Aldehyde umpolung by N-heterocyclic carbenes: NMR characterization of the breslow intermediate in its keto form, and a spiro-dioxolane as the resting state of the catalytic system

Article abstract of DOI:10.1002/anie.200907275

Surprises from a classic: The Breslow intermediate of triazolylidene- catalyzed benzoin condensations was characterized for the first time by NMR spectroscopy in its keto form (K, energetic minimum). The hitherto unknown spiro-dioxolane S, generated from

Full text of DOI:10.1002/anie.200907275

Communications
DOI: 10.1002/anie.200907275
Organocatalysis
Aldehyde Umpolung by N-Heterocyclic Carbenes: NMR
Characterization of the Breslow Intermediate in its Keto Form, and a
Spiro-Dioxolane as the Resting State of the Catalytic System**
Albrecht Berkessel,* Silvia Elfert, Kerstin Etzenbach-Effers, and J. Henrique Teles
Dedicated to Professor Ronald Breslow
The enormous potential of N-heterocyclic carbenes (NHCs)
as organocatalysts has become evident in recent years.[1]
Furthermore, NHCs are well-known as excellent ligands in
metal-based catalytic reactions.[2] The most intriguing use of
NHCs as organocatalysts is based on their ability to render
aldehydes nucleophilic, thereby inverting the typical electro-
philic nature of aldehydes (“umpolung”).[3] A prototypical
reaction based on the umpolung of aldehydes is the benzoin
condensation. In 1943, Ukai et al. recognized that not only
cyanide ions but also thiazolium salts can be used as catalysts
for the benzoin condensation.[4] Stetter et al. were among the
first to recognize the catalytic potential of 3-alkylthiazolium
salts in benzoin-type condensations of aliphatic aldehydes,
which cannot be effected by cyanide.[5] Recent years have
seen impressive enantioselective variants and versatile homo-
enolate chemistry resulting from conjugate umpolung of enals
or related compounds.[1,6] Similarly, the benzoin condensation
is of interest to industry, for example for the catalytic
Scheme 1. Catalytic cycle of the benzoin condensation as proposed by
Breslow.[8]
condensation of formaldehyde to glycolaldehyde.[7]
In 1958, Breslow proposed a mechanism for the thiazo-
lium-catalyzed benzoin condensation (Scheme 1).[8] The thia-
zolium salt I is deprotonated at its most acidic position to
form the thiazolin-2-ylidene II, the catalytically active species.
Nucleophilic attack of the carbene II onto the aldehyde III
generates the tetrahedral intermediate IV. A subsequent
proton shift affords the enaminol V, commonly referred to as
the Breslow intermediate. This acyl anion equivalent V reacts
with the carbonyl group of a second aldehyde molecule,
generating intermediate VI. A second proton transfer follows
and the elimination of benzoin VII regenerates the carbene
catalyst II.
Several experimental and theoretical investigations have
resulted in the identification of intermediates early in the
catalytic cycle. The initial adduct IVand also its O-protonated
form VIII have been identified by NMR spectroscopy[9] and
mass spectrometry[10] in thiazolium-catalyzed reactions.
Enders, Teles and co-workers succeeded in preparing and
characterizing a 5-(hydroxymethyl)triazolium salt as a tria-
zolium-based analogue of structure VIII, starting from a
triazolium salt and formaldehyde.[7]
In contrast, spectroscopic characterization of the Breslow
intermediate itself (V) is scarce. Jordan et al. studied the
reaction of thiazolium salts with benzaldehydes and formu-
lated the 2-(a-hydroxybenzyl)thiazolium ion VIII as a likely
intermediate.[9b] UV spectroscopy pointed to the presence of
the enaminol V.[9b] To our knowledge, there has been no
unambiguous identification of the key intermediate in NHC
umpolung catalysis, namely the Breslow intermediate. We
therefore decided to undertake a thorough NMR spectro-
scopic investigation of the NHC–aldehyde interaction using a
stable and readily accessible carbene, 1,3,4-triphenyl-4,5-
dihydro-1H-1,2,4-triazol-5-ylidene 1, introduced by Enders,
Teles and co-workers.[11]
[*] Prof. Dr. A. Berkessel, S. Elfert, Dr. K. Etzenbach-Effers
Cologne University, Department of Chemistry
Greinstrasse 4, 50939 Kꢀln (Germany)
Fax: (+49)221-470-5102
E-mail: berkessel@uni-koeln.de
Homepage: http://www.berkessel.de
Dr. J. H. Teles
BASF SE, GCB/X-M311
67056 Ludwigshafen (Germany)
[**] Support by BASF SE and by the Fonds der Chemischen Industrie is
gratefully acknowledged. The authors thank D. Mꢁller for providing
13C-labeled triazolylidene.
