Structures and reactivities of O-methylated Breslow intermediates

Article abstract of DOI:10.1002/anie.201204524

As close as you can get: Since Breslow intermediates usually exist in their keto form, their O-protected tautomers may be considered as their closest isolable relatives. A series of these compounds have been synthesized, their structures determined, and the kinetics of their reactions with electrophiles investigated. Copyright

Full text of DOI:10.1002/anie.201204524

Angewandte
Chemie
DOI: 10.1002/anie.201204524
Organocatalysis
Structures and Reactivities of O-Methylated Breslow Intermediates**
Biplab Maji and Herbert Mayr*
Dedicated to Professor Dieter Seebach on the occasion of his 75th birthday
Since the report by Ukai et al. in 1943,[1] thiamine and related
thiazolium ions A have been known to be catalysts for the
umpolung[2] of aldehydes. The mechanism generally accepted
for these reactions was proposed by Breslow in 1958,[3] when
he described that the thiazolium ring first undergoes depro-
tonation at the most acidic position to give an ylide or carbene
B (Scheme 1). The subsequent nucleophilic addition of B to
an aldehyde generates the zwitterion C, which undergoes
a proton shift to give the Breslow intermediate D, a nucleo-
philic acyl anion equivalent. The reaction of D with a second
molecule of aldehyde followed by a proton shift and release of
B generates the benzoin.[3]
Breslow intermediates derived from thiazoles were generated
by Jordan et al. in [D5]pyridine solution and characterized by
1H NMR spectroscopy.[9a] Three years later, Bordwell, Jordan,
and co-workers determined the pKa values of the conjugate
acids.[9b] Recently, Berkessel et al. characterized the keto form
of the Breslow intermediate derived from 1,2,4-triphenyltria-
zol-5-ylidene.[7c] While the authors succeeded in identifying
a spirodioxolane as the resting state of the catalytic cycle, the
enol form of the Breslow intermediate could be neither
detected nor trapped.[7c]
The presence of the enol group makes the intermediates
D inherently unstable and difficult to isolate or characterize.
Rovis et al. recently succeeded in isolating and characterizing
aza analogues of the Breslow intermediates derived from
chiral triazole carbenes, in which the hydroxy group of the
Breslow intermediates is formally replaced by a methylphe-
nylamino group.[10] We now report on the synthesis of O-
methylated Breslow intermediates 1 derived from thiazole,
imidazole, and triazole carbenes and benzaldehyde, which can
be considered to be the closest relatives of Breslow inter-
mediates that can be isolated as stable entities (Scheme 2).
Scheme 1. Breslow’s mechanistic proposal for thiazole–ylidene-cata-
lyzed benzoin condensation reaction.
Scheme 2. O-methylated Breslow intermediates 1.
The first isolation and characterization of stable N-
heterocyclic carbenes (NHCs) by Arduengo et al. in 1991[4]
triggered extensive investigations on the use of these species
for umpolung reactions of aldehydes and also for the
umpolung of a,b-unsaturated aldehydes and related Michael
systems.[5,6] However, our knowledge of the structure and
reactivity of Breslow intermediates has so far been based
predominantly on theoretical investigations[7] since attempts
to isolate Breslow intermediates or their O-protected deriv-
atives have been unsuccessful.[7c,8] In 1987, O-protected
The N-methylated azolium triflates 2a–c, precursors of
1a–c, are readily accessible by quaternization of the nitrogen
atom of 3 with MeOTf in Et2O (Scheme 3).[11]
[*] M. Sc. B. Maji, Prof. Dr. H. Mayr
Department Chemie, Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13 (Haus F), 81377 Mꢁnchen (Germany)
E-mail: herbert.mayr@cup.uni-muenchen.de
Homepage: http://www.cup.lmu.de/oc/mayr
Scheme 3. Synthesis of the N-methylazolium triflates 2a–c.
[**] We thank the Deutsche Forschungsgemeinschaft (SFB 749) for
financial support, Dr. Peter Mayer for the determination of the X-ray
structures, and Dr. Sami Lakhdar, Dr. Jçrg Bartl, and Dr. Armin R.
Ofial for helpful discussions.
The N-aryl substituted azolium chlorides 2d,e were
synthesized by slow addition of diluted n-pentane/toluene
solutions of the corresponding carbenes into n-pentane/
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204524.
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toluene solutions of [chloro(methoxy)methyl]benzene, which
was generated from benzaldehyde dimethyl acetal and acetyl
chloride in toluene (Scheme 4).
Scheme 4. Synthesis of the N-aryl-substituted azolium chlorides 2d,e.
