Enamines from terminal epoxides and hindered lithium amides

Article abstract of DOI:10.1021/ja031770o

A new reactivity mode of lithium amides with epoxides leads to hindered enamines. The reaction of some of these enamines with unactivated primary and secondary alkyl halides is described, which expands the range of electrophiles that one can use in the synthesis of mono-alkylated aldehydes. Copyright

Full text of DOI:10.1021/ja031770o

Published on Web 05/12/2004
Enamines from Terminal Epoxides and Hindered Lithium Amides
David M. Hodgson,* Christopher D. Bray, and Nicholas D. Kindon†
Department of Chemistry, UniVersity of Oxford, Chemistry Research Laboratory, Mansfield Road,
Oxford OX1 3TA, United Kingdom
Received December 17, 2003; E-mail: david.hodgson@chem.ox.ac.uk
Reactions of epoxides with lithium amides have been investigated
demonstrates that enamine formation does not proceed via a simple
in considerable detail.1 The conversion of epoxides to allylic
alcohols is one important transformation mediated by lithium
amides, and often proceeds by a â-elimination process.2 Epoxides
may also undergo R-deprotonation by lithium amides. The resulting
transient R-lithiated epoxides, e.g., 1 (also called oxiranyl anions),3
possess carbenoid character and typically undergo intramolecular
C-H insertion.4 In 1994, Yamamoto and co-workers described the
rearrangement of terminal epoxides to aldehydes using lithium
2,2,6,6-tetramethylpiperidide (LTMP).5 A deuterium-labeling study
showed that the reaction proceeded by R-deprotonation, and it was
suggested that the aldehyde was obtained from the R-lithiated
epoxide by rearrangement to an enolate. In the present report we
disclose that this reaction in fact proceeds, remarkably, by insertion
of the R-lithiated epoxide into the lithium amide, resulting in a
new method for enamine synthesis. We also report on the alkylation
chemistry of these hindered enamines.
epoxide ring-opening/elimination pathway.
By analogy with the formation of alkenes from epoxides and
organolithiums,1a,10 a suggested reaction pathway for the formation
of enamine 2a from the lithiated epoxide 1 is shown below.
7
Comparison of the Li NMR spectra of the reaction 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), prior to aqueous workup, reveals that they contain the same
lithium byproduct, presumably Li2O.10,11
Given the synthetic utility of enamines,7 we sought to examine
the scope of this new, previously unrecognized reaction (Table 1).
Table 1. Enamines 2 from Epoxides and LTMP
During our studies on the synthesis of trans-R,â-epoxysilanes
from terminal epoxides using LTMP and TMSCl in situ,6 we
repeated the reaction of 1,2-epoxyoctadecane with LTMP (2.5
equiv, THF, 25 °C, 16 h) described by Yamamoto.5 In agreement
with the latter work, we obtained octadecanal in 77% yield (lit.5
79%) after column chromatography (SiO2). However, the 1H NMR
spectrum of the crude product (following aqueous workup, but prior
to column chromatography) did not show the expected characteristic
signals of octadecanal; instead, it contained signals consistent with
an E-olefin [1H NMR δ 5.78 (dt, J ) 14 and 1 Hz, 1H), 5.30 (dt,
J ) 14 and 7 Hz, 1H)]. Purification of the crude product by filtration
through SiO2, which had been previously stirred with Et3N for 12
h, gave enamine 2a in 78% yield. Enamine 2a could not be
independently synthesized from octadecanal by standard condensa-
tion techniques.7 However, enamine 2b (Table 1, entry 1), prepared
from 1,2-epoxypentane and LTMP by the same method used for
2a, could also be synthesized, albeit in only 32% yield, by the
addition of commercially available n-BuMgCl to N-formyl-TMP8
according to the procedure of Hansson and Wickberg.9 NMR
monitoring of the reaction between 1,2-epoxypentane and LTMP
in THF-d8 indicated formation of enamine 2b was complete within
5 min; this experiment shows that enamine 2b does not form by
condensation between pentanal and 2,2,6,6-tetramethylpiperidine
(TMP) during the reaction workup stage. Addition of LTMP (1.5
equiv) to the lithium alkoxide of N-(2-hydroxyoctadec-1-yl)-TMP
(THF, 25 °C, 1 h) did not give enamine 2a, the starting material
being returned in quantitative yield instead; this experiment
a Isolated yield. b 5 equiv of LTMP.
As well as epoxides bearing simple alkyl chains (entries 1,2),
those possessing a range of functional groups could be used:
olefinic and aryl substitution (entries 3,4), as well as suitably