In an initial experiment, we combined triazolylidene 1
with propionic aldehyde 2 in a 1:1 molar ratio. To our delight,
the keto tautomer 3 of the Breslow intermediate formed
smoothly and was isolated by column chromatography
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200907275.
7120
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 7120 –7124

Angewandte
Chemie
Scheme 2. Synthesis of the 5-propionyl-1,2,4-triazoline 3.
Scheme 4. Ketone 6 derived from triazolylidene 1 and benzaldehyde,
enol 7a, and silyl enol ether 7b.
(Scheme 2). With the ketone 3 in hand, we performed 1H and
13C NMR spectroscopic studies.
In solution (e.g. [D8]THF) the keto form 3 of the Breslow
intermediate showed significant oxygen sensitivity, resulting
in 1,3,4-triphenyl-4,5-dihydro-1H-1,2,4-triazol-5-one and pro-
pionic acid as the cleavage products, which were identified by
NMR spectroscopy.
Under rigorous exclusion of oxygen, treatment of ketone
3 with catalytic amounts of acid (e.g. TFA, p-TsOH) did not
result in detectable tautomerization to the enaminol (E/Z)-4a
or enol (E/Z)-4b (Scheme 3). In the presence of catalytic
amounts of NaH and two equivalents of silylating agent BSA
(N,O-bis(trimethylsilyl)acetamide), ketone 3 was converted
into the silyl enol ether (Z)-5b (Scheme 3). The Z-config-
uration of 5b was established by NOE spectroscopy.[12] No
evidence for the formation of silyl enol ether (E/Z)-5a was
obtained in this study.
position. After base treatment and addition of two equiv-
alents of silylating agent BSA, a complex mixture resulted,
from which, however, the free carbene 1 was clearly
discernible due to its carbon resonance at d = 214.8 ppm in
[D8]THF (in situ NMR spectroscopic experiments performed
at T= 253–298 K). Thus far, attempts to trap a potential
enolate intermediate by silylation did not result in unambig-
uous identification of 7b.[16] According to our DFT calcula-
tions the enol form 7a of the ketone 6 is disfavored by
55.2 kJmolÀ1 ((Z)-7a) and 49.0 kJmolÀ1 ((E))-7a) relative to
the keto form.[13]
We then studied the time dependence of the reaction of
propionic aldehyde 2 with the triazolylidene 1. To this end,
the triazolylidene 1*, labeled with 13C at the carbene carbon
C5, was employed to trace the fate of the carbene carbon
atom. The course of the reaction was monitored by broad-
band proton-decoupled 13C NMR, using the DEPTQ pulse
sequence.[17] The time course of a typical experiment, using [5-
13C]triazolylidene 1* and unlabeled propionic aldehyde 2 in a
1:1 molar ratio, is shown in Figure 1. When the system reaches
equilibrium (92 h reaction time; trace e), the spectrum is
dominated by just one species, namely the keto tautomer 3 of
the Breslow intermediate (d = 88.9 ppm). Recording the
spectra at shorter reaction times reveals the occurrence of
an intermediate that has not yet been invoked in mechanistic
discussions. Immediately after mixing of triazolylidene 1* and
propionic aldehyde 2, the 13C NMR spectrum is dominated by
the signals from the free carbene 1* (d = 214.8 ppm) and a
hitherto unknown intermediate with a quaternary carbon
Scheme 3. Ketone 3, potential tautomers and their silylated analogs.
a) Base, silylating agent.
The outcome of the above experiments is in accordance
with the relative free energies obtained by DFT calculations
for the ketone 3 and the enols 4 and 5 (for computed
optimized structures see the Supporting Information).
