Transfer of 1-alkenyl groups between secondary amines. Relative stability and reactivity of enamines from popular organocatalysts

Article abstract of DOI:10.1021/ol501044u

Enamines from 3-methylbutanal and several Pro- and Phe-derived secondary amines were prepared in DMSO-d₆, CD₃CN, and CDCl ₃. For the first time, the relative thermodynamic stabilities of these and other enamines were compared, and rapid exchanges of 1-alkenyl groups were demonstrated. Competition experiments showed that the most favored enamines (without significant steric inhibition of resonance) react more rapidly with electrophiles.

Full text of DOI:10.1021/ol501044u

Letter
pubs.acs.org/OrgLett
Transfer of 1‑Alkenyl Groups between Secondary Amines. Relative
Stability and Reactivity of Enamines from Popular Organocatalysts
Hector Carneros, Dani Sanchez, and Jaume Vilarrasa*
́
́
Departament de Química Organ
̀
ica, Facultat de Química, Universitat de Barcelona, Diagonal 645, 08028 Barcelona, Catalonia, Spain
S
* Supporting Information
ABSTRACT: Enamines from 3-methylbutanal and several Pro- and Phe-derived secondary amines were prepared in DMSO-d6,
CD3CN, and CDCl3. For the first time, the relative thermodynamic stabilities of these and other enamines were compared, and
rapid exchanges of 1-alkenyl groups were demonstrated. Competition experiments showed that the most favored enamines
(without significant steric inhibition of resonance) react more rapidly with electrophiles.
a
1
Scheme 1. Keq Values Determined by H NMR
symmetric aminocatalysis is an extremely useful tool for
Athe synthesis of chiral building blocks (chiroblocks,
chirons).1,2 Among the most popular enantiopure secondary
amines used as organocatalysts, apart from α-amino acid
proline (Pro), are the Phe-derived MacMillan catalysts3 and
Pro-derived Jørgensen−Hayashi catalysts.4 Primary amines
prepared from Cinchona alkaloids1b,e,5 are also worth noting.
Choosing the most suitable aminocatalyst for the generation
of the desired enamines is often an empirical process. To be
aware of the relative thermodynamic stability of the enamines
(of all the stereoisomers and conformers) could help in the
selection, if it could be rapidly determined by NMR or
calculated. This is our objective. Moreover, the relative
percentage of the possible enamines in equilibrium (for
example, when two carbonyl groups and/or two secondary
amines are present) may also be useful to explain or predict the
course of cascade or domino reactions.
The NMR spectra of mixtures of 3-methylbutanal (iso-
valeraldehyde) with chiral secondary amines (containing a
pyrrolidine ring, mainly proline or prolinol derivatives, but also
imidazolidinones) were registered in DMSO-d6, CD3CN, and
CDCl3. After reaching equilibrium (in general, within 15 min),
the Keq values for the formation of enamines 1a−7a were
calculated from the integrations (Scheme 1, for details see the
Supporting Information). For the sake of comparison, although
it is of no interest from the point of view of asymmetric
synthesis, we also prepared the enamine of diisopropylamine
(8a). We chose 3-methylbutanal because, in relation to linear
aliphatic aldehydes, a very low percentage of aldol adducts were
formed. Some of their enamines have been described,6 but we
were interested in the comparison of the Keq of a long series, in
an attempt to find a useful general rule.
a
Ar = 3,5-bis(trifluoromethyl)phenyl. Holes in the series (n.d. = not
determined) are due to the partial hydrolysis of the O−Si bond of 5
and the lack of detection of 8 in the less polar solvent.
will interact more strongly with the CO group, so the first
equilibrium will be shifted further toward the hemiaminal(s), or
N,O-acetal(s), a study of the relative stability of which is
As expected, the equilibria were shifted furthest to the right
(Scheme 1) for those pyrrolidines substituted with groups of
smaller size and/or of weaker electron-withdrawing character.
