The stability of imidazolidinones is the primary influence on the catalytic activity of proline amides and proline sulfonamides in enamine catalysis using alkyl aldehyde substrates

Article abstract of DOI:10.1002/ejoc.201201174

Some N-substituted proline derivatives catalyse the reactions of alkyl aldehydes with electrophilic partners, and others give negligible amounts of product. The key reaction between the aldehyde and the proline derivative has been studied, and a rationale for the reactivity observed is presented. Simple proline amides derived from aromatic amines (poor catalysts) form stable imidazolidinones quite rapidly at the expense of enamines, the latter being detected, if at all, for less than an hour. Less basic proline amides form a kinetic diastereomer of an imidazolidinone that very slowly inverts its stereochemistry to give a final thermodynamic product. The stereochemistry of these diastereomers was fully assigned by ¹H NMR, NOE, and TOCSY experiments. A proline amide derived from an alkylamine (good catalyst) forms high concentrations of enamine that is only slowly (days) converted into a single diastereomer of an inert imidazolidinone. In contrast, another good catalyst, a proline sulfonamide, immediately forms a reactive imidazolidinone, that rapidly ring-opens and exchanges with other aldehydes. This presumably drip-feeds iminium ions and enamines into the catalytic cycle. Thus, there are two quite different mechanistic regimes that lead to efficient catalysis. These mechanistic insights should now allow some element of rational design of prolinamides for enamine reactions using aldehydes. Some proline amides are poor catalysts when aldehydes are used as substrates since the catalysts irreversibly form imidazolidinones. Proline amides with more basic amide groups form long-lived enamines, which allows catalysis to proceed. Proline sulfonamides only form imidazolidones, but these are unstable. Copyright

Full text of DOI:10.1002/ejoc.201201174

FULL PAPER
DOI: 10.1002/ejoc.201201174
The Stability of Imidazolidinones is the Primary Influence on the Catalytic
Activity of Proline Amides and Proline Sulfonamides in Enamine Catalysis
Using Alkyl Aldehyde Substrates
Sergey Tin,[a] José A. Fuentes,[a] Tomas Lebl,[a] and Matthew L. Clarke*[a]
Keywords: Organocatalysis / Reaction mechanisms / Reactive intermediates / Michael addition / Enamines
Some N-substituted proline derivatives catalyse the reactions
of alkyl aldehydes with electrophilic partners, and others
give negligible amounts of product. The key reaction be-
tween the aldehyde and the proline derivative has been
studied, and a rationale for the reactivity observed is pre-
sented. Simple proline amides derived from aromatic amines
(poor catalysts) form stable imidazolidinones quite rapidly at
the expense of enamines, the latter being detected, if at all,
for less than an hour. Less basic proline amides form a kinetic
diastereomer of an imidazolidinone that very slowly inverts
its stereochemistry to give a final thermodynamic product.
The stereochemistry of these diastereomers was fully as-
signed by 1H NMR, NOE, and TOCSY experiments. A pro-
line amide derived from an alkylamine (good catalyst) forms
high concentrations of enamine that is only slowly (days)
converted into a single diastereomer of an inert imidazolidi-
none. In contrast, another good catalyst, a proline sulfon-
amide, immediately forms a reactive imidazolidinone, that
rapidly ring-opens and exchanges with other aldehydes. This
presumably drip-feeds iminium ions and enamines into the
catalytic cycle. Thus, there are two quite different mechan-
istic regimes that lead to efficient catalysis. These mechan-
istic insights should now allow some element of rational de-
sign of prolinamides for enamine reactions using aldehydes.
tro-Michael reactions of alkyl aldehydes gave low yields of
the products, and we traced this deficiency in the substrate
scope to the formation of a stable imidazolidinone (N,N-
acetal) derived from the alkyl aldehyde and ProNap (Fig-
ure 1). The stability of this imidazolidinone is in complete
contrast to the imidazolidone that is formed from the active
substrate, acetone, with ProNap. The use of β-ProNap, a
proline amide that presumably cannot form an imidazol-
Introduction
Proline amides and other N-substituted proline deriva-
tives have been described as “the most commonly used
group of proline derivatives used in enamine catalysis”.[1]
They certainly attract attention as catalyst candidates in
many laboratories investigating enamine-type catalysis. Pro-
line amides have primarily been investigated for reactions
in which an enamine intermediate is formed from a ketone.
In most examples of this process, a large excess of a ketone
is used, and presumably required.[2,3] The use of ketones as
nucleophiles, especially in excess, is far more common than
the use of alkyl aldehydes, which are generally regarded as
challenging substrates with a range of catalysts. In catalytic
reactions using enolisable aldehydes as substrates, one or
two proline amides and proline sulfonamides have given
good results, but others have given low conversions, even
after long reaction times.[2,3] We previously investigated a
rather unusual Proline amide catalyst that self-assembles
with complementary co-catalysts to make libraries of cata-
lysts (Figure 1).[3] During the mechanistic investigation of
the reactions of these catalysts,[3b] we observed that the ni-
[a] School of Chemistry, University of St Andrews, EaStCHEM,
St Andrews, Fife, UK, KY16 9ST
Fax: +44-1334-463808
E-mail: mc28@st-andrews.ac.uk
Homepage: http://www.st-andrews.ac.uk/chemistry/contact/
academic/#mc28
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201174.
Figure 1. Proline amide and proline sulfonamide catalysts.
