The role of imine-enamine tautomerism in effecting cross-aldol condensations

Article abstract of DOI:10.1016/j.tetlet.2007.08.096

An indirect method to effect cross-aldol coupling of two nonequivalent enolizable aldehydes is reported that involves initial conversion of one aldehyde to an imine derivative possessing an N-3° alkyl substituent. In sharp contrast to the related couplings (e.g., the use of α-lithiated imines at low temperature), condensation between the imine and several representative aldehydes occurs readily at ambient temperature in the presence of a catalytic amount of cobalt(II) chloride.

Full text of DOI:10.1016/j.tetlet.2007.08.096

Tetrahedron Letters 48 (2007) 7665–7667
The role of imine–enamine tautomerism in effecting
cross-aldol condensations
James H. Babler,* Matthew C. Atwood, Jonathan E. Freaney and Anthony R. Viszlay
Department of Chemistry, Loyola University of Chicago, Chicago, IL 60626, United States
Received 14 August 2007; accepted 27 August 2007
Available online 31 August 2007
Abstract—An indirect method to effect cross-aldol coupling of two nonequivalent enolizable aldehydes is reported that involves ini-
tial conversion of one aldehyde to an imine derivative possessing an N-3° alkyl substituent. In sharp contrast to the related couplings
(e.g., the use of a-lithiated imines at low temperature), condensation between the imine and several representative aldehydes occurs
readily at ambient temperature in the presence of a catalytic amount of cobalt(II) chloride.
Ó 2007 Elsevier Ltd. All rights reserved.
The aldol condensation1 is arguably considered to be the
most important carbon–carbon bond-forming reaction
in organic synthesis. During the past several decades,
aldol technology has advanced to the stage where the
formidable challenge of direct cross-aldol coupling of
two nonequivalent enolizable aldehydes (Eq. 1) can be
achieved using L-proline as a catalyst.2 This novel mod-
ification of the cross-aldol condensation is not without
limitation, since its success is contingent on the alde-
hydes functioning as two distinct components: a nucleo-
philic donor and an electrophilic acceptor. The
obtention of a single regioisomer of the cross-aldol
product, along with the suppression of homodimeriza-
tion of both the donor and the acceptor aldehydes,
would still appear to be a formidable synthetic chal-
lenge, especially if the donor aldehyde has a steric envi-
ronment similar to that of the acceptor aldehyde and
both aldehydes are enolizable (e.g., the reactants in the
Table 1, entry 4).
with enol silyl ethers in the presence of TiCl4,4 and the
reaction of carbonyl compounds with an a-lithiated
imine at low temperature.5 Since enamine derivatives
of highly reactive aldehydes (e.g., propanal) are more
difficult to obtain in high yield than the corresponding
imine derivatives of such aldehydes, we decided to inves-
tigate the possible use of imine derivatives of enolizable
aldehydes in cross-aldol condensations with carbonyl
compounds in the presence of a suitable Lewis acid cat-
alyst. This strategy was based on the knowledge that
imines derived from enolizable aldehydes are known to
react via their secondary enamine tautomeric form
(present in undetectable concentration at equilibrium)
with electrophilic olefins to yield Michael adducts.6
The present Letter presents the results and limitations
of this investigation (Scheme 1).
In order to test the feasibility of a Lewis acid-catalyzed
coupling of an imine (1) with an aldehyde (3), various
R1R2CHCH@O þ R3R4CHCH@O cat: l-proline R R CHCHðOHÞCðR R ÞCH@O
ð1Þ
ƒƒƒƒƒ!
