Deprotonation of β,β-disubstituted α,β-unsaturated amides -Mechanism and stereochemical consequences

Article abstract of DOI:10.1139/V06-112

A detailed study of the lithium dialkylamide induced deprotonation of β,β-disubstituted α,β-unsaturated amides is presented. The preferential γ-Z-deprotonation and stereochemical outcome of substituents on the γ-Z carbon atom are rationalized in terms of a cyclic eight-membered transition state, which is supported by DFT calculations. Analogous deprotonations on cyclohexylidenecarboxamides reveal a delicate balance of the preference for the eight-membered cyclic transition state with the effects of existing substituents on the ring and the intervention of a twist-boat transition state.

Full text of DOI:10.1139/V06-112

1397
Deprotonation of ␤,␤-disubstituted ␣,␤-unsaturated
amides — Mechanism and stereochemical
consequences1
James R. Green, Marek Majewski, and Victor Snieckus
Abstract: A detailed study of the lithium dialkylamide induced deprotonation of β,β-disubstituted α,β-unsaturated
amides is presented. The preferential γ-Z-deprotonation and stereochemical outcome of substituents on the γ-Z carbon
atom are rationalized in terms of a cyclic eight-membered transition state, which is supported by DFT calculations.
Analogous deprotonations on cyclohexylidenecarboxamides reveal a delicate balance of the preference for the eight-
membered cyclic transition state with the effects of existing substituents on the ring and the intervention of a twist-boat
transition state.
Key words: dienolate, amide, deprotonation mechanism, transition state, enolization, regioselectivity, stereoselectivity.
Résumé : On a effectué une étude détaillée de la déprotonation induite par les dialkylamides de lithium d’amides α,β-
insaturés et β,β-disubstitués. La déprotonation préférentielle en γ-Z- et le résultat stéréochimique des substitutions sur
l’atome de carbone γ-Z sont rationalisés en termes d’un état de transition cyclique à huit chaînons qui est supporté par
des calculs de la théorie de la densité fonctionnelle. Des déprotonations analogues sur les cyclohexylidènecarboxamides
mettent en évidence la délicate balance de la préférence en faveur de l’état de transition cyclique à huit chaînons avec
les effets des substituants déjà présents sur le cycle et l’intervention d’un état de transition en forme de bateau croisé.
Mots clés : diénolate, amide, déprotonation, mécanisme, état de transition, énolisation, régiosélectivité, stéréosélectivité.
[Traduit par la Rédaction] Green et al. 1410
Introduction
8) and spectroscopic (9) evidence for lithium base carbonyl
complexation associated with proton abstractions has been
advanced (10), although the strict cyclohexane-like chair na-
ture of the transition state has required revision in light of
computational analysis (11).
The prediction of the stereochemistry of enolate formation
is of fundamental significance to the large number of valu-
able C—C bond-forming synthetic strategies of which the
aldol condensation is arguably the most prominent (1). A
body of data (2) on the stereoselection of enolization has
been rationalized by the pericyclic chairlike transition state
model (structure 1 in Fig. 1) originally proposed by Ireland
et al. (3) in which deprotonation occurs perpendicular to the
plane of the carbonyl coordinated to the lithium dialkyl-
amide (4). This model is based on allylic strain (5) and
stereoelectronic (4, 6) considerations. Compelling kinetic (7,
In spite of the extensive synthetic use of β,β-disubstituted,
α,β-unsaturated carbonyl compounds (2) and related deriva-
tives (12, 13), the stereoselectivity aspects of dienolate for-
mation (γ-Z or γ-E proton abstraction) have not been
systematically addressed (14–17). Although the preferential
deprotonation of γ-Z over equivalently substituted γ-E pro-
tons has been established (12a, 14a–14c, 18, 19), the scope
and limitations of this feature as it pertains to differential
substitution at the γ-Z and γ-E sites, a systematic study of
the stereochemical fate of γ-Z substituents, and the stereo-
chemical disposition of the proton undergoing abstraction
have not been dealt with in depth. Originating with our inter-
est in the synthetic utility of α,β-unsaturated amides (16k),
we addressed this question (18, 19) and herein present
extended detailed studies, which significantly amplify our
preliminary results, may have broader application to other
α,β-unsaturated functionalized systems (20), and thereby
may shed further light on this interesting question, which
has considerable synthetic and mechanistic interest.
Received 24 February 2006. Accepted 19 May 2006.
Published on the NRC Research Press Web site at
http://canjchem.nrc.ca on 29 September 2006.
Dedicated to Alfred Bader, for the chemistry he created
amongst all chemists and in appreciation of his tenacious
support of Canadian chemistry.
J.R. Green. Department of Chemistry, University of
Windsor, Windsor, ON N9B 3P4, Canada.
M. Majewski. Department of Chemistry, University of
Saskatchewan, Saskatoon, SK S7N 5C9, Canada.
V. Snieckus.2,3 Department of Chemistry, University of
Waterloo, Waterloo, ON N21 3G1, Canada.
Concerning the site of deprotonation of
senecioamides
1This article is part of a Special Issue dedicated to Dr. Alfred
Bader.
2Current address: Department of Chemistry, Queen’s
University, Kingston, ON K7L 3N6, Canada.
3Corresponding author (e-mail: cjc@chem.queensu.ca).
Previous work using unsaturated esters does not allow un-
ambiguous generalization concerning the syn vs. anti γ-H
site of deprotonation to analogous systems (14r, 14m, 14q,
Can. J. Chem. 84: 1397–1410 (2006)
doi:10.1139/V06-112
© 2006 NRC Canada

1398
Can. J. Chem. Vol. 84, 2006
Fig. 1. Deprotonation in carbonyls and unsaturated carbonyls.