In the first step, it is likely that the most nucleophilic N atoms
Received: April 10, 2014
Published: May 13, 2014
© 2014 American Chemical Society
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beyond the scope of this work. In the second step, the
dehydration step, the most stable enamines (those in which the
resonance is not inhibited or diminished by steric effects and/or
by an EWG close to the N atom) will be formed in larger
amounts. Thus, both steps depend on the “practical” electron-
donating ability of the N atom.
The equilibria were more shifted to the right in DMSO-d6
than in CD3CN and CDCl3 (Scheme 1). Apart from the
polarity, the hygroscopic nature of DMSO may also play a
role.7
It is clear that the sterically less hindered amines, such as O-
TBDPS-prolinol (1, first examined by Peng et al.8), methyl
prolinate (2), and N,N-dibenzylprolinamide (3)9 give the most
stable enamines (1a−3a). The Jørgensen−Hayashi catalyst (4)
and Jørgensen’s tetrakis-CF3 derivative (5) follow. At the other
extreme, the most crowded amines, the first- and second-
generation MacMillan catalysts (6 and 7) and diisopropylamine
(8), afford the lowest concentrations of enamines (6a−8a).10
The Keq values that are very high or very low are
approximate. They were obtained by mixing equimolar
amounts of pairs of amines and adding up to 120 mol % of
3-methylbutanal (see spectra in the Supporting Information)
and referred to reliable values, highlighted in bold. For
equilibria shifted too far to the left or to the right the Keq
values cannot be obtained directly, properly, as they come from
Figure 2. 1H NMR spectra of the exchange of the 3-methyl-1-buten-1-
yl group between 4a and 1 in CD3CN: (a) portion of the spectrum of
4a, with a small amount of aldehyde remaining in the equilibrium; (b)
10 min after the addition of 1 equiv of O-TBDPS-prolinol (1), 4a
almost disappeared, while 1a largely predominated.
1
the integrations of the corresponding H NMR peaks, some of
which can hardly be seen. What matters is the relative order.
Exchange experiments were in agreement with the relative
order shown in Scheme 1. For example, when a solution of 2a
in DMSO-d6, prepared independently (Figure 1a), was treated
Enamines from primary amines cannot be included in the
scale of Scheme 1, as they give imines. Enamine signals were
not detected. Nevertheless, using PhCH2CHO (phenylacetal-
dehyde), which is more prone than 3-methylbutanal to give
enamines because of the conjugation of the enamino with the
Ph group, a comparison is feasible (Figure 3). In practice, when
Figure 3. Relative stabilities of enamines from PhCH2CHO.
isopropylamine was treated with PhCH2CHO, the expected
imine (δ 7.72) was formed, which slowly (overnight) but fully
isomerized to its enamine, 9b. On the other hand, when the
experiment was carried out in the presence of PhCOOH (1
equiv), 9b appeared immediately.
Mixing equimolar amounts of 1a and 2b, prepared
independently, a slow exchange was observed, with appearance
of the crossed enamines, 2a and 1b. Three days later, the H
NMR spectrum indicated a mixture of 1a (20%), 1b (9%), 2a
(32%), and 2b (40%).
Figure 1. 1H NMR spectra of the exchange of the 3-methyl-1-buten-1-
yl group between 2a and 1 in DMSO-d6: (a) Portion of the spectrum
of 2a; (b) 10 min after the addition of 1 equiv of O-TBDPS-prolinol
(1), enamine 1a already predominated.
1
Experiments with 2-indanone, a ketone prone to yielding
enamines, and representative amines, including (9R)-6′-
methoxycinchonan-9-amine,1b,e,5,11 are shown in Figure 4.
The parallelism between Scheme 1, Figure 3, and Figure 4
indicates that there are general rules or patterns, so the ordering
may be extended with other enamines.
with O-TBDPS-prolinol (1) in an NMR tube, the equilibrium
was reached in 10−15 min, with partial transfer of the alkenyl
group, to give enamine 1a (Figure 1b). In CD3CN, the addition
of 1 to 4a (Figure 2a) gave quickly an equilibrium shifted far to
the right (Figure 2b).
