Formation and stability of prolinol and prolinol ether enamines by NMR: Delicate selectivity and reactivity balances and parasitic equilibria

Article abstract of DOI:10.1021/ja111544b

Enamine key intermediates in organocatalysis, derived from aldehydes and prolinol or Jorgensen-Hayashitype prolinol ether catalysts, were generated in different solvents and investigated by NMR spectroscopy. Depending on the catalyst structure, trends for their formation and amounts are elucidated. For prolinol catalysts, the first enamine detection in situ is presented and the rapid cyclization of the enamine to the oxazolidine ("parasitic equilibrium") is monitored. In the case of diphenylprolinol, this equilibrium is fully shifted to the endo-oxazolidine ("dead end") by the two geminal phenyl rings, most probably because of the Thorpe-Ingold effect. With bulkier and electron-withdrawing aryl rings, however, the enamine is stabilized relative to the oxazolidine, allowing for the parallel detection of the enamine and the oxazolidine. In the case of prolinol ethers, the enamine amounts decrease with increasing sizes of the aryl meta-substituents and the O-protecting group. In addition, for small aldehyde alkyl chains, Z-configured enamines are observed for the first time in solution. Prolinol silyl ether enamines are evidenced to undergo slow desilylation and subsequent rapid oxazolidine formation in DMSO. For unfortunate combinations of aldehydes, catalysts, solvents, and additives, the enamine formation is drastically decelerated but can be screened for by a rapid and facile NMR approach. Altogether, especially by clarifying the delicate balances of catalyst selectivity and reactivity, our NMR spectroscopic findings can be expected to substantially aid synthetically working organic chemists in the optimization of organocatalytic reaction conditions and of prolinol (ether) substitution patterns for enamine catalysis.

Full text of DOI:10.1021/ja111544b

ARTICLE
pubs.acs.org/JACS
Formation and Stability of Prolinol and Prolinol Ether
Enamines by NMR: Delicate Selectivity and Reactivity
Balances and Parasitic Equilibria
Markus B. Schmid, Kirsten Zeitler,* and Ruth M. Gschwind*
Institut f€ur Organische Chemie, Universit€at Regensburg, D-93053 Regensburg, Germany
S Supporting Information
b
ABSTRACT: Enamine key intermediates in organocatalysis,
derived from aldehydes and prolinol or JørgensenꢀHayashi-
type prolinol ether catalysts, were generated in different sol-
vents and investigated by NMR spectroscopy. Depending on
the catalyst structure, trends for their formation and amounts
are elucidated. For prolinol catalysts, the first enamine detection
in situ is presented and the rapid cyclization of the enamine to
the oxazolidine (“parasitic equilibrium”) is monitored. In the
case of diphenylprolinol, this equilibrium is fully shifted to the
endo-oxazolidine (“dead end”) by the two geminal phenyl rings, most probably because of the ThorpeꢀIngold effect. With bulkier
and electron-withdrawing aryl rings, however, the enamine is stabilized relative to the oxazolidine, allowing for the parallel detection
of the enamine and the oxazolidine. In the case of prolinol ethers, the enamine amounts decrease with increasing sizes of the aryl
meta-substituents and the O-protecting group. In addition, for small aldehyde alkyl chains, Z-configured enamines are observed for
the first time in solution. Prolinol silyl ether enamines are evidenced to undergo slow desilylation and subsequent rapid oxazolidine
formation in DMSO. For unfortunate combinations of aldehydes, catalysts, solvents, and additives, the enamine formation is
drastically decelerated but can be screened for by a rapid and facile NMR approach. Altogether, especially by clarifying the delicate
balances of catalyst selectivity and reactivity, our NMR spectroscopic findings can be expected to substantially aid synthetically
working organic chemists in the optimization of organocatalytic reaction conditions and of prolinol (ether) substitution patterns for
enamine catalysis.
’ INTRODUCTION
often poor. Only recently we could detect and characterize in situ
the first enamine intermediate27 in the archetypical proline-
catalyzed intermolecular aldol reaction.13 At the same time, the
first crystal structure of an enamine intermediate in an aldolase
antibody was reported.28 Nevertheless, to our knowledge, not a
single prolinol-derived enamine in solution has been reported so
far. For prolinol silyl ether-type organocatalysts, on the other
hand, two enamines could be isolated and characterized,29ꢀ31 but
in situ only one dienamine intermediate32 and one product
enamine33 have been observed. Hence, very little is known about
the formation trends and the stabilities of prolinol- and prolinol
ether-derived enamines, even though this information should be
highly appreciated by synthetically working organic chemists for
the optimization of organocatalytic reaction conditions.