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 141
Eur. J. Org. Chem. 2013, 141–147

S. Tin, J. A. Fuentes, T. Lebl, M. L. Clarke
FULL PAPER
idinone, or the use of pyrrolidines functionalised with terti- action[7] between hexanal and β-nitrostyrene. Proline sulf-
ary amines or tertiary amides[2e,2i] results in the efficient onamide 4[2b] and simple proline amide 3 (along with struc-
catalysis of Michael reactions with aldehydes. Clearly, un- turally related catalysts that give better selectivity)[2g] have
derstanding the chemistry of imidazolidones is potentially been reported as effective catalysts for this transformation,
important for enamine catalysis using proline amides. In and they promoted the reaction in our hands also (see Exp.
fact, imidazolidonones derived from ketones and proline Section). Some interesting mechanistic details have emerged
amides have been studied in detail by Arriba et al., but the recently for nitro-Michael reactions catalysed by a trimeth-
formation of ketone-imidazolidones does not preclude reac- ylsilyl-ether-protected diaryl proline derivative that cannot
tivity in the reactions studied.[3b,4] Since the ketone-imid- form troublesome N,N- or N,O-acetals.[7d] While some or
azolidinones ring-open very readily, their presence might many of these insights may well also be relevant to the cata-
imply that the catalyst is entering an equilibrium that leads lytic cycle of the proline amide catalysts, an equally impor-
to the reactive enamine intermediates. However, additives tant issue, particularly for developers of new catalysts, is to
that can inhibit the formation of ketone imidazolidonones define what allows some catalysts to enter and maintain
can increase the rate of reaction,[5] but so too can additives entry into this catalytic cycle, and what structural features
that promote the formation of these resting states.[5,3b] In prevent other proline amides from doing this.
any case, while that paper did describe the synthesis of two
The electronically different proline amides 1 and 2 (poor
aldehyde-imidazolidinones (both from the same proline catalysts) were compared in their reactions with isovaleral-
amide), their reactivity, as a function of aldehyde or proline dehyde (Scheme 1). This aldehyde was used it gives a higher
amide structure, has never been investigated.[4]
concentration of enamines than other aldehydes, it gives
Meanwhile, quite a lot of work has recently been done on NMR resonances that are clear enough to characterise, and
the corresponding N,O-acetals (oxazolidonones)[6] derived the data can be compared with previous studies on this type
from aldehydes and ketones, and this has shown that these of enamine.[3a,6c] The less electron-donating amide, 1 imme-
species are unstable resting states that are in rapid chemical diately formed an imidazolidonone, with no sign of any en-
exchange with other species in the catalyst manifold. Some amine present, even after a reaction time of only 10 min.
evidence indicates that the relative concentrations of N,O- After 10 min, a tiny trace of another compound that was
acetals vs. enamines have a relatively small effect on the subsequently confirmed to be the other diastereomer of
rate or enantioselectivity of certain reactions studied,[6f] but imidazolidonone 1d was just about observable. As time
other studies suggest that these can also reduce the effi- went on, the kinetically favoured diastereomer converted
ciency of catalysts.[6d] Given the interest in and significance slowly into the second one. A 50:50 mixture was reached
of proline amides, we felt that it was important to under- after 1 d, and Ͼ 99% conversion to the thermodynamically
stand the contrasting reactivity that different catalysts exhi- favoured diastereomer was seen after 48 d. The stereochem-
bit when used with alkyl aldehyde substrates. In particular, istry of each of these diastereomers was assigned using a
the fact that rather electron rich proline amide 3, and very TOCSY experiment on a ca. 60:40 mixture of 1c and 1d,
electron-poor proline sulfonamide 4 are both able to cata- as shown in Figure 2, and a 1H NMR NOE experiment
lyse reactions of alkyl aldehydes, when ProNap shows such (Figure 3).
a clear tendancy towards catalyst deactivation, was a com-
The more electron-rich proline amide 2 formed, within a
plete mystery that we wanted to solve. If the performance few minutes, a mixture containing enamine 2b (10%) and
of different catalysts can be understood in terms of their one major diastereomer 2c (40%) of imidazolidonone. This
structural features, then it becomes much easier for re- major diastereomer was assigned the same configuration as
searchers to select the best catalysts to investigate for en- the kinetic diastereomer (i.e., 1c) formed from 1. The en-
amine-promoted reactions. In this paper, we demonstrate amine disappeared within 2 h, but by that time, a mixture
that imidazolidinones derived from N-substituted proline consisting of 95% 2c and 5% 2d had formed, and their
derivatives and alkyl aldehydes show rather complex chem- relative concentrations did not change further with time.
istry; the rates and degrees of formation of enamines and Thus, for the catalyst with the less basic amide group, the
imidazolidonones from proline amides and proline sulfon- imidazolidinone diastereomers interconverted very slowly,
amides, and the reactivity of the imidazolidonones, are pro- and took a long time to form one single stable diastereomer,
foundly affected by relatively small changes in catalyst whereas proline amide 2 rapidly and irreversibly formed a
structure. These observations can be correlated to the per- mixture of two stable diastereomers. Although the imid-
formance of these proline derivatives in catalysis.
azolidones derived from 1 gradually interconverted to reach
the most stable stereoisomer, neither 1 nor 2 were involved
in the type of fast exchange that would be needed for decent
levels of catalytic turnover, as verified by the exchange reac-
tion discussed later in connection with Scheme 2. Com-
Results and Discussion
The Proline derivatives used in this study were prepared pounds 1d (once fully formed from 1c after 48 d), 2c, and
by adapting literature methods, as described in the experi- 2d were all stable, and could be isolated by column
mental section. Rather like ProNap, neither electron-poor 1 chromatography. The reaction of acetone (4 equiv.) with
nor electron-rich amide 2 was an effective catalyst for a typ- electronically different proline amides 1 and 2 was also fol-
ical model aldehyde-enamine reaction: the nitro-Michael re- lowed. This type of experiment has already been done for
142
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 141–147

Catalytic Activity of Proline Amides and Sulfonamides
Scheme 1. Electronic effects on the rates, products, and stereochemical outcomes of the reactions between isovaleraldehyde and N-
substituted proline derivatives 1–4. In the case of 4, only 4d was detectable, and 4 was insoluble.
