Synthesis and C-alkylation of hindered aldehyde enamines

Article abstract of DOI:10.1021/jo802016t

A new reactivity mode of hindered lithium amides with terminal epoxides is described whereby aldehyde enamines are produced via a previously unrecognized reaction pathway. Some of these aldehyde enamines display unprecedented C-alkylation reactivity toward unactivated primary and secondary alkyl halides. For comparison, the reactivity of aldehyde enamines synthesized via a traditional condensation method was examined. C-rather than N-alkylation was the dominant reaction pathway found with a range of electrophiles, making this route to α-alkylated aldehydes more synthetically useful than previously reported.

Full text of DOI:10.1021/jo802016t

Synthesis and C-Alkylation of Hindered Aldehyde Enamines
David M. Hodgson,* Christopher D. Bray, Nicholas D. Kindon,† Nigel J. Reynolds,
Steven J. Coote,‡ Joann M. Um,§ and K. N. Houk§
Department of Chemistry, Chemistry Research Laboratory, UniVersity of Oxford, Mansfield Road,
Oxford OX1 3TA, U.K.
daVid.hodgson@chem.ox.ac.uk
ReceiVed September 12, 2008
A new reactivity mode of hindered lithium amides with terminal epoxides is described whereby aldehyde
enamines are produced via a previously unrecognized reaction pathway. Some of these aldehyde enamines
display unprecedented C-alkylation reactivity toward unactivated primary and secondary alkyl halides.
For comparison, the reactivity of aldehyde enamines synthesized via a traditional condensation method
was examined. C- rather than N-alkylation was the dominant reaction pathway found with a range of
electrophiles, making this route to R-alkylated aldehydes more synthetically useful than previously reported.
SCHEME 1. Reaction Pathways of Epoxides
Introduction
Epoxides are widely utilized as synthetic intermediates, and
the epoxide functional group is also found in a number of
interesting natural products.1 Much of the chemistry of epoxides
involves nucleophilic cleavage of the strained heterocyclic ring
(Scheme 1, path a); however, another aspect of epoxide
chemistry is that which occurs upon reaction with a strong base,
typically an organolithium or hindered lithium amide. As well
as simple ring-opening,2 abstraction of a ꢀ-proton can occur,
which leads to the formation of allylic alcohols (path b), a
process known as ꢀ-elimination.3,4 As a result of the electron-
withdrawing effect of the oxygen and the acidifying nature of
the strained ring, abstraction of an R-proton can also occur (path
c) to give an R-metallated epoxide (oxiranyl anion).5
Since R-metallated epoxides were first proposed6 and evi-
dence for their existence first presented,7 their place in organic
chemistry has evolved from initially being viewed as uncontrol-
lable transient species4b,5b to that of useful synthetic intermedi-
ates.5g,h,8 For example, we have reported an experimentally
straightforward method for the synthesis of R,ꢀ-epoxysilanes
(e.g., 2) from simple terminal epoxides (1) via direct deproto-
nation using lithium 2,2,6,6-tetramethylpiperidide (LTMP) as
base in combination with an in situ silylating agent (Me3SiCl)
(Scheme 2).9
† AstraZeneca R&D Charnwood, Medicinal Chemistry, Bakewell Road,
Loughborough LE11 5RH, U.K.
‡ GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road,
Stevenage SG1 2NY, U.K.
During this program of work we uncovered a new reactivity
mode of terminal epoxides with hindered lithium amides that
§ Department of Chemistry and Biochemistry, University of California, Los
Angeles, CA 90095-1569.
Present address: Queen Mary University of London, School of Biological
and Chemical Sciences, Mile End Road, London E1 4NS, U.K.
(1) (a) Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.;
Wiley-VCH: Weinheim, Germany, 2006. (b) ComprehensiVe Heterocyclic
Chemistry III; Padwa, A., Ed.; Elsevier: Oxford, 2008; Vol. 1.
(2) Harris, C. E.; Fisher, G. B.; Beardesley, D.; Lee, L.; Goralski, C. T.;
Nicholson, L. W.; Singaram, B. J. Org. Chem. 1994, 59, 7746–7751.
(3) Haynes, L. J.; Heilbron, I. M.; Jones, E. R. H.; Sondheimer, F. J. Chem.
Soc., Abstr. 1947, 1583–1585.
(4) For recent reviews, see: (a) Eames, J. Eur. J. Org. Chem. 2002, 393–
401. (b) Magnus, A.; Bertilsson, S. K.; Andersson, P. G. Chem. Soc. ReV. 2002,
31, 223–229. (c) Eames, J. In Science of Synthesis: Houben-Weyl Methods of
Molecular Transformations; Snieckus, V., Majewski, M., Eds.; Thieme: Stuttgart,
Germany, 2005; Vol. 8a, pp 171-242. (d) Hodgson, D. M.; Humphreys, P. G.
In Science of Synthesis: Houben-Weyl Methods of Molecular Transformations;
Clayden, J. P., Ed.; Thieme: Stuttgart, Germany, 2007; Vol. 36, pp 583-665.
(5) For reviews, see: (a) Crandall, J. K.; Apparu, M. Org. React. 1983, 29,
345–443. (b) Satoh, T. Chem. ReV. 1996, 96, 3303–3325. (c) Doris, E.; Dechoux,
L.; Mioskowski, C. Synlett 1998, 337–343. (d) Hodgson, D. M.; Gras, E. Synthesis
2002, 1625–1642. (e) Hodgson, D. M.; Tomooka, K.; Gras, E. In Topics in
Organometallic Chemistry; Hodgson, D. M., Ed.; Springer: Berlin/Heidelberg,
Germany, 2003; pp 217-250. (f) Chemla, F.; Vrancken, E. In The Chemistry of
Organolithium Reagents; Rappoport, Z., Marek, I., Eds.; J. Wiley and Sons:
New York, 2004; pp 1165-1242. (g) Reference 1a, pp 145-184. (h) Capriati,
V.; Florio, S.; Luisi, R. Chem. ReV. 2008, 108, 1918–1942.
(6) Cope, A. C.; Tiffany, B. D. J. Am. Chem. Soc. 1951, 73, 4158–4161.
(7) House, H. O.; Ro, R. S. J. Am. Chem. Soc. 1958, 80, 2428–2433.
(8) (a) Hodgson, D. M.; Bray, C. D.; Humphreys, P. G. Synlett 2006, 1–22.
(b) Hodgson, D. M.; Humphreys, P. G.; Hughes, S. P. Pure Appl. Chem. 2007,
79, 269–279.
(9) Hodgson, D. M.; Reynolds, N. J.; Coote, S. J. Tetrahedron Lett. 2002,
43, 7895–7897.
10.1021/jo802016t CCC: $40.75
Published on Web 12/23/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1019–1028 1019

Hodgson et al.
SCHEME 2. r,ꢀ-Epoxysilane Synthesis from Terminal
initial product of the reaction (Scheme 4). Upon column
chromatography, the wet and slightly acidic nature of silica gel
led to the expected hydrolysis product dodecanal, in 64% yield.
Epoxides9
SCHEME 4. Initial Observation of the Epoxide-Enamine
Transformation
leads to aldehyde enamines.10 In the present paper, we present
full details of these findings, including a comparison of reactivity
toward simple alkyl halides of the aldehyde enamines generated
by this newly identified process with that of aldehyde enamines
synthesized via a traditional condensation route.
Evidently, enamine formation had not been recognized by
Yamamoto and his co-workers, since they made no comment
as to the nature of the crude products obtained from treating
terminal epoxides with LTMP. Similarly, in a subsequent (and
as yet only other) reported application of this methodology for
terminal epoxide isomerization (the synthesis of 3,3-dimethyl-
butyraldehyde from tert-butyloxirane) by Katritzky et al., no
mention of enamine formation was made.13
Results and Discussion
In 1994, Yamamoto and co-workers reported the selective
and high-yielding isomerization of a variety of terminal epoxides
to aldehydes using sterically hindered lithium amides.11 LTMP,
generated from commercially available 2,2,6,6-tetramethylpi-
peridine (TMP) using n-BuLi, was found to provide the best
results (LTMP (2.5 equiv), 20 °C, 12 h) for aldehyde formation
(75-83% yields). With evidence from experiments using
deuterium-labeled epoxides, Yamamoto et al. suggested a
reaction pathway for this transformation (Scheme 3).