To fill this gap, we designed in situ NMR studies on reactive
prolinol and prolinol ether enamines. In this paper, we present
the first detailed study on the formation and stability of enamines,
derived from aldehydes and prolinol (ether)-type organocata-
lysts, by means of NMR spectroscopy in solution. Our findings
by 1H NMR reaction monitoring reveal trends for the formation
Detailed knowledge on the formation and the stability of
intermediate species is essential for an improved understanding
and hence control of organic reactions. Especially in the increas-
ingly important and still rapidly growing field of modern asym-
metric organocatalysis,1ꢀ5 detailed mechanistic insights into
intermediate properties should largely facilitate the development
of novel catalytic systems and the optimization of reaction
conditions. As one of the most successfully and widely applicable
principles of modern organocatalysis, enamine catalysis by
secondary amines, typically originating from the chiral pool,6ꢀ10
has emerged to an extension of the original proline catalysis11ꢀ13
in recent years. Among a variety of different catalyst scaffolds, in
particular JørgensenꢀHayashi-type prolinol ethers14ꢀ19 have
demonstrated excellent performances in asymmetric enamine
organocatalysis, and though a lot less pronouncedly, prolinol-
type organocatalysts20 have also found applications based on
enamine intermediates.21ꢀ24
Still, in view of the vast number of synthetic applications,
studies on the mechanistic understanding of enamine catalysis
must be termed insufficient.25 While computational studies have
proven to be very useful for the prediction of stereoselectivities,26
knowledge on the appearance of active reaction intermediates is
Received: December 22, 2010
Published: April 18, 2011
r
2011 American Chemical Society
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Chart 1. (A) Aldehydes and Organocatalysts Examined in
This Study and (B) General Atom Nomenclature Used for
Enamines Derived Thereof
Chart 2. Overview on the Investigated Enamines Derived
from Aldehydes 1 and 2 and Catalysts AꢀGa
rates of such enamines depending on the catalyst structure and
for the amounts of enamine formed. Furthermore, information
on the enamine resistance against cleavage of the hydroxyl
protecting group and against ring closure to the isomeric
oxazolidines (“dead ends”) is provided.
’ RESULTS AND DISCUSSION
Model Enamines. Following the experience from our ear-
lier investigations on proline enamines,27 mixtures of prolinol
(ether)-type organocatalysts and R-unbranched aldehydes
(Chart 1) in DMSO were envisaged as the best conditions for
achieving sufficient enamine stabilization. Thereby, the observa-
tion of prolinol (ether) enamines was furthermore expected
to be aided by the well-known fact that, in contrast to proline,
prolinol (ether)-type organocatalysts do not promote alde-
hyde self-aldolizations as readily.8 Various secondary amines
(AꢀG),14ꢀ16 derived from proline, that are typically and very
successfully used as organocatalysts for enamine catalysis were
selected for our studies. They were mixed with two different
aldehydes, 3-methylbutyraldehyde (1) and propionaldehyde (2).
Especially, we chose 1 for the enamine formation study as we had
found earlier that the unwanted aldehyde self-aldolization of this
substrate is minimized even under proline catalysis.27 Therefore,
the superimposition of enamine formation and the potentially
subsequent aldol reaction is expected to be less problematic for 1.
By comparison with 2, the impact of the size of the aldehyde alkyl
chain was to be studied. DMSO was used predominantly as the
solvent in order to achieve the maximum amounts and stabilities
of the enamines, especially in the case of prolinol-type catalysts;27
the obtained results were then verified for selected other
solvents (methanol, acetonitrile, chloroform, dichloromethane,
and toluene). All experiments mentioned hereafter (if not stat-
ed otherwise) were performed within NMR tubes by mixing
aAll enamines are displayed in the (more stable) s-trans conformation
with respect to the exocyclic NꢀC bond.
equimolar amounts of aldehyde and catalyst in perdeuterated
solvents to obtain concentrations of 50 mmol/L each, and NMR
spectra were recorded at 300 K (see Experimental Section for
details).
Enamine Detection and NMR Characterization. Overall 14
different enamines formed from the aldehydes 1 and 2 and the
organocatalysts AꢀG (designated as “catalyst character-alde-
hyde number”, e.g., A-1; Chart 2) were obtained in different
solvents and investigated in situ (See Charts S1 and S2 in the
Supporting Information for full NMR assignments).
The detection of the ene moiety of the enamines was
straightforwardly accomplished on the basis of its characteristic
1
resonances in one-dimensional H spectra;27 in particular, the
doublet for H1 proved to be characteristic and easily recognizable
because of its appearance in the noncrowded spectral region
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between 6.3 and 5.9 ppm. (Only the H1-resonances of the
diarylprolinol enamines derived from BꢀD appear between
5.42 and 5.20 ppm due to significant ring current effects.34)
For all aldehydeꢀamine combinations, the major conformer was
evidenced to be E-configured at the enamine double bond by
3
their scalar coupling constant JH1,H2 of 13.5ꢀ13.9 Hz.35 In
addition, for E-2 and F-2, i.e., for enamines formed in high
amounts and bearing a relatively small alkyl chain, the
Z-configured isomers were detected for the first time besides
the E-isomers in solution. They are characterized by their upfield-
shifted (about 0.2ꢀ0.3 ppm relative to the E-enamines) H1
doublets of about 8.8 Hz,35 but they accounted for only about
1.5% of the total enamine amount in DMSO, MeCN, and PhMe.
(A putative Z-enamine of D-1 amounting to only 0.4% of the
enamine concentration in DMSO could not be verified un-
ambiguously.) Because of their low concentrations, the Z-enam-
ines could not be investigated further so far; consequently, we
can only speculate whether their presence may actually compro-
mise the selectivity of prolinol ether enamine catalysis. Our
experimental detection of the favoring of the E-configuration
over the Z-configuration agrees with other experimental findings
reported earlier: the detection of the E-configuration for isolated
prolinol ether enamines by NMR in solution and by X-ray
analyses in the crystal29,30 and for an in situ prolinol ether
dienamine.32 Our in situ NMR findings on a substantial pre-
ference of the E-configuration are moreover in good agreement
with an empirical estimation of the relative stability of enamine
E/Z-isomers36,37 and also with the results from theoretical
calculations.30,32,38ꢀ41 Nevertheless, examples E-2 and F-2 reveal
the additional presence of a small amount of Z-configured second
request for this correction enamines, derived from aldehydes and
amine organocatalysts, in solution. For the E-enamines, compre-
hensive homo- and heteronuclear NMR experiments were
performed on the example of F-2 (see Chart S3B in the
Supporting Information). Thereby, in analogy to our previous
investigations,27 the covalent connection of the ene unit to the
pyrrolidine ring of the catalyst was proven via the 1H,13C HMBC
by crosspeaks from H1 to CR and Cδ and vice versa from HR
and Hδ1 to C1, obviously conflicting with a previously calculated
4,5
enol mechanism.42 This finding was confirmed by
J
H,H
long-range couplings from H1 and H2 to Hδ1,2, observed in
the 1H,1H-COSY spectrum.