Scheme 2. Reagents and conditions: (a) (i) LDA, THF, –78 °C;
(ii) CuI; (iii) MeOD, –78 °C. (b) (i) NaH; (ii) n-BuLi:
(iii) F3CCO2D + D2O; (iv) NH4Cl. (c) (i) NaH; (ii) ClP(O)(OEt)2.
(d) (i) Me2CuLi, –78 to –40 °C; (ii) NH4Cl.
γ
-Z
X
R1
Li
H
O
O
R2
L
R2
N
L
X
O
R1
O
a
γ
-E
2
Z-3b +
1
NMe2
NMe2
75%
8
D
9
Scheme 1. Reagents and conditions: (a) (i) LDA, THF; (ii) MeI,
57 : 43
0 °C to room temperature.
O
O
O
O
b
E
E
E
O
a
O
OLi
NMe2
NMe2
NMe2
NMe2
NMe2
D
11
10
4
Z-3 a, E = SiMe3
b
5
c
, E = D
d
(EtO)2(O)PO
D
O
O
O
OLi
NMe2
a
E-3b
NMe2
NMe2
NMe2
E
E
E
12
7
6
E-3 a, E = SiMe3
b
, E = D
2
Fig. 2. H NMR based relative deuterium incorporation levels.
δ
1.92
5% of D incorp
14n, 14k, 14a–14d, 19). We decided to approach this ques-
tion for unsaturated amides in conjunction with ongoing stud-
ies. γ-Silylated carboxamides Z-3a and E-3b (Scheme 1),
available as a result of our work on amide dienolate reactiv-
ity (13c, 21), were subjected to LDA deprotonation at room
temperature (RT) and the resulting dienolates 4a and 6a
were quenched with methyl iodide to give products 5a (Z, E)
and 7a in 90% and 84% yields, respectively. The products
δ
1.93
93% of D incorp
O
D
O
NMe2
NMe2
D
H
H
δ
5.71
5% of D incorp
δ
5.71
7% of D incorp
δ
1.57
90% of D incorp
1
were readily distinguished by H NMR spectroscopy (see
Z-3b
E-3b
the Experimental section), which showed that compounds Z-
3a and E-3a gave exclusively compounds 5a and 7a, respec-
tively. The issues of acidifying and steric effects led us to
consider replacement of silicon by deuterium as a positional
γ marker that would minimally perturb the system under
study.
78% of D incorp
10% of D incorp
D
O
O
NMe2
4% of D incorp
NMe2
D
12% of D incorp
10% of D incorp
86% of D incorp
Using conditions previously developed in our laboratories
for regio- and stereo-selective introduction of electrophiles
into γ-cis methyl positions of senecioamdies (16k), the
dimethyl amide 8 (Scheme 2) was subjected to LDA
deprotonation at –78 °C followed by treatment with CuI, ac-
cording to the protocol of Katzenellenbogen for favoring γ-
functionalization, and D2O in sequence to give a mixture of
γ- and α-deuterated products Z-3b and 9 in a 57:43 ratio.
Exclusion of CuI in this sequence led to lower γ:α product
ratios. The corresponding E-3b isomer was prepared accord-
ing to the excellent and dependable Sum and Weiler proce-
dure (22) involving γ-deuteration of 10 to give 11 followed
by stereoselective β-methylation via the enol phosphonate
12. The location and content of deuterium in the products
5b
7b
essentially no deuteration in the vinyl group but significant
deuterium incorporation in the allylic methyl group (see the
Experimental section and Fig. 2). More conclusive data was
2
obtained from the H NMR spectra (Fig. 2), which showed
relative deuterium incorporation at the vinyl, α-carbon, and
allylic methyl in a ratio of 78:12:10 for 5b and 10:4:86 for
7b. These results indicate that γ-Z over γ-E deprotonation
has occurred to the extent of 89% and 96% in the two sub-
strates Z-3b and E-3b, respectively, and therefore implicate
the intermediacy of the dienolates 4b and 6b, respectively.
Thermodynamic deprotonation of these systems is ruled out
by the observation that E-3a did not proceed via dienolate
4a. The results of our studies with Z-3b and E-3b mirror the
observations of Harris and Weiler (19) on the corresponding
carboxylic acids and esters.
2
depicted in Scheme 2 were determined by MS and H NMR
(see the Experimental section). For compound E-3b, 2H NMR
analysis showed approximately 5% contamination with the
Z-3b isomer.
Deprotonation of Z-3b and E-3b under identical condi-
tions (LDA, THF, 0 °C, 0.5 h) and subsequent methylation
of the resulting dienolates gave 5b (78%) and 7b (68%), re-
Substituent effects on ␥-deprotonation
1
spectively. The H NMR spectrum of Z-5b showed signifi-
cant deuteration in the vinyl site but not in the allylic methyl
group, while the corresponding spectrum of E-5b indicated
In seeking a more detailed understanding of the factors af-
fecting the geometry of dienolate formation, we investigated
© 2006 NRC Canada

Green et al.
1399
Table 1. Stereoselectivity in deprotonations of Z-3a and 18.
Entry
Amide
R1
R2
Producta
trans:cis Ratio
1
2b
3
4
5
6
7
8
18g
18g
18a
18b
18c
18d
18f
Me
Me
Me
Me
Et
Et
19g (80)
19g (71)
19a (54)
19b (89)
19c (75)
19d (54)
19e (84)
5a (90)
79:21
92:8
79:21
41:59
<3:>97
8:92
n-Bu
s-Bu
t-Bu
s-Bu
n-Bu
Me
Me
i-Pr
OMe
SiMe3
<3:>97
79:21
Z-3a
aYields in parentheses.
bReaction conducted at 78 °C.
Scheme 3. Reagents and conditions: (a) 2Ph3P=CHCO2Et.
(b) 270 °C, -0.4 Torr. (c) (i) R2R3CuLi, THF, –78 °C; (ii) H3O+;
(iii) SoCl2, C6H6; (iv) HNMe2, Et2O.