The workup for this reaction involved addition of saturated
aqueous NH4Cl. Enamine 3a could, in principle, simply have
been formed during workup by condensation of dodecanal with
the TMP generated in situ. However, adding dodecanal to a
solution of LTMP in THF, which had already been quenched
by the addition of saturated aqueous NH4Cl, did not generate
enamine 3a. Similarly, azeotropic distillation of dodecanal with
TMP in the presence of catalytic p-TSA, a standard method for
synthesizing enamines, failed to give enamine 3a. Carlson and
Nilsson have described the synthesis of aldehyde enamines using
TiCl4 as both a Lewis acid and dehydrating agent;14 however,
even application of these forcing condition failed to give
enamine 3a. These results imply that enamine 3a was formed
during the reaction, rather than during the aqueous workup. To
test this hypothesis, a crossover experiment was designed:
4-hydroxy-2,2,6,6-tetramethylpiperidine was protected as its tert-
butyldimethylsilyl ether and subsequently deprotonated with
n-BuLi to give lithium amide 4-Li. The isomerization of 1,2-
epoxydodecane 1a was conducted as described above; however,
prior to aqueous workup, lithium amide 4-Li (2.5 equiv) was
added. Enamine 3b was not observed as a product,15 indicating
that enamine 3a was generated during the reaction and not as
a result of a subsequent condensation (Scheme 5).
SCHEME 3. Originally Proposed Reaction Pathway for
Isomerization of Epoxides to Aldehydes11
This report was of interest in connection with our studies on
thedirect-deprotonation/electrophiletrappingofsimpleepoxides9,12
and initially led to our development of a method for the
straightforward synthesis of R,ꢀ-epoxysilanes from terminal
epoxides (Scheme 2). During the development of this latter
procedure, we had recourse to examine the LTMP-induced
isomerization of 1,2-epoxydodecane 1a as a prior check of
experimental technique. Intriguingly, we found that the crude
product of this reaction was not dodecanal, as expected. Analysis
SCHEME 5. Crossover Experiment To Discount a
Condensation Route to Enamine 3a
1
of the H NMR spectrum of the reaction mixture following
aqueous workup (NH4Cl) but prior to column chromatography
indicated that all of the starting epoxide had been consumed.
However, it showed only a trace of the characteristic aldehyde
proton signal [9.72 (t, J ) 1.8 Hz, CHO)]. Instead, two mutually
It was possible to independently synthesize an example of
such a highly hindered enamine via the method described by
Hannson and Wickberg.16 N-Formyl-2,2,6,6-tetramethylpiperi-
dine was obtained in 80% yield from TMP according to the
procedure of Blum and Nyberg (Scheme 6).17 Prolonged
reaction of this amide with excess n-BuMgCl gave enamine 3c
in 32% yield (unoptimized).
1
coupled resonances in the H NMR spectrum were displayed,
consistent with an E-olefin [5.66 (1 H, dt, J ) 13.6 and 1.0
Hz) and 5.16 (1 H, dt, J ) 13.6 and 7.2 Hz)]. Combining this
information with the molecular ion observed by mass spec-
trometry led us to conclude that enamine 3a was in fact the
(10) Preliminary communication: Hodgson, D. M.; Bray, C. D.; Kindon, N. D.
J. Am. Chem. Soc. 2004, 126, 6870–6871.
(11) Yanagisawa, A.; Yasue, K.; Yamamoto, H. J. Chem. Soc., Chem.
Commun. 1994, 2103–2104.
(12) (a) Hodgson, D. M.; Reynolds, N. J.; Coote, S. J. Org. Lett. 2004, 6,
4187–4189. (b) Hodgson, D. M.; Kirton, E. H. M.; Miles, S. M.; Norsikian,
S. L. M.; Reynolds, N. J.; Coote, S. J. Org. Biomol. Chem. 2005, 3, 1893–1904.
(13) Katritzky, A. R.; Fang, Y.; Prakash, I. J. Indian Chem. Soc. 2000, 77,
635–636.
(14) Carlson, R.; Nilsson, A. Acta Chem. Scand., Ser. B 1984, 38, 49–53.
(15) Use of 4-Li with epoxide 1a gave 3b, as expected.
(16) Hansson, C.; Wickberg, B. J. Org. Chem. 1973, 38, 3074–3076.
(17) Blum, Z.; Nyberg, K. Acta Chem. Scand., Ser. B 1981, 35, 743–745.
1020 J. Org. Chem. Vol. 74, No. 3, 2009

Hindered Aldehyde Enamines
SCHEME 6. Synthesis of Enamine 3c from an N-Formyl
Piperidine
strategy for the synthesis of enamines, formally constituting the
addition of a lithium amide to a vinyl cation equivalent.22
SCHEME 8. Proposed Reaction Pathway for the
Epoxide-Enamine Transformation
Unequivocal proof that enamines (3) were being formed by
a new reactivity mode of lithium amides with epoxides and not
by simple condensation of an aldehyde with TMP was obtained
1
by in situ H NMR monitoring of the reaction between 1,2-
epoxypentane and LTMP in THF-d8. After only 5 min, complete
consumption of the starting material was observed and the
resonances due to the vinylic protons of 3c could clearly be
1
seen in the H NMR spectrum.
A possible reaction pathway leading to enamines from
terminal epoxides could involve direct epoxide ring-opening
with LTMP,2 followed by R-amino lithiation and subsequent
elimination of Li2O. However, this was shown to be unlikely
by the following experiments. Direct ring-opening of 1,2-
epoxyoctadecane (1b) with 2,2,6,6-tetramethylpiperidine (TMP)
(3 equiv, i-PrOH, 100 °C, 24 h) gave aminoalcohol 5 (Scheme
7). Treatment of the lithium alkoxide of 5 (generated by
deprotonation with n-BuLi (1 equiv)) with LTMP (1.5 equiv,
THF, 25 °C, 1 h) returned 5 quantitatively following aqueous
workup; enamine 3d was not observed.
The process proposed above is analogous to that described
by Crandall and Lin for the reductive alkylation of epoxides
with organolithiums.23,20b-f Supporting evidence for this analogy
came through comparison of the 7Li NMR spectra of the
reactions between 1,2-epoxypentane and LTMP (1.95 equiv,
THF, 25 °C, 1 h) and of that between 1,2-epoxypentane and
n-BuLi (1.95 equiv, THF, 25 °C, 1 h).24 They contain the same
lithium byproduct, presumably Li2O.25
Though the first chemistry of enamines dates back to 1884,26
the name itself was not coined until 1927 when Wittig
emphasized the analogy of this class of compounds with enols.27
Even so, the synthetic potential of the reaction of enamines with
electrophiles was not realized until 1954 when the pioneering
work of Stork et al. demonstrated their use for R-alkylations
and R-acylations of carbonyl compounds.28 With this method,
enamines react with such electrophiles to give iminium ions,
which are subsequently hydrolyzed to yield R-alkylated carbonyl
or 1,3-dicarbonyl compounds. Reactions of enamines with
electrophiles have been extensively reviewed.29 Unfortunately,
reactions of aldehyde enamines with simple alkyl halides are
generally problematic; competing N- over C-alkylation often
SCHEME 7. Evidence To Disprove a Direct Ring-Opening/
Elimination Pathway
A new reactivity mode of lithium amides with epoxides is
therefore proposed that could explain the formation of enamines.
Collum et al. have demonstrated that R-lithiation of cyclooctene
oxide by LTMP in THF proceeds predominantly via a mono-
solvated dimer 6 (Scheme 8).18 Coordination of a terminal
epoxide to this monosolvated dimer 6 could precede R-trans-
deprotonation using one molecule of LTMP. The second,
proximal molecule of LTMP could then add to the electrophilic19
R-lithiated epoxide 7, either in an SN2 manner or via a 1,2-
metallate shift,20 to give the dianion 8. It should be noted that
Yamamoto et al. reported that the use of only 1 equiv of LTMP
in the isomerization of terminal epoxides led to yields of
aldehydes <50%.11 Finally, syn-elimination of Li2O from the
dianion 8 gives enamine 3. It cannot be assumed that the
elimination of Li2O, which is highly ionic, occurs like the
elimination of a typical organic fragment. The high lattice
enthalpy of Li2O (calculated to be 2799 kJ mol-1) would suggest
that co-ordination between lithium and oxygen would be highly
favorable.21 This process represents a fundamentally new
(21) (a) Jenkins, H. D. B. In CRC Handbook of Chemistry and Physics 1999-
2000; Lide, D. R., Ed.; CRC Press: Boca Raton, FL, 1998. (b) Bouyacoub, A.;
Hadjadj-Aoul, R.; Volatron, F. Eur. J. Org. Chem. 2008, 4466–4474.
(22) For an approach based on an amino-Cope rearrangement, see: (a) Allin,
S. M.; Button, M. A. C.; Shuttleworth, S. J. Synlett 1997, 725–727. For cross-
coupling based approaches, see: (b) Barluenga, J.; Fernandez, M. A.; Aznar, F.;
Valdes, C. Chem. Commun. 2002, 2362–2363. (c) Willis, M. C.; Brace, G. N.