Enamine Stability, Formation, and Degradation. Prolinol
Enamines. The employment of O-unprotected prolinol
derivatives20 in enamine organocatalysis is a lot less common
than the corresponding methyl or silyl ethers since, for example
in combination with aldehydes, considerable amounts of the
catalysts are said to be irreversibly removed from the catalytic
cycle by formation of stable oxazolidines (frequently also referred
to as hemiaminals).38 Accordingly, only a few superior applica-
tions of prolinol enamines have been reported so far.21ꢀ24 To
shed some light on the properties and the behavior of prolinol
enamines, we investigated the formation and stability of enam-
ines derived from 1 or 2 and the (diaryl)prolinols AꢀD,
respectively, i.e., A-1, A-2, B-1, B-2, C-1, C-2, D-1, and D-2.
Similarly to the proline-derived enamines,27 prolinol enamines
could not be detected in MeOH-d4, MeCN-d3, CDCl3, or
PhMe-d8 but only in the dipolar aprotic solvent DMSO-d6, as
was tested on the example of diphenylprolinol (C). This finding
again underlines our previous statement that the stabilizing
interaction between solvent molecules with exclusive hydro-
gen-bond-acceptor properties and the carboxylic/hydroxylic
Figure 1. Evolution of the amounts of enamines and oxazolidines
derived from the aldehydes 1 (diagram A) and 2 (diagram B) and the
prolinol-type organocatalysts A (green) and C (blue) in DMSO-d6 over
1
time as monitored by 1D H NMR spectroscopy. (Note: The total
amount of aldehyde-derived species, detected in the first spectrum, was
set to 100%.) (C) Proposed equilibria38 between the starting material,
iminium ions, enamines, and oxazolidines.
proton of the enamine intermediate may be crucial for the
detectability of proline/prolinol enamines in equilibrium with
their cyclized oxazolidinone/oxazolidine tautomers.27 First, by
comparison of prolinol (A) and diphenylprolinol (C), we
investigated the general influence of the two geminal phenyl
rings on the formation and stability of prolinol enamines. The
evolution of the amounts of enamines in the reaction mixtures of
aldehydes 1 or 2 and catalysts A or C, respectively, in DMSO-d6
is depicted in Figure 1A and B.
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For diphenylprolinol (C), only low amounts of the enamines
C-1 and C-2 (below 20% of all aldehyde-derived species) can be
detected in the reaction mixture, and their observation by NMR
is temporally restricted to the first 1.5 h, since their amounts
decrease rapidly and the isomeric oxazolidine is in fact formed
almost quantitatively (Figure 1A,B).38 Only the endo-oxazolidine
(with the proline side chain and the aldehyde alkyl chain in the
same half-space of the oxazolidine ring; see Figure 1C) is
observed;43 this is in agreement with previous findings on the
preferred oxazolidine formation of diphenylprolinol (C).44,45 For
prolinol (A), on the other hand, the enamines A-1 and A-2 and
the corresponding kinetic endo-oxazolidines are found in the
beginning, too, but the enamines do not disappear in favor of the
endo-oxazolidines during the time interval observed. Instead, the
endo-oxazolidine and the enamine amounts decrease in parallel at
a constant ratio of about 6:1 in the case of aldehyde 1 and of
about 11:1 in the case of 2 (after an induction period of about 30
min) throughout the observation period. In turn, along with the
vanishing of the endo-oxazolidine and the enamine, the thermo-
dynamically favorable exo-oxazolidine appears, and its molar ratio
increases over time and approaches asymptotically a constant
value of about 60% in the case of aldehyde 1. Thereby, the
formation rate of the exo-oxazolidine (Figure 1A) is the highest
when the concentration of the endo-oxazolidine and the enamine
is the highest, i.e., in the beginning of the reaction. Similarly for
propionaldehyde (2), the eventual formation of the exo-oxazo-
lidine is observed, but its amount increases substantially slower
than in the case of 1.