According to our calculations, the ketone 3 turned out to be
the most stable species, while the Z-enol (Z)-4b and the E-
enol (E)-4b are 37.5 and 50.5 kJmolÀ1 higher in energy,
respectively.[13] Most interestingly, the isomeric enaminols
(Z)-4a and (E)-4a with the hydroxy group cis and trans to N1
are even higher in energy compared to ketone 3 by as much as
57.2 and 63.3 kJmolÀ1, respectively.[14]
Constitutional isomerism as in the case of 4a,b and 5a,b
(Scheme 3) cannot occur in enols derived from the carbene
catalyst and benzaldehyde. When combining the triazolyli-
dene 1 and benzaldehyde in a 1:1 molar ratio, NMR
spectroscopy revealed the formation of the ketone 6 with a
characteristic resonance at d = 6.10 ppm (H5) in the 1H NMR
spectrum and d = 90.5 ppm (C5) in the 13C NMR spectrum in
[D8]THF (Scheme 4).[15]
Once again, treatment of keto form 6 with acid or base did
not result in detectable formation of the enaminol 7a.
Nevertheless, upon addition of base (KOtBu, NaH), loss of
the proton resonance at d = 6.10 ppm (H5 of ketone 6) was
observed, indicating that proton abstraction is possible in this
Figure 1. Multiplicity-edited 13C DEPTQ NMR spectra of a reaction
mixture containing [5-13C]triazolylidene 1* and unlabeled propionic
aldehyde 2 in a 1:1 molar ratio, recorded at different times after mixing
([D8]THF, 298 K, 150 MHz). Chemical shifts of the intensive signals
caused by the labeled carbon atom are given once.
Angew. Chem. Int. Ed. 2010, 49, 7120 –7124
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7121

Communications
(d = 112.8 ppm; Figure 1, trace a). Applying the [5-
The composition of the new intermediate rac-8 is further
supported by a strong signal at m/z 414 in the ESI-MS
spectrum of the reaction mixture.[19]
13
À
C]triazolylidene 1* revealed the expected C H/C couplings
and thus additionally confirmed the chemical shift assign-
1
ments of the ketone 3: d = 5.62 ppm (d, JCH = 156.8 Hz, H5)
In principle, spirocycle 8 can exist as four diastereomeric
pairs of enantiomers. However, according to our in situ NMR
spectroscopic analysis, only one diastereomeric form is
produced exclusively. To aid the assignment of relative
configuration by NMR, we undertook a configurational
analysis of the spiro-dioxolanes 8 with DFT methods.
From the optimized geometries of the series of diastereo-
mers with 5R configuration of the spirocenter (arbitrarily
assigned), we obtained the dioxolane H,H distances, which
are significantly shorter in the cis isomers (2.53 and 2.51 ꢀ;
Figure 2) compared to the trans isomers (3.74 and 3.75 ꢀ; see
the Supporting Information). Based on the strong NOE
between the protons H7 and H9 (1D NOE experiments[12]), a
cis configuration was assigned to the spirocycle 8. In the trans
isomers, no NOEs are expected, as the distance between the
interacting nuclei is almost 4 ꢀ.
1
=
and d = 208.0 ppm (d, JCC = 49.2 Hz, C O).
Upon analyzing the system under conditions that closely
resemble catalytic conditions, that is, in a 10:1 molar ratio of
aldehyde to carbene, the carbene was exclusively converted
into the species having the quaternary carbon resonance at
d = 112.8 ppm (for spectra, see the Supporting Information).
No further transformation to the keto form 3 of the Breslow
intermediate was observed under these conditions. In other
words, the newly found species (with d = 112.8 ppm) is not the
thermodynamic minimum of the 1:1 carbene–aldehyde
system, but it represents the resting state of the system
under catalytic conditions, that is, in the presence of large
excess of the carbonyl component with respect to the
triazolylidene catalyst. The question then arises as to the
identity of the structure of this new species with a quaternary
carbon resonance at d = 112.8 ppm.
1
We also calculated H and 13C NMR chemical shifts for
We reasoned that a signal from a quaternary carbon atom
at about 110 ppm points to an orthoamide-like structure.[18]
Based on 2D correlation NMR experiments, we propose
structure 8, a spirocyclic orthoamide and 1,3-dioxolane, for
this newly found resting state of the catalytic system
(Figure 2; for spectra, see the Supporting Information). Its
formation can be explained by the addition of a second
molecule of aldehyde 2 to the initial zwitterionic carbene–
aldehyde adduct 9 (Scheme 5).
the isomers of 8 with DFTusing the GIAO method (Table 1).