Although the enamines from pyrrolidine6a,12 have no interest
in asymmetric catalysis, we determined their relative Keq ratios
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Figure 4. Relative stabilities of 2-indanone enamines. 6MQ4 = 6-
methoxyquinolin-4-yl.
Figure 5. (a) Mixture of enamines 1b (Hβ doublet at δ 5.30) and 4b
(Hβ doublet at δ 5.15) in CD3CN, in 1.12:1.00 ratio; (b) 10 min after
addition of 20 mol % of nitrostyrene, the ratio was 0.92:1; (c) 10 min
after the addition of further 30 mol % of nitrostyrene, the ratio
diminished to 0.69:1; (d) 10 min after the addition of further 50 mol
% of nitrostyrene, the 1b/4b ratio was 0.55:1.
for comparison. As it could be expected, they are
thermodynamically more stable than 1a, 1b, and 1c: 1.1
(DMSO-d6), 1.7 (CD3CN), and 1.4 (CDCl3) in series a; 2.8
(DMSO-d6) in series b; 20 (DMSO-d6) and 10 (CD3CN) in
series c.
Mechanistically, the exchanges between enamines and
amines shown in Scheme 1 and Figures 1 and 2 may be
mediated by water (that is, via hydrolysis). However, it is more
interesting to evaluate if the exchanges may also take place by
formation of an aminal (enamine A + amine B = aminal =
amine A + enamine B), in other words, via an addition−
elimination mechanism (hydroamination of the double bond of
an enamine), either noncatalyzed or catalyzed by a trace of acid.
The chemistry of aminals is known,13 but the question is to
demonstrate a significant participation in the exchanges
reported here. At rt we never detected the corresponding
aminals by mixing equivalent amounts of enamines and amines,
nor by mixing 200 mol % of pyrrolidine with 3-methylbutanal
in CD3CN. However, in this last case decreasing the
temperature to −30 °C (VT-1H NMR) the aminal appeared
(1:3 aminal/enamine ratio, methine of the aminal at δH 3.21, t,
J = 6.3 Hz, methine δC 75.8, see the Supporting Information
for more details). Also, even at rt, aminal signals were clearly
detected by adding an excess of pyrrolidine (5 equiv) to
pyrrolidine−3-methylbutanal enamine in DMSO-d6 at rt; EXSY
peaks correlating enamine and aminal (δ 6.09/3.21, δ 3.96/
1.35) were clearly observed in the NOESY spectrum (see the
Supporting Information). A detailed study of the relative
stability of aminals is outside the scope of this communication,
but the experiments just mentioned indicate that aminals can be
involved as reaction intermediates in the exchange reactions of
Figures 1 and 2.
Figure 6. (a) Mixture of enamines 1b (see Hβ doublet at δ 5.30) and
4b (Hβ doublet at δ 5.15) in CD3CN, in 1:1 ratio; (b) 10 min after
addition of 10 mol % of DEAD (40% in toluene), the ratio was 0.75:1;
(c) 10 min after the addition of further 40 mol % of DEAD, the ratio
diminished to 0.35:1; (d) with 100 mol % of DEAD, 1b disappeared
completely, while 4b was still detectable.
These preliminary experiments suggest that the thermody-
namically more favored enamines (the less crowded enamines,
if there are no strong EWG in the close neighborhood) may be
the most reactive as nucleophiles.15
Until now, we have dealt only with thermodynamics.14 Let us
now comment on the kinetic differences between enamines.
