Relative tendency of carbonyl compounds to form enamines

Article abstract of DOI:10.1021/ol203157s

Equilibria between carbonyl compounds and their enamines (from O-TBDPS-derived prolinol) have been examined by NMR spectroscopy in DMSO-d ₆. By comparing the exchange reactions between pairs (enamine A + carbonyl B → carbonyl A + enamine B), a quite general scale of the tendency of carbonyl groups to form enamines has been established. Aldehydes quickly give enamines that are relatively more stable than those of ketones, but there are exceptions to this expected rule; for example, 1,3-dihydroxyacetone acetals or 3,5-dioxacyclohexanones (2-phenyl-1,3-dioxan-5-one and 2,2-dimethyl-1,3- dioxan-5-one) show a greater tendency to afford enamines than many α-substituted aldehydes.

Full text of DOI:10.1021/ol203157s

ORGANIC
LETTERS
2012
Vol. 14, No. 2
536–539
Relative Tendency of Carbonyl
Compounds To Form Enamines
ꢀ
ꢀ
Dani Sanchez, David Bastida, Jordi Bures, Carles Isart, Oriol Pineda, and
Jaume Vilarrasa*
´
ꢁ
Departament de Quımica Organica, Facultat de Quımica, Universitat de Barcelona,
Diagonal 645, 08028 Barcelona, Catalonia, Spain
´
jvilarrasa@ub.edu
Received November 25, 2011
ABSTRACT
Equilibria between carbonyl compounds and their enamines (from O-TBDPS-derived prolinol) have been examined by NMR spectroscopy in
DMSO-d6. By comparing the exchange reactions between pairs (enamine A þ carbonyl B f carbonyl A þ enamine B), a quite general scale of the
tendency of carbonyl groups to form enamines has been established. Aldehydes quickly give enamines that are relatively more stable than those
of ketones, but there are exceptions to this expected rule; for example, 1,3-dihydroxyacetone acetals or 3,5-dioxacyclohexanones (2-phenyl-1,
3-dioxan-5-one and 2,2-dimethyl-1,3-dioxan-5-one) show a greater tendency to afford enamines than many R-substituted aldehydes.
The renaissance of enamine chemistry1 over the past
10 years, as secondary amine-catalyzed direct reactions of
carbonyl compounds with electrophiles (enamine cataly-
sis), has already given rise to around 1300 reports and 110
reviews.2 Due to our interest in Michael reactions,3 includ-
ing organocatalytic reactions involving nitroalkenes,3cꢀf
and in the conversion of the nitro groups into carbonyl
compounds by procedures mild enough to be applicable to
complex polyfunctional fragments,4 we focused on very
recent, outstanding studies by Seebach et al.,5a Gschwind
et al.,5b and List et al.5c in which special examples of
stable enamines were characterized.5 These papers promp-
ted us to report the results that we obtained with O-tert-
butyldiphenylsilyl-(S)-prolinol, 1, the catalytic performance
of which was first examined by Peng et al.6 We chose this
catalyst because the bulky substituent (TBDPS group) is
away from the R position of the pyrrolidine ring, which
permits the attack of its amine not only on aldehydes but
also on much less reactive ketones (with which catalysts
suchasthoseof MacMillan and JørgensenꢀHayashi, more
hindered sterically, do not form detectable amounts of
enamines). In this context, we disclose here which enoliz-
able carbonyl compounds show a higher tendency to form
enamines with pyrrolidine derivative 1 (Scheme 1).
(1) For historical reviews, see: (a) Hickmott, P. W. Tetrahedron 1982,
38, 1975–2050. (b) Stork, G. Med. Res. Rev. 1999, 19, 370–387. (c) Stork,
G. Tetrahedron 2011, 67, 9754–9764. Also see:(d) Seebach, D.; Beck,
A. K.; Badine, D. M.; Limbach, M.; Eschenmoser, A.; Treasurywala,
A. M.; Hobi, R.; Prikoszovich, W.; Linder, B. Helv. Chim. Acta 2007, 90,
425–471.