For prolinol (A), the parallel decrease of the concentrations of
the endo-oxazolidines and the corresponding enamines indicates
that there is a rapid equilibration between these tautomeric
species (possibly via the commonly proposed iminium ions;
Figure 1C)38 and that the oxazolidine formation is hence
reversible (similarly to the enamineꢀoxazolidinone equilibrium
as in the case of proline catalysis).27 This interpretation is backed
experimentally by an EXSY cross-peak from the endo-oxazoli-
dine, formed from amine A and propanal (2), to the enamine A-2
(data not shown). Most notably, however, in striking contrast to
the direct enamine formation from oxazolidinones in proline
catalysis in DMSO,27 the vanishing of the diphenylprolinol-
derived enamines C-1 and C-2 in favor of the endo-oxazolidines
(Figure 1A and B) clearly reveals that the enamines are not
formed directly from the oxazolidines. Hence, the commonly
postulated equilibria including the hypothetical iminium ions
(Figure 1C)38 may well be justified in the case of diarylproli-
nolꢀaldehyde adducts. Comparing the enamines A-1 and A-2 in
their equilibria with the endo-oxazolidines, the lower ratio endo-
oxazolidine:enamine in the case of 1 may be rationalized
thermodynamically by the steric destabilization of the endo-
oxazolidine and the inductive stabilization of the enamine owing
to the larger aldehyde alkyl chain present in 1 (isopropyl residue)
than in 2 (methyl residue). Starting from this rapid exchange
between the endo-oxazolidine and the enamine in the case of
prolinol (A), the thermodynamic equilibrium between these two
species and the exo-oxazolidine is slowly established. For this
eventual formation of the thermodynamic exo-oxazolidine, the
iminium ion E/Z isomerization (Figure 1C) has to occur either
directly, via the starting aldehyde, via putative carbinolamines, or
via the s-cis/s-trans isomerization of the enamine species. How-
ever, in our reaction mixture of A and aldehydes 1 and 2 in
DMSO, neither iminium ions nor carbinolamines were detected
and only tiny amounts of the free aldehyde (far below 1%) so that
these species can hardly be expected to provide sufficient
amounts of the thermodynamically unfavorable Z iminium ion
for the substantial formation of the exo-oxazolidine. Instead, the
enamines are readily observed and the maximum concentration
of A-1 corresponds well to the maximum formation rate of the
exo-oxazolidine. Moreover, in a parallel study, we could evidence
on the example of A-2 for the first time a significant population of
the s-cis-enamine conformation.34 In addition, the s-trans/s-cis
equilibration must be fast, since only one enamine signal set is
observed NMR spectroscopically.34 Altogether, these findings
strongly suggest that the thermodynamic exo-oxazolidine is
formed from its kinetic endo isomer mainly via ring-opening to
the enamine, s-cis/s-trans isomerization on the enamine stage,
and subsequent ring closure. On this basis, the faster formation of
the exo-isomer in the case of aldehyde 1 may be explained by the
stronger steric repulsion in the endo-oxazolidine of 1 compared
to 2, which facilitates the ring-opening reaction to the enamine.
In contrast to A, for diphenylprolinol (C), the enamines C-1
and C-2 rapidly vanish in favor of the endo-oxazolidine, and no
exo-oxazolidines are detected. Considering the small structural
difference between C and A, the strikingly higher stability of the
endo-oxazolidine derived from C is rather surprising. The experi-
mental discrepancies between catalysts A and C must hence be
attributed to the impact of the two geminal phenyl rings present
in the diphenylprolinol (C) only, namely, to their steric demand
and to the well-known ThorpeꢀIngold effect.46,47 In line with
our assumptions in a previous study27 on proline enamines, this
structural motif promotes the ring closure to the endo-oxazolidine
and moreover stabilizes the oxazolidine ring, once formed,
thermodynamically, as evidenced by the absence of the enamines
C-1 and C-2 after more than 1.5 h. The inability to detect the exo-
isomer in the case of C suggests, in combination with the low
ability of DMSO to stabilize anions,48 that this effect is as strong
as that of the lifetime of the open-chain species (iminium ion and
enamine) and/or that the extent of the oxazolidine ring-opening
is insufficient to allow for an isomerization process between the
oxazolidines; this might also be reflected by the inability to detect
iminium species in our study. Thus, the conversion of the endo-
oxazolidine to the exo form is unfeasible for C, since it would
need to proceed via an open-chain intermediate. In contrast, the
endo-oxazolidine derived from 1 or 2, respectively, and catalyst A,
being devoid of the geminal phenyl rings, is less stabilized and
thus opens more easily. This leads to the enamine for which,
because of the lower steric demand of the CH2OH-moiety in A,
the thermodynamic preference of the s-trans-enamines over the
s-cis-enamines (likewise the preference of the E over the Z
iminium ion) is lower than in the case of C.29,30,32,38ꢀ40 This
allows the easy population of the s-cis conformation31 and hence
the formation of the exo-oxazolidines. Most interestingly, the
in situ observation of higher enamine concentrations in the
case of A in comparison to C as well as the suggested s-cis/s-trans
isomerization of the enamine are also in good agreement
with the typical performances of A and C in enamine catalysis:
Higher reactivities are reported for A but better selectivities
for C.49ꢀ52
However, the overall performance of C as an organocatalyst
for aldol reactions is very poor. This can now be rationalized for
the first time on an experimental basis by the lack of reasonable
amounts of enamine over a sufficiently long time. In contrast,
different diarylprolinol organocatalysts with substituted phenyl
rings, for instance the di-m-methyl- or di-m-trifluoromethyl-
substituted analogs B and D, have demonstrated substantially
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hydroxylic group of the enamine that has been suggested to be
essentially involved in the enamine stabilization (see the solvent
dependence of prolinol enamines above and our previous study
on proline enamines27). However, such influences should be
observable straightforwardly with the help of 1H NMR chemical
shifts as sensors for local electron densities.
The results of the 1D 1H reaction monitoring in DMSO-d6 as
well as the relevant chemical shifts of the enamines formed from
1 and 2 with diarylprolinols BꢀD are summarized in Figure 2.