Figure 2. Expansion of 2D 1H,1H-gs-TOCSY (blue trace) and 1H,1H-gs-DQF-COSY (red trace) acquired for a mixture of 1c and 1d,
showing correlations of 1-H and 3-H resonances (purple dashed line) through the heterocyclic ring and the aliphatic side chain, respec-
tively. The same number of cross-peaks and their similar chemical shifts imply that 1c and 1d have the same regiochemistry and are likely
to be stereoisomers.
some similar proline amides,[4] so the results are included in under vacuum to remove some of the excess acetone, the
the Supporting Information. These experiments confirmed amount of acetone-imidazolidinone reduces, and the start-
that for these specific proline amides 1 and 2, the acetone- ing proline amide is regenerated. The ketone chemistry
derived imidazolidinones are unstable. Thus, when an equi- therefore contrasts with that of aldehydes, but it is consis-
librium mixture of the acetone-imidazolidinone is placed tent with the previous reports discussed in the introduction.
Eur. J. Org. Chem. 2013, 141–147
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
143

S. Tin, J. A. Fuentes, T. Lebl, M. L. Clarke
FULL PAPER
Figure 3. a) 1H NMR spectrum acquired for a mixture of 1c and 1d. b,c) 1D gs-NOESY (selnogpzs) with a mixing time d8 = 800 ms and
selective irradiation set on the 1-H resonance of 1c and 1d, respectively. In the case of 1c, the NOE signal observed for 3-H implies cis
stereochemistry. In contrast, 1d shows an NOE between 1-H and 4-H, which is consistent with trans stereochemistry.
of a stable imidazolidone 3c could be isolated by column
chromatography and characterised.
Proline sulfonamide 4 was completely insoluble in almost
any solvent, and could not be compared in exactly the same
way as compounds 1–3. However, the imidazolidinone
formed from 4 was soluble in CDCl3. The reaction of 4
with isovaleraldehyde gave a single diastereomer of imid-
azolidinone 4d within 2 h (the stereochemistry was assigned
as described for 1c/d). The stability of this imidazolidone
was then investigated. It could not be isolated in the same
way as compounds 1d, 2c/d, and 3c. A similar experiment
to that already described for the reaction of 1 with acetone
was carried out. Simply removing excess aldehyde under
Scheme 2. Only imidazolidinone 4d is observable by NMR spec-
troscopy, and it undergoes a rapid exchange reaction with hexanal,
in contrast to compounds 1d, 2c, and 3c.
We then turned our attention towards the active cata- vacuum resulted in the amount of 4d being reduced, and
lysts, 3 and 4 (Scheme 1). These N-substituted prolines are a white precipitate of 4 being formed. This behaviour is
very different from one another electronically, and the re- analogous to what is observed when catalysts and ketones
sults obtained using 1 and 2 show that electronic effects are that do take part in Michael reactions form imidazolidones.
significant in these reactions. At this stage, we were unsure Since 4d could not be isolated and there is none of the pro-
whether this line of investigation would be able to reconcile line sulfonamide (i.e., 4) dissolved in solution, the only suit-
the fact that the results in ref.[2g] imply that very electron- able experiment that could provide at least a qualitative
rich nitrogen substituents are a good thing for catalysis, measure of the rate of exchange for this catalyst was an
while ref.[2b] implies that very electron-poor nitrogen sub- exchange reaction between the imidazolidinone and an-
stituents are needed. However, as discussed below, 3 and 4 other aldehyde. Catalyst 4 was first converted into 4d using
show quite contrasting reactivities in imidazolidinone for- isovaleraldehyde (1.2 equiv.). n-Hexanal (1.2 equiv.) was
1
mation, and this explains how they can both act as catalysts then added. The H NMR spectrum was recorded 20 min
while 1 and 2 do not.