(2) For very recent, representative reviews, see: (a) Jensen, K. L.;
Dickmeiss, G.; Jiang, H.; Albrecht, L.; Jørgensen, K. A. Acc. Chem. Res.
2011, DOI: 10.1021/ar200149w. (b) Nielsen, M.; Worgull, D.; Zweifel, T.;
Gschwend, B.; Bertelsen, S.; Jørgensen, K. A. Chem. Commun. 2011, 47,
632–649. (c) Trost, B. M.; Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600–
1632. (d) Roca-Lopez, D.; Sadaba, D.; Delso, I.; Herrera, R. P.; Tejero, T.;
Merino, P. Tetrahedron: Asymmetry 2010, 21, 2561–2601. (e) Xu, L.-W.;
Li, L.; Shi, X.-H. Adv. Synth. Catal. 2010, 352, 243–279. Also see: (f)
Wiesner, M.; Upert, G.; Angelici, G.; Wennemers, H. J. Am. Chem. Soc.
2010, 132, 6–7 and refs 2 and 3 therein.
When standard enolizable aldehydes, such as benzene-
acetaldehye (phenylethanal), isovaleraldehyde (3-methyl-
butanal), cyclohexanecarboxaldehyde, or isobutyraldehyde
(2-methylpropanal), were mixed with equimolar amounts of
1 in anhydrous DMSO-d6 and the NMR spectra were
(3) (a) Olivella, A.; Rodrıguez-Escrich, C.; Urpı, F.; Vilarrasa, J.
J. Org. Chem. 2008, 73, 1578–1581. (b) Esteban, J.; Costa, A. M.;
Gomez, A.; Vilarrasa, J. Org. Lett. 2008, 10, 65–68. (c) Rodrıguez-
ꢀ
(4) That is, to be used in advanced steps of the total synthesis of
ꢀ
complex natural products. See: (a) Bures, J.; Isart, C.; Vilarrasa, J. Org.
Escrich, C. Master Thesis, Universitat de Barcelona (UB), 2003. (d) Isart,
ꢀ
ꢀ
C. Master Thesis, UB, 2005. (e) Sanchez, D. Master Thesis, UB, 2009. (f)
Lett. 2007, 9, 4635–4638 and references therein. (b) Bures, J.; Vilarrasa,
ꢁ
ꢀ
Carneros, H. Master Thesis, UB, 2011. (g) Llacer, E. Ph.D. Thesis (Total
J. Tetrahedron Lett. 2008, 49, 441–444. (c) Bures, J.; Isart, C.; Vilarrasa,
Synthesis of Fluvirucins), UB, 2012.
J. Org. Lett. 2009, 11, 4414–4417.
r
10.1021/ol203157s
Published on Web 01/06/2012
2012 American Chemical Society

Scheme 1. Formation of Enamines from 1
1
Figure 1. Representative aldehyde enamines, with relevant H
and 13C chemical shifts in DMSO-d6. For the olefin protons of
2a and 2b, 3JHH = 13.9 Hz.
registered immediately, the signals corresponding to the
expected enamines were clearly observed (2aꢀd, Figure 1).
NOESY experiments indicated that these were the main
conformers (s-trans), in agreement with other aldehyde
enamines.5 In all these cases, the equilibria were strongly
shifted toward the formation of the respective enamines. As
hemiaminal-type intermediates (drawn in Scheme 1) were
not detected, we concluded that their dehydration is very
fast, in a hygroscopic solvent such as DMSO; iminium
hydroxydes were not detected either.
Figure 2. Representative ketone enamines, with relevant chemi-
cal shifts in DMSO-d6 (R = TBDPS).
With ketones such as cyclohexanone and cyclopenta-
none, the equilibrium positions were not so readily
attained;they took around 30 min;and they were not so
shifted toward the corresponding enamines 3e and 3f
(Figure 2). NOESY experiments indicated intense cross
peaks of their olefin proton with the CH of the pyrrolidine
ring and with the NCH2 protons on the other side, as well
as less intense cross peaks with the CH2O protons; we
believe that the two major conformations (with the rings
almost coplanar) are in rapid equilibrium. At the probe
temperature, the equilibrium constant for the formation of
ꢂ
(5) (a) Groselj, U.; Seebach, D.; Badine, D. M.; Schweizer, W. B.;
Beck, A. K.; Krossing, I.; Klose, P.; Hayashi, Y.; Uchimaru, T. Helv.