Tetrahedron Lett. 2002, 43, 9085–9088. (d) Barluenga, J.; Fernandez, M. A.;
Aznar, F.; Valdes, C. Chem. Eur. J. 2004, 10, 494–507. For routes based on
hydroamination of alkynes, see: (e) Seayad, A. M.; Jackstell, R.; Beller, M.
Angew. Chem., Int. Ed. 2003, 42, 5615–5619.
(23) (a) Crandall, J. K.; Lin, L.-H. C. J. Am. Chem. Soc. 1967, 89, 4527–
4528. See also: (b) Doris, E.; Dechoux, L.; Mioskowski, C. Tetrahedron Lett.
1994, 35, 7943–7946.
(24) See Supporting Information.
(25) Attempts to obtain the 7Li NMR spectrum of commercial Li2O, for direct
comparison, failed because of its complete insolubility in THF.
(26) Collie, J. N. Liebigs Ann. Chem. 1884, 226, 294–322.
(27) Wittig, G.; Blumenthal, H. Ber. 1927, 60B, 1085–1094.
(28) (a) Stork, G.; Terrell, R.; Szmuszkovicz, J. J. Am. Chem. Soc. 1954,
76, 2029–2030. (b) Stork, G.; Landesman, H. K. J. Am. Chem. Soc. 1956, 78,
5128–5129. (c) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.;
Terrell, R. J. Am. Chem. Soc. 1963, 85, 207–222.
(18) Wiedemann, S. H.; Ram´ırez, A.; Collum, D. B. J. Am. Chem. Soc. 2003,
125, 15893–15901.
(19) Boche, G.; Lohrenz, J. C. W. Chem. ReV. 2001, 101, 697–756.
(20) The concept of a 1,2-metallate shift follows related suggestions; see:
(a) Kasatkin, A. N.; Whitby, R. J. Tetrahedron Lett. 2000, 41, 5275–5280. (b)
Hodgson, D. M.; Stent, M. A. H.; Wilson, F. X. Org. Lett. 2001, 3, 3401–3403.
(c) Hodgson, D. M.; Stent, M. A. H.; Wilson, F. X. Synthesis 2002, 1445–1453.
(d) Hodgson, D. M.; Fleming, M. J.; Stanway, S. J. J. Am. Chem. Soc. 2004,
126, 12250–12251. (e) Hodgson, D. M.; Fleming, M. J.; Stanway, S. J. J. Org.
Chem. 2007, 72, 4763–4773. (f) Hodgson, D. M.; Humphreys, P. G.; Fleming,
M. J. Org. Synth. 2008, 85, 1–9.
(29) (a) Enamines: Synthesis, Structure, and Reactions, 2nd ed.; Cook, A. G.,
Ed.; Marcel Dekker: New York, 1987. (b) Hickmott, P. W. Tetrahedron 1982,
38, 1975–2050. (c) Hickmott, P. W. Tetrahedron 1982, 38, 3363–3446. (d) Dyke,
S. F. The Chemistry of Enamines; Cambridge University Press: Cambridge, 1973.
(e) The Chemistry of Enamines, Pt. 1; Rappoport, Z., Ed.; Wiley: Chichester,
1994. (f) Adams, J. P. Perkin Trans. 1 2000, 125–139. (g) Sammakia, T.;
Abramite, J. A. Sammons, M. F. In Science of Synthesis: Houben-Weyl Methods
of Molecular Transformations; Molander, G., Ed.; Thieme: Stuttgart, Germany,
2006; Vol. 33, pp 405-441.
J. Org. Chem. Vol. 74, No. 3, 2009 1021

Hodgson et al.
TABLE 1. Substrate Scope in Enamine Formation
leads to poor yields of R-substituted aldehydes. Reports by
Curphey30 and later by Allin22a have demonstrated that C-
alkylation is promoted over N-alkylation if the aldehyde
enamines are sterically encumbered around the nitrogen.
Nevertheless, reactions with simple alkyl iodides (e.g., n-BuI)
are reported to give low yields (24-34%)30b of R-alkylated
product, and there are relatively few examples of such reactions.
The direct mono-R-alkylation of aldehydes is not a trivial
task.31 For the most part, methods routinely employed to achieve
this transformation are indirect and usually involve alkylation
of a substrate at a higher oxidation state (e.g., an amide or ester)
followed by a subsequent reduction to give an aldehyde, either
directly or via reduction to the alcohol and subsequent oxidation.
Paradoxically, there has been a great deal of interest in the area
of organocatalysis, where catalytic quantities of chiral amines
react with aldehydes to generate chiral enamines.32 Even so,
organocatalytic intermolecular alkylations of aldehydes using
simple alkyl halides are not currently possible.33 In light of this,
we were intrigued to examine the scope for the synthesis of
highly hindered aldehyde enamines by this newly identified
process from epoxides and to discover whether the products
obtained would undergo efficient C-alkylation.
Up until this point, the enamines 3a-c isolated had been
contaminated with small proportions (5-10%) of the corre-
sponding aldehydes as a result of hydrolysis. Under reaction
conditions otherwise identical to those employed by Yamamoto
et al.11 (LTMP (2.5 equiv), THF, 0-25 °C, 1 h), various other
aqueous workup procedures were examined (pH 7 buffer
solution, 0.5 M HCl, saturated aqueous NaHSO3, or water).
Unfortunately, contamination by hydrolysis products was always
observed (3-30%, as judged by 1H NMR spectroscopy).
Attempted purification by column chromatography (NEt3 doped
silica (∼1%), basic alumina, or Florisil) also resulted in further
hydrolysis, whereas attempted distillation resulted in decom-
position. These results indicated that the use of an aqueous
workup was incompatible with the isolation of such enamines.
However, it was found that a rapid filtration of the reaction
mixture through a short pad of silica that had been deactivated
by stirring with neat NEt3 overnight (∼16 h), followed by
removal of all volatile compounds under high vacuum gave
spectroscopically pure samples of enamines 3. Using this
isolation procedure, 1,2-epoxypentane gave enamine 3c in 75%
yield (Table 1, entry 1). A brief survey of alternative solvents
in the epoxide-enamine transformation gave less satisfactory
results: using Et2O, enamine 3c was obtained in 32% yield,
whereas in hexane a yield of 33% was observed. Returning to
THF as solvent, 1,2-epoxyoctadecane gave the corresponding
enamine 3d in 78% yield (entry 2). In comparison, isomerization
of this epoxide according to the procedure of Yamamoto et al.
gave octadecanal in 77% yield (lit.11 79%), indicating that this
operationally simple method of isolation of the enamine was
a Isolated yields. b Observed by 1H NMR but not isolatable. c 5.0
equiv of LTMP. d 8:1 3l:3m mixture. e Et2O as solvent. f Starting
material returned.
(30) (a) Curphey, T. J.; Hung, J. C. Y. Chem. Commun. 1967, 510. (b)
Curphey, T. J.; Hung, J. C. Y.; Chu, C. C. C. J. Org. Chem. 1975, 40, 607–614.
(31) (a) Caine, D. In ComprehensiVe Organic Synthesis; Pattenden, G., Ed.;
Pergamon: New York, 1991; Vol. 3, pp 1-63. (b) Go¨ttlich, R. In Science of
Synthesis: Houben-Weyl Methods of Molecular Transformations; Bru¨ckner, R.,
Ed.; Thieme: Stuttgart, Germany, 2006; Vol. 25, pp 355-366.
as efficient as the more traditional one used to isolate the
corresponding aldehydes. The scope of this new, previously
unrecognized process was further explored. Isopropyl oxirane
gave enamine 3e in 60% yield (entry 3), which demonstrated
that increased substitution in the γ-position is tolerated. 1,2-
Epoxy-4-phenylbutane24 gave enamine 3f in 72% yield (entry
4), whereas 1,2-epoxy-9-decene gave enamine 3g in 83% yield
(entry 5). These latter results demonstrate that benzylic and
allylic protons, which are potentially labile,34 do not compromise
the process. To further demonstrate the utility of this protocol
for enamine formation over pre-existing acid-catalyzed meth-
(32) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. ReV. 2007,
107, 5471–5569.
(33) (a) Vignola, N.; List, B. J. Am. Chem. Soc. 2004, 126, 450–451. See
also: (b) Ibrahem, I.; Co´rdova, A. Angew. Chem., Int. Ed. 2006, 45, 1952–1956.
(c) Beeson, T. D.; Mastracchio, A.; Hong, J. B.; Ashton, K.; MacMillan, D. W. C.
Science 2007, 316, 582–585. (d) Jang, H.; Hong, J. B.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2007, 129, 7004–7005. (e) Enders, D.; Wang, C.; Bats, J. W.