Treatment of the azolium salts 2 with NaH in the presence
of catalytic amounts of KOtBu in anhydrous THF followed by
evaporation of the solvent and extraction of the organic
materials with anhydrous toluene yielded the O-methylated
Breslow intermediates 1a–e, which can be stored in an argon-
filled glove box at ꢀ308C for several weeks without signifi-
cant decomposition (Scheme 5).
Figure 1. Crystal structures of (Z)-1a (top) and (E)-1e (bottom).
Ellipsoids at the 50% probability level.
configuration (Z isomer) in the solid state.[14] In both
compounds, the phenyl ring is slightly twisted (288 in 1a and
378 in 1e), and the O-methyl group is oriented almost
perpendicular to the exocyclic double bond, as is seen for the
OH group in the quantum chemically calculated structures of
their nonprotected analogues.[15]
In order to elucidate the relationship between structure
and reactivity we have studied the kinetics of the reactions of
the O-methylated Breslow intermediates 1 with the stabilized
benzhydrylium ions 4a–g (Table 1), which have been used as
reference electrophiles to develop the most comprehensive
Scheme 5. Synthesis of the O-methylated Breslow intermediates 1a–e.
Table 1: Benzhydrylium ions 4a–g employed as reference electrophiles in
this work.
The thiazole derivatives 1a,b are formed as mixtures of Z
and E isomers (ratio Z/E = 2:1 in C6D6 solution, NOESY)[9a]
and the triazole derivative 1e is formed as Z/E = 1:10 mixture.
The olefinic character of these species is revealed by
13C NMR signals at d = 135–145 ppm for NCZ and at d =
114–128 ppm for C-OMe. X-ray crystallographic analyses of
(Z)-1a and (E)-1e[12] (Figure 1) show that the exocyclic
double bond adopts a planar geometry with bond lengths (1a:
134.9 pm, 1e: 135.8 pm) similar to those of the corresponding
deoxy-Breslow intermediates (ca. 136 pm)[13] and their aza
analogues (136 pm).[10] The S···O distance in 1a (285.0 pm) is
shorter than the sum of the corresponding van der Waals radii
(332 pm) suggesting an intramolecular nonbonding 1,4-S–O
interaction which might be responsible for the preferred
Electrophile
E[a]
R=N(CH2CH2)2O
R=NMe2
R=N(CH2)4
4a
4b
4c
ꢀ5.53
ꢀ7.02
ꢀ7.69
n=2
n=1
4d
4e
ꢀ8.22
ꢀ8.76
n=2
n=1
4 f
4g
ꢀ9.45
ꢀ10.04
[a] Electrophilicity parameters E for 4a–g from Ref. [16a].
2
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Table 2: Second-order rate constants k [mꢀ1 sꢀ1] for the reactions of the
O-methylated Breslow intermediates 1a–e and the deoxy-Breslow
intermediate 6 with the reference electrophiles 4 (counterions: BF4ꢀ, in
THF at 208C).
nucleophilicity scale presently available on the basis of
Equation (1).[16] Herein, nucleophiles are characterized by
lg k ¼ sNðN þ EÞ
ð1Þ
[a]
Nucleophile
N, sN
Electrophile
k [mꢀ1 sꢀ1
]
two solvent-dependent parameters (nucleophilicity parame-
ter N and sensitivity parameter sN), electrophiles are charac-
terized by one solvent-independent parameter (electrophilic-
ity E), and k is the second-order rate constant [mꢀ1 sꢀ1] at
208C.[16]
Representative combinations of the O-methylated Bre-
slow intermediates 1a,b with diarylcarbenium tetrafluorobo-
rates or chlorides 4[17] showed that the electrophiles attack at
the exocyclic double bond of 1 to give the azolium salts 5a,b
(Scheme 6), which were isolated and characterized as de-
scribed in the Supporting Information.
1a
14.77, 0.80
4d
4e
4 f
4g
1.93ꢂ105
5.22ꢂ104
2.28ꢂ104
5.67ꢂ103
1b
1c
10.45, 0.81
16.61, 0.68
4a
4b
4c
9.26ꢂ103
5.63ꢂ102[b]
1.71ꢂ102[c]
4d
4e
4 f
4g
5.88ꢂ105
1.64ꢂ105
8.48ꢂ104
2.89ꢂ104
1e
15.65, 0.52
15.58, 0.57
4c
4d
4e
4 f
4g
1.16ꢂ104
9.85ꢂ103
2.67ꢂ103
1.52ꢂ103
8.61ꢂ102
6
4c
4d
4e
4 f
2.79ꢂ104
2.20ꢂ104
6.09ꢂ103
3.31ꢂ103
Scheme 6. Reactions of 1a,b with diarylcarbenium ions.
