formation of the hexahydro[1,4]thiazino[3,2-b]-
Scheme 4. Generation of the Breslow intermediate (BI) 3cd from the thiazolin-
-ylidene 1c and polymeric trifluoroacetaldehyde (poly-2d).
2
1
,4-thiazine 6.
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Angewandte Chemie International Edition
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COMMUNICATION
In conclusion, we have for the first time characterized, by X-
ray crystallography, a Breslow intermediate (BI) derived from a
thiazolin-2-ylidene – the catalytic principle of Nature's umpolung
Richter, M. Schedler, F. Glorius, Nature 2014, 510, 485-496; d) D. J.
Nelson, S. P. Nolan, Chem. Soc. Rev. 2013, 42, 6723-6753; e) X.
Bugaut, F. Glorius, Chem. Soc. Rev. 2012, 41, 3511-3522; f) A.
Grossmann, D. Enders, Angew. Chem. 2012, 124, 320-332; Angew.
Chem. Int. Ed. 2012, 51, 314-325; g) D. Enders, O. Niemeier, A.
Henseler, Chem. Rev. 2007, 107, 5606-5655.
1
catalyst, vitamin B . In addition, we provide the first character-
ization, by both XRD and NMR, of a protonated primary inter-
mediate (PI) based on the thiazolium nucleus. Additionally, the
first Breslow intermediate derived from a thiazolin-2-ylidene and
an aliphatic aldehyde has been prepared in solution and charac-
terized by NMR.
[
5]
A. Berkessel, S. Elfert, V. R. Yatham, J.-M. Neudӧrfl, N. E. Schlӧrer, J.
H. Teles, Angew. Chem. 2012, 124, 12537-12541; Angew. Chem. Int.
Ed. 2012, 51, 12370-12374.
[6]
A. Berkessel, V. R. Yatham, S. Elfert, J.-M. Neudörfl, Angew. Chem.
2
013, 125, 11364-11369; Angew. Chem. Int. Ed. 2013, 52, 11158-
1
1162.
Experimental Section
[
7]
V. R. Yatham, J.-M. Neudörfl, N. E. Schlörer, A. Berkessel Chem. Sci.
015, 6, 3706–3711.
2
1
3
3
cb COH (XRD): All operations described
Dipp
N
[8]
[9]
J. H. Teles, J.-P. Melder, K. Ebel, R. Schneider, E. Gehrer, W. Harder,
H C
below need to be done in a glovebox. A
small vial was charged with a solution of
13.5 mg (121 µmol, 1.1 equiv) potassium
tert-butoxide in 0.5 mL abs. THF and a
small magnetic stir bar. The azolium
(41.0 mg, 110 µmol, 1.0 equiv) was added
3
OH
S. Brode, D. Enders, K. Breuer, G. Raabe, Helv. Chim. Acta 1996, 79,
6
1-83.
S
C6F
H C
3
5
a) C. J. Collett, R. S. Massey, O. R. Maguire, A. S. Batsanov, A. C.
O'Donoghue, A. D. Smith, Chem. Sci. 2013, 4, 1514-1522; b) Y.-T.
Chen, G. L. Barletta, K. Haghjoo, J. T. Cheng, F. Jordan, J. Org. Chem.
3cb
perchlorate 1c•HClO
4
1
994, 59, 7714-7722.
10] A. Berkessel, S. Elfert, K. Etzenbach-Effers, J. H. Teles, Angew. Chem.
010, 122, 7275-7279; Angew. Chem. Int. Ed. 2010, 49, 7120-7124.
11] a) D. A. DiRocco, K. M. Oberg, T. Rovis, J. Am. Chem. Soc. 2012, 134,
slowly with vigorous stirring. After completion of the addition, a
deeply yellow mixture results. Volatiles were removed under
reduced pressure. Employing the solvent of choice, the free
carbene can be re-dissolved, and the solid potassium per-
chlorate can be removed by means of a syringe filter. For the
isolation of the Breslow intermediate 3cb COH in crystalline
form, 20.5 mg (75 µmol, 1.0 equiv) of the carbene 1c were dis-
solved in 0.5 mL abs. THF or abs. benzene, and 10 µL (75 µmol,
[
[
2
6
6
143-6145; b) D. A. DiRocco, T. Rovis, Angew. Chem. 2012, 124,
006-6008; Angew. Chem. Int. Ed. 2012, 51, 5904-5906.
1
3
[
[
12] B. Maji, H. Mayr, Angew. Chem. 2012, 124, 10554-10558; Angew.
Chem. Int. Ed. 2012, 51, 10408-10412.