Enamine species were detected transiently or permanently in all
1
samples investigated. Concerning the enamine H chemical
shifts, one distinct trend becomes obvious: From B via C to D,
i.e., with stronger electron-withdrawing properties of the aryl
rings, downfield shifts of the protons OH (from 4.87/4.88
ppm to 6.37/6.39 ppm with aldehydes 1/2), HR (from 4.31/
4.33 ppm to 4.79/4.77 ppm with 1/2), and also of H2 (from
3.89/3.81 ppm to 3.93/3.88 ppm with 1/2) are observed. On the
other hand, the low influence of the catalyst substituents on the
chemical shift of H1 indicates that all diaryl prolinol enamines
adopt basically the same conformation around the exocyclic
CꢀC bond.34 In all cases, the enamines were predominantly
converted into the endo-oxazolidines and again the exo-oxazoli-
dines were not observed at all (see Figure S1 in the Supporting
Information). However, the degree and the rate of this conver-
sion are largely dependent on the nature of the aryl substituents.
For the dimethyl-substituted catalyst B, the formation of the
endo-oxazolidine from the enamines with both aldehydes is
similarly fast as for diphenylprolinol (C), but the amounts of
the enamines of B are significantly higher than for C: With
propionaldehyde (2), the enamine B-2 can be detected for about
3 h in solution, while for 3-methylbutyraldehyde (1), the
enamine B-1 does not disappear during more than 12 h but
rather coexists with the endo-oxazolidine in a constant ratio of
0.6:99.4 (after an induction period). On the other hand, the
concentrations of the enamines D-1 and D-2, derived from the
trifluoromethyl-substituted catalyst D, decrease remarkably
more slowly than the ones of C-1 and C-2. In addition, D-1
and D-2 are detected easily throughout the observation time of
more than 6 h (D-1 was observed even after more than 3 days)
and show constant ratios with the oxazolidines of 3.6:96.4
in the case of D-1 (after an induction period) and of 2:98
(asymptotically decreasing to this value) in the case of D-2. In the
case of D-2, not only the conversion of the enamine into the
oxazolidine is significantly decelerated but also the formation of
the enamine itself. This may be rationalized by the detection of an
additional intermediate species that was tentatively identified on
Figure 2. Evolution of the amounts of enamines derived from the
aldehydes 1 (A) and 2 (B) and the diarylprolinol-type organocatalysts B
(orange), C (blue), and D (red) in DMSO-d6 at 300 K over time as
monitored by 1D 1H NMR spectroscopy. (Note: The total amount of
aldehyde-derived species, detected in the first spectrum, was set to
100%.) Relevant 1H chemical shifts (in ppm) are given in green.
better catalytic properties in promoting aldol reactions.23,24 Most
interestingly, reaction times of several days are reported for these
prolinol-catalyzed reactions, which is in seeming contradiction to
the disappearance of the diphenylprolinol enamines C-1 and C-2
within less than 2 h in DMSO. To shed more light on this issue of
prolinol enamine catalysis, the formation and stability of enam-
ines derived from the aldehydes 1 and 2 and the diarylprolinols
BꢀD were investigated. The choice of B and D with phenyl
substituents of similar sizes (CH3 and CF3) but with different
electron demands (electron release by CH3 and electron with-
drawal by CF3) should, by comparison with C, allow one to
identify and to distinguish steric and electronic contributions to
the relative enamine stabilization with respect to the isomeric
endo-oxazolidines. On the one hand, the increased size of the aryl
substituents in B and D (referred to as Ar1 and Ar2, respectively,
in the following) compared to C may destabilize the endo-
oxazolidine because of unfavorable steric repulsions. Owing to
the similar sizes of Ar1 [=3,5-(CH3)2C6H3] and Ar2
[=3,5-(CF3)2C6H3], this effect should be comparable for cata-
lysts B and D. On the other hand, the electronic contributions of
the electron-donating CH3 and the electron-withdrawing CF3
groups in B and D, respectively, should be the inverse and should
also have an opposite effect on the enamine amounts with respect
to C as the reference catalyst. These electronic influences may
impact on the enamine stability either by influencing the enamine
π system or by changing the H-bond donor ability of the
1
the basis of its H chemical shifts as a carbinolamine of D and
2 (Figure 2B; to our knowledge, the detection of a prolinol-
derived carbinolamine has not been reported before; see Chart
1
S3A in the Supporting Information for the H chemical shift
assignment).
For the rationalization of the different enamine amounts
observed with the different catalysts BꢀD, steric and electronic
effects of the phenyl substituents must be taken into account.
The common observation of higher enamine amounts with both
aldehydes for the CH3- and CF3-substituted catalysts B and D
than for the unsubstituted C indicates the common increase of
the steric bulk as one of the contributions to the relative enamine
stabilization. This may be caused by the increased steric repu-
lsion and the associated destabilization of the isomeric endo-
oxazolidine. The yet increased enamine amounts with catalyst D
in comparison to B furthermore suggest that the enamine
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Scheme 1. Performance of Diarylprolinol Organocatalysts
BꢀD in a Direct Crossed-Aldol Reaction of Acetaldehyde
According to Hayashi et al.23 and Comparison of the Reported
Yields with the Time Windows in Which the NMR-Detected
Amounts of the Enamines B-1, C-1, and D-1 in DMSO-d6 in
Our Study Exceed 1%
π system is stabilized by electron-withdrawing N-substituents.
The impact of electronegativity changes of the pyrrolidine
R-substituent on the enamine π-system is also evidenced by
the slight downfield shift of the proton H2 from catalyst B to D.