Angew. Chem., Int. Ed. 2008, 47, 7539–7542. (f) Nicewicz, D. A.; MacMillan,
D. W. C. Science 2008, 322, 77–80.
1022 J. Org. Chem. Vol. 74, No. 3, 2009

Hindered Aldehyde Enamines
odology, silyloxyepoxide24 1c, dioxolane-containing epoxide
1d,24 and 5-(N-Boc-N-methylamino)-1,2-epoxypentane9 1e were
each converted to the corresponding enamines in good yield
(entries 6-8). During a traditional acid-catalyzed condensation
of an aldehyde with a secondary amine, these protecting groups
could well be labile, and so the present route is complimentary
to that approach. Yamamoto et al. described the conversion of
1,2,7,8-diepoxyoctane into octanedial in 71% yield.11 Pleasingly,
formation of bis-enamine 3k from this epoxide proceeded in
69% yield (entry 9).
synthetic applications of the highly hindered aldehyde enamines
we had prepared, specifically, their R-alkylation.
Enamine 3c (1.0 mmol), which was readily prepared on a
multigram scale, was heated to reflux with MeI (2.0 equiv) in
MeCN-d3, and the progress of the reaction was followed by in
situ 1H NMR spectroscopy. After 3 h, the starting enamine was
completely consumed, as judged by the disappearance of the
olefinic signals and the appearance of a signal presumably due
to an iminium ion [8.51 (d, 1H, J ) 11 Hz, NdCH)]. However,
after hydrolysis with acidic buffer (1:1:2 NaOAc/AcOH/H2O)30b
and subsequent aqueous workup, 2-methylvaleraldehyde was
isolated in only 30% yield following column chromatography.
Under similar conditions employing benzyl bromide as elec-
trophile, a 1:1 mixture of valeraldehyde and 2-benzylvaleral-
dehyde was obtained. Reaction with allyl bromide, propargyl
bromide and methyl R-bromoacetate led to similar mixtures of
alkylated and unalkylated products. Re-examination of the in
An epoxide bearing a chloro substituent was also examined
to see if it was compatible with the epoxide-enamine transfor-
mation. Treatment of 1-chloro-5,6-epoxyhexane24 with LTMP
using the typical procedure gave an 8:1 mixture of the desired
chlorine containing enamine 3l (entry 10) and an enamine
identifiable [13C NMR δ 139.0 and 115.0] as that derived from
additional elimination of HCl, 3m. Conclusive proof of the
structure of this elimination product was sought by attempted
formation of enamine 3m (entry 11) from commercially
available 1,2-epoxy-5-hexene. Enamine formation from this
epoxide proceeded in only 33% yield; however, the spectral
characteristics of the product obtained matched that of the
elimination product obtained previously. The poor yield obtained
for enamine 3m was initially surprising given that it had already
been shown that tethered olefins are tolerated in this process
(entry 5). With 1,2-epoxy-5-hexene, it was found that the
formation of bicyclic alcohol 9 was a competitive process;
indeed changing to Et2O as solvent (since such conditions had
been found earlier to reduce enamine formation) gave the
bicyclic alcohol 9 in 52% yield. Ultimately, this latter observa-
tion led to the development of the intramolecular cyclopropa-
nation of unsaturated terminal epoxides.35 All of the successful
enamine-forming reactions that had been carried out thus far
had functionality in rather a remote position. In order to probe
whether functionality could be tolerated much closer to the
epoxide moiety, two substrates were examined. Initially, it
seemed that 3-morpholinopropylene oxide had produced the
1
situ H NMR spectra of the reaction between enamine 3c and
MeI revealed, after 1 h, the presence of a series of unexpected
olefinic signals that were not due to the starting material.
The possibility was considered that enamine 3c was not
thermally stable. However when a solution of this enamine was
heated to 100 °C for 3 h (MeCN-d3, sealed tube), the in situ 1H
NMR spectrum revealed no appreciable decomposition. Enamine
3c could also have been unstable with respect to reaction with
the iminium ion generated through its own alkylation. Indeed,
when enamine 3c was heated (82 °C) with a deficiency of MeI
(0.5 equiv, MeCN-d3, 3 h), in situ 1H NMR monitoring revealed
complete consumption of the starting material. The signal due
to the iminium ion was very weak, and there were spurious
vinylic signals reminiscent of the starting enamine 3c. These
observations led us to speculate that the activation energy
required for enamine 3c to abstract the R-iminium proton from
its alkylated product is competitive with that for MeI alkylation
itself. With this inherent instability, although one could poten-
tially increase the number of equivalents of electrophile to
improve the selectivity for alkylated products, the ultimate aim
of LTMP derived enamines (3) reacting with unactivated alkyl
halides was unfortunately unlikely to be realized.
1
desired enamine; however, closer inspection of the H NMR
spectrum of the product, which was not pure, revealed that in
fact the initially formed enamine had likely isomerized to give
a morpholino-enamine [δ 5.98 (d, 1H, J ) 14 Hz, NCH), 4.73
(dt, 1H, J ) 14 and 7 Hz, dCH); the larger difference in
chemical shift between the olefinic protons (1.25 ppm) being
diagnostic; see later discussion]. Similarly, under identical
reaction conditions, reaction of tert-butylglycidyl ether with
LTMP likely initially formed an enamine, which then isomerized
to a tert-butylvinyl ether [δ 6.08 (d, 1H, J ) 14 Hz, OCH),
4.90 (dt, 1H, J ) 14 and 7 Hz, dCH)]. Finally, methylenecy-
clododecane oxide was examined as a substrate; however, as
has previously been observed,9,36 this material was unreactive
toward LTMP at least under the conditions examined here,20d-f
and the starting material was returned (entry 13).
In hindsight, the problematic reactivity of enamines such as
3c with electrophiles might have been anticipated on the basis
1
of the difference in chemical shift in the H and 13C NMR
spectra between the vinylic protons.37 For a typical aldehyde
enamine, one would expect this difference to be ∼1.5-2 ppm
29
1
in the H NMR and >30 ppm in the 13C NMR spectra. For
enamine 3c these differences were only ∆δH 0.48, ∆δC 6.0.
These values are similar to those observed for the structurally
related alkene (E)-1-pentenylcyclohexane [∆δH 0.19, ∆δC 9.1],38
which indicates minimal n f π* donation for enamine 3c. It
was surmised that enamine 3c may preferentially adopt a
conformation whereby the nitrogen lone pair and the π* orbital
of the olefin are orthogonal. Such a conformation would likely
minimize the steric interaction between the gem-dimethyl groups
on the piperidine ring and the vinylic protons (Ha, Figure 1)
Quantum mechanical studies support this hypothesis. Density
functional calculations at the B3LYP39/6-31G(d)40 level show
that the lowest energy conformation of enamine 3*41 is indeed
one where the nitrogen lone pair and π* orbital of the olefin
Having examined the mechanistic details and the scope of
this new enamine-forming reaction, our attention turned toward
(34) Mordini, A.; Peruzzi, D.; Russo, F.; Valacchi, M.; Reginato, G.; Brandi,
A. Tetrahedron 2005, 61, 3349–3360.
(35) (a) Hodgson, D. M.; Chung, Y. K.; Paris, J.-M. J. Am. Chem. Soc. 2004,
126, 8664–8665. (b) Hodgson, D. M.; Chung, Y. K.; Paris, J.-M. Synthesis 2005,
2264–2266. (c) Hodgson, D. M.; Chung, Y. K.; Nuzzo, I.; Freixas, G.;
Kulikiewicz, K. K.; Cleator, E.; Paris, J.-M. J. Am. Chem. Soc. 2007, 129, 4456–
4462. (d) Alorati, A. D.; Bio, M. M.; Brands, K. M. J.; Cleator, E.; Davies,
A. J.; Wilson, R. D.; Wise, C. S. Org. Process Res. DeV. 2007, 11, 637–641.
(36) Yasuda, A.; Yamamoto, H.; Nozaki, H. Bull. Chem. Soc. Jpn. 1979,
52, 1705–1708.
(37) Kempf, B.; Hampel, N.; Ofial, A. R.; Mayr, H. Chem. Eur. J. 2003, 9,
2209–2218.
(38) Pelter, A.; Smith, K.; Elgendy, S. M. A. Tetrahedron 1993, 49, 7119–
7132.