[a] N and sN as defined by Equation (1). [b] Equilibrium constant K=(3–
5)ꢂ103 mꢀ1. [c] Equilibrium constant K=(1–5)ꢂ102 mꢀ1
The rates of the reactions of 1 with the electrophiles 4
were measured photometrically by following the decay of the
absorbances of 4 in anhydrous THF at 208C by using
a stopped-flow instrument as described previously[16] and
specified on page S21 of the Supporting Information. A large
excess of 1 was used in order to achieve pseudo-first-order
conditions. Except for the reaction of 1b with 4b and 4c, the
benzhydrylium ions 4 were consumed completely in all
reaction investigated. The end absorbances of 4b and 4c
observed with variable concentrations of 1b were used to
calculate the equilibrium constants given in footnotes [b] and
[c] of Table 2.
.
The plots of lgk against the empirical electrophilicity
parameters E of the diarylcarbenium ions 4 are linear
(Figure 2), indicating that Equation (1) can be used to
derive the N and sN parameters of the O-methylated Breslow
intermediates 1 (Table 2).
The different slopes of the correlation lines in Figure 2
imply that the relative reactivities of the electron-rich p-
systems 1 depend slightly on the electrophilicity of the
reaction partners. As none of the reference electrophiles 4a–g
has been combined with all nucleophiles listed in Table 2, the
correlations for 1a and 1c have been extrapolated to obtain
rate constants for their reactions with 4c, which are compared
with directly measured rate constants for the other p-
nucleophiles in Scheme 7.
Figure 2. Plot of lgk (Table 2) for the reactions of 1 with the electro-
philes 4 in THF at 208C versus the corresponding electrophilicity
parameters E (Table 1).
Scheme 7 shows that the methyl-protected Breslow inter-
mediate 1b is 163 times less reactive than its deoxy analogue
6
[18] owing to the inductive electron-withdrawing effect of the
Scheme 7. Relative reactivities of the O-methylated Breslow intermedi-
ates 1 and comparison with 6 (towards 4c, THF, 208C). [a] From rate
constant calculated by using Equation (1), N and sN from Table 2, and
E(4c) from Table 1.
methoxy group, which destabilizes the positively charged
thiazolium ion 5 formed by electrophilic attack. Thus, the
mesomeric electron-donating effect of the methoxy group,
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which raises the HOMO of 1b relative to 6, does not lead to
an increase of krel (and of N) but to an increase of the
sensitivity sN, which implies that the reactivity ratio 6/1b
decreases with increasing electrophilicity of the reaction
partner. Analogous effects have been observed previously for
ordinary alkenes[16c,19] and enol ethers.[16f]
Scheme 7 also shows that replacement of the benzoanne-
lated ring by two methyl groups (1b!1a) increases the
nucleophilic reactivity by a factor of 2700. An even higher
activation (factor 6800) is observed when the sulfur atom in
1b is replaced by the better mesomeric electron donor NMe
(1b!1c). The 100-fold lower reactivity of the triazole-
derived Breslow intermediate (1c!1e) may be due to the
electron-withdrawing effect of the extra nitrogen or the
exchange of NMe by the NPh groups.
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In summary, we have developed a method to synthesize
and isolate stable O-methylated Breslow intermediates 1 by
deprotonation of the corresponding azolium salts 2. This
allowed us to perform X-ray analyses of these compounds and
to derive their nucleophilic reactivities from the kinetics of
their reactions with stabilized benzhydrylium ions 4. If the
ratios 1b/6 and 1c/1b are considered to be representative, one
can conclude that O-methylated Breslow intermediates are
102 times less nucleophilic than the corresponding deoxy-
Breslow intermediates and that O-methylated Breslow inter-
mediates derived from thiazoles are 103–104 times less
reactive than those derived from structurally analogous
imidazoles.
Received: June 11, 2012
Published online: && &&, &&&&
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Keywords: benzoin condensation · kinetics ·
N-heterocyclic carbenes · structure–reactivity relationship ·
umpolung
.
[11] Use of MeOTf is superior to the use of Me3O+BF4 which has
ꢀ
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4
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Organocatalysis
B. Maji, H. Mayr*
&&&& — &&&&
Structures and Reactivities of O-
Methylated Breslow Intermediates
As close as you can get: Since Breslow
intermediates usually exist in their keto
form, their O-protected tautomers may be
considered as their closest isolable rela-
tives. A series of these compounds have
been synthesized, their structures deter-
mined, and the kinetics of their reactions
with electrophiles investigated.
6
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Angew. Chem. Int. Ed. 2012, 51, 1 – 6
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