For the cis-(5R,7R,9R) isomer, the proton H7 is expected to
Table 1: Selected experimental and computed 1H and 13C NMR chemical
shifts for possible diastereomers of dioxolane 8.[13]
dexp
[ppm]
cis[b]
5R,7R,9R
cis[b]
5R,7S,9S
trans[b]
5R,7R,9S
trans[b]
5R,7S,9R
[a]
C5
C7
C9
H7
H9
112.8
105.3
83.3
4.45
4.15
119.8
110.2
84.5
5.49
4.33
119.2
110.9
89.8
4.16
4.19
121.1
114.8
86.9
5.25
4.24
120.8
113.0
80.0
4.67
4.39
[a] Measured in [D8]THF (600 MHz, 298 K). [b] Computed NMR chem-
ical shifts dDFT in ppm (GIAO-DFT).
appear approximately 1.2 ppm downfield compared to proton
H9, which was not observed experimentally. Therefore, we
reason that the cis-(5R,7S,9S) diastereomer of 8 is exclusively
formed under the reaction conditions (as a racemic mixture).
This assumption is further supported by the free relative
energies obtained from our DFT calculations, which indicate
that (5R,7S,9S)-8 is the most stable diastereomer of the 5R
series (Table 2).
Figure 2. Computed optimized structures of the cis isomers of the 5R
series of possible diastereomers of 8. Phenyl groups are drawn as
single carbon atoms for clarity. H,H distances are given in [ꢂ]. Trans
isomers are not shown (see the Supporting Information).
Table 2: Relative free energies of the possible diastereomers of 8.[13]
cis
cis
trans
trans
5R,7R,9R
5R,7S,9S
5R,7R,9S
5R,7S,9R
DG[a]
+1.8
0.0[b]
+8.3
+7.6
[a] kJmolÀ1. [b] Taken as the zero point.
For a deeper insight into the formation of the dioxolane
intermediate 8, this reaction step was analyzed using DFT
methods. Figure 3 shows the structures at the calculated
stationary points involved in the formation of dioxolane
(5R,7S,9S)-8 and their relative free energies. Together with
the zwitterionic adduct of triazolylidene 1 and propionic
Scheme 5. Reversible formation of spirocyclic dioxolane rac-8.
7122
www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 7120 –7124

Angewandte
Chemie
a-positions of the keto
form of the Breslow
adduct, enaminol forma-
tion is disfavored.
Experimental Section
All reactions were performed
under inert gas atmosphere
using Schlenk and glovebox
techniques. THF was dried
over Na/benzophenone and
distilled prior to use. NMR
spectra were recorded on a
Bruker Avance II 600 instru-
ment (1H: 600.20 MHz, 13C:
150.92 MHz) except for 1D
NOE spectra, which were
obtained on a Bruker DRX
Figure 3. Relative free energies (DG, in kJmolÀ1) of the stationary points involved in the formation of dioxolane
(5R,7S,9S)-8.[13] Phenyl groups are drawn as single carbon atoms for clarity. Selected bond lengths are given in
[ꢂ] and dihedral angles in [8].
500
instrument
(1H:
13C:
500.13 MHz,
125.76 MHz). Spectra were
recorded at room tempera-
ture unless otherwise stated. Chemical shifts (d) are reported in ppm
relative to tetramethylsilane (TMS).
3: Triazolylidene 1 (500 mg; 1.7 mmol,
1.0 equiv) was dissolved in THF (10 mL)
aldehyde 2, a second molecule of aldehyde 2 forms the
starting complex 10. Our calculations indicate that the
nucleophilic attack of the zwitterion on the carbonyl carbon
atom of the second aldehyde 2 and the attack of the carbonyl
oxygen atom at atom C5 of the triazolium proceed in a
concerted but asynchronous manner. Overall, the ring
formation requires an activation energy of 22.3 kJmolÀ1 and
should therefore proceed readily at room temperature, at
which the reaction was followed by NMR spectroscopy. The
spirocyclic dioxolane (5R,7S,9S)-8* formed is a rotational
isomer with respect to the ethyl group compared to the
minimum structure (5R,7S,9S)-8 (see the Supporting Infor-
mation). The energy barrier for the interconversion of these
two rotamers is very small (7.9 kJmolÀ1).