Scheme 4. Reagents and conditions: (a) (i) LDA, THF; (ii) MeI,
0 °C to room temperature.
R1
R2
H
O
a
O
CO2Et
R1
NMe2
R1
a
b
Cl
R1
CONMe2
CH3
CO2Et
R1
PPh3
R2
O
H
5a 19
15
13
14
-
Z 3a 18
,
,
R1
CO2Et
O
d
c
R1
X
17
18
, X = OH
, X = NMe2
H
H3C
SiMe3
Me3Si
H
R2
R2
16
CONMe2
CH3
CONMe2
CH3
H3C
H
H
1
1
i
1
t
13 15 a
–
b
c
d
For
For
, R = CH3; , R = Pr; , R = Bu; , R1 = OMe
Z-5a
E-5a
?
, R1 = CH3, R2 = R3
c, R1 = CH3, R2 = tBu, R3 = Me; d, R1 = iPr, R2 = R3
e, R1 = tBu, R2 = R3 = sBu; f, R1 = OMe, R2 = R3 nBu
Bu; , R = CH3, R2 = R3
b
= =
sBu;
n
1
3.44 (C6D6)
4J = 1.13 Hz
?
16 18 a
–
3.04 (C6D6)
4J = 0.73 Hz
=
sBu;
=
H
CH3
H
OMe
the deprotonation chemistry of a variety of β,γ-disubstituted
acrylamides. In particular, we were interested in the effect of
substituents anchored at the site of deprotonation. For this
purpose, a series of stereochemically homogeneous β,β-
disubstituted acrylamides 18 were prepared by adapting
cuprate-addition chemistry to ethyl-2-alkynoates (Scheme 3)
(23). Condensation of acyl halides 13a–13d with carbo-
ethoxymethylene triphenylphosphorane using the procedure
described by Hanack et al. (24) as modified by Markl (25)
afforded the acyl phosphoranes 14a–14d, which normally
were not isolated but directly pyrolyzed to give the 2-
alkynoate esters 15a–15d. Treatment of esters 15a–15d with
lithium dialkyl cuprates furnished the stereochemically pure
α,β-unsaturated esters 16a–16f in variable yields (37%–
81%). The conversion of esters 16a–16f into the requisite
dimethyl amides 18a–18f was carried out under standard
conditions via the intermediate carboxylic acids 17a–17f.
Amide 18g (R1 = Me, R2 = Et) was prepared using a
Horner–Wadsworth–Emmons procedure (see the Experimen-
tal section). The structures and stereochemistry of all amides
18 were assigned by 1H NMR spectroscopy: with one excep-
tion (18f), the CH2 group cis to the amide carbonyl appears
as expected downfield (δ 2.3) from the one located trans to
the carbonyl (δ 2.15). Furthermore, the cis-CH2 resonances
experienced an aromatic solvent-induced shift to lower field
(δ 2.47) upon replacement of CDCl3 with C6D6 as solvent (26).
Compounds 18a–18g were deprotonated with LDA in
THF at room temperature, except for entry 2, and quenched
H3C
H3C
CONMe2
CH3 CH3
CONMe2
H
19f
H
CH3
19c
22% and 11% NOE
enhancements
17% NOE
enhancement
with methyl iodide to give mixtures of products trans-19a–
19d, 19f, and 19g and cis-19a–19d, 19f, and 19g4
(Scheme 4, Table 1). Attempted deprotonation of 18e re-
sulted in extensive decomposition and thus was not pursued
further. For the sake of completeness, the deprotonation of
Z-3a is included (Table 1, entry 8). The trans to cis ratio
1
was established by integration of the H NMR methine reso-
nance of the two isomers with chemical shifts δ separated by
a consistent value of approximately 0.3 ppm (3.3 ppm for
trans and 3.6 ppm for cis isomers). Stereochemical assign-
ments at the newly formed double bond were determined by
the four-bond vinyl-to-methyl coupling constant in accor-
dance with the literature (Scheme 4) (27). In addition, the
stereochemistry of compounds trans-19c and trans-19f was
confirmed by NOE difference experiments.
The mechanism of ␥-deprotonation
On the basis of the above results, we propose that
deprotonation of β,β-disubstitued α,β-unsaturated amides oc-
4 Z/E nomenclature is not used because of priority changes in R2 in the progression of the series.
© 2006 NRC Canada

1400
Can. J. Chem. Vol. 84, 2006
Fig. 3. Deprotonation transition state for 18f.
Scheme 5.
H
MeO
Bu-
n
Me2N
O
H
Li
NiPr2
20b
R1 = OMe, R2 = -Bu
n
Scheme 6. Reagents and conditions: (a) (i) LDA, THF, RT;
(ii) MeI, 0 °C to room temperature.
a
CONMe2
CONMe2
Z-24
Z-23
of entries 4 and 6 (Table 1) suggests that an increase in the
size of Rl enhances the energy difference between transition
states 20a and 20b. In this context, the result obtained with
the TMS (entry 8) shows no size effect in spite of the fact
that this group has an A value similar to i-Pr (28). The case
of the OMe substituent (Table 1, entry 7) is striking in that,
on the basis of steric arguments, preferential formation of
trans-19f was expected. The exclusive formation of cis-19f
strongly suggests that lithium–OMe coordination (Fig. 3) in
the transition state is significant although the tentative nature
of this proposal is recognized in view of reports on the
dimeric (29) and tetrameric (30) nature of dienolates in the
solid state. Finally, a comparison of the results of
deprotonation of 19g at –78 °C and room temperature (Ta-
ble 1, entries 1 and 2) shows the expected enhancement in
selectivity with decreased temperature consistent with a 0.8–
0.95 kcal/mol (1 kcal = 4184 J) difference in activation
energy for the respective dienolate isomer formation. To
confirm that the products result from kinetic deprotonation
and that double bond isomerization about Cβ—Cγ does not
occur in the dienolate, the β,γ-unsaturated amide Z-23 was
prepared according to Baldwin and co-workers (16j) and
subjected to the standard LDA deprotonation conditions.