3
4
1
2
nucleophilic donor
electrophilic acceptor
Various indirect methods1 for effecting cross-aldol cou-
pling between two non-identical carbonyl compounds
have been reported, including the reaction of aldehydes
with enamines,3 the coupling of carbonyl compounds
imine derivatives of propanal were prepared using
standard conditions.7 Subsequent reaction of imine
1[R1 = CH3; R = (CH2)5 CH3 or CH2Ph] with 2-methyl-
propanal in the presence of a catalytic amount of cobal-
t(II) chloride in various organic solvents containing an
excess of anhydrous calcium sulfate8 at ambient temper-
ature failed to yield the desired coupling product [4,
R1 = CH3; R2 = CH(CH3)2]. This was surprising since
*
Corresponding author. Tel.: +1 773 508 3764; fax: +1 773 508
3086; e-mail: jbabler@luc.edu
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.096

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J. H. Babler et al. / Tetrahedron Letters 48 (2007) 7665–7667
Table 1. Co+2—catalyzed coupling of imine 1a with representative aldehydesa
Entry
1
Aldehyde 3
Representative 1H NMR data
(CDCl3, 300 MHz) for imine product 4
Overall yieldb (%) of aldehyde 5
2-Methylpropanalc
d 7.73 (s, 1H), 5.62 (d of q, J = 9.3, 1.2 Hz, 1H), 2.75 (m, 1H),
1.84 (d, J = 1.2 Hz, 3H), 1.60 (s, 2H), 1.21 (s, 6H), 1.02
(d, J = 6.6 Hz, 6H), 0.93 (s, 9H)
d 7.95 (s, 1H), 7.40 (m, 5H), 6.76 (br s, 1H), 2.15 (br s, 3H),
1.65 (s, 2H), 1.27 (s, 6H), 0.95 (s, 9H)
d 7.83 (s, 1H), 6.53 (d, J = 12 Hz, 1H), 6.26 (br d, J = 12 Hz, 1H),
1.95 (br s, 3H), 1.89 (br s, 3H), 1.85 (br s, 3H), 1.62 (s, 2H), 1.23
(s, 6H), 0.92 (s, 9H)
73
2
3
Benzaldehyde
81d
61
3-Methyl-2-butenal
4
Hexanal
d 7.26 (s, 1H), 5.81 (t of q, J = 7.2, 1.2 Hz, 1H), 2.22 (m, 2H), 1.84
(d, J = 1.2 Hz, 3H), 1.60 (s, 2H), 1.22 (s, 6H), 0.93 (s, 9H), 0.92
(t, J = 5.7 Hz, 3H)
83
a See Ref. 21 for the general procedure.
b Isolated yield. All aldehyde products were characterized by 1H and 13C NMR spectroscopy and compared with available literature data.
c Distilled prior to use, to remove traces of isobutyric acid (which catalyzes hydrolysis of imines).
d See Ref. 22 for full spectral characterization of this aldehyde.
Scheme 1.
imines possessing an N-benzyl group have been shown
to be in equilibrium with their secondary enamine
tautomer9 and thus capable of reacting with electro-
philes. Although a similar reaction using N-propylidene-
cyclohexanamine10 (1, R1 = CH3; R = cyclohexyl) and
2-methylpropanal afforded some of the desired cross-
coupled imine, a complex mixture of products was ob-
tained. The latter problem was overcome by the use of
an imine possessing a bulky N-tert-octyl group. Indeed,
the reaction of 2,4,4-trimethyl-N-propylidene-2-pentan-
amine11 (1a) with 2-methylpropanal in a solution of
2:1 (v/v) isopropyl ether: toluene12 containing an excess
of powdered DrieriteÒ (CaSO4 containing CoCl2 as an
indicator) at ambient temperature proceeded smoothly,
affording 75% yield of the desired cross-coupled adduct
[4a, R2 = CH(CH3)2], substantially free of any impuri-
ties.13 To confirm the identity of the cross-coupled
adduct, the latter imine was hydrolyzed using aqueous
acetic acid containing sodium acetate at room tempera-
ture14 to afford the previously reported15 E-2,4-di-
methyl-2-pentenal, the identity and purity of which
were ascertained by NMR spectroscopy.16
overall yields of conjugated enals 5 were generally quite
good. The obtention of a single adduct in this imine-
aldehyde cross-coupling process was further confirmed
by the coupling of hexanal and imine 1a (Table 1, entry
4) to afford, after hydrolysis, (E)-2-methyl-2-octenal17 as
the sole product in 83% overall yield. The coupling of
imine 1a with an a, b-unsaturated aldehyde (Table 1,
entry 3) proved to be rather slow, thereby allowing
in situ hydrolysis of 1a to occur via a competitive
reaction pathway. Thus, in contrast to the other systems
that were examined, the coupled imine [4a,
R2 = CH@C(CH3)2] obtained from 3-methyl-2-butenal
and imine 1a was contaminated with a significant
amount (approximately 20% of the product mixture)
of the N-tert-octyl imine derivative of (E)-2-methyl-2-
pentenal (4a, R2 = CH2CH3)—the product obtained
via ‘homodimerization’ of imine 1a,18 accompanied by
an equivalent amount of the N-tert-octyl imine deriva-
tive of 3-methyl-2-butenal. Subsequent hydrolysis of
the crude reaction mixture resulted in a 61% overall
yield (based on 3-methyl-2-butenal) of the desired
(2E)-2,5-dimethyl-2,4-hexadienal.19
In order to determine the scope of this cross-coupling,
imine 1a was allowed to react with several representative
aldehydes; and, as indicated by the results in the Table 1,
In conclusion, a process has been developed for the
cross-coupling of an N-tert-alkyl imine derivative of an
enolizable alkyl aldehyde (1) with several types of alde-

J. H. Babler et al. / Tetrahedron Letters 48 (2007) 7665–7667
7667
characterization, they were hydrolyzed promptly to afford
the known aldehydes (5).