later. Two species were present, and while most of the peaks
Proline amide 3 was treated with isovaleraldehyde, and were overlapping, two distinct peaks were observed in a 1:2
showed drastically different behaviour. The major species ratio corresponding to the N,N-acetal protons of imid-
formed was E-enamine 3b (assigned by a 1H/13C NMR cor- azolidinone 4d and the hexanal-imidazolidone, respectively
relation). This enamine remained a major species in solu- (see the Supporting Information). No further change in this
tion for many hours. It was only after 16 h that significant ratio was observed when the solution was left for a longer
amounts of an imidazolidinone, assigned as 3c using NOE time. In contrast, when the same experiment was carried
and TOCSY experiments (see the Supporting Information) out with imidazolidones 1d, 2c, and 3c, only 20% conver-
as described for compound 1, were observed (45% after sion to the new imidazolidinone was observed from 1d after
16 h). The reaction mixture of aldehyde, enamine, catalyst, 20 min. 2c and 3c (derived from more basic amides) did not
and imidazolidinone observed after around 20 h was sub- show any exchange at all after 20 min. After much longer
1
jected to an H NMR EXSY experiment. This established reaction times (20 h), 49% exchange was seen with 1d, only
that proline amide 3 was in rapid exchange with the en- traces were observed with 2c, and no exchange was ob-
amine, but that no exchange was detectable from imid- served at all with imidiazolidone 3c. Thus, catalyst 3 is pro-
azolidone 3c. After 48 h, the reaction mixture showed sev- ductive for the period of time before it is converted into
eral additional uncharacterised species, but a small amount inert 3c, in agreement with the EXSY experiment pre-
144
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 141–147

Catalytic Activity of Proline Amides and Sulfonamides
at room temperature unless otherwise stated, and the solvent for a
particular spectrum is given in parentheses. Carbon chemical shifts
are referenced to the carbon signal of the deuterated solvents. En-
amine studies were performed with a Bruker Avance 500 spectro-
meter equipped with a 5 mm inverse probe. Infrared spectra were
recorded with a Perkin–Elmer Paragon 1000 Spectrum GX FTIR
system. Chemical ionisation mass spectroscopy was performed with
a Micromass LCT spectrometer, operated by Mrs Caroline Hors-
burgh at St Andrews University, or at the ESPSRC National Mass
Spectrometry Service Centre, Swansea University, by using a Finni-
gan MAT 900 XLT Instrument. Only major peaks are reported,
and intensities are quoted as percentages of the base peaks. Optical
rotations were measured on a Perkin–Elmer 341 polarimeter, using
a 1 mL cell with a 1 dm path length at 20 °C, using the sodium D-
line.
Boc-1:[8] A solution of Boc-l-proline (1.000 g, 4.65 mmol) in dry
THF (12.0 mL) was cooled to 0 °C. Triethylamine (0.65 mL,
4.66 mmol) was added, then ethyl chloroformate (0.44 mL,
4.60 mmol) was added dropwise, and the resulting mixture was
stirred at 0 °C for 70 min. Then p-(trifluoromethyl)aniline
(0.58 mL, 4.65 mmol) was added dropwise over 15 min. The reac-
tion mixture was left to stir for a further 60 min at 0 °C, and then
the ice/water bath was removed. The resulting mixture was heated
under reflux for 3 h, and then stirred at room temperature over the
weekend. After this time, the solution was filtered, and the solvent
was removed from the filtrate with a rotary evaporator. The re-
sulting residue was redissolved in ethyl acetate (50 mL) and washed
with hydrochloric acid (0.5 m, 5ϫ 20 mL). The organic layer was
separated and dried with MgSO4, and the solvent was removed
under reduced pressure. The resulting solid was purified by column
chromatography on silica gel (hexane/ethyl acetate, 3:1) to give the
desired product as a white solid (0.819 g, 49%). 1H NMR
(300 MHz, CDCl3): δ = 9.86 (br. s, 1 H), 7.47 (br. d, J = 6.5 Hz, 2
H), 7.34 (br. s, 2 H), 4.46 (br. s, 1 H), 3.56–3.24 (br. m, 2 H), 2.40–
1.80 (br. m, 4 H), 1.43 (br. s, 9 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 171.2, 155.4, 142.0, 126.3, 128.3–120.1 (m, overlapping
ArC-CF3), 119.4, 81.5, 61.0, 47.7, 28.8, 28.5, 25.0 ppm. 19F NMR
(282 MHz, CDCl3): δ = –62.66 (s, CF3) ppm. MS (ES+): m/z (%)
= 380.93 (100) [M + Na]+, 280.96 (7), 258.98 (23). HRMS (ES+):
calcd. for C17H21N2F3O3Na [M + Na]+ 381.1402; found 381.1404.
viously discussed. This behaviour correlates with the per-
formance in catalysis and the other experiments performed
for 1–3 already discussed.
Conclusions
A consistent trend emerges for these proline derivatives
whereby more basic amide substituents lead to an imid-
azolidone that is stable and formed irreversibly. However,
for the most basic proline amide (i.e., 3), very large amounts
of enamine, amongst the highest concentrations observed
in enamine catalysis, are formed, and are long-lived species,
which allows catalysis to occur and to deliver high yields
of product before the irreversible degradation to the stable
imidazolidinone takes place. Less basic proline amide 1
shows signs of the imidazolidone being less stable, insofar
as a kinetically formed diastereomer is converted into an-
other diastereomer very slowly over time, but not on the
timescales that are needed for effective catalysis. Proline sul-
fonamide 4 readily and rapidly forms an imidazolidone,
with no enamine detectable, but it is an unstable compound
that reaches equilibrium in an exchange experiment as soon
as data can be collected, i.e., on a timescale that would
make the supply of reactive enamines into the catalytic cy-
cle relatively facile, as it is with trimethylsilyl-ether-pro-
tected prolinol derivatives. This lack of stability makes
imidazolidinone 4d a reactive resting state rather than a de-
composition product. This study also has implications for
catalyst recycling or use in continuous flow mode. Electron-
rich catalysts will probably not be suitable for recycling in
any reaction using alkyl aldehyde substrates, since they are
relatively short-lived, whereas the mechanism of action of
the sulfonamide is consistent with the requirements for a
long-lived recyclable catalyst. This study reconciles the ob-
servations that both very electron-rich and very electron-
poor nitrogen substituents are beneficial for enamine cataly-
sis with alkyl aldehydes, and it is hoped that it will allow
organocatalysis researchers to choose catalysts, and indeed
design new catalysts effective for enamine catalysis.