The product Z-24 showed retention of double bond geome-
try, which must stem from the thermodynamically less stable
dienolate, thereby providing confirmation of kinetic
deprotonation (Scheme 6). Because of the lack of proximity
of the carbonyl oxygen and the deprotonation site, our
model clearly does not contribute to an understanding of the
mechanism of deprotonation of E-α,β-unsaturated esters and
acids (16a, 16f, 16j).
curs through a cyclic eight-membered ring transition state
(20a and 20b), which highlights lithium carboxamide oxy-
gen coordination according to the established complex-
induced proximity effect (CIPE) (7) (Scheme 5). Since the
γ-Z carbon is in closer proximity to the amide carbonyl than
the γ-E carbon atom, deprotonation occurs preferentially
from the former leading to dienolates cis-21 and trans-21,
which undergo reaction with the electrophile at the α site to
give products cis-22 and trans-22. To rationalize substitutent
effects, we begin with the assumption that deprotonation oc-
curs perpendicular to the plane of the unsaturated amide (3).
While semiempirical calculations (MNDO) have indicated a
H-C-C-O torsion angle for ketone deprotonation of only
about 60° (11), DFT5 calculations on 20 reveal that the
eight-membered ring transition state incorporates an optimal
H-C-C-C torsion angle (89.5°) for senecioamide deproto-
nation, with a minimal twist (24.4°) from coplanarity of the
unsaturated carbonyl. With small R2 substituents, the γ-R1
group prefers to be oriented away from the carboxamide in
transition state 20a, leading preferentially to dienolate trans-
21 and ultimately to alkylated product trans-22. As the size
of the R2 group is increased (Et < s-Bu < t-Bu), the steric re-
pulsion between R1 and R2 increases, giving rise to greater
amounts of deprotonation from transition state 20b, which
cascades to dienolate cis-21 and product cis-22. Comparison
The earlier observations of Pfeffer and Silbert (16u),
Krebs (16r), and Kende and Toder (16p) on the deproto-
nation of Z-unsaturated esters and acids (Z-25 to E-26 in
Scheme 7) are in agreement with our proposed model of
deprotonation (Scheme 5). In all these earlier investigations,
compounds with no β-E substitutents were employed
(Scheme 5, R2 = H). As a consequence, the R1 – carbonyl
oxygen interaction constitutes the only significant repulsive
interaction. A transition state analogous to 20a is therefore
expected, which ultimately leads to the corresponding
5 DFT calculations were carried out using the B88-PW91 method, and a DZVP basis set, using CAChe® version 6.1.12.33 (see Supporting
information). All stationary points were confirmed via frequency calculations.
© 2006 NRC Canada

Green et al.
1401
Scheme 7. Reagents and conditions: (a) (i) LDA, HMPA, THF,
–78 °C; (ii) E+. (b) (i) LDA, THF; (ii) H+, –98 °C. (c) (i) base,
THF, –78 °C; (ii) Me3SiCl.
Scheme 8. Reagents and conditions: (a) (i) LDA, THF, RT;
(ii) MeI, 0 °C to room temperature.
CONMe2
Me
CONMe2
Me
R1
R1
Me
a
a
CO2R
CO2R
Bu-
t
Bu-
E
t
31
R = H, Et
32
Z-25
E-26
CONMe2
Me
Me
CONMe2
Me
R1
R1
a
b
CO2Et
CO2Et
Bu3Sn
Bu-
Bu3Sn
t
Bu-
t
E
27
R1 = Me, -CH2CH2OTBDMS
33
34
Z-28
Scheme 9. Reagents and conditions: (a) (i) LDA, THF, RT;
(ii) MeI, 0 °C to room temperature.
c
OSiMe3
OSiMe3
OR
CONMe2
Me
CONMe2
CO2R
N
+
N
OR
N
a
D
D
Z-30
29
Base
LDA
KDA
E-30
100
50
95%
0
50
Bu-
t
Bu-
t
R = Me, Et3Si
36
35
dienolate trans-21 and product trans-22. In addition, Piers
and Gavai (16l) and Schlessinger and co-workers (15d) have
reported on the low-temperature deprotonation of β-stannyl
(27) and β-pyrrolidino (29) substituted unsaturated esters.
Piers and Gavai found that LDA deprotonation of 27 fol-
lowed by proton quench produced only the Z-28 isomer,
which is consistent with the relatively small conformational
A value of tin (either 0.94 (31)) or 1.06 (32)). Piers and
Gavai also observed that the presence of an oxygen function
in 27, R = CH2CH2OTBDMS, does not alter the stereo-
chemical outcome of deprotonation. This may be due to the
oxygen function being too distant to participate in coordina-
tion to lithium or the inhibition of coordination by the bulky
TBDMS group. In the Schlessinger study, deprotonation of
the β-pyrrolidino system 29 with LDA gave exclusively the
cis-enolate as reflected in the formation of the O-silyl
dienolate product E-30, a result in qualitative agreement
with our results (Table 1) if one considers the large A value
(2.1) of a dialkylamino group (33). The lack of selectivity
shown by KDA in the deprotonation of 29 to give E-30 and
Z-30 may reflect an earlier transition state and weaker
metal-to-carbonyl coordination. Our study of the effect of
base on the deprotonation of 18g led to inconclusive results
(13c).
CONMe2
Me
Me
CONMe2
Me
Me
CONMe2
Me
a
+
87%
-Bu
t
-Bu
t
-Bu
t
37
38
39
ca. 1:1
tion would manifest itself in axial proton abstraction in
cyclohexylidene carboxamides. For this purpose, we pre-
pared diastereomers 31 and 33 using cuprate conjugate addi-
tion and Peterson olefination chemistry (see Supplementary
material)6 and subjected them to the standard LDA
deprotonation – methyl iodide quench conditions to give the
deconjugated amides 32 and 34, respectively (Scheme 8).