Chim. Acta 2009, 1225–1259 (NMR and X-ray of the enamine from
diphenylprolinol trimethylsilyl ether and 2-phenylethanal). (b) Schmid,
M. B.; Zeitler, K.; Gschwind, R. M. Angew. Chem., Int. Ed. 2010, 49,
4997–5003 (detection by EXSY NMR of enamines from proline). (c)
Bock, D. A.; Lehmann, C. W.; List, B. Proc. Natl. Acad. Sci. U.S.A.
2010, 107, 20636–20641 (crystal structures of proline enaminones). For
related, additional examples, see: (d) Peelen, T. J.; Chi, Y.; Gellman,
S. H. J. Am. Chem. Soc. 2005, 127, 11598–11599 (enamine from a
MacMillan catalyst and 3-phenylpropanal). (e) Marquez, C.; Metzger,
J. O. Chem. Commun. 2006, 1539–1541 (ESI-MS of the enamine from
proline and acetone). (f) Bertelsen, S.; Marigo, M.; Brandes, S.; Diner, P.;
Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 12973–12980 (dienamine
Figure 3. 1H NMR spectra (partial) in DMSO-d6 of the reaction
of enamine 3e with (CH3)2CHCH2CHO (3-methylbutanal) to
give enamine 2b and cyclohexanone: (a) spectrum of 3e; (b) after
addition of 0.3 equiv of 3-methylbutanal; (c) þ further 0.4 equiv
of 3-methylbutanal; (d) þ 0.4 equiv of 3-methylbutanal, again.
ꢂ
from 2-pentenal). (g) Seebach, D.; Groselj, U.; Badine, D. M.; Schweizer,
W. B.; Beck, A. K. Helv. Chim. Acta 2008, 91, 1999–2034 (preceding
communication of ref 5a). (k) Zhu, X.; Tanaka, F.; Lerner, R. A.;
Barbas, C. F.; Wilson, I. A. J. Am. Chem. Soc. 2009, 131, 18206 (an
enaminone intermediate). (i) Domınguez de Marıa, P.; Bracco, P.;
Castelhano, L. F.; Bargeman, G. ACS Catal. 2011, 1, 70–75 (NMR,
enamine from O-methylprolinol and 2-methylpropanal). For enamines
from prolinol ethers and propanal or 3-methylbutanal (appeared when
the draft of this Ms was already written), see: (j) Schmid, M. B.; Zeitler,
K.; Gschwind, R. M. Chem. Sci. 2011, 2, 1793–1803. (k) Schmid, M. B.;
Zeitler, K.; Gschwind, R. M. J. Am. Chem. Soc. 2011, 133, 7065–7074.
cyclohexanone enamine 3e, determined from the proton
areas in DMSO-d6, was 0.78 (henceforward 0.8). This
Keq value is 2 or 3 orders of magnitude lower than those of
aldehyde enamines 2aꢀd. In fact, when we added 3-
methylbutanal to an NMR tube with a DMSO-d6 solution
of 3e (prepared from mixing 1 and cyclohexanone in the
presence of activated 4-A MS), there was a quick exchange
(completed by adding stoichiometric amounts of the alde-
hyde, see Figure 3) to give 2b and “free” cyclohexanone.
Cyclopentanone enamine 3f was formed in a higher
percentage than 3e (Keq = 2.33, hereafter 2.3). Dioxanone
ꢀ
Also see: (l) Hein, J. E.; Bures, J.; Lam, Y.; Hughes, M.; Houk, K. N.;
Armstrong, A.; Blackmond, D. G. Org. Lett. 2011, 13, 5644–5647
(enamine from proline and propanal). For pioneering papers, see refs
9 and 10 in ref 1d, as well as: (m) Blarer, S. J.; Seebach, D. Chem. Ber
1983, 116, 3086–3096 (β-tetralone enamines). (n) Seebach, D.; Missbach,
M.; Calderari, G.; Eberle, M. J. Am. Chem. Soc. 1990, 112, 7625–7638
(several enamines).