Boc-2:[9] A solution of Boc-l-proline (0.501 g, 2.33 mmol) in dry
THF (6.0 mL) was cooled to 0 °C. Triethylamine (0.32 mL,
2.30 mmol) was added, then ethyl chloroformate (0.22 mL,
2.30 mmol) was added dropwise, and the resulting mixture was
stirred at 0 °C for 70 min. Then a solution of p-anisidine (0.317 g,
2.57 mmol) in THF (3.0 mL) was added dropwise over 15 min. The
reaction mixture was left to stir for a further 75 min at 0 °C and
then the ice/water bath was removed. The resulting mixture was
heated under reflux for 3 h, and then stirred at room temperature
over the weekend. After this time, the solution was filtered, and the
solvent was removed from the filtrate with a rotary evaporator. The
resulting crude product was subjected to silica gel column
chromatography (hexane/ethyl acetate, 2:1) to give a mixture of the
desired product contaminated with p-anisidine. To remove the
amine, the mixture was dissolved in ethyl acetate (20 mL), and
washed with hydrochloric acid (0.5 m, 3ϫ 20 mL). The organic
phase was collected and dried with MgSO4, and the solvent was
removed under reduced pressure to give the desired product as a
Experimental Section
General Remarks: Dry dichloromethane was obtained from an In-
novative Technologies Puresolve 400 solvent still. Other solvents
were bought and used as received without further purification. All
manipulations were carried out under an atmosphere of nitrogen
unless otherwise stated. Compound 3 was prepared according to
literature procedures.[2f] Solvents were removed by rotary evapora-
tion on a Heidolph labrota 4000. Flash column chromatography
was performed on Davisil silica gel Fluorochem 60 Å, particle size
35–70 μm. HPLC analysis was determined with a Varian Prostar,
operated by Galaxie workstation software. NMR spectra were re-
corded with Bruker Avance 300 and 400 instruments. Proton chem-
ical shifts are referenced to internal residual solvent protons. Pro-
ton signal multiplicities are given as s (singlet), d (doublet), t (trip-
let), q (quartet), m (multiplet), br. (broad) or a combination of the
above. When appropriate, coupling constants (J) are quoted in Hz,
and are reported to the nearest 0.1 Hz. All spectra were recorded
1
white solid (0.533 g, 71%). H NMR (400 MHz, CDCl3): δ = 9.25
(s, 1 H), 7.34 (d, J = 8.9 Hz, 2 H), 6.74 (br. s, 2 H), 4.48–4.14 (br.
m, 1 H), 3.69 (s, 3 H), 3.57–3.18 (br. m, 2 H), 2.49–1.76 (br. m, 4
H), 1.41 (br. s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.8,
156.0, 155.9, 131.8, 121.2, 114.0, 80.8, 60.4, 55.5, 47.2, 28.4, 27.6,
Eur. J. Org. Chem. 2013, 141–147
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
145

S. Tin, J. A. Fuentes, T. Lebl, M. L. Clarke
FULL PAPER
24.6 ppm. MS (ES+): m/z (%) = 343.00 (100) [M + Na]+, 243.03
(10). HRMS (ES+): calcd. for C17H24N2O4Na [M + Na]+ 343.1634;
found 343.1631.
dehyde (13 μL, 0.12 mmol) was added, and the reaction was moni-
tored by 1H NMR spectroscopy. When the monitoring was com-
plete, a small amount of 2c was isolated by chromatography on
SiO2 using EtOAc as eluent; yellow oil. [α]2D0 = –28.8 (c = 0.4,
Compound 1:[10] Trifluoroacetic acid (1.6 mL, 21.5 mmol) was
CHCl ). IR (neat): ν = 2955, 2870, 2046, 1876, 1700, 1609,
˜
3
added to
a solution of Boc-l-(4-trifluoromethyl)prolinamide
1513 cm–1. H NMR (400 MHz, CDCl3): δ = 6.98 (d, J = 9.0 Hz,
1
(0.781 g, 2.18 mmol) in CH2Cl2 (10 mL), and the resulting solution
was left to stir overnight at room temperature. After this time, the
solvent was removed under reduced pressure, and the crude prod-
uct was dried under vacuum for 2 h. The resulting brown oil was
washed with petroleum ether (2ϫ 5 mL), and dissolved in water
(10 mL), and the solution was made basic with NaOH (aq.). The
resulting aqueous solution was extracted with CH2Cl2 (4ϫ 30 mL).
The organic extracts were washed with water (5 mL) and dried with
anhydrous Na2SO4, and the solvent was removed under reduced
pressure. The resulting solid was left to dry in vacuo for 5 h to
2 H), 6.86 (d, J = 9.0 Hz, 2 H), 5.03 (dd, J = 10.7, J = 3.8 Hz, 1
H), 3.80 (dd, J = 8.8, J = 4.5 Hz, 1 H), 3.74 (s, 3 H), 2.89–2.83 (m,
1 H), 2.60–2.52 (m, 1 H), 2.23–2.06 (m, 2 H), 1.91–1.72 (m, 3 H),
1.47–1.30 (m, 2 H), 0.89 (d, J = 6.5 Hz, 3 H), 0.85 (d, J = 6.7 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 177.0, 158.4, 129.5,
127.5, 114.6, 76.0, 65.9, 55.5, 45.9, 38.0, 25.5, 24.7, 24.4, 23.8,
21.7 ppm. MS (ES+): m/z (%) = 310.91 (100) [M + Na]+, 288.97
(50) [M
+
H]+. HRMS (ES+): calcd. for C17H24N2O2Na
[M + Na]+ 311.1735; found 311.1728.