J. Org. Chem. Vol. 74, No. 3, 2009 1023

Hodgson et al.
classical enamine character in terms of their reactivity toward
electrophiles. Yamamoto et al. had previously reported that, as
well as LTMP, terminal epoxides can be “isomerized” to
aldehydes with lithium dicyclohexylamide (LiNCy2) (1,2-
epoxyoctadecane gave octadecanal in 63% yield).11 1,2-Epoxy-
pentane was therefore treated with LiNCy2 (2.5 equiv, THF,
25 °C, 1 h), and following filtration and evaporation to dryness,
the signals due to the desired enamine 10 (Scheme 9) were
1
clearly present in the H and 13C NMR spectra of the residue
[δΗ 5.97 (dt, 1H, J ) 14 and 1 Hz, NCH), 4.06 (dt, 1H, J ) 14
and 7 Hz, NCHdCH); δC 132.5 (NCH), 93.9 (NCHdCH)]. The
difference in chemical shift between the two olefinic protons
was now much larger (1.91 ppm), indicating greatly increased
n f π* donation compared to enamine 3c. However, it was
also apparent that amino alcohol 11, the result of direct ring-
opening of the epoxide with the base, was also present [δC 67.9
and 55.0]. This was expected, since Yamamoto et al. reported
a similar byproduct (17% isolated yield) in their isomerization.11
Attempted reduced pressure distillation of this mixture resulted
in decomposition, presumably due to the high boiling point of
enamine 10.
SCHEME 9. Epoxide-Enamine Transformation using
LiNCy2
Following on from this, we examined the reactivity of lithium
tert-butylisopropylamide (LTBIPA) toward terminal epoxides.
Although this lithium amide had not been employed by
Yamamoto et al. in their isomerizations, it was considered that
it would be sterically more encumbered than LiNCy2 but would
give an enamine that was more volatile. In the event, treatment
of 1,2-epoxyhexane with LTBIPA (2.5 equiv, THF, 1 h, 20 °C)
gave enamine 12 in 42% yield following reduced pressure
distillation (Scheme 10). The double bond geometry was
assigned as trans on the basis of the 14 Hz coupling constant
FIGURE 1. Predicted ground state conformations of enamine 3*.
are orthogonal to each other (cf. GS1, chair).42 Moreover, the
energy difference between the latter (GS1) and the conjugated
chair conformer GS2 was calculated to be +4.6 kJ mol-1. An
additional conjugated twist conformer GS3 was found to be
14.2 kJ mol-1 higher in energy than GS1. For both of the
conjugated conformers there was minimal contraction in the
N-alkene bond length compared to the nonconjugated conformer,
which provides further evidence for the nonclassical nature of
the enamines (3).
1
observed between the two olefinic signals in the H NMR
spectrum. Traces of the corresponding amino alcohol, as well
as 2-ene-1,4-diols resulting from R-lithiated epoxide dimeriza-
tion,43 were also observed but not isolated. Again, the use of
other solvents (Et2O, hexane) resulted in greatly diminished
yields, whereas the inclusion of additives (e.g., LiCl, TMEDA)
did not result in an increase in yield for enamine 12.
Next, we examined the reactivity of lithium amides slightly
less hindered than LTMP with terminal epoxides. It was hoped
that we might discover enamines that were accessible via this
new epoxide-enamine transformation but that displayed more
SCHEME 10. Epoxide-Enamine Transformation using
LTBIPA
(39) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652. (b) Becke, A. D.
J. Chem. Phys. 1993, 98, 1372–1377. (c) Lee, C.; Yang, W.; Parr, R. G. Phys.
ReV. B 1988, 37, 785–789.
(40) (a) Ditchfield, R.; Hehre, W. J.; Pople, J. A. J. Chem. Phys. 1971, 54,
724–728. (b) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972, 56,
2257–2261. (c) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28, 213–
222.
(41) Replacement of the experimentally used n-propyl group with a methyl
group in the calculations should still provide an accurate indication of the relative
energies of the various conformations, since the energy differences mainly arise
from (1) strain between the vinyl protons and the gem-dimethyl groups (GS1
versus GS2) and (2) differing ring stabilities (GS2 versus GS3). Truncating the
alkyl chain by two carbons reduces the number of possible conformations 9-fold
and makes the computational study feasible.
The yield of enamine 12 was lower than what might have
been anticipated on the basis of the yields obtained by
Yamamoto et al. when using LiNCy2 as base. To test whether
this was due to partial enamine hydrolysis during the isolation,
the isomerization of 1,2-epoxyoctadecane with LTBIPA (2.5
equiv, THF, 16 h, 20 °C) was carried out. This produced
octadecanal in 42% yield, indicating that the isolation technique
used was highly efficient. This isomerization was also carried
out using LiNCy2 (2.5 equiv, THF, 16 h, 20 °C); however, this
proceeded in only 40% yield, and despite numerous attempts
(42) All calculations were carried out for the gas phase using the Gaussian
03 suite of programs: Frisch, M. J. Gaussian 03, rev. C02; Gaussian Inc.:
Wallingford, CT, 2004. See Supporting Information for full reference.
1024 J. Org. Chem. Vol. 74, No. 3, 2009

Hindered Aldehyde Enamines
on a variety of reaction scales, this could not be improved upon.
In the present work when using LiNCy2 as base, yields
comparable to that reported by Yamamoto et al. for the
isomerization of 1,2-epoxyoctadecane to octadecanal (lit.11 63%)
were not attainable.
CHdN+)], likely due to protonation of 12 following elimination
of HI from the electrophile; the desired alkylation did not occur
(entry 12).
As efficient (for the most part) as the alkylations described
above were, they were based on an enamine (12) that could
only be formed in 42% yield. A lithium amide was therefore
sought whose steric encumbrance was intermediate in nature
between LTMP and LTBIPA. Lithium N-tert-butylpinacoyla-
mide was selected as a potential candidate, since the parent
amine could be readily prepared in multigram quantities by
reductive amination of pinacolone with t-BuNH2.24 Reaction
of this lithium amide (2.5 equiv, THF, 1 h, 20 °C) with 1,2-
epoxyhexane gave enamine 14 in 58% yield (Scheme 11). It
should be noted that the increasing yields obtained for the
formation of enamines 12, 14, and 3c (42%, 58%, and 75%,
respectively) bear a near linear relationship with the decreasing
Returning to R-alkylation, enamine 12 was found to dem-
onstrate unprecedented reactivity toward a range of electro-
philes.10 Reaction with benzyl bromide, allyl bromide, propargyl
bromide, methyl R-bromoacetate, and MeI (2 equiv) proceeded
smoothly at 15 °C to give the corresponding R-branched
aldehydes 13a-e in excellent yields (Table 2, entries 1-5)
following aqueous workup and column chromatography. More
than 40 years after its introduction in the mid 1950s, Stork noted
that enamine alkylation (of unsubstituted R-methylene alde-
hydes) is “the only method for the controlled alkylation of such
aldehydes with electrophilic olefins”;44 therefore, it was pleasing
that reaction of enamine 12 with acrylonitrile and methyl
acrylate proceeded well to give aldehydes 13f and 13g (entries
6 and 7). Enamine addition reactions using such Michael
acceptors are known to lead to different intermediates (cyclobu-
tanes and/or more substituted enamines), compared with the
iminium ions formed in substitution reactions using organoha-
lides.29 For example, direct 1H NMR analysis at the end of the
reaction of enamine 12 with acrylonitrile tentatively indicated
that an approximately equal mixture of the corresponding
cyclobutane and substituted enamine were present.24 Enamine
11 also reacted with simple alkyl halides. Reaction with
iodoethane occurred on moderate heating to give aldehyde 13h
in quantitative yield (entry 8); this is impressive given the
potential for competing elimination of HI with liberation of
ethene.45 In addition, reaction with 1-iodobutane and 1-iodode-
cane proceeded in excellent yield (entries 9 and 10), further
demonstrating that increased steric bulk around the nitrogen
favors C- over N-alkylation. Enamine 12 also reacted with
2-iodopropane in good yield (entry 11), although three equiva-
lents of electrophile needed to be employed in order that the
reaction went to completion within a reasonable time scale. To
the best of our knowledge,29 this is the first example of an
R-alkylated aldehyde being generated from an enamine by
substitution of a secondary alkyl halide. Enamine 12 was then
reacted with tert-BuI, but unfortunately the iminium ion that
was observed in situ was a triplet [δH 8.44 (t, 1H, J ) 7 Hz,
1
differences in chemical shift observed in the H NMR spectra
for the vinylic protons of these compounds (∆δH 1.45, 0.89,
and 0.48, respectively).
SCHEME 11. Epoxide-Enamine Transformation using
Lithium N-tert-Butylpinacoylamide
Enamine 14 retained its ability to act as a C-nucleophile.
Reaction with 1-iodobutane gave aldehyde 13i in 84% yield
(Table 3, entry 1); moreover reaction with i-PrI gave aldehyde
13k in 49% yield (entry 2). Unfortunately, reaction with
1-iododecane was less efficient; this reaction never became
homogeneous as was usually observed as the iminium ion
formed, and the isolated yield of aldehyde 13j was only 33%
(entry 3).