By addition of standard Michael acceptors, such as (E)-1-
nitro-2-phenylethene (E-PhCHCHNO2, henceforward “ni-
trostyrene”) to pairs of two enamines in practically identical
percentage (prepared independently and mixed in appropriate
ratios into the NMR tube), we observed that the most favored
enamine disappeared more rapidly. For example, a mixture of
1b and 4b in CD3CN, treated from 0 °C to rt with nitrostyrene
(CD3CN solution added in portions), caused a more rapid
disappearance of 1b than of 4b (see Figure 5).
In conclusion, series of enamines of 3-methylbutanal,
phenylacetaldehyde, and 2-indanone from the most popular
organocatalysts have been compared for the first time. The
relative thermodynamic stabilities of these enamines are
predictable (mainly on the basis of the steric effects). Their
reactivity as nucleophiles is also related, not unexpectedly, on
their “true enamine character” (again depending on the more
or less large inhibition of resonance by steric and electronic
factors). Standard, cheap, quick NMR experiments such as
those shown here can throw light on the understanding of
some organocatalytic reactions and can assist the selection and/
or development of appropriate catalysts, as we hope to show in
the near future.
Besides, the reaction of an equimolar mixture of 1b and 4b in
CD3CN with DEAD (toluene solution, added in portions),
from −40 °C to rt, gave rise to the disappearance of 1b rather
than of 4b (see Figure 6).
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(3) (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am.
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ASSOCIATED CONTENT
■
S
* Supporting Information
(4) (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 794−797. (b) Hayashi, Y.; Gotoh, H.;
Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212−4215.
Experimental procedures and copies of NMR and 2D NMR
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
(5) (a) Brunner, H.; Bugler, J.; Nuber, B. Tetrahedron: Asymmetry
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1995, 6, 1699. (b) Liu, T.-Y.; Cui, H.-L.; Zhang, Y.; Jiang, K.; Du, W.;
He, Z.-Q.; Chen, Y.-C. Org. Lett. 2007, 9, 3671−3674. (c) McCooey,
S. H.; Conon, S. J. Org. Lett. 2007, 9, 599−602. (d) Zhou, J.;
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(6) (a) Carlson, R.; Nilsson, A. Acta Chem. Scand. 1984, B38, 49−53.
(enamine from pyrrolidine). (b) Reference 2g. (c) Reference 2h
(from the Jørgensen catalyst).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jvilarrasa@ub.edu.
Notes
The authors declare no competing financial interest.
(7) The values given are without addition of molecular sieves or
other dehydrating agents into the vials or NMR tubes. We only did
this in independent vials to increase the peaks in CDCl3 in order to
attribute enamine signals that we were hardly able to observe starting
from the less nucleophilic amines.
(8) (a) Liu, F.; Wang, S.; Wang, N.; Peng, Y. Synlett 2007, 2415−
2419. (b) Wang, C.; Yu, C.; Liu, C.; Pen, Y. Tetrahedron Lett. 2009, 50,
2363−2366.
ACKNOWLEDGMENTS
■
Grants CTQ-2009-13590, CTQ-2012-39230 (Spanish Govern-
ment), and 2009SGR825 (AGAUR) are acknowledged. H.C.
was a master student in our research group (currently, he is a
doctorate student financed by CTQ-2012). D.S. holds a
studentship of the University of Barcelona (UB). Discussions
with Dr. X. Ariza (of our department) and Prof. A. Studer
(9) (a) Walpole, C.; Ko, S. Y.; Brown, M.; Beattie, D.; Campbell, E.;
Dickenson, F.; Ewan, S.; Hughes, G. A.; Lemaire, M.; Lerpiniere, J.;
Patel, S.; Urban, L. J. Med. Chem. 1998, 41, 3159−3173. (b) Gensini,
M.; de Meijere, A. Chem.Eur. J. 2004, 10, 785−790. (c) Palomo, C.;
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Vera, S.; Mielgo, A.; Gomez-Bengoa, E. Angew. Chem., Int. Ed. 2006,
(Univ. Munster) regarding the chances of the hydroamination
̈
mechanism are also acknowledged.
45, 5984−5987.
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