1
give the desired product as a white solid (0.507 g, 90%). H NMR
Compound 2d: Amine 2 (0.022 g, 0.10 mmol) was dissolved in
CDCl3 (0.7 mL) and placed in an NMR tube. Then isovaleral-
dehyde (13 μL, 0.12 mmol) was added, and the reaction was moni-
tored by 1H NMR spectroscopy. When the monitoring was com-
plete, a small amount of 2d was isolated by chromatography on
SiO2 using EtOAc as eluent; yellow oil. [α]2D0 = +29.5 (c = 0.8,
(300 MHz, CDCl3): δ = 9.89 (s, 1 H), 7.66 (d, J = 8.5 Hz, 2 H),
7.50 (d, J = 8.7 Hz, 2 H), 3.80 (dd, J = 9.3, J = 5.2 Hz, 1 H), 3.08–
2.87 (m, 2 H), 2.25–1.91 (m, 3 H), 1.79–1.63 (m, 2 H) ppm. 13C
4
NMR (75 MHz, CDCl3): δ = 174.3, 141.3, 126.6 (q, JC,F
=
3.6 Hz), 125.6 (q, 3JC,F = 32.7 Hz), 124.2 (q, 3JC,F = 271 Hz), 119.3,
61.4, 47.8, 31.2, 26.9 ppm. 19F NMR (282 MHz, CDCl3): δ =
–62.51 (s, CF3) ppm. MS (ES+): m/z (%) = 258.96 (100) [M + H]+.
HRMS (ES+): calcd. for C12H14F3N2O [M + H]+ 259.1058; found
259.1055.
CHCl ). IR (neat): ν = 2956, 2869, 2049, 1875, 1695, 1609,
˜
3
1512 cm–1. H NMR (400 MHz, CDCl3): δ = 7.28 (d, J = 9.1 Hz,
1
2 H), 6.85 (d, J = 9.1 Hz, 2 H), 4.60 (dd, J = 9.9, J = 2.9 Hz, 1
H), 3.91 (dd, J = 9.1, J = 4.4 Hz, 1 H), 3.74 (s, 3 H), 3.24–3.19 (m,
1 H), 2.67–2.61 (m, 1 H), 2.18–1.96 (m, 2 H), 1.87–1.71 (m, 3 H),
1.45–1.28 (m, 2 H), 0.85 (d, J = 6.6 Hz, 3 H), 0.84 (d, J = 6.7 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 173.9, 157.4, 130.0,
124.5, 114.5, 81.6, 64.5, 56.3, 55.5, 43.1, 27.4, 25.0, 24.6, 23.6,
21.5 ppm. MS (ES+): m/z (%) = 310.87 (100) [M + Na]+. HRMS
(ES+): calcd. for C17H24N2O2Na [M + Na]+ 311.1735; found
311.1728.
Compound 2:[9] Trifluoroacetic acid (1.5 mL, 20.2 mmol) was added
to a solution of Boc-l-(4-methoxyphenyl)prolinamide (0.496 g,
1.55 mmol) in CH2Cl2 (5 mL), and the resulting solution was left
to stir overnight at room temperature. After this time, the solvent
was removed under reduced pressure and dried under vacuum for
2 h. The resulting brown oil was washed with petroleum ether (2ϫ
5 mL), and dissolved in water (9 mL), and the solution was made
basic with NaOH (aq.). The resulting aqueous solution was ex-
tracted with CH2Cl2 (4ϫ 15 mL). The organic extracts were
washed with water (5 mL) and dried with anhydrous Na2SO4, and
the solvent was removed under reduced pressure. The resulting so-
lid was left to dry under vacuum for 5 h to give the desired product
Compound 3c: Amine 3 (0.022 g, 0.10 mmol) was dissolved in
CDCl3 (0.7 mL) and placed in an NMR tube Then isovaleral-
dehyde (13 μL, 0.12 mmol) was added, and the reaction was moni-
tored by 1H NMR spectroscopy. When the monitoring was com-
plete, an analytically pure sample of 2d was isolated by chromatog-
raphy on SiO2 using EtOAc as eluent; yellow oil (15 mg, 52%).
1
as a white solid (0.327 g, 96%). H NMR (400 MHz, CDCl3): δ =
9.52 (s, 1 H), 7.44 (d, J = 9.0 Hz, 2 H), 6.79 (d, J = 9.1 Hz, 2 H),
3.78 (dd, J = 9.2, J = 5.2 Hz, 1 H), 3.72 (s, 3 H), 3.05–2.97 (m, 1
H), 2.94–2.87 (m, 1 H), 2.19–2.08 (m, 1 H), 2.02–1.89 (m, 2 H),
1.76–1.61 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.5,
156.4, 131.6, 121.2, 114.5, 61.4, 55.9, 47.8, 31.2, 26.7 ppm. MS
(ES+): m/z (%) = 242.99 (100) [M + Na]+. HRMS (ES+): calcd. for
C12H17N2O2 [M + H]+ 221.1290; found 221.1296.