Disappointingly, deprotonation had occurred at the γ-E
methylene to the exclusion of γ-Z methine proton. We con-
sidered that the factor responsible for the unwanted γ-E
deprotonation is the presence of the equatorial γ-methyl or
the δ-t-Bu groups. Therefore, we prepared (see Supplemen-
tary material)6 γ-deuterated (35) and the t-Bu γ-methyl (37)
derivatives and treated these under the normal
deprotonation–methylation conditions. Unfortunately, com-
pound 35 also underwent deprotonation at the γ-E-methy-
lene site to give deconjugated product 36 (Scheme 9).
Furthermore, compound 37 gave a mixture of compounds 38
and 39 (approx. 1:1) indicating γ-E-methylene and γ-Z-
methine deprotonation, respectively. We surmise that the
presence of the γ-methyl function in the cyclohexylidene
amides either causes the six-membered ring to adopt a twist-
boat conformation or prevents the proper orientation of the
These arguments concerned with substituent effects on γ-
deprotonation appear to be applicable and lead to similar
conclusions for α,β-unsaturated systems with other carbonyl
acidifying functionality (20), such as phosphonates and
phosphine oxides (34) and sulfones (35).
At this point in the study, we were interested in determin-
ing whether the requirement for perpendicular C-H orienta-
6 Supplementary data for this article are available on the journal Web site (http://canjchem.nrc.ca) or may be purchased from the Depository
of Unpublished Data, Document Delivery, CISTI, National Research Council Canada, Ottawa, ON K1A 0R6, Canada. DUD 5078. For more
information on obtaining material, refer to http://cisti-icist.nrc-cnrc.gc.ca/irm/unpub_e.shtml.
© 2006 NRC Canada

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Can. J. Chem. Vol. 84, 2006
1
Fig. 4. Selected H NMR spectral data of cyclohexylidene
amides.
Scheme 11. Reagents and conditions: (a) (i) LDA, THF, –78 °C;
(ii) CF3CO2D + D2O. (b) (i) Me3SiCH2CONMe2, LDA, THF,
–78 °C; (ii) 44, –78 °C to room temperature.
CONMe2
CONMe2
CH3
H3
H3
D
H2
O
-Bu
O
t
-Bu
t
a
CH3
H2
3.44 ppm,
J2,3 = 2.60 Hz
3.45 ppm,
J2,3 = 3.52 Hz
33
31
-Bu
t
-Bu
t
43
44
CONMe2
H5
Me2NOC
CONMe2
D
2.16 ppm,
J5,6 = 5.0 Hz
b
H
-Bu
t
D
H6
+
79%
37
t-Bu
t-Bu
-
Z 45
E-45
Scheme 10. Reagents and conditions: (a) (i) base, THF, –78 °C;
(ii) MeI.
34:66
R2
R2
R2
Scheme 12. Reagents and conditions: (a) (i) LDA, THF;
(ii) MeI, 0 °C to room temperature.
R1
R1
a
R1
R1
CO2Et
R1
CO2Et
CO2Et
+
9% of
deuterium
20% of
deuterium
Me
40
41
42
He' CONMe2
CONMe2
-Bu
t
Entry
41:42 Ratio
Base
LiICA
-Bu
t
He
Ha
R1 = H, R2 = H
R1 = H, R2 = Me
1.
0
100
0
Hv
25% of
deuterium
Ha'
2.
3.
4.
LDA/HMPA
100
40
0
65% of
deuterium
R
1 = D, R2 = Me
R1 = H, R2 = Me
60
LDA/HMPA
LDA
26% of
deuterium
55% of
deuterium
100
-Bu
t
-Bu
t
amide carbonyl for formation of the required transition state
20 (Scheme 5). In the H NMR of cyclohexanones, axial hy-
Me
CONMe2
a
1
CONMe2
drogens resonate at lower fields than the corresponding
equatorial hydrogen (36). This is clearly not the case for the
corresponding hydrogens H2 in the cyclohexylidene amides
31 and 33 (Fig. 4). Similarly, the axial hydrogen H6 in 37
resonates at δ 2.16, but more importantly shows coupling
with the adjacent methine hydrogen with J = normal prac-
tice 5 Hz. Spectroscopic characterization of 35 does not al-
low the identification of the conformation of the
cyclohexane ring. It appears, however, that the tert-butyl
function at the position γ to the carbonyl is sufficient to
block deprotonation at the γ-Z site.
Our difficulties in deprotonating cyclohexylidene amide
systems are reminiscent of the results observed by White
(14t), Gesson (14o), and Weiler (14h) and their co-workers
on cyclohexene carboxylate esters 40 (Scheme 10). Exami-
nation of the entries shows that the seemingly trivial modifi-
cation of substituents of the base (compare entries 2 and 3 or
2 and 4 in Table 1) leads to dramatic changes in ratios of
deconjugated products 41 and 42. Considering that the γ-Z
deprotonation in the unperturbed cases has been demon-
strated by our previous results (Table 1 and Scheme 1), we
chose to prepare compound 43 (Scheme 11), which incorpo-
rates a t-Bu group in a location remote from the site of
deprotonation. Treatment of 3-tert-butylcyclohexanone 43
with LDA followed by deuteration afforded 44, albeit with
modest incorporation of deuterium (d1 = 40%, d2 = 10%)
(37). Peterson olefination of 44 with the lithio enolate of α-
silyl acetamide gave a mixture of Z-45 and E-45 in a ratio of
92%
D
D
-45
46
Z
66:34, which were separated by column chromatography to
give pure Z-45. The mass spectrum of Z-45 indicated 37%
d1 and 9% d2 incorporation, while the H NMR showed ap-
2
proximately 55%, 25%, and 20% relative deuteration at Ha,
He, and γ-E sites, respectively. When Z-45 was subjected to
deprotonation and methylation under normal conditions,
2
compound 46 was obtained in high yield and its H NMR
spectrum showed relative deuterium incorporation of 65%,
26%, and 9% at Hv, Ha, and He, respectively (Scheme 12).