TABLE 3. Alkylation of Enamine 14
TABLE 2. Alkylation of Enamine 12
entry
electrophile (E)
temp (°C)
time (h)
yield (%)a
1
2
3
n-BuI (2 equiv)
i-PrI (3 equiv)
n-C10H21I (2 equiv)
84
94
82
96
96
96
13i
13k
13j
84
49
33
a Isolated yield.
entry
electrophile (E)a
temp (°C)
time (h)
yield (%)b
1
2
3
4
5
6
7
8
PhCH2Br
CH2dCHCH2Br
HCt CCH2Br
MeO2CCH2Br
MeI
acrylonitrile
methyl acrylate
EtI
15
15
15
15
15
84
84
50
75
84
84
84
18
18
15
16
18
19
22
18
23
22
40
<1
13a
>99
96
>99
91
86
91
70
99
97
95
80
0
13b
13c
13d
13e
13f
13g
13h
13i
The reactivity of two other hindered lithium amides toward
terminal epoxides was examined. Reaction between lithium
2,2,5,5-tetramethylpyrrolidide24 (2.5 equiv, THF) and 1,2-
epoxyoctadecane returned the starting material after 1 h at 25
°C. The starting material was consumed, however, when the
same reaction was heated to reflux for 16 h. Following aqueous
workup, 1H NMR spectroscopy revealed that as well as
octadecanal, a small amount of enamine [δΗ 5.83 (dt, 1H, J )
9
n-BuI
10
11
12
C10H21I
13j
13k
13l
i-PrIc
t-BuI
(43) Hodgson, D. M.; Bray, C. D.; Kindon, N. D. Org. Lett. 2005, 7, 6870–
6871.
a 2 equiv unless otherwise stated. b Isolated yield (%). c 3 equiv.
J. Org. Chem. Vol. 74, No. 3, 2009 1025

Hodgson et al.
TABLE 4. Alkylation of Enamines Synthesized via a Classical
Condensation
14 and 1 Hz, dCH), 4.18 (dt, 1H, J ) 14 and 7 Hz, NCH)]
remained unhydrolyzed. The difference in chemical shift
1
observed in the H NMR spectrum between the two olefinic
protons was 1.65 ppm. However, following purification by
column chromatography (SiO2), octadecanal was obtained in
only 25% yield. This was perhaps unsurprising since it would
be expected that the intermediate R-lithiated epoxide would be
labile in refluxing THF. At ambient temperature this reaction
proved unworkably sluggish, proceeding to less than 50%
conversion in 7 days. Lithium N-trityl-N-tert-butylamide46 was
also examined as base for the formation of enamines from
terminal epoxides. Treatment of 1,2-epoxyoctadecane with
LiN(t-Bu)Tr (2.5 equiv, THF, 25 °C, 16 h) returned the starting
material in quantitative yield. Repeating this reaction at reflux
(16 h) gave the same result. The lack of reactivity of this base
with a terminal epoxide could be due to its highly hindered
nature, or because it is simply not basic enough to abstract a
proton from the epoxide ring.
Finally, the possibility of using a mixture of lithium amides
for enamine formation from terminal epoxides was examined.
It was considered that a highly basic and hindered lithium amide
could deprotonate the terminal epoxide and a second less
hindered/more nucleophilic lithium amide could act as a
nucleophile with the resulting R-lithiated epoxide. It was
anticipated that the products of such a reaction would display
more classical enamine character, but could be formed in high
yield. However, even when employing a highly nucleophilic
lithium amide such as lithium pyrrolidide alongside LTMP,
mixtures of enamines were observed along with considerable
amounts of amino alcohols. The fact that LTMP is able to
compete as a nucleophile with such a powerful nucleophile
serves to indicate the high electrophilicity of R-lithiated ep-
oxides.19 In addition, it might also indicate that the use of a
lithium amide dimer is crucial in obtaining good yields of
enamine such that the nucleophilic lithium amide is intimately
bound in aggregate during the deprotonation step and is then
nearby to intercept the transient lithiated epoxide as soon as it
is formed (cf. Scheme 8). Though it is known that the
R-lithiation of cyclooctene oxide proceeds via a monosolvated
LTMP dimer (vide supra),18 it is not clear how this mechanism
would translate on replacing that epoxide with a terminal one
or how the structure of other dimeric lithium amides would be
affected.20d-f,43
entry R1
R2 enamine yield (%)
R3
aldehyde yield (%)
1
2
3
4
5
6
n-Pr n-Bu
15
66
64
n-Bu
n-Bu
C10H21
i-Pr
n-Bu
i-Pr
13m
13i
54
74
57
48
62
50
n-Bu n-Bu
n-Bu n-Bu
n-Bu n-Bu
n-Bu i-Bu
n-Bu i-Bu
16a
16a
16a
16b
16b
13j
13k
13i
73
13k
this manner with those achieved via our route from terminal
epoxides and lithium amides. Base-catalyzed (K2CO3) conden-
sation of n-butylisobutylamine with hexanal proceeded in 64%
yield to give enamine 16a. Reaction of enamine 16a with n-BuI
(2 equiv, MeCN, ∆, 20 h) gave aldehyde 13i in 74% yield, and
although reaction with n-C10H21I was less facile, aldehyde 13j
was obtained in 57% yield. Given these unexpectedly high
yields, we attempted to alkylate enamine 16a with i-PrI, which
gave aldehyde 13k in 48% yield. The amine employed thus
far, n-butylisobutylamine, was prepared via the inelegant
reaction between i-BuNH2 (3 equiv) and n-BuBr (55% yield,
lit.30b 69%); therefore the use of a commercial amine, namely,
i-Bu2NH, was also examined. Base-catalyzed (K2CO3) conden-
sation of hexanal with this amine gave enamine 16b in 73%
yield. Reaction of enamine 16b with n-BuI (2 equiv, MeCN,
∆, 20 h) gave 2-butylhexanal 12i in 62% yield and with i-PrI
gave aldehyde 13k in 50% yield.
The realization that this traditional method is significantly
higher yielding than previously thought should promote a re-
evaluation of current thinking concerning the reactivity of such
enamines toward simple haloalkane electrophiles. Despite this,
the two-step synthesis of aldehyde 13i from hexanal via enamine
16a is achieved in 47% overall yield, and for aldehyde 13k the
yield is 31%.30b,48 In comparison, our newly developed method
starting from 1,2-epoxyhexane gives aldehyde 13i in 49% and
aldehyde 13k in 29% overall yields, which indicates our new
method is of comparable efficiency.
Conclusions
In summary, the reactivity modes of hindered lithium amides
with epoxides have been explored. Furthermore, some of the
enamines derived by this process react with activated and simple
alkyl halides in synthetically useful yields.49 A re-examination
of the alkylation of “traditional” enamines (synthesized by
condensation of secondary amines with aldehydes) has revealed
that these reactions are significantly more efficient than previ-
ously reported.
In order that we could accurately compare the yields for the
synthesis of R-alkylated aldehydes via our new method with
those obtained via a traditional condensation route, it was
considered prudent to repeat some of the early results of
Curphey.30 As a prior check of experimental technique, the base-
catalyzed (K2CO3) condensation of n-butylisobutylamine with
valeraldehyde was carried out as previously described by
Curphey;30 this gave enamine 15 in 66% yield (Table 4, entry
1; lit.30b 71%).47 Interestingly however, reaction of enamine 15
with n-BuI (2 equiv, MeCN, ∆, 20 h) gave 2-n-propylhexanal
13m in 54% isolated yield, whereas the reported yield for this
reaction was considerably lower (lit.30b 24% (GC)). In light of
this unusually high yield, we sought to synthesize aldehydes
13i-k in order that we could compare the yields obtained in
Experimental Section
General experimental details are described in Supporting
Information. General Procedure for LTMP-Induced Epox-
ide-Enamine Transformation. 2,2,6,6-Tetramethyl(octadec-1-
en-1-yl)piperidine (3d). To a solution of 2,2,6,6-tetramethylpi-
peridine (0.50 cm3, 2.96 mmol) in THF (6 cm3) at 0 °C was added
n-BuLi (1.6 mol dm-3 in hexanes; 1.85 cm3, 2.96 mmol) dropwise.
The solution was allowed to warm to 25 °C over 15 min before a
solution of 1,2-epoxyoctadecane (318 mg, 1.19 mmol) in THF (1.5
cm3) was added in one portion. The reaction mixture was stirred at
25 °C for 1 h before being filtered through a pad of silica (∼5 cm2
× 5 cm, deactivated by stirring for 16 h in neat NEt3). The pad
(44) Stork, G. Med. Res. ReV. 1999, 19, 370–387.