[α]2D0 = –24.1 (c = 0.5, CHCl ). IR (neat): ν = 2960, 1691, 1495,
˜
3
1409, 1294, 1163, 1103 cm–1. 1H NMR (400 MHz, CDCl3): δ =
7.30–7.18 (m, 5 H), 5.33 (q, J = 7.2 Hz, 1 H), 4.35 (dd, J = 11.7,
J = 2.8 Hz, 1 H), 3.66–3.63 (m, 1 H), 2.75–2.72 (m, 1 H), 2.40–
2.34 (m, 1 H), 2.16–2.01 (m, 2 H), 1.83–1.57 (m, 4 H), 1.54 (d, J
= 7.2 Hz, 3 H), 1.49–1.42 (m, 1 H), 0.77 (d, J = 6.7 Hz, 3 H), 0.44
(d, J = 6.5 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 176.9,
138.8, 128.5, 127.4, 127.2, 74.1, 65.3, 49.6, 46.2, 38.5, 25.4, 24.6,
24.2, 24.1, 20.9, 18.6 ppm. MS (ES+): m/z (%) = 309.05 (100) [M
+ Na]+, 287.1 (32), 219.1 (41), 190.09 (29). HRMS (ES+): calcd.
for C18H26N2ONa [M + Na]+ 309.1943; found 309.1939.
Compound 1d: Amine 1 (0.026 g, 0.10 mmol) was dissolved in
CDCl3 (0.7 mL) and placed in an NMR tube. Then isovaleral-
dehyde (13 μL, 0.12 mmol) was added, and the reaction was moni-
tored by 1H NMR spectroscopy. When the monitoring was com-
plete, a small amount of 1d was isolated by chromatography on
SiO2 using EtOAc as eluent; yellow oil. [α]2D0 = –35.3 (c = 1.3,
Compound 4d: A mixture of amine 4 (0.023 g, 0.10 mmol) and isov-
aleraldehyde (13 μL, 0.12 mmol) in CDCl3 (0.7 mL) was stirred for
2 h and then placed in an NMR tube. The reaction was then moni-
tored by 1H NMR spectroscopy. Unstable compound 4d was char-
acterised by NMR (1H, 1D gs-NOESY, 13C HSQC) spectroscopy,
and by MS and HRMS. 1H NMR (400 MHz, CDCl3): δ = 4.77
(dd, J = 10.0, J = 4.1 Hz, 1 H), 3.89–3.82 (m, 1 H), 3.48–3.43 (m,
1 H), 3.14–3.06 (m, 2 H), 2.55–2.48 (m, 1 H), 2.13–1.39 (m, 7 H),
0.86 (d, J = 6.7 Hz, 3 H), 0.85 (d, J = 6.6 Hz, 3 H) ppm. MS
(ES+): m/z (%) = 301.03 (100) [M + H]+. HRMS (ES+): calcd. for
C11H20N2O2F3S [M + H]+ 301.1198; found 311.1201. Exchange ex-
periment with hexanal (see Figure S7 in the Supporting Infor-
mation, compound 4e): The exchange of 4d with hexanal was con-
CHCl ). IR (neat): ν = 2958, 2872, 1914, 1705, 1615, 1521 cm–1.
˜
3
1H NMR (300 MHz, CDCl3): δ = 7.63 (d, J = 8.9 Hz, 2 H), 7.56
(d, J = 8.6 Hz, 2 H), 4.80 (dd, J = 10.0, J = 2.8 Hz, 1 H), 3.94 (dd,
J = 9.1, J = 4.3 Hz, 1 H), 3.26–3.19 (m, 1 H), 2.65–2.63 (m, 1 H),
2.30–1.68 (m, 5 H), 1.50–1.32 (m, 2 H), 0.93 (d, J = 6.6 Hz, 3 H),
0.87 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
175.3, 140.9, 126.7 (br. s), 128.3–120.1 (m, overlapping ArC-CF3),
121.0, 80.9, 65.1, 56.4, 43.1, 27.8, 25.3, 25.2, 24.0, 21.9 ppm. MS
(ES+): m/z (%) = 349.0 (100) [M + Na]+. HRMS (ES+): calcd. for
C17H21N2OF3Na [M + Na]+ 349.1504; found 349.1511.
Compound 2c: Amine 2 (0.022 g, 0.10 mmol) was dissolved in
CDCl3 (0.7 mL) and placed in an NMR tube. Then isovaleral-
146
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 141–147

Catalytic Activity of Proline Amides and Sulfonamides
firmed by 1H NMR spectroscopy on the 1:2 mixture (4d/4e) formed
and further corroborated by HRMS. MS (ES+): m/z (%) = 315.03
22, 840; i) M. Wiesner, G. Upert, G. Angelici, H. Wennemers,
J. Am. Chem. Soc. 2010, 132, 6; j) L. S. Zu, H. X. Xie, H. Li,
J. Wang, W. Wang, Org. Lett. 2008, 10, 1211; k) X. Q. Dong,
H. L. Teng, C. J. Wang, Org. Lett. 2009, 11, 1265; l) L. S. Zu,
J. Wang, H. Li, W. Wang, Org. Lett. 2006, 8, 3077; m) J. Wang,
H. Li, B. S. Lou, L. S. Zu, H. Guo, W. Wang, Chem. Eur. J.
2006, 12, 4321.
(100) [M
+
H]+. HRMS (ES+): calcd. for C12H22N2O2F3S
[M + H]+ 315.1354; found 315.1350.
General Procedure for the Conjugate Addition of a Ketone (Alde-
hyde) to
a Nitroolefin: Catalyst (10 mol-%) and nitroolefin
[3] a) M. L. Clarke, J. A. Fuentes, Angew. Chem. 2007, 119, 948;
Angew. Chem. Int. Ed. 2007, 46, 930; b) J. A. Fuentes, T. Lebl,
A. M. Z. Slawin, M. L. Clarke, Chem. Sci. 2011, 2, 1997.
[4] a) A. L. F. de Arriba, L. Simon, C. Raposo, V. Alcazar, F. Sanz,
F. M. Muniz, J. R. Moran, Org. Biomol. Chem. 2010, 8, 2979;
b) For the detection of another imidazolidinone, see A. L. Fu-
entes de Arriba, L. Simon, C. Raposo, V. Alcazar, J. R. Moran,
Tetrahedron 2009, 65, 4841.