This relative enamine stabilization in D-1 and D-2 is in line with
the long-standing observation that enamineꢀimine tautomeric
equilibria are shifted toward the enamine by electron-accepting
N-substituents and that this effect is most pronounced in polar
solvents.53 In addition, one may speculate that the higher OH
acidity of enamines derived from D than from B or C, as
evidenced by the downfield-shift of the OH resonance, is
accompanied by a higher H-bond donor ability. This may lead
to a stronger intramolecular H-bond to the enamine nitrogen34
and to more favorable interactions with dipolar aprotic solvents
such as DMSO and thereby cause an additional relative stabiliza-
tion of the enamine species. The explanation of the influence of
the aldehyde substitution pattern on the enamine amounts is in
parallel to our previous study on proline enamines:27 The higher
enamine amounts for 1 than for 2 can be accounted for by the
stronger stabilizing þIꢀ and hyperconjugation effects in the
enamine and by the stronger steric destabilization of the endo-
oxazolidine by the isopropyl group in 1.
In contrast to the amounts of enamines, the different rates of
their formation and formal cyclization to the oxazolidines
depending on the catalyst structure cannot be explained as
straightforwardly at this stage of our investigations. Hence, we
cannot yet give a conclusive rationale why the formation of the
oxazolidine is so much faster for 3-methylbutyraldehyde (1) than
for propionaldehyde (2). Likewise, the origin of the stabilization
of the carbinolamine by catalyst D and the reason for the only
slow establishment of the enamineꢀoxazolidine equilibrium in
the case of D will be addressed in a separate, more comprehen-
sive study on this issue. However, on the basis of the amounts and
lifetimes of the enamines observed for the different diarylprolinol
catalysts BꢀD, i.e., with the help of their “parasitic equilibria”
with the isomeric oxazolidines, we can now explain the better
conversions in prolinol enamine-catalyzed reactions by D than by
Figure 3. Evolution of the amounts of enamines derived from 3-methyl-
butyraldehyde (1) (A) and propanal (2) (B) and the prolinol ether-type
1
organocatalysts EꢀG in DMSO-d6 over time as monitored by 1D H
NMR spectroscopy. Also shown is the increase of the endo-oxazolidine
concentration formed from F-2 upon desilylation (B). (Note: The total
amount of aldehyde-derived species in the first spectrum was set to
100%.).
B or C as well as the required long reaction times23,24 on an
experimental basis. Accordingly, prolinol enamine catalysis ap-
pears to be only successful in the case of sufficient enamine
equilibrium concentrations over a reasonably long period of time,
as is illustrated most impressively by the results of the Hayashi
group on the prolinol enamine-catalyzed crossed-aldol reaction
of acetaldehyde (Scheme 1).23
Prolinol Ether Enamines. By analogy with the study on
prolinol enamines and in order to reveal trends concerning
formation, stability, and degradation of organocatalytically more
relevant enamines, we investigated mixtures of 1 with the
diarylprolinol ether organocatalysts EꢀG8,17,18 in different sol-
vents. This choice was due to the fact that such O-protected
diarylprolinol derivatives are more broadly applicable and more
successfully used for enamine catalysis, particularly as they
cannot fall victim to parasitic deactivation by oxazolidine ring
closure. Accordingly, enamines of EꢀG were readily formed
(in situ yields in DMSO-d6 between 70%54 and 90% for catalysts
E and F, cf. less than 30% for AꢀD) and, in contrast to the
enamines of AꢀD, they were easily detected even in solvents
other than the dipolar aprotic DMSO (see Chart S2 in the
Supporting Information). For the example of E-2, which had
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shown the highest enamine quantities, a rapid screening for the
solvent dependence of the enamine amount was performed.
While E-2 accounted for 85% of the propanal (2)-derived species
after 0.5 h in DMSO-d6, this ratio was only 30% in PhMe-d8, 22%
in MeCN-d3, 16% in CDCl3, and 15% in MeOH-d4.55 Hence, just
like for prolinol enamines, DMSO provides the best conditions
for the stabilization of prolinol ether enamines, too. Most of the
experiments mentioned hereafter were therefore performed in
DMSO-d6 as the solvent. The time-dependent evolution of the
enamine amounts in the reaction mixtures of aldehydes and
prolinol ether catalysts in DMSO-d6 is depicted in Figure 3.
Two trends are clearly visible therein: First, the absolute
amount of enamine decreases depending on the catalyst struc-
ture from E over F to G. While the equilibrium between the
enamine (and water) and the starting materials 1, 2, and EꢀG is
shifted almost completely toward the enamine in the case of the
diphenylprolinol methyl ether 7, the sterically more demanding
TMS (trimethylsilyl) moiety of F causes lower amounts of the
enamine and substitution of the phenyl ring by the even bulkier
Ar2 in G further reduces the concentration of the enamine
significantly.56 From a thermodynamical point of view, this
reveals that the relative stability of the enamine with respect to
the starting material decreases with increasing bulkiness of the
R-substituent of the pyrrolidine ring. This in turn indicates that
the effective shielding of one face of the enamine by the bulky
R-substituent, desired for high stereoselectivities of the catalyst,
comes along with unfavorable steric interactions between the
“obese” substituent and the aldehyde alkyl chain that lead to a
certainly undesired reduction of the active enamine intermediate
concentration. The fact that this trend is brought about by
enlarging the O-protecting group as well as the meta-substituents
on the phenyl ring is in line with the finding from our conforma-
tional investigations on such enamines that both of these groups
interact with the enamine moiety and play a role in the stereo-
selection in enamine catalysis by prolinol (ether) derivatives.34
Second, the nature of the O-protecting group and the phenyl
meta-substituents of the catalysts EꢀG also have an impact on
the formation rate and the persistence of the corresponding
enamines. The enamine E-1 is formed within minutes in
DMSO-d6 and proved to be stable over the period of time
observed. The enamines E-2, F-1, and F-2 appear rapidly, too;
however, their amounts decrease over time. In the case of E-2,
this is due to the consumption of the enamine by unproductive
reactions, but not due to the demethylation of the catalyst
moiety. In contrast, for F-1 and F-2 and likewise for G-1 and
G-2, the loss of the TMS-protecting group is observed and the
subsequent cyclization to the oxazolidine (see above) is mainly
responsible for the decrease of the enamine concentration.57
This cleavage of the silyl ether has already been alluded to in the
literature30,58,59 but is monitored here experimentally for the first
time (Figure 3B). Hence, according to our findings in DMSO-d6,
the replacement of TMS by Me to increase the stability of the
catalyst against cleavage of the O-protecting group and hence to
facilitate, for instance, mechanistic investigations60 seems well
justified.