This corresponds to an approximately 20:80 ratio favoring
equatorial deprotonation. The mass spectrum of 46 showed
27% d1 and 8% d2 content, which is consistent with predom-
inant equatorial deprotonation.
We believe that the explanation of these results lies in the
classic work of Fraser and Champagne (4) who demon-
strated that protonation or deprotonation in conformationally
locked systems can occur via perpendicular attack by base
through a twist-boat transition state, and in the proposal that
these transition states are responsible for equatorial proto-
nation or deprotonation in cyclohexanones (38). The pre-
dominant equatorial deprotonation of Z-45 is due to an
analogous twist-boat cyclohexylidene conformation 46
(Scheme 13) in which the axial hydrogen He is suitably ori-
© 2006 NRC Canada

Green et al.
1403
Scheme 13. Twist-boat deprotonation model of Z-45.
ented. DFT calculations5 on the transition state for the
deprotonation of protio-Z-45, employing lithium dimethyl-
amide for simplification of the calculations, support the as-
sertion that He deprotonation occurs through a twist-boat
transition state (47). As the transition state for Ha deproto-
nation through the chair (48) is 2.2 kcal/mol lower in energy
relative to 47 according to DFT calculations (again employ-
ing lithium dimethylamide), it is entirely possible that the
observed results are due to a primary deuterium isotope ef-
fect in Z-45 impeding axial Ha deprotonation via 48; the de-
gree of the contribution of this isotope effect, however, is
unknown at this time. Deprotonation of Ha through a com-
plementary twist-boat conformation (49) may also be deduced
computationally (50), with approximately the same energy
as 47 (within 0.1 kcal/mol).
tories, Phoenix, Arizona. Melting points were determined on
a Büchi SMP-20 instrument and are uncorrected. Infrared
spectra were determined on a PerkinElmer 983 spectro-
1
photometer. H NMR spectra were determined with Bruker
WP-80 and Bruker AM-250 spectrometers. The spectra were
recorded at 80 or 250 MHz in CDCl3 with tetramethylsilane
as an internal standard unless otherwise stated. 2H NMR
spectra were determined using a Bruker AM-250 spectrome-
ter in C6H6 or CHCl3, with C6D6 or CDCl3, respectively, as
internal standards. Spectral features are tabulated in the fol-
lowing order: chemical shift (δ, ppm); multiplicity (singlet
(s), doublet (d), triplet (t), quartet (q), septet (sept), multiplet
(m), broad (br)), coupling constant (J, Hz); number of pro-
tons; assignment. Low-resolution mass spectra were deter-
mined on a VG 7070F instrument at 20 eV (1 eV = 1.602 19 ×
10–19 J) unless otherwise stated. High-resolution mass spec-
tra were determined on a VG ZAB-E spectrometer. Analyti-
cal gas chromatography (GC) was performed on either a
Hewlett Packard 5840 A instrument or a Varian 6500 instru-
ment using commercially available 10% SE-30 packed and
capillary columns, respectively. Preparative HPLC was done
on a Waters PREP-500 with an SiO2 column. Analytical thin
layer chromatography (TLC) was performed using Merck
precoated silica gel 60F-254 or aluminum oxide 150F-254
neutral (type T) sheets. Preparative TLC was performed us-
ing Merck silica gel 60GF-254 with a plate thickness of
1 mm. Column chromatography was carried out using silica
gel 60 (0.063–0.20 mm and 0.04–0.063 mm). Flash chroma-
tography refers to the method reported by Still et al. (40).
Conclusions
We believe that the results reported herein advance our
understanding of vinylogous deprotonation reactions in α,β-
unsaturated carbonyl systems. The conditions for regio- and
stereoselective γ-deprotonation of systems 2 (X = NR2)
followed by simple electrophile quench may be usefully
extended to functionalized, and therefore more useful,
electrophiles and thereby lead to γ-chain extended intermedi-
ates of synthetic value. As one illustration, the construction
of terpenoid frameworks could be achieved in a direct man-
ner rather than in several steps. Finally, in view of the prog-
ress in the area of enantioselective deprotonation chemistry
(39), potentially important results for construction of chiral
building blocks may be anticipated.
All dry solvents were employed after distillation from the
appropriate drying agent (41). Diethyl ether (Et2O), benzene,
and tetrahydrofuran (THF) were distilled from benzophe-
none-ketyl immediately prior to use. Solutions of n-BuLi,
s-BuLi, and t-BuLi were titrated with 2,5-dimethoxybenzyl
alcohol (42) as a standard. Diisopropylamine was dried and
distilled over CaH2 and stored in brown bottles over 4 Å mo-
Experimental section
General methods
Elemental analyses were performed by M-H-W Labora-
© 2006 NRC Canada

1404
Can. J. Chem. Vol. 84, 2006
lecular sieves in a dessicator containing CaCl2. All other re-
agents were purified according to literature procedures (41).
All lithiation reactions were carried out under high purity ni-
trogen or argon.