13] In this paper, the compound numbers 1a-d denote the N-heterocyclic
carbenes used in this study, while 2a-d stand for the aldehydes.
Breslow intermediates (BIs) are numbered 3, and e.g. 3bc indicates
that this aminoenol is composed of carbene 3b and aldehyde 2c. The
protonated primary intermediate (pPI) characterized in this study has
1
3
1
.0 equiv) pentafluorobenzaldehyde (2b CHO) were added at
r.t.. Evaporation of the solvent from the deeply yellow solution
furnished crystals of 3cb suitable for X-ray crystallography.
[
29]
3
cd (NMR): An inert NMR tube containing a
[D ]THF solution of carbene 1c (see above)
13
the number 4cb', as the pentafluorobenzaldehyde component 2b CHO
Dipp
N
8
H C
3
has been converted to 2,3,5,6-tetrafluoro-4-hydroxybenzaldehyde
OH
was charged with solid polyfluoral (poly-2d)
in the top portion and closed with a septum.
The sample was cooled to 10 °C in the
spectrometer without allowing the poly-
fluoral (poly-2d) to fall into the solution. The
13
(
2b' CHO). Keto tautomers are numbered 5, e.g. 5ca contains the
structural elements of carbene 1c and aldehyde 2a.
S
CF3
H C
3
[
[
14] a) J. P. Wagner, P. R. Schreiner, Angew. Chem. 2015, 127, 12446-
3
cd
1
2471; Angew. Chem. Int. Ed. 2015, 54, 12274-12296; b) P. R.
Schreiner, Beilstein J. Org. Chem. 2018, 14, 3076-3077.
15] a) V. R. Yatham, W. Harnying, D. Kootz, J.-M. Neudörfl, N. E. Schlörer,
A. Berkessel, J. Am. Chem. Soc. 2016, 138, 2670–2677; b) M. Paul, M.
Breugst, J.-M. Neudörfl, R. B. Sunoj, A. Berkessel, J. Am. Chem.
Soc. 2016, 138, 5044–5051.
sample was taken out of the spectrometer and shaken vigorous-
ly, until the polyfluoral (poly-2d) had dissolved. Upon dissolution
of the polymer poly-2d, the yellow solution turned orange-red.
Subsequent NMR analysis provided clean spectra of the desired
Breslow intermediate 3cd. Solutions of 3cd are stable for up to
ca. 2 h, after which decomposition sets in.
[
[
16] M. Paul, P. Sudkaow, A. Wessels, N. E. Schlörer, J.-M. Neudörfl, A.
Berkessel, Angew. Chem. 2018, 130, 8443-8448; Angew. Chem. Int.
Ed. 2018, 57, 8310-8315.
1
Characteristic NMR resonances ([D
C 151 MHz; F: 377 MHz):
Carbene 1c: C NMR: δ = 254.2 ppm.
Breslow intermediate 3cd: H NMR: δ = 5.41 ppm (brs, OH);
8
]THF, 298 K; H: 600 MHz,
1
3
19
17] A. J. Arduengo III, J. R. Goerlich, W. J. Marshall, Liebigs Ann./Receuil
1997, 365-374.
1
3
1
13
C
[18] a) Y. S. Balazs, I. Saltsman, A. Mahammed, E. Tkachenko, G.
Golubkov, J. Levine, Z. Gross, Magn. Reson. Chem. 2004, 42, 624-
635; b) J. Sankar, S. Mori, S. Saito, H. Rath, M. Suzuki, Y. Inokuma, H.
Shinokubo, K. S. Kim, Z. S. Yoon, J.-Y. Shin, J. M. Lim, Y. Matsuzaki,
O. Matsushita, A. Muranaka, N. Kobayashi, D. Kim, A. Osuka, J. Am.
Chem. Soc. 2008, 130, 13568-13579.
1
NMR: δ = 138.4 ppm (C-2), 126.1 ppm (q, JCF = 268.4 Hz, CF
3
),
08.2 ppm (q, JCF = 36.6 Hz, C-OH); F NMR: δ = -65.35 ppm
CF ).
2
19
1
(
3
Keywords: carbenes · Breslow intermediate · NMR · reaction
mechanisms · Umpolung · XRD.
[
19] For earlier X-ray crystallographic characterizations of 2-(α-hydroxy-
benzyl)thiazolium salts, see: a) K. Dodi, I. P. Gerothanassis, N.
Hadjiliadis, A. Schreiber, R. Bau, I. S. Butler, P. J. Barrie, Inorg. Chem.