Org. Lett., Vol. 14, No. 2, 2012
537

enamine 3g was much more stable than 3f (Keq ≈ 75). In fact,
as shown in Figure 4, addition of 1,3-dihydroxyacetone
isopropylidene acetal (2,2-dimethyl-1,3-dioxan-5-one) to a
3e solution caused a full exchange reaction to give 3g and
cyclohexanone (better followed by13C NMR, as there is an
1
overlap of signals in H NMR). 2-Phenyl-1,3-dioxan-5-
one gave a more stable enamine (3h) yet, in fact, a 1:1.2
mixture of two diastereomers (δH 5.54 and δC 97.3 for one
“dCH”, δH 5.48 and δC 97.1 for the second).
Figure 4. 13C NMR spectra (partial) in DMSO-d6 of the reaction
of enamine 3e with 2,2-dimethyl-1,3-dioxan-5-one: (a) spectrum
of 3e; (b) after addition of 2,2-dimethyl-1,3-dioxan-5-one
(1 equiv), registered immediately; (c) 1 h later.
Figure 5. Equilibrium constants for the formation of enamines
from 1, as determined by 1H NMR in DMSO-d6 at 25 °C. R =
TBDPS. The configurational isomers and major conformations
depicted for each enamine are those indicated by NMR spectra.
The values for several members of the series (especially, the first
five and last four values) are approximate, although qualita-
tively correct, as they were obtained by addition of 1 to pairs of
close carbonyl compounds mixed in different ratios. The en-
amines of the two last ketones could not be detected (n.d.), even
with pyrrolidine instead of 1 and with large excesses of their ketones.
In the case of phenylacetaldehyde (first substrate), a minor con-
former (s-cis, 15%) was noted just after mixing 1 and PhCH2CHO
(δ 5.55 and 6.97, 3J = 15.6 Hz), which decreased soon to e7%.
Since in CDCl3 the percentages of enamines in the
equilibria were orders of magnitude lower (e.g., almost
103 times lower for 2b and 3g), we went on using DMSO-d6
for subsequent comparisons.
The two most stable enamines we examined;see the
first row of Figure 5;are those with the double bond
conjugated with an aromatic ring; in these two cases there
is no steric inhibition or hindrance to the electronic
delocalization.1a,5 In this regard, the case of the enamine
of 1-phenylacetone, PhCH2COCH3 (fifth row), when it is
compared to phenylethanal, PhCH2CHO, is dramatic: the
CH3 group causes a decrease from Keq ≈ 3000 to Keq ≈ 0.6.
An additional Ph at the more substituted position of
PhCH2COCH3 (see Ph2CHCOCH3, last row of Figure 5)
is also contraindicated, as no enamine was detected.
As expected, aldehydes RCH2CHO gave enamines
that are relatively more stable (for example, 2b)7 than those
of R-branched aldehydes (2c and 2d) and than those of most
ketones. The exceptions to this rule are the astonishingly
stable dioxanone enamines 3g and 3h. During the treatment
of an equimolar mixture of cyclohexanone and a dioxanone
(or of a complex molecule that contained both types of
cyclic carbonyl groups) with a catalytic amount of a sec-
ondary amine such as 1, the percentage of 3e would be 100
times lower than that of 3g or 400 times lower than that of
3h; unless the reactivity of 3e with a sort of electrophiles was
really much higher than that of 3 g/3 h, no products coming
from 3e would be obtained. Furthermore, enamines 3g and
3h are formed in larger percentages than those of several
R-branched aldehydes; for example, the relative equilibrium
constant for the formation of 3g (Keq ≈ 75) is several times
higher than that for R-OTBS-propanal enamine (Keq ≈14).8
(8) It could explain why the cross-aldol reaction (enamine of 3g attacking
the aldehyde group of R-OTBS-propanal) predominates over self-aldol
reactions when both carbonyl groups are treated with proline. For a review
of organocatalytic aldol reactions of 1,3-dioxan-5-ones; see: (a) Enders, D.;
Narine, A. A. J. Org. Chem. 2008, 73, 7857–7870. For a computational
(6) (a) Liu, F.; Wang, S.; Wang, N.; Peng, Y. Synlett 2007, 2415–2419.