Z- and E-N,N,2,3-Tetramethyl-4-trimethylsilyl-3-
butenamide (Z- and E-5a)
Compound Z-3a (0.9212 g, 4.62 mmol) was lithiated ac-
cording to procedure C and alkylated with iodomethane
(0.4 mL) in the normal manner. After a standard workup, the
crude product was subjected to column chromatography
(ethyl acetate – hexane, 1:1–2:1) to give a mixture of Z- and
E-5a (0.8860 g, 90%); bp 40–43 °C at 0.005 Torr (1 Torr =
The term “–78 °C” refers to the temperature of a CO2–ac-
etone bath (normally –75° to –78 °C). The phrase “workup
in the usual manner” or “standard workup” refers to the ad-
dition of satd. aq. NH4Cl to the reaction mixture, followed
by evaporation of the organic solvent under reduced pres-
sure, extraction of the residue with CH2Cl2 or diethyl ether
(Et2O), drying of the organic extract over MgSO4, filtration,
and then evaporation to dryness under reduced pressure to
afford the crude product. Subsequent chromatography and
(or) recrystallization and (or) distillation of the crude mate-
rial afforded pure products.
Cuprate reactions were worked up in the following man-
ner. The organic solvent was evaporated under reduced pres-
sure, diethyl ether was added, and the mixture was filtered.
The ethereal layer was separated and the remaining aqueous
layer was further extracted with diethyl ether. The combined
ether layers were then back-extracted with aq. NH4OH and
satd. NaCl, then dried over MgSO4, filtered, and concen-
trated under reduced pressure.
1
133.322 4 Pa). IR (neat, cm–1) νmax: 1649, 1611. H NMR
(C6D6) δ: 0.10 and 0.07 (2s, 9H, 3SiCH3), 1.35, 1.38 (2d, J =
7 Hz, 3H, CH3), 1.75, 1.79 (2d, J = 0.73, 1.17 Hz, 3H, CH3),
2.40, 2.67 (2s, 6H, 2NCH3), 3.04, 3.41 (2q, J = 7 Hz, 1H,
CH), 5.26, 5.36 (2m, 1H, vinyl CH). MS m/e (rel. intensity):
213 (M+, 9), 199(33), 198(100), 140(24), 101(36), 73(43).
Anal. calcd. for C11H23NOSi: C 61.91, H 10.86, N 6.56;
found: C 62.10, H 11.05, N 6.73.
Preparative HPLC (hexane – ethyl acetate, 3:1) success-
fully separated small amounts of Z-5a and E-5a. The follow-
ing peaks in the 1H NMR spectrum were assigned to
represent the E isomer: 0.10, 1.35, 1.75 (J = 0.73 Hz), 3.04,
5.36. The following peaks in the 1H NMR spectrum were as-
signed to represent the Z isomer: 0.079, 1.38, 1.79 (J =
1.17 Hz), 3.41, 5.26. By peak heights of the various distin-
guishable signals and the integrated areas under the δ 3.04
and δ 3.41 peaks, the ratio of E-5a to Z-5a in the unsepa-
rated mixture was established to be 79:21.
General procedure for the formation of lithium dienolates
Preparation of LDA
N,N,2-Trimethyl-3-trimethylsilylmethyl-3-butenamide
(7a)
Diisopropylamine (5 mmol, 0.70 mL) was dissolved in
THF (25 mL), and cooled to 0 °C. n-BuLi (5 mmol) was
added by syringe injection over a period of about 30 s. The
solution was then stirred for a further 0.5 h at 0 °C.
Compound E-3a (0.7191 g, 3.61 mmol) was lithiated ac-
cording to procedure B and alkylated with iodomethane
(0.4 mL) in the normal manner. After a standard workup, the
crude product was subjected to flash chromatography
(CH2Cl2–acetone,15:1) to give 0.6993 g (84%) of 7a; bp 60–
62 °C at 0.01 Torr (lit. value (15k) bp 65–70 °C at
0.015 Torr).
Lithiation with LDA — Procedure A
The amide in question was added by syringe to 1.05 equiv.
of LDA in THF at –78 °C so that the concentration in solu-
tion was roughly 0.2 mol/L. This solution was stirred at
–78 °C for 1 h prior to electrophile addition.
4-Deuterio-N,N,3-trimethyl-2-butenanide (Z-3b)
N,N-Dimethylsenecioamide (1.34 mL, 9.8 mmol) was
lithiated according to procedure A. To the resulting dienolate
at –78 °C was added CuI (1.822 g, 9.6 mmol). The mixture
was stirred for a further 1 h at –78 °C and 1.7 mL (excess)
MeOD was added. The reaction was allowed to warm to RT
over 6 h, before 2.0 mL of D2O was added. After a standard
workup, the crude product was subjected to column chroma-
tography (ethyl acetate – hexane, 3:2) to give 0.9562 g
(75%) of a 57:43 mixture of Z-3b and its double bond iso-
mer 9, as determined by the relative areas of vinyl reso-
nances in the 1H NMR spectrum. Preparative HPLC
(CH2Cl2–acetone, 10:1) enabled the separation of a small
amount of pure Z-3b; bp 35–40 °C at 0.004 Torr (lit. value
Lithiation with LDA — Procedure B
The amide in question was added by syringe to
1.05 equiv. of LDA in THF at 0 °C so that the concentration
in solution was roughly 0.2 mol/L. This solution was stirred
at 0 °C for 0.5 h prior to electrophile addition.
Lithiation with LDA — Procedure C
The amide in question was added by syringe to 1.05 equiv.
of LDA in THF at room temperature (RT) so that the con-
centration of the amide or amide dienolate in solution was
roughly 0.2 mol/L. This solution was stirred at RT for 1 h
prior to electrophile addition.
1
(43) bp 62–64 °C at 3.0 Torr). H NMR (C6D6) δ: 1.55 (s,
2
3H, CH3), 1.96 (s, 2.45H, CH2D). H NMR (C6H6, decoup-
led) δ: 1.93 (86% of D, CH2D), 2.84 (7% of D, CHD from
9), 5.71 (7% of D, CD). MS m/e (rel. intensity): 129, 128,
127 (M+, d2:d1:d0, corrected, 1:75:24).
Alkylation of lithium dienolates
The temperature of the solution of the lithium dienolate
was adjusted to 0 °C at which time an excess of the
electrophile was added by syringe. The resulting mixture
was allowed to stir for 0.5 h at 0 °C before the ice bath was
removed. The mixture was allowed to come to room temper-
ature, after which a standard workup was performed.