1996, 35, 6513-6519; b) W. Shin, J. Pletcher, M. Sax, J. Am. Chem.
Soc.1979, 101, 4365-4371; c) J. Pletcher, M. Sax, G. Blank, M. Wood,
J. Am. Chem. Soc. 1977, 99, 1396-1403.
[
[
[
1]
2]
3]
R. Breslow, J. Am. Chem. Soc. 1957, 79, 1762-1763.
R. Breslow, J. Am. Chem. Soc. 1958, 80, 3719-3726.
nd
S. Díez-Gonzáles (ed.) N-Heterocyclic Carbenes, 2 ed., RSC Cataly-
sis Series No. 27, The Royal Society of Chemistry, Cambridge, UK
[20] a) X. Zhao, G. S. Glover, K. M. Oberg, D. M. Dalton, T. Rovis, Synlett
2
017.
a) R. S. Menon, A. T. Biju, V. Nair, Beilstein J. Org. Chem. 2016, 12,
44-461; b) D. M. Flanigan, F. Romanov-Michailidis, N. A. White, T.
Rovis, Chem. Rev. 2015, 115, 9307-9387; c) M. N. Hopkinson, C.
2013, 1229-1232; b) The mass spectrum (EI) taken from a crystal of
1
3
[
4]
compound 4cb' COH shows a strong peak of m/z = 194, correspond-
1
3
4
ing to 2,3,5,6-tetrafluoro-4-hydroxybenzaldehyde (2b' CHO); see
Figure S2.6 of the Supporting Information for the mass spectrum, and
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ref. 20c for the preparation of this aldehyde by F-OH-exchange; c) H.
Gopee, X. Kong, Z. He, I. Chambrier, D. L. Hughes, G. J. Tizzard, S. J.
Coles, A. N. Cammidge, J. Org. Chem. 2013, 78, 9505-9511.
[25] R. W. Alder, M. E. Blake, L. Chaker, J. N. Harvey, F. Paolini, J. Schütz,
Angew. Chem. 2004, 116, 6020-6036; Angew. Chem. Int. Ed. 2004, 43,
5896-5911.
[
21] a) D. Meyer, P. Neumann, E. Koers, H. Sjuts, S. Lüdtke, G. M.
Sheldrick, R. Ficner, K. Tittmann, Proc. Natl. Acad. Sci. USA 2012, 109,
[26] R. W. Alder, L. Chaker, F. P. V. Paolini, Chem. Commun. 2004, 2172-
2173.
1
0867-10872; b) P. Neumann, K. Tittmann, Curr. Opinion Struct. Biol.
014, 29, 122-133. c) For comparison, the saturated ketones 5da, 5dc
[27] See ref. 28 for our recent gas-phase ion mobility study on modes of
NHC dimerization.
2
and 5ea were prepared and characterized as well, see Supporting
Information, section S3.3.
[28] M. Paul, E. Detmar, M. Schlangen, M. Breugst, J.-M. Neudörfl, H.
Schwarz, A. Berkessel, M. Schäfer, Chem. Eur. J. 2019, 25, 2511-2518.
[29] CCDC 1889767-1889773 contain the supplementary crystallographic
[
22] K. Ogawa,T. Nagai, M. Nonomura, T. Takagi, M. Koyama, A. Ando, T.
Miki, I. Kumadaki, Chem. Pharm. Bull. 1991, 39, 1707-1712.
23] W. K. Busfield, E. Whalley, Can. J. Chem. 1965, 43, 2289-2295.
24] K. A. Ogawa, A. J. Boydston, Chem. Lett. 2014, 43, 907-909.
1
3
2
data for compounds 3cb, 4cb' COH, 5ca, disulfide (7-H) , 6, 5da, and
[
[
5ea. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via: www.ccdc.cam.ac.uk /data_request
/
cif.
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Mathias Paul, Jörg-M. Neudörfl, and
Albrecht Berkessel*
Page No. – Page No.
Breslow Intermediates from a Thiazol-2-
ylidene and Fluorinated Aldehydes: First
XRD Characterization, and Solution
Phase NMR
1
Back to Nature! In vitamin B catalyzed Umpolung, the Breslow intermediate (BI) is
formed from an aromatic thiazolin-2-ylidene and the substrate aldehyde. The
combination of a N-Dipp substituted thiazolin-2-ylidene with pentafluorobenzalde-
hyde allowed the isolation and first XRD characterization of a BI derived from a
thiazolin-2-ylidene. When trifluoroacetaldehyde was used, the first BI derived from a
thiazolin-2-ylidene and an aliphatic aldehyde was generated, and characterized by
NMR.
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