and propionic aldehyde
2
(147 mL;
2.0 mmol, 1.2 equiv) was added. The reac-
tion mixture was stirred at room temper-
ature for 60 h. The solvent was removed in
vacuo and ketone 3 was isolated by column
chromatography on silica gel (dichlorome-
thane, Rf = 0.75) as a yellow oil. Yield:
305 mg (51%). ESI-MS: m/z 354 [MÀH2 +
H]+, 356 [M + H]+, 378 [M + Na]+; HR-
ESI-MS: exact mass for C23H21N3O5H [M +
H]+: 356.1763, found: 356.176 (Du =
0.0015); 1H NMR (600 MHz, [D8]THF):
d = 7.63 (d, 3JHH = 6.8 Hz, 2H; H16–H20), 7.32 (m, 3H), 7.22 (m,
Upon using [5-13C]triazolylidene 1* and propionic alde-
hyde 2 in a 1:1 molar ratio, we observed further trans-
formation of the initially formed dioxolane 8 to the keto form
3 (Figure 1), which indicates that the dioxolane formation is
reversible. The activation energy for the reverse reaction is
calculated to be 67.3 kJmolÀ1. Thus, the cleavage of the
spirocyclic ring and the release of the second aldehyde
molecule 2 to regenerate the initial adduct 9 is feasible under
the reaction conditions (room temperature).
In summary, we have discovered novel features of the
mechanism of benzoin-type condensations.[8] Under catalytic
conditions (i.e. excess of aldehyde substrate with respect to
carbene catalyst), the spirocyclic orthoamide 8 turned out to
be the resting state of the catalytic system for aliphatic
aldehydes. Retro-cleavage of the spirocycle 8 affords the keto
form 3 of the Breslow adduct, which represents the thermo-
dynamic minimum of the 1:1 carbene–aldehyde system. The
sluggish reactivity of aliphatic aldehydes in carbene-catalyzed
Umpolung reactions can be attributed to the following
effects: 1) aliphatic aldehydes form a spiro-dioxolane as the
resting state of the catalytic system. Retro-cleavage of this 1:2
carbene–aldehyde adduct is necessary for entering the
catalytic cycle. 2) In the proton abstraction from competing
4H), 7.09 (t, 3JHH = 7.3 Hz, 1H; H24), 7.02 (d, 3JHH = 7.3 Hz, 2H;
3
H10–H14), 6.95 (d, 3JHH = 7.3 Hz, 2H; H22–H26), 6.81 (t, JHH
=
=
3
7.3 Hz, 1H; H12), 5.62 (s, 1H; H5), 2.80 (dq, 2JHH = 18.4, JHH
7.4 Hz, 1H; H7), 2.57 (dq, 2JHH = 18.4, 3JHH = 7.4 Hz, 1H; H7),
0.99 ppm (dd (“t”), 3JHH = 3JHH = 7.4 Hz, 3H; H8); 13C NMR
(150 MHz, [D8]THF): d = 208.0 (1C; C6), 149.2 (1C; C3), 145.4
(1C; C9), 143.8 (1C; C21), 130.4 (1C; C18), 130.0 (2C; C11–C13),
129.9 (2C; C23–C25), 129.6 (2C; C17–C19), 129.1 (1C; C15), 128.5
(2C; C16–C20), 126.1 (1C; C24), 124.7 (2C; C22–C26), 120.5 (1C;
C12), 113.4 (2C; C10–C14), 88.9 (1C; C5), 29.7 (1C; C7), 7.5 ppm
(1C; C8); FT-IR (ATR): n˜ = 3058 (w), 3030 (w), 2976 (w), 2935 (w),
2354 (w), 1718 (s), 1594 (s), 1491 (s), 1446 (m), 1398 (m), 1345 (s),
1286 (m), 1249 (m), 1177 (w), 1144 (m), 1099 (w), 1066 (m), 1031 (m),
904 (w), 763 (s), 748 (s), 692 cmÀ1 (s).