(45) For a recent example of this problem in synthesis, see: Hodgson, D. M.;
Galano, J.-M. Org. Lett. 2005, 7, 2221–2224.
(46) Busch-Petersen, J.; Corey, E. J. Tetrahedron Lett. 2000, 41, 2515–2518.
(47) See also Be´langer, G.; Dore´, D.; Me´nard, F.; Darsigny, V. J. Org. Chem.
2006, 71, 7481–7484.
1026 J. Org. Chem. Vol. 74, No. 3, 2009

Hindered Aldehyde Enamines
was washed with 5% NEt3 in light petrol (250 cm3). The solvent
and amines were removed in vacuo (down to 0.1 mbar, 50 °C) to
give enamine 3d (361 mg, 78%) as a glassy solid; IR (cm-1) 2924s,
2853s, 1641w (CdC), 1465m, 1376w, 1382w, 1265w, 1246w,
1174w, 1131w, 1080w, 1033w; 1H NMR (500 MHz, C6D6) δ 5.79
(d, 1H, J ) 14 Hz), 5.32 (dt, 1H, J ) 14 and 7 Hz), 2.08 (dt, 2H,
J ) 7 and 7 Hz), 1.51-1.18 (m, 34H), 1.13 (s, 12H), 0.91 (t, 3H,
J ) 7 Hz); 13C NMR (125 MHz, C6D6) δ 131.8 (NCHd), 126.2
(dCH), 53.7 (2 × CMe2), 41.6 (2 × CMe2CH2), 32.4 (dCHCH2),
32.1 (CH2), 31.1 (CH2), 30.9 (CH2), 30.2-29.7 (10 × CH2), 28.0
(2 × NCMe2), 23.1 (CH2), 18.1 (CH2), 14.4 (Me); HRMS m/z (M
+ H+) found 392.4254. C27H54N requires 392.4251.
δ 138.5 (NCH), 95.8 (dCH), 60.3 (NCH2i-Pr), 51.8 (NCH2), 34.4,
30.7, 29.5, 27.4, 22.3, 20.7, 20.6, 14.3 (Me), 14.2 (Me); HRMS
m/z (M + H+) found 212.2381. C14H30N requires 212.2378.
(Hex-1-en-1-yl)diisobutylamine (16b). Prepared in the same
manner as described for 16a: K2CO3 (14.00 g), diisobutylamine
(17.3 cm3, 100 mmol), and hexanal (10.0 g, 100 mmol) gave
enamine 16b (15.39 g, 73%) as a colorless oil; bp 102 °C/18 mbar;
IR (cm-1) 3049w, 2954s, 2926s, 2869s, 1651s (CdC), 1467s,
1383m, 1366m, 1333w, 1294w, 1227m, 1208w, 1102m; 1H NMR
(500 MHz, C6D6) δ 5.89 (d, 1H, J ) 14 Hz), 4.15 (dt, 1H, J ) 14
and 7 Hz), 2.60 (d, 4H, J ) 7 Hz), 2.10 (dt, 2H, J ) 7 and 7 Hz),
1.85 (sept. 2H, J ) 7 Hz), 1.42-0.85 (m, 19H); 13C NMR (125
MHz, C6D6) δ 138.9 (NCH), 95.8 (dCH), 61.0 (NCH2), 34.7 (CH2),
31.2 (CH2), 27.4 (2 × CHMe2), 22.5 (CH2), 20.6 (2 × CHMe2),
14.3 (Me); HRMS m/z (M + H+) found 212.2384. C14H30N requires
212.2378.
tert-Butyl(hex-1-en-1-yl)isopropylamine (12). To a solution of
N-tert-butylisopropylamine (1.50 cm3, 9.46 mmol) in THF (15 cm3)
at -78 °C was added n-BuLi (1.6 mol dm-3 in hexanes; 5.91 cm3,
9.46 mmol) dropwise. The solution was allowed to warm to 25 °C
over 15 min before a solution of 1,2-epoxyhexane (378 mg, 3.78
mmol) in THF (5 cm3) was added in one portion. The reaction
was stirred at 25 °C for 1 h before being filtered through a pad of
celite (∼5 cm2 × 5 cm). The pad was washed with Et2O (250 cm3).
The solvent was removed in vacuo, and the residue was purified
by bulb-to-bulb distillation to give enamine 12 (314 mg, 42%) as
a colorless oil; bp 90 °C/0.1 mbar; IR (cm-1) 2970s, 2925s, 2873s,
General Procedure for Enamine Alkylation. 2-Benzyl-
hexanal10 (13a). A solution of enamine 12 (227 mg, 1.15 mmol)
and BnBr (273 µL, 2.30 mmol) in MeCN-d3 (1.0 cm3) was allowed
to stand (with occasional shaking) at 15 °C (rt) in a NMR tube
fitted with a PTFE valve, until consumption of enamine 12 was
1
judged complete by H NMR spectroscopy (18 h). Acidic buffer
solution (made up of AcOH (0.5 g), AcONa (0.5 g), and water
(1.0 g)) (0.5 cm3) was added, and the mixture was allowed to stand
at the same temperature as before, for 1 h with occasional shaking
before being separated between H2O (10 cm3) and Et2O (10 cm3).
The aqueous phase was washed with Et2O (10 cm3), the combined
organic layers were washed with brine (20 cm3), dried (MgSO4),
and filtered, and the solvent was removed in vacuo. Purification
by column chromatography (SiO2, 5% Et2O/light petrol) gave
2-benzylhexanal 13a (217 mg, quant) as a colorless oil; Rf 0.26
(5% Et2O/light petrol); IR (cm-1) 3086w, 3063w, 3028m, 2957s,
2931s, 2859s, 2711m, 2360w, 2340w, 1725s (CdO), 1604w,
1496m, 1466m, 1454s, 1392w, 1379w, 1030w; 1H NMR (400 MHz)
δ 9.67 (d, 1H, J ) 3 Hz), 7.33-7.26 (m, 2H), 7.25-7.15 (m, 3H),
2.99 and 2.73 (AB-part of ABX, 2H, JAX ) 7, JBX ) 7, JAB ) 14
Hz), 2.67-2.58 (m, 1H), 1.72-1.22 (m, 6H), 0.89 (t, 3H, J ) 7
Hz); 13C NMR (100 MHz) δ 204.8 (CHO), 138.9 (ArC), 129.0 (2
× ArC -H), 128.5 (2 × ArC -H), 126.3 (ArC -H) 53.4 (CHCHO),
35.0 (CH2Ph), 29.1 (CH2), 28.3 (CH2) 22.7 (CH2), 13.8 (Me).
2-n-Butylhexanal (13i). According to the procedure described
for 2-benzylhexanal 13a, a solution of enamine 12 (144 mg, 0.73
mmol) and n-BuI (166 µL, 1.46 mmol) at 75 °C for 23 h gave
2-n-butylhexanal 13i (110 mg, 97%) as a colorless oil; Rf 0.21 (1%
Et2O/light petrol); IR (cm-1) 2958s, 2931s, 2873s, 2860s, 2693w,
1727s (CdO), 1467m, 1379w; 1H NMR (400 MHz) δ 9.54 (d, 1H,
J ) 3 Hz), 2.26-2.16 (m, 1H), 1.66-1.55 (m, 2H), 1.48-1.37
(m, 2H), 1.36-1.19 (m, 8H), 0.88 (t, 6H, J ) 7 Hz); 13C NMR
(100 MHz) δ 205.6 (CHO), 51.9 (CHBu2), 29.2 (2 × CH2), 28.6
(2 × CH2) 22.7 (2 × CH2), 13.8 (2 × Me).
1
1645s (CdC), 1465w, 1377m, 1363m, 1302m, 1220m; H NMR
(400 MHz) δ 5.93 (dt, 1H, J ) 14 and 1 Hz), 4.48 (dt, 1H, J ) 14
and 7 Hz), 3.56 (dsept, 1H, J ) 14 and 1 Hz), 1.99-1.93 (m, 2H),
1.35-1.30 (m, 4H), 1.23-1.18 (m, 15H), 0.91 (t, 3H, J ) 7 Hz);
13C NMR (100 MHz) δ 129.9 (NCHd), 105.3 (dCH), 55.5 (NC),
46.1 (NC), 33.8 (CH2), 31.5 (CH2), 29.0 (CMe3), 22.1 (CH2), 20.9
(CMe3), 14.0 (Me); HRMS m/z (M + H+) found 198.2228. C13H28N
requires 198.2222.
tert-Butyl(hex-1-en-1-yl)(3,3-dimethylbut-2-yl)amine (14). To
a solution of N-tert-butylpinacoylamine24 (1.00 g, 6.37 mmol) in
THF (15 cm3) at -78 °C was added n-BuLi (1.6 mol dm-3 in
hexanes; 3.98 cm3, 6.37 mmol) dropwise. The solution was allowed
to warm to 25 °C over 15 min before a solution of 1,2-epoxyhexane
(255 mg, 2.55 mmol) in THF (5 cm3) was added in one portion.