(b) Wang, C.; Yu, C.; Liu, C.; Peng, Y. Tetrahedron Lett. 2009, 50,
2363–2366.
(7) Butanal and pentanal showed a slightly higher tendency than
3-methylbutanal to give enamines with 1, but a higher percentage of
aldol reaction products were soon formed (the NMR spectra were not so
clean).
ꢀ
€
ꢀ
study, see: (b) Calderon, F.; Doyaguez, E. G.; Cheong, P. H.-Y.; Fernandez-
Mayoralas, A.; Houk, K. N. J. Org. Chem. 2008, 73, 7916–7920. For
pioneering work on dioxanones, see: (c) Majewski, M.; Gleave, D. M.;
Nowak, P. Can. J. Chem. 1995, 73, 1616–1626.
538
Org. Lett., Vol. 14, No. 2, 2012

With acyclic ketones, it was more difficult to detect the
corresponding enamines. Therefore, we mixed 1 with
10ꢀ20 equiv of ketone (we admit that the solvent polarity
changes, but we had no other choice). As we could not
determine with accuracy the corresponding equilibrium
constants, in order to better compare the tendency of
diverse carbonyl groups to give enamines, we prepared
series of NMR tubes; they contained pairs of carbonyl
compounds in equimolar amounts and later in different
amounts(with a large excess of the carbonylcompound the
enamine of which was formed in lower percentage), to
which 1 was added. The relative Keq values that we obtained
from integration of the areas of the olefin protons, taking
enamine 3f as the reference, are also shown in Figure 5.
The last ketones of Figure 5 (2-pentanone, 2-butanone,
etc.), the enamines of which with 1 could hardly be
observed, were compared to the preceding partners by
using pyrrolidine9 (see Supporting Information). This
afforded values of Keq larger than with 1, although the
relativeorderwasmaintained).ThevaluesgiveninFigure5
take into account the corresponding correction. Thus, the
henceforward the comparisons of aldehydes and ketones
can be established on a quantitative basis.10d For example,
when, via a secondary amine-catalyzed reaction, a linear
aldehyde reacts with an electrophile, the product, which
becomes an R-branched-like aldehyde, shows a 10ꢀ100
times weaker tendency to form its enamine (fortunately,
otherwise the newly created stereocenter would soon race-
mize and, with strong electrophiles, double substitution
could occur);11 if a ketone RCH2COCH2R0 reacts via one
of its enamines with an electrophilic carbon atom, the
product, let us say RCH2COCHR0R00, will show a ten-
dency >1000 times weaker to form an enamine.
In short, the trend to afford enamines with 1 (and
pyrrolidine) can be summarized as follows:
ArCH2CHO .
benzo[c]cycloalkanones ≈ linear aldehydes .
3,5-dioxacyclohexanones ≈ R-branched aldehydes .
cycloalkanones (Keq ≈ 2.3ꢀ0.8, DMSO) ≈
YCH2COCH3 (Y = OR, Ph) .
2-Me-cyclohexanone > linear ketones ≈ PhCOCH3
R-branched ketones
K
eq values of the penultimate row of Figure 5 are approx-
Thus, there are two groups of ketones with a higher
tendency than several aliphatic aldehydes to afford enam-
ines: (a) those cyclic ketones that can give fully conjugate
enamines (e.g., benzo[c]cycloalkanones), as expected;1,5
(b) cyclic 1,3-dihydroxyacetone derivatives, such as the
known 2,2-dimethyl-1,3-dioxan-5-one8 and the amazing
2-phenyl-1,3-dioxan-5-one, enamines of which (see 3g and
3h), to the best of our knowledge, have been spectro-
scopically characterized and reported here for the first
time.
imate (but an approximate scale is better than nothing).