hydes (3) and offers an efficient methodology to obtain
conjugated enals if 3 is a simple aliphatic aldehyde.
Not unexpectedly, all efforts to couple imines of general
structure 1 to representative ketones (e.g., 2-heptanone
and cyclohexanone) failed to yield any coupled adduct.
Indeed, various ketones, as well as esters and alcohols,20
were used successfully as co-solvents in this cross cou-
pling process during the preliminary studies. Hence the
process may be feasible for a variety of functionalized
aldehydes.
14. This hydrolysis procedure was adapted from a similar one
reported on page 2074 of the following article: Cummins,
C. H.; Coates, R. M. J. Org. Chem. 1983, 48, 2070–2076.
15. Spangler, C. W.; Tan, R. P. K.; Gibson, R. S.; McCoy,
R. K. Synth. Commun. 1985, 15, 371.
16. 1H NMR (CDCl3, 300 MHz, ppm) d 9.38 (s, 1H), 6.29 (d
of q, J = 9.6, 1.2 Hz, 1H), 2.84 (m, 1H), 1.75 (d,
J = 1.2 Hz, 3H), 1.09 (d, J = 6.6 Hz, 6H).
17. 1H NMR (CDCl3, 300 MHz, ppm) d 9.40 (s, 1H), 6.50 (t
of q, J = 7.2, 1.2 Hz, 1H), 2.35 (br q, J = 7.2 Hz, 2H), 1.75
(d, J = 1.2 Hz, 3H), 1.51 (br pentet, J = 7.5 Hz, 2H), 1.38–
1.28 (m, 4H), 0.91 (br t, J = 7 Hz, 3H). For a previous
synthesis of (E)-2-methyl-2-octenal, see: Ekogha, C. B. B.;
Ruel, O.; Julia, S. A. Tetrahedron Lett. 1983, 24, 4825.
18. This imine was characterized by the following spectral
data: 1H NMR (CDCl3, 300 MHz, ppm) d 7.76 (s, 1H),
5.79 (br t, J = 7.2 Hz, 1H), 2.25 (m, 2H), 1.84 (br s, 3H),
1.60 (s, 2H), 1.21 (s, 6H), 1.04 (t, J = 7.5 Hz, 3H), 0.92 (s,
9H). After hydrolysis of the mixture of imines, (E)-2-
methyl-2-pentenal can be separated from the desired
dienal by evaporative distillation at reduced pressure.
19. This dienal was characterized by the following spectral
data: 1H NMR (CDCl3, 300 MHz, ppm) d 9.46 (s, 1H),
7.09 (br d, J = 12 Hz, 1H), 6.33 (br d, J = 12 Hz, 1H), 1.97
(br s, 3H), 1.96 (br s, 3H), 1.83 (br s, 3H); 13C NMR
(CDCl3, 75 MHz) d 195.4, 147.7, 145.1, 135.4, 121.2, 27.1,
19.0, 9.2. For a previous synthesis of this dienal, see Ref.
22.
References and notes
1. Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH:
Weinheim, 2004; Vol. 1 and 2.
2. Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2002, 124, 6798, and references cited therein.