Figure 4. Evolution of the amounts of enamine derived (A) from
propanal (2) and the diarylprolinol ether G in PhMe-d8 and (B) from 2
and the diphenylprolinol ether F with 100 mol % K2CO3 in DMSO-d6
over time as monitored by 1D 1H NMR spectroscopy. (Note: The total
amount of aldehyde-derived species in the first spectrum was set to
100%.) (C) 1H NMR resonances of HR (left column) and HN (right
column) of G in PhMe-d8 (first row), of G in DMSO-d6 (second row), of
F in DMSO-d6 (third row), and of F in DMSO-d6 with 100 mol % of
K2CO3 (fourth row): Additional resonance splittings of the signals for G
In addition, by comparison with F-1 and F-2, the formation
rates of the enamines G-1 and G-2 in DMSO-d6 are drastically
reduced so that their maximum concentrations are reached only
after more than 4 h. Certainly, a reduced rate of enamine
formation might be a critical point for the application of prolinol
ether-type organocatalysts in enamine catalysis. To understand
and to avoid this potentially detrimental effect, we searched for
3
and F/K2CO3 in DMSO-d6 are indicative of the presence of JH,H
couplings to HN.
different experimental conditions (solvent, basic additives,61
etc.) that either promote or prevent the delayed enamine
formation: Interestingly, the enamine formation is not slowed
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down in DMSO-d6 when the substituents Ar2 of G are replaced
by Ph (see F-1 and F-2 in Figure 3). Likewise, the delayed
enamine buildup is not observed for G and 2 if the solvent is
changed from DMSO-d6 to PhMe-d8 (see Figure 4A). On the
other hand, the enamine formation is decelerated when F is used
in DMSO-d6 together with K2CO3 as an additive (see Figure 4B).
These observations lead us to the conclusion that unfortunate
combinations of catalysts, additives, and solvents (with regard to
Figure 2 also of aldehydes) can cause delayed enamine forma-
tions in solution. Interestingly, distinct experimental observa-
tions and parameters are connected to the decelerated enamine
formation: On the one hand, in the case of the prolinol enamine
D-2, a carbinolamine as a further intermediate on the way to
the enamine seems to be stabilized, which can delay the enamine
formation (see Figure 2B). A similar species, possibly the prolinol
ether F-derived analog, was observed in the case of F/K2CO3 as
the catalytic system in DMSO (data not shown). On the other
hand, a deceleration of the NH proton exchange was observed for
prolinol ethers (see below). This may be caused by steric
crowding in proximity to the pyrrolidine nitrogen atom and
solvent and/or additive molecules that are H-bonded to the NH
proton. Such an effective shielding of the nitrogen of the prolinol
ether catalyst may hamper the enamine formation with the
aldehyde: In the case of the sterically crowded catalyst G, DMSO
as the solvent may be assumed to block the nitrogen, whereas in
the case of the less crowded F an additional small and multiple
H-bond acceptor such as the carboxylate ion can exert this effect.
If this hypothesis is true, one should be able to prove the steric
shielding of the nitrogen atom experimentally by a reduced
exchange rate of the nitrogen-bound proton HN. For instance,
such reduced exchange rates can be evidenced NMR spectros-
copically by the observation of homonuclear scalar couplings to
the exchangeable proton or by identical diffusion coefficients of
exchangeable and nonexchangeable protons within the same
molecule. Indeed, both of these NMR spectroscopic features
were observed on the level of catalyst/additive solvent combina-
tions only in those cases, for which decelerated enamine forma-
tion was observed, too, i.e. for G in DMSO-d6 and for F/K2CO3
(likewise for F/Na2CO3) in DMSO-d6, but most notably not for
F with other basic additives such as acetates (NaOAc, KOAc) or
NEt3. First, the hampered HN exchange manifests itself in
Figure 5. Graphical summary of the screening methods for the
decelerated formation of prolinol (ether) enamines on the early level
of the catalyst/additive solvent combination.
screening method and Charts S4 and S5 in the Supporting
Information for the NMR assignments of the catalysts). This
may help to avoid the resulting, potentially disadvantageous
effects in diarylprolinol silyl ether catalysis; for instance, one may
speculate that the delayed enamine formation is one of the
reasons for the inferior performance of G in DMSO than in other
solvents62 and for the even more detrimental effect of K2CO3
than of other basic additives (NaOAc and NEt3) to F in
DMSO.63
’ CONCLUSION
In summary, we have investigated the formation and stability
of enamines derived from prolinol (ether)-type organocatalysts
with two different aldehydes in various solvents by means of
NMR spectroscopy. For all enamines studied, the E-configura-
tion is adopted predominantly. For prolinol ether enamines with
small aldehyde alkyl chains, we could evidence for the first time
the presence of the Z-isomer besides the E-enamine in solution.