† AstraZeneca R&D Charnwood Medicinal Chemistry, Bakewell Road,
Loughborough, Leics LE11 5RH, U.K.
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J. AM. CHEM. SOC. 2004, 126, 6870-6871
10.1021/ja031770o CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
protected alcohols, amines, and ketones (entries 5-7) are tolerated.
A bis-enamine (entry 8) was also formed. â-Disubstituted epoxides
were found to be inert under these conditions.6,12
Enamine 3a reacted with a variety of activated alkyl halides and
electron-deficient olefins to give a range of R-substituted aldehydes
in excellent yields (Table 2, entries 1-6), indicating that, despite
being highly hindered, it had retained its nucleophilic nature.
Moreover, enamine 3a reacted not only with MeI and EtI (Table
2, entries 7 and 8) in excellent yields, but also with 1-iodobutane,
1-iododecane, and even 2-iodopropane (entries 9-11). Next, we
sought a lithium amide whose steric hindrance was intermediate
in nature between that of LTBIPA and LTMP. Upon reaction with
1,2-epoxyhexane, lithium N-tert-butylpinacoylamide16 (2.5 equiv
THF, 25 °C, 16 h) was found to produce enamine 3b in 58% yield
(NCHdCH; ∆δH ) 0.89); this could subsequently be alkylated with
1-iodobutane (entry 12) and 2-iodopropane (entry 13). Entries 9-13
represent the first examples of enamines reacting with such
unreactive electrophiles in synthetically useful yields.
Due to the well-known problem of N-alkylation, there are few
examples of C-C bond-forming reactions of aldehyde enamines
with unactivated alkyl halides,7 although this process expands the
range of electrophiles that one could use in the synthesis of mono-
alkylated aldehydes. It has been shown by Curphey et al. that
increasing steric bulk around nitrogen promotes C- over N-
alkylation.13 However, reaction of enamine 2b with even reactive
electrophiles such as MeI failed to yield R-substituted aldehydes
in satisfactory yields (30%). For hindered enamines 2a-i the
nitrogen lone pair and π* orbital of the olefin may be orthogonal,
as evidenced by the very small difference in chemical shift observed
in the 1H NMR spectra between the two olefinic protons (e.g. ∆δΗ
) 0.48 for 2b).7c,14
In conclusion, we have uncovered a new reactivity mode of
lithium amides with epoxides which leads to hindered enamines
and have demonstrated that some of the latter are capable of reacting
with unactivated primary and secondary alkyl iodides. That hindered
lithium amides react as nucleophiles with R-lithiated epoxides serves
to emphasize the high electrophilicity of these carbenoids.17
Attention therefore focused on the use of other lithium amides
that would facilitate enamine formation from epoxides and where
the enamine would be capable of reacting with electrophiles. Aside
from LTMP, LiNCy2 has been reported to rearrange epoxides to
aldehydes, albeit in lower yields.5 Although we were unable to
isolate the enamine derived from 1,2-epoxyhexane and LiNCy2,
reaction with the lithium amide LTBIPA derived from commercially
available N-tert-butylisopropylamine produced enamine 3a in 42%
yield. Traces of the 1,2-amino alcohol derived from direct epoxide
ring opening were also observed.5,15 The use of other solvents (e.g.,
Et2O, hexane) or the addition of additives (e.g., TMEDA, LiCl)
did not increase the yield of enamine 3a. It is interesting to note
Acknowledgment. We thank the EPSRC and AstraZeneca for
an Industrial CASE award, Wadham College for a T. C. Keeley
Senior Scholarship (to C.D.B.), the EPSRC for a research grant
(GR/S46789/01) and the EPSRC National Mass Spectrometry
Service Centre for mass spectra.
Supporting Information Available: Experimental procedures and
NMR spectra of 2a-i, 3a-b, 4a-k, and details regarding starting
epoxides. This material is available free of charge via the Internet at
http://pubs.acs.org.
1
that the difference in chemical shift observed in the H NMR be-
tween the olefinic protons of enamine 3a (∆δH ) 1.45) approaches
that more typical of aldehyde enamines (∆δH ≈ 1.5-2.0).7c,14
Table 2. Alkylation of Enamines 3a and 3b
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18
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49
a 2 equiv unless otherwise stated. b Isolated yield of aldehyde following
acid hydrolysis (NaOAc:AcOH:H2O; 1:1:2), aqueous workup and column
chromatography.
JA031770O
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