3. Takazawa, O.; Kogami, K.; Hayashi, K. Bull. Chem. Soc.
Jpn. 1985, 58, 2427.
4. Mukaiyama, T. Angew. Chem., Int. Ed. Engl. 1977, 16,
817.
5. Wittig, G.; Frommeld, H. D.; Suchanek, P. Angew. Chem.,
Int. Ed. Engl. 1963, 2, 683.
6. Pfau, M.; Ribiere, C. J. Chem. Soc., Chem. Commun. 1970,
66.
7. Imines 1 were prepared in quantitative yield via reaction
of the aldehyde with a 1° amine in dichloromethane
containing anhydrous sodium sulfate at temperatures of
10-20 °C and were subsequently characterized by 1H
NMR spectroscopy. Imine 1a exhibited the following
data: (CDCl3, 300 MHz, ppm) d 7.56 (t, J = 4.8 Hz, 1H),
2.25 (q of d, J = 7.8, 4.8 Hz, 2H), 1.60 (s, 2H), 1.19 (s, 6H),
1.07 (t, J = 7.8 Hz, 3H), 0.92 (s, 9H).
8. An efficient drying agent was essential due to the antic-
ipated ease of hydrolysis of imines 1 and 4 by water
liberated during the coupling process.
9. Jabin, I.; Revial, G.; Pfau, M.; Decroix, B.; Netchitailo, P.
Org. Lett. 1999, 1, 1901.
20. Among the co-solvents that were successfully used in the
coupling reaction were methyl isobutyl ketone, cyclopen-
tanone, ethyl propionate, tert-butyl acetate, and 2-methyl-
2-butanol.
21. General procedure for the imine-aldehyde coupling: A
mixture of 1.6 g of powdered DrieriteÒ (CaSO4 containing
CoCl2 as an indicator, crushed using a mortar and pestle
and subsequently dried at 200 °C for 2 days) and 6.0 mL
of 2:1 (v/v) isopropyl ether: toluene was stirred for 2 h at
22 °C under a nitrogen atmosphere, after which 0.65 mmol
of aldehyde 3 (substantially free of traces of the corre-
sponding carboxylic acid) and 120 lL (approx.
0.63 mmol) of imine 1a were added to the reaction flask.
This reaction mixture was subsequently stirred vigorously
at room temperature for 8–10 h, after which it was diluted
with 25 mL of hexane and solid material was removed by
filtration through a small pad of Hyflo Super-CelÒ filtering
aid. Removal of the volatile organic solvents by evapora-
tion at reduced pressure, followed by removal of residual
traces of toluene under high vacuum, afforded the crude
imine product occasionally contaminated with a trace of
CoCl2. The latter was conveniently removed by addition
of 25 mL of hexane, and filtration once again through a
small pad of Hyflo Super-CelÒ filtering aid. Removal of
the hexane by evaporation at reduced pressure afforded
the imine product (4).
10. Tanis, S. P.; Brown, R. H.; Nakanishi, K. Tetrahedron
Lett. 1978, 869.
11. Bourdieu, C.; Foucaud, A. Tetrahedron Lett. 1986, 27,
4725.
12. Other solvent mixtures that were examined led to a lower
yield of the desired adduct (4), usually arising from in situ
hydrolysis of the starting imine (1a). It was also important
to use a dilute solution (approximately 0.1 M in both
imine and reactant aldehyde) to prevent in situ hydrolysis
of 1a, thereby avoiding the formation of propanal (which
can react as an electrophilic acceptor) and the imine
derivative of the reactant aldehyde. It is noteworthy that a
previous study3 of the reaction of enamines with aldehydes
in the presence of Lewis acids reported the formation of b-
hydroxy carbonyl compounds and the absence of sub-
sequent dehydration even when an excess of the acid
catalyst was added to the mixture.
22. For full spectral characterization (1H NMR, 13C NMR,
IR) of this aldehyde, see: Lahmar, N.; Aatar, J.; Ben Ayed,
T.; Amri, H.; Bellassoued, M. J. Organomet. Chem. 2006,
691, 3018–3026.
13. Since the unsaturated imines (4) were sensitive to heat,
light, and atmospheric moisture, after spectroscopic