(0.25 mmol) were dissolved in CDCl3 (1 mL). The relevant ketone
(or aldehyde) (1.2 mmol) was added to the catalyst solution. The
resulting mixture was stirred for the time and temperature required.
The reaction was quenched with HCl (1 m, 1 mL), the mixture was
diluted with CH2Cl2 (1 mL) and H2O (1 mL), and the aqueous
phase was extracted with CH2Cl2 (3ϫ 5 mL). The combined or-
ganic extracts were dried with anhydrous MgSO4, filtered and con-
centrated under reduced pressure. The residue was purified by flash
column chromatography to give the Michael products. For the
Michael addition reaction of hexanal to β-nitrostyrene: Catalyst 1
(32 h, trace product); Catalyst 2 (32 h, trace product); Catalyst 3
(32 h, 50%); Catalyst 4 (48 h, 99%), (ref.[2f] 48 h, 98%, 1.5 equiv.
valeraldehyde, CH2Cl2).
[5] a) C. Andreu, T. Varea, G. Asensio, Tetrahedron 2011, 67, 8705;
b) N. El-Hamdouni, X. Companyo, R. Rios, A. Moyano,
Chem. Eur. J. 2010, 16, 1142.
[6] a) B. List, L. Hoang, H. J. Martin, Proc. Natl. Acad. Sci. USA
2004, 101, 5839; b) D. A. Bock, C. W. Lehmann, B. List, Proc.
Natl. Acad. Sci. USA 2010, 107, 20636; c) M. B. Schmid, K.
Zeitler, R. M. Gschwind, Angew. Chem. Int. Ed. 2010, 49, 4997;
d) M. B. Schmid, K. Zeitler, R. M. Gschwind, J. Am. Chem.
Soc. 2011, 133, 7065; e) J. E. Hein, J. Bures, Y. H. Lam, M.
Hughes, K. N. Houk, A. Armstrong, D. G. Blackmond, Org.
Lett. 2011, 13, 5644; f) D. Seebach, U. Groselj, D. M. Badine,
W. B. Schweizer, A. K. Beck, Helv. Chim. Acta 2008, 91, 1999;
g) P. D. de Maria, P. Bracco, L. F. Castelhano, G. Bargeman,
ACS Catal. 2011, 1, 70; h) C. Isart, J. Burés, J. Vilarrasa, Tetra-
hedron Lett. 2008, 49, 5414; i) For a review on mechanisms in
enamine catalysis, see: M. Nielsen, D. Worgull, T. Zweifel, B.
Gschwend, S. Bertelsen, K. A. Jørgensen, Chem. Commun.
2011, 47, 632.
[7] a) S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 1701; b) J. L. Vic-
ario, D. Badia, L. Carrillo, Synthesis 2007, 2065; c) D. Enders,
C. Wang, J. X. Liebich, Chem. Eur. J. 2009, 15, 11058; d) J.
Bures, A. Armstrong, D. G. Blackmond, J. Am. Chem. Soc.
2011, 133, 8822; e) For similar fundings, see: K. Patora-Komis-
arska, M. Benohoud, H. Ishikawa, D. Seebach, Y. Hayashi,
Helv. Chim. Acta 2011, 94, 719.
Supporting Information (see footnote on the first page of this arti-
cle): Further experimental details, further experiments cited in the
text, NMR spectra of the proline amides and imidazolidinone in-
termediates, and EXSY, NOE, and TOCSY NMR experiments.
Acknowledgments
The authors thank the Engineering and Physical Sciences Research
Council (EPSRC) for funding, and all the technical staff in the
School of Chemistry for their efforts.
[1] G. Guillena, C. Najera, D. J. Ramon, Tetrahedron: Asymmetry
2007, 18, 2249.
[2] a) G. Guillena, M. D. Hita, C. Najera, Tetrahedron: Asymmetry
2006, 17, 729; b) W. Wang, J. Wang, H. Li, Angew. Chem. 2005,
117, 1393; Angew. Chem. Int. Ed. 2005, 44, 1369; c) D. Almasi,
D. A. Alonso, C. Najera, Tetrahedron: Asymmetry 2007, 18,
299; d) J. Wang, H. Li, L. S. Zu, W. Wang, Adv. Synth. Catal.
2006, 348, 425; e) J. M. Betancort, C. F. Barbas III, Org. Lett.
2001, 3, 3737; f) F. Kelleher, S. Kelly, J. Watts, V. McKee, Tetra-
hedron 2010, 66, 3525; g) J. Watts, L. Luu, V. McKee, E. Carey,
F. Kelleher, Adv. Synth. Catal. 2012, 354, 1035; h) J. W. Xu,
X. K. Fu, C. L. Wu, X. Y. Hu, Tetrahedron: Asymmetry 2011,
[8] M. Nakajima, I. Miyoshi, K. Kanayama, S.-I. Hashimoto, M.
Noji, K. Koga, J. Org. Chem. 1999, 64, 2264.
[9] X. Wu, Y. Li, C. Wang, L. Zhou, X. Lu, J. Sun, Chem. Eur. J.
2011, 17, 2846.
[10] J. Collin, J. Fiaud, S. Zeror, L. A. Zouioueche, Adv. Synth. Ca-
tal. 2008, 350, 197.
Received: August 31, 2012
Published Online: November 9, 2012
Eur. J. Org. Chem. 2013, 141–147
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
147