(Z)-5b: Ketone 3 was dissolved in [D8]THF in the glovebox and
0.2 equiv of NaH were added. The mixture was stirred for 4 h and
then transferred to a NMR tube. After addition of 2.0 equiv of BSA,
the NMR tube was sealed under rigorous
exclusion of oxygen. 1H NMR (600 MHz,
[D8]THF): d
= 7.58–7.55 (m, 2H; Harom),
7.29–7.20 (m, 10H; Harom), 7.12–7.08 (m, 1H;
Harom), 7.07–7.04 (m, 2H, Harom), 5.72 (s, 1H;
H5), 5.17 (q, 3JHH = 6.8 Hz, 1H; H7), 1.63 (d,
3JHH = 6.8 Hz, 3H; H8), 0.06 ppm (s, 9H;
H9); 13C NMR (150 MHz, [D8]THF): d =
149.5 (1C; C6), 149.0 (1C; C3), 147.0 (1C;
Angew. Chem. Int. Ed. 2010, 49, 7120 –7124
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7123

Communications
Carom), 143.8 (1C; Carom), 129.9 (1C; Carom), 129.7 (1C; CHarom), 129.5
Niemeier, T. Balensiefer, Angew. Chem. 2006, 118, 1491 – 1495;
Angew. Chem. Int. Ed. 2006, 45, 1463 – 1467; c) J. Read deAlaniz,
T. Rovis, Synlett 2009, 1189 – 1207; d) J. Read deAlaniz, M. S.
Kerr, J. L. Moore, J. Org. Chem. 2008, 73, 2033 – 2040; e) V. Nair,
C. R. Sinu, B. P. Babu, V. Varghese, A. Jose, E. Suresh, Org. Lett.
2009, 11, 5570 – 5573; f) V. Nair, S. Vellalath, B. P. Babu, Chem.
Soc. Rev. 2008, 37, 2691 – 2698; g) K. Hirano, A. T. Biju, I. Piel, F.
Glorius, J. Am. Chem. Soc. 2009, 131, 14190 – 14191; h) C.
Burstein, S. Tschan, X. Xie, F. Glorius, Synthesis 2006, 2418 –
2439; i) Y. Kawanaka, E. M. Phillips, K. A. Scheidt, J. Am.
Chem. Soc. 2009, 131, 18028 – 18029; j) B. E. Maki, A. Chan,
E. M. Phillips, K. A. Scheidt, Tetrahedron 2009, 65, 3102 – 3109;
k) P.-C. Chiang, Y. Kim, J. W. Bode, Chem. Commun. 2009,
4566 – 4568; l) P.-C. Chiang, M. Rommel, J. W. Bode, J. Am.
Chem. Soc. 2009, 131, 8714 – 8718.
(2C; CHarom), 129.4 (2C; CHarom), 128.9 (2C; CHarom), 128.5 (2C;
CHarom), 126.1 (2C; CHarom), 125.9 (1C; CHarom), 119.6 (1C; CHarom),
113.9 (2C; CHarom), 108.7 (1C; C7), 88.6 (1C; C5), 11.3 (1C; C8),
0.9 ppm (3C; C9).
8: NMR tubes were charged with 0.1
equiv of labeled triazolylidene 1* in
[D8]THF in a glovebox and sealed with a
septum. 1.0 equiv of propionic aldehyde 2
was added with a syringe and the reaction
was followed by NMR. 1H NMR
3
(600 MHz, [D8]THF): d = 4.45 (t, JHH
=
5.5 Hz, 1H; H7), 4.15 (dt, 3JHH = 7.2 (t),
2JCH = 1.8 Hz (d), 1H; H9), 1.98 (m, 2H;
3
H12), 1.68 (m, 2H; H10), 1.07 (t, JHH
=
=
3
7.5 Hz, 3H; H13), 0.86 ppm (t, JHH
[7] J. H. Teles, J.-P. Melder, K. Ebel, R. Schneider, E. Gehrer, W.
Harder, S. Brode, D. Enders, K. Breuer, G. Raabe, Helv. Chim.
Acta 1996, 79, 61 – 83.
[8] R. Breslow, J. Am. Chem. Soc. 1958, 80, 3719 – 3726.