For prolinol-derived catalysts, the first in situ detection
of enamine intermediates is presented. Similarly to proline
enamines, they can be observed only in the dipolar aprotic
solvent DMSO, but not in methanol, acetonitrile, chloroform,
or toluene. In contrast to proline, however, these prolinol
enamines are shown to coexist in a “parasitic equilibrium” with
the isomeric oxazolidines, since they rapidly undergo cyclization.
In the case of prolinol, the oxazolidine formation is easily
reversible and the thermodynamic equilibrium between the
enamine and both oxazolidines is slowly established. For diphe-
nylprolinol, the geminal phenyl rings shift this equilibrium,
presumably through the ThorpeꢀIngold effect, virtually com-
pletely toward the exclusively detected endo-oxazolidine, which is
then appropriately termed a “dead end” of prolinol enamine
catalysis. Yet, this state can be overcome by destabilizing the
endo-oxazolidine and by stabilizing the prolinol enamine with the
help of bulkier and electron-withdrawing aryl substituents. In this
context, also the first prolinol-derived carbinolamine was de-
tected in situ.
3
the appearance of scalar protonꢀproton couplings JH,H
between HN and the adjacent protons HR and Hδ1,2 in the
1
one-dimensional H spectra (see Figure 4C). Second, the slow
HN exchange is also evidenced from DOSY investigations (data
not shown): For F/K2CO3 in DMSO-d6, identical diffusion
coefficients are observed for HN and the nonexchangeable
protons of the catalyst F. In contrast, in the absence of K2CO3
the diffusion of HN appears to be a lot faster than the one of the
nonexchangeable protons of F because of the exchange of HN
with the faster diffusing residual water in the sample during the
diffusion period of 50 ms. Both the 3JH,H scalar couplings to HN
and the diffusion coefficients of HN indicate a substantially slower
exchange of the nitrogen-bound proton HN for G or F/K2CO3 in
DMSO than in all the other cases and are therefore in line with
our hypothesis of a combination of steric crowding and H-bond-
ing interactions at the nitrogen atom that compromises the
tendency of the nitrogen to form enamines.
Diarylprolinol ether enamines are detected readily in situ.
Their amounts decrease with increasing sizes of the aryl rings and
of the O-protecting group, probably owing to steric conflicts with
the enamine moiety. Methyl ether enamines are more robust
than silyl ethers as, for the latter, we could monitor the desilyla-
tion and subsequent cyclization to the oxazolidine in DMSO. A
drastically delayed formation of the prolinol ether enamines is
These two NMR spectroscopic characteristics may hence be
regarded as a very simple and rapid method to check catalyst/
additive solvent combinations for the delayed enamine formation
with aldehydes (see Figure 5 for a graphical summary of this
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Journal of the American Chemical Society
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observed for unfortunate combinations of aldehydes, catalysts,
solvents, and additives, possibly caused by the stabilization of
carbinolamines and/or by the steric shielding of the nitrogen
atom. Based on its concordance with a reduced exchange rate of
the nitrogen protons, a rapid and facile 1D 1H- or DOSY-based
screening method on the level of the catalytic systems themselves
is presented for this potentially detrimental effect.
’ AUTHOR INFORMATION
Corresponding Author
kirsten.zeitler@chemie.uni-regensburg.de; ruth.gschwind@chemie.
uni-regensburg.de
’ ACKNOWLEDGMENT
On the basis of the examples of prolinol- and prolinol ether-
derived enamines, we illustrate the impact of both the size and
the electronic properties of the pyrrolidine substituent on the
delicate interplay between intermediate selectivities and reac-
tivities in terms of the conformational preferences (s-cis/
s-trans) of enamines, their amounts, and their robustness.
Our results hence provide a broad experimental basis for an
improved understanding of enamine catalysis by diarylprolinol
(ether)s. They should also inspire further studies on the
elucidation of the prolinol (ether) enamine formation pathway,
including the role of oxazolidines and carbinolamines therein
and the issue of the enamine formation rate. Likewise, they are
expected to pave the way for conformational investigations
aiming at the origin of stereoselection exerted by prolinol
(ether) organocatalysts. From a more practical point of view,
helpful advice for the optimization of reaction conditions is
provided for synthetically working organic chemists. Despite
their tremendous success in enamine catalysis, there is still
sufficient space for improving the scaffolds of prolinol ether
organocatalysts, for instance, by avoiding O-deprotection in
solution or too long reaction times, caused by low enamine
amounts and formation rates. In this context, our rapid screen-
ing method may facilitate the future optimization of the prolinol
(ether) catalyst scaffold by substituent variations. On this basis,
also the fine-tuning of the selectivityꢀreactivity balance for
prolinol catalysts (“parasitic equilibrium”) should be facilitated
and might help to expand the scope of prolinol derivatives for
enamine catalysis.
This work was supported by the DFG (SPP 1179). Scholar-
ships from the Cusanuswerk and the Studienstiftung des
deutschen Volkes are gratefully acknowledged.
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Enamines were created in situ inside a standard 5 mm NMR tube by
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(56) Interestingly, the steric destabilization of the prolinol ether
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stabilization by Ar2 that was observed for prolinol enamines. This can be
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