By comparing cyclohexanone (Keq = 0.8) with 2-
methylcyclohexanone (Keq = 0.02), the sensitivity of the
relative enamine stabilities to the steric effects1a is corro-
borated again. Despite the fact that cyclic ketones are
much better substrates for aldol-like reactions than analo-
gous acyclic ketones, a simple R-Me substituent shifts the
equilibria with both regioisomeric enamines toward the
left. If the side chain is bulkier (for example, if the substrate
is an aldol product, such as the dioxanone at the ultimate
row of Figure 5), no enamine could be detected; this
occurred even by mixing PhCOCH3 and such an aldol in
a 1:20 ratio and using an excess of pyrrolidine. Its relative
Acknowledgment. This study was started with funds
from Grant No. CTQ-2006-15393 (Spanish Government)
and continued with Grant No. CTQ2009-13590 (2010ꢀ
2012) and with a gift from the AGAUR (2009SGR-
825). D.S. holds a studentship of the University of Barce-
lona (UB), C.I. had a similar studentship (2007ꢀ2010),
and J.B. was an instructor (Ajudant LOU, 2008ꢀ2009)
Keq is below our detection limit.
We have carried out calculations (see the Supporting
Information) at a DFT level in DMSO for the geometry
optimizations, followed by single-point calculations of the
total energies at MP2 level in DMSO, to compare the
conformers of several enamines of Figure 5. The results
agree qualitatively with those obtained by NMR.
In summary, by standard NMR experiments we have
confirmed or rediscovered rules for enamines that do not
differ from those known or assumed for a long time,1,10 but
ꢀ
and then a postdoctoral fellow of Fundacio Cellex de
Barcelona (Sep 2009ꢀJune 2010). Thanks are also due
ꢀ
to the graduate student L. Perez for preliminary
calculations in the fall of 2009 and to the Master
student H. Carneros for a sample of 2-phenyl-1,3-
dioxan-5-one.
(9) With pyrrolidine, more aldol-like products were formed, but the
spectra could be better analyzed since the signals of the side chain
(CH2OSi) of 1 and its enamines were avoided.
Supporting Information Available. Experimental de-
1
tails and copies of H and 13C NMR spectra and 2D
(10) (a) Enamines of RCH2CHO, especially if these enamines are
conjugated (R = Ar, EWG), are the most stable (as known or expected).
(b) A methyl or linear alkyl group on the other side of the carbonyl group
(e.g., any RCH2COCH3) is very detrimental for the formation of any
possible enamine, unless the conjugation of the enamine system with an
aromatic ring or EWG is feasible (i.e., not inhibited by steric effects), as
known. (c) Enamines of cyclic ketones (entropic component of the steric
effect) are relatively more stable than those of the analogous or similar
acyclic ketones. (d) Branching at R or R0 positions of a CO group is
deleterious, as equilibrium constants may be reduced by a factor of
10ꢀ100 for an aldehyde and by 103ꢀ105 for a ketone, being branching at
both R and R0 positions, obviously, more deleterious yet. These details
are key in practice: if enamines are not formed at all or are hardly
formed, no “enamine-catalyzed” or enamine-involving reactions will
occur.
NMR experiments, as well as results of calculations at the
MP2//DFT level. This material is available free of charge
via the Internet at http://pubs.acs.org.
(11) Acetaldehyde (ethanal) is a particular case. After the first
substitution by reaction with an electrophile (Rδþ or Eδþ), the inter-
mediate enamine (RꢀCHdCHꢀNR02 or EꢀCHdCHꢀNR02), of a
RCH2CHO-type aldehyde, is still very amenable to a second substitu-
tion. For examples, see: (a) Chandler, C.; Galzerano, P.; Michrowska,
A.; List, B. Angew. Chem., Int. Ed. 2009, 48, 1978–1980. (b) Coeffard, V.;
Desmarchelier, A.; Morel, B.; Moreau, X.; Greck, C. Org. Lett. 2011, 13,
5778–5781 and ref 4 cited therein.
Org. Lett., Vol. 14, No. 2, 2012
539