[9] a) R. Breslow, R. Kim, Tetrahedron Lett. 1994, 35, 699 – 702;
b) Y.-T. Chen, G. L. Barletta, K. Haghjoo, J. T. Cheng, F. Jordan,
J. Org. Chem. 1994, 59, 7714 – 7722; c) M. J. White, F. J. Leeper,
J. Org. Chem. 2001, 66, 5124 – 5131.
7.6 Hz, 3H, H11); 13C NMR (150 MHz,
[D8]THF): d = 112.8 (1C; C5), 105.3 (1C; C7), 83.3 (dispersion
signal, 1C; C9), 26.3 (1C; C10), 22.6 (1C; C12), 11.0 (1C; C13),
8.8 ppm (1C; C11). When the experiment is carried out with non-
labeled carbene 1, proton H9 appears as simple triplet (owing to non-
detectable 2JCH coupling). Aromatic resonances could not be assigned
with certainty.
Computational details and references are included in the
Supporting Information.
[10] W. Schrader, P. P. Handayani, C. Burstein, F. Glorius, Chem.
Commun. 2007, 716 – 718.
[11] D. Enders, K. Breuer, G. Raabe, J. Runsink, J. H. Teles, J.-P.
Melder, K. Ebel, S. Brode, Angew. Chem. 1995, 107, 1119 – 1122;
Angew. Chem. Int. Ed. Engl. 1995, 34, 1021 – 1023.
[12] K. Stott, J. Keeler, Q. N. Van, A. J. Shaka, J. Magn. Reson. 1997,
125, 302 – 324.
[13] Gibbs free energies at 298 K in the gas phase.
[14] The same order in energy was found for the four corresponding
silyl enol ethers (Z)-5b, (E)-5b, (Z)-5a, and (E)-5a (see the
Supporting Information).
Received: December 24, 2009
Published online: August 19, 2010
Keywords: carbenes · NMR spectroscopy · organocatalysis ·
.
reaction mechanisms · umpolung
[1] a) A. Berkessel, H. Grꢁger, Asymmetric Organocatalysis, Wiley-
VCH, Weinheim, 2005. For selected reviews, see: b) D. Enders,
O. Niemeier, A. Henseler, Chem. Rev. 2007, 107, 5606 – 5655;
c) N. Marion, S. Diez-Gonzalez, S. P. Nolan, Angew. Chem. 2007,
119, 3046 – 3058; Angew. Chem. Int. Ed. 2007, 46, 2988 – 3000;
d) D. Enders, T. Balensiefer, Acc. Chem. Res. 2004, 37, 534 – 541.
[2] For selected reviews, see: a) D. Bourissou, O. Guerret, F. P.
Gabbaꢂ, G. Bertrand, Chem. Rev. 2000, 100, 39 – 91; b) W. A.
Herrmann, Angew. Chem. 2002, 114, 1342 – 1363; Angew. Chem.
Int. Ed. 2002, 41, 1290 – 1309.
[3] D. Seebach, Angew. Chem. 1979, 91, 259 – 278; Angew. Chem.
Int. Ed. Engl. 1979, 18, 239 – 258.
[4] T. Ukai, R. Tanaka, T. Dokawa, J. Pharm. Soc. Jpn. 1943, 63,
296 – 300 (Chem. Abstr. 1951, 45, 5148).
[5] H. Stetter, R. Y. Rꢃmsch, H. Kuhlmann, Synthesis 1976, 733 –
735.
[6] Selected recent examples and surveys: a) D. Enders, J. Han, A.
Henseler, Chem. Commun. 2008, 3989 – 3991; b) D. Enders, O.
[15] B. Alcaide, G. Escobar, R. Perez-Ossorio, J. Plumet, Anal. Quim.
Ser. C 1985, 81, 85 – 87.
[16] For an alternative approach to the silylated enaminol form,
resulting in decomposition, see: a) A. E. Mattson, A. R. Bhar-
adwaj, A. M. Zuhl, K. A. Scheidt, J. Org. Chem. 2006, 71, 5715 –
5724; b) A. E. Mattson, K. A. Scheidt, Org. Lett. 2004, 6, 4363 –
4366.
[17] P. Bigler, R. Kꢄmmerle, W. Bermel, Magn. Reson. Chem. 2007,
45, 469 – 472.
[18] I. Wawer, J. Osek, J. Chem. Soc. Perkin Trans. 2 1985, 1669 –
1671.
[19] m/z 414 could also be assigned to an intermediate later in the
catalytic cycle (analogous to VI, Scheme 1), but such a structure
would not match the quarternary carbon resonance at d =
112.8 ppm observed for the labeled [5-13C] atom in the
13C NMR spectra.
7124
www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 7120 –7124