The reaction was stirred at 25 °C for 1 h before being filtered
through a pad of celite (∼5 cm2 × 5 cm). The pad was washed
with Et2O (250 cm3). The solvent was removed in vacuo, and the
residue was purified by bulb-to-bulb distillation to give enamine
14 (353 mg, 58%) as a colorless oil; bp 125 °C/0.03 mbar; IR
(cm-1) 2957s, 2924s, 1646 (CdC), 1457m, 1370m, 1259w, 1195w;
1H NMR (500 MHz, C6D6) δ 5.83 (dt, 1H, J ) 14 and 1 Hz), 4.94
(dt, 1H, J ) 14 and 7 Hz), 2.92 (q, 1H, J ) 7 Hz), 2.05 (dt, 2H,
J ) 7 and 7 Hz), 1.42-1.35 (m, 4H), 1.15 (s, 9H), 1.05 (d, 3H, J
) 7 Hz), 0.96 (s, 9H), 0.91(t, 3H, J ) 7 Hz); 13C NMR δ 133.0
(NCHd), 117.3 (dCH), 58.6 (NCH), 55.5 (NC), 36.3 (CHCMe3),
33.5 (dCHCH2), 31.5 (CH2), 29.3 (CMe3), 28.6 (CMe3), 22.7 (CH2),
14.2 (Me), 14.2 (Me); HRMS m/z (M + H+) found 240.2692.
C16H34N requires 240.2691.
Similarly, a solution of enamine 14 (119 mg, 0.50 mmol) and
n-BuI (113 µL, 1.00 mmol) at 82 °C for 96 h gave 2-n-butylhexanal
13i (65 mg, 84%) as a colorless oil; data as above.
A solution of enamine 16a (198 mg, 0.94 mmol) and n-BuI (214
µL, 1.88 mmol) at 82 °C for 20 h gave 2-n-butylhexanal 13i (108
mg, 74%) as a colorless oil; data as above.
A solution of enamine 16b (160 mg, 0.76 mmol) and n-BuI (170
µL, 1.51 mmol) at 82 °C for 22 h gave 2-n-butylhexanal 13i (73
mg, 62%) as a colorless oil; data as above.
2-n-Butyldodecanal (13j). According to the procedure described
for 2-benzylhexanal 13a, a solution of enamine 12 (212 mg, 1.07
mmol) and C10H21I (458 µL, 2.14 mmol) at 82 °C for 22 h gave
2-n-butyldodecanal 13j as a colorless oil (244 mg, 95%); Rf 0.29
(2% Et2O/light petrol); IR (film) (cm-1) 3434w, 2926s, 2855s,
2692m (CHO), 1728s (CdO), 1466s, 1378m, 1239m, 1143w,
1016w; 1H NMR (400 MHz) δ 9.54 (d, 1H, J ) 3 Hz), 2.26-2.16
(m, 1H), 1.67-1.16 (m, 24H), 0.92-0.83 (m, 6H); 13C NMR (100
MHz) δ 205.7 (CHO), 51.9 (CHCHO), 31.9 (CH2), 29.7 (CH2),
29.6 (CH2), 29.5 (CH2), 29.4 (CH2), 29.3 (CH2), 29.2 (CH2), 28.9
Butyl(hex-1-en-1-yl)isobutylamine (16a). Prepared by analogy
to the procedure reported by Curphey.30b To a stirred solution of
n-butylisobutylamine (11.19 g, 86.7 mmol) in dry Et2O (22 cm3)
at 0 °C under argon was added anhydrous K2CO3 (12.12 g) followed
by freshly distilled hexanal (8.67 g, 86.7 mmol) dropwise. The
reaction was stirred at room temperature for a further 16 h before
being filtered through an oven-dried sintered glass filter. The filtrate
was fractionally distilled to give enamine 16a (11.68 g, 64%) as a
colorless oil; bp 106 °C/17 mbar; IR (cm-1) 3049m, 2955s, 2926s,
2870s, 1651s (CdC), 1466m, 1378m, 1290m, 1262w, 1225m,
1
1202m, 1113m; H NMR (400 MHz) δ 5.88 (d, 1H, J ) 14 Hz),
4.02 (dt, 1H, J ) 7 and 7 Hz), 2.87 (t, 3H, J ) 7 Hz), 2.63 (d, 2H,
J ) 7 Hz), 1.93 (dt, 2H, J ) 7 and 7 Hz), 1.80 (sept. 1H, J ) 7
Hz), 1.59-1.08 (m, 8H) 1.04-0.77 (m, 12H); 13C NMR (100 MHz)
(48) For a one-pot procedure, see: Ho, T.-L.; Wong, C. M. Synth. Commun.
1974, 4, 147–149.
(49) For a recent asymmetric development of this process, see: Hodgson,
D. M.; Kaka, N. S. Angew. Chem., Int. Ed. 2008, 47, 9958–9960.
J. Org. Chem. Vol. 74, No. 3, 2009 1027

Hodgson et al.
(CH2), 28.6 (CH2), 27.0 (CH2), 22.7 (CH2), 22.6 (CH2), 14.0 (Me),
13.8 (Me); HRMS m/z (M + NH4+) found 258.2801. C16H36NO
requires 258.2797.
A solution of enamine 16b (183 mg, 0.87 mmol) and i-PrI (190
µL, 1.90 mmol) at 82 °C for 20 h gave 2-isopropylhexanal 13k as
a colorless oil (62 mg, 50%); data as above.
A solution of enamine 16a (200 mg, 0.95 mmol) and C10H21I
(400 µL, 1.90 mmol) at 82 °C for 44 h gave 2-n-butyldodecanal
13j (131 mg, 57%) as a colorless oil; data as above.
Acknowledgment. We thank the EPSRC and AstraZeneca
for an Industrial CASE award, Wadham College for a Keeley
Senior Scholarship (to C.D.B.), the EPSRC and Glaxo-Smith-
Kline for a CASE award (to N.J.R.), the EPSRC for a research
grant (GR/S46789/01), the National Institutes of General
Medical Sciences, National Institutes of Health (G36700), N. S.
Kaka (Oxford) for additional data and helpful discussion, and
the EPSRC National Mass Spectrometry Service Centre for mass
spectra.
2-Isopropylhexanal (13k). According to the procedure described
for 2-benzylhexanal 13a, a solution of enamine 12 (136 mg, 0.69
mmol) and i-PrI (135 µL, 1.38 mmol) at 82 °C for 40 h gave
2-isopropylhexanal 13k as a colorless oil (79 mg, 80%); Rf 0.29
(2% Et2O/light petrol); IR (cm-1) 2961s, 2873s, 1725s (CdO),
1
1466w, 1371w, 1264w, 1128w, 1066w; H NMR (400 MHz) δ
9.61 (d, 1H, J ) 3 Hz), 2.06-1.91 (m, 2H), 1.69-1.57 (m, 1H),
1.51-1.40 (m, 1H), 1.37-1.13 (m, 4H), 0.96 (d, 6H, J ) 7 Hz),
0.89 (t, 3H, J ) 7 Hz); 13C NMR (100 MHz) δ 206.1 (CHO), 58.3
Note Added after ASAP Publication. A previous version
of the Supporting Information file was published ASAP on
December 23, 2008. The correct version was published ASAP
on January 13, 2009.
(CHCHO), 29.8 (CH2), 28.3 (CMe2), 25.8 (CH2), 22.8 (CH2), 20.2
+
(CMe(Me)), 19.8 (CMe(Me)), 13.9 (Me); HRMS m/z (M + NH4
found 160.1700. C9H2NO requires 160.1701.
)
Similarly, a solution of enamine 14 (198 mg, 0.83 mmol) and
i-PrI (248 µL, 2.49 mmol) at 82 °C for 96 h gave 2-isopropylhexanal
13k as a colorless oil (58 mg, 48%); data as above.
A solution of enamine 16a (201 mg, 0.95 mmol) and i-PrI (190
µL, 1.90 mmol) at 82 °C for 20 h gave 2-isopropylhexanal 13k as
a colorless oil (65 mg, 48%); data as above.
Supporting Information Available: Spectra for compounds,
experimental details of compounds prepared via routine meth-
ods, and computational data. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO802016T
1028 J. Org. Chem. Vol. 74, No. 3, 2009