N,N-Dimethyl-3-oxobutanamide (10)
Compound 10 was prepared by literature methods (44) in
67% yield; bp 80–83 °C at 0.9 Torr (lit. value (44) bp 109°
at 10 Torr).
© 2006 NRC Canada

Green et al.
1405
78% of D, CHD). MS m/e (rel. intensity): 128, 127, 126
(M+ – 15, d2:dl:d0, corrected, 4:65:31).
4-Deuterio-N,N-dimethyl-3-oxobutanamide (11)
To a suspension of NaH (1.6917 g, 66 mmol) in THF
(125 mL) was slowly added 10 (4.2925 g, 33.2 mmol). After
stirring for 20 min, the resulting white gel was cooled to
0 °C and n-BuLi (36.5 mmol) added. The resulting mixture
was stirred for 20 min at 0 °C. In a separate flask, D2O
(3 mL) was added to trifluoroacetic anhydride (7 mL) at
0 °C and the resulting solution was rapidly added to the first
flask. After stirring for 15 min at 0 °C, the reaction was
worked up in the following manner. Saturated aqueous am-
monium chloride was added and the mixture was concen-
trated under reduced pressure. The resulting mixture was
extracted several times with CH2Cl2. The combined CH2Cl2
layers were washed with saturated aq. NaHCO3, dried over
MgSO4, filtered, and concentrated under reduced pressure.
The resulting crude product was distilled to give 11
3-Deuteriomethyl-N,N,2-trimethyl-3-butenanide (7b)
Compound E-3b (0.4149 g, 3.24 mmol) was lithiated ac-
cording to procedure B and the resulting dienolate was
alkylated with iodomethane (0.30 mL) in the normal manner.
Following a standard workup, the crude product was sub-
jected to column chromatography (ethyl acetate – hexane,
4:1) to give 7b (0.3124 g, 68%); bp 30–35 °C at 0.08 Torr
(Kugelrohr). 1H NMR (C6D6) δ: 1.26 (d, J = 7 Hz, 3H, CH3),
1.62 (m, 2H, CH2D), 2.42, 2.67 (2br s, 6H, 2NCH3), 3.03 (q,
2
J = 7 Hz, 1H, CH), 4.72 (s, 2H, CH2). H NMR (C6H6, de-
coupled) δ: 1.60 (87% of D, CH2D), 2.97 (4% of D, CD),
4.72 (10% of D, CHD). MS m/e (rel. intensity): 85, 84, 83
(M+ – 59, d2:dl:d0, corrected, 11:65:24).
1
(2.8935, g, 67%); bp 95 to 96 °C at 1.9 Torr. H NMR δ:
1.91, 2.24 (2m, 2H, CH2D), 2.98, 3.00 (2s, 6H, 2NCH3),
3.54 (s, 1.15H, CH2), 4.14 (s, 0.43H, vinyl CH). MS m/e
(rel. intensity): 131, 130, 129 (M+, d2:d1:d0, corrected,
9:72:19).
Ethyl 3-oxo-2-triphenylphosphoranylidenepentanoate
(14a) and ethyl 2-pentynoate (15a)
Ethyl 3-oxo-2-triphenylphosphoranylidenepentanoate(14a)
was prepared from the reaction of ethyl phosphoranylidene
acetate and propanoyl chloride as described by Hanack et al.
1
1
(24). Compound 14a was identified by H NMR only. H
NMR δ: 0.85 (t, J = 7 Hz, 3H, CH3), 1.40 (t, J = 8 Hz, 3H,
CH3), 3.17 (q, J = 8 Hz, 2H, CH2), 3.81 (q, J = 7 Hz, 2H,
OCH2), 7.71 (m, J = 15 Hz, 3H, C6H5). The crude 14a was
heated in a flask fitted with a Vigreux column at 260–280 °C
and 0.4 Torr for 4 h and the distillate was collected in a flask
at –78 °C. The distillate was redistilled under reduced pres-
sure to give 15a (2.7577 g, 71% based on propanoyl chlo-
ride); bp 64–66 °C at 9 Torr (lit. value (45) bp 178.5 °C).
Z-4-Deuterio-3-[(diethylphosphoryl)oxy]-N,N-dimethyl-2-
butenamide (12) and E-4-deuterio-N,N,3-trimethyl-2-
butenamide (E-3b)
To a suspension of NaH (0.5780 g, 26.1 mmol) in THF
(125 mL) was slowly added 11 (2.8363 g, 21.8 mmol). After
stirring for 20 min, diethyl chlorophosphate (3.40 mL,
22.9 mmol) was added. The resulting yellow suspension was
stirred for 0.5 h. A standard workup gave 12. IR (neat, cm–1)
1
ν
max: 1679, 1631, 1275. H NMR δ: 1.35 (td, J = 7, 1.0 Hz,
6H, 2CH3), 2.11 (br s, 2H, CH2D), 2.96, 3.05 (2s, 6H,
2NCH3), 4.18 (dq, J = 7, 7 Hz, 4H, 2OCH2), 5.42 (s, 1H,
CH). MS m/e (rel. intensity): 267, 266, 265 (M+, d2:dl:do,
corrected, 14:68:17), 266 (M+, 20), 222(29), 194(22),
166(44), 156(36), 155(100), 127(72). The crude 12 was not
purified, but was carried on directly to the next step.
Ethyl E-3-ethyl-2-heptenoate (16a)
To a solution of lithium di-n-butylcuprate (5.5 mmol) in
THF (25 mL) at –78 °C was added 15a (0.6341 g,
5.03 mmol) in a minimum amount of THF (-2 mL). The
mixture was stirred at –78 °C for 1.5 h, after which ethanol
and then satd. aq. NH4Cl were added dropwise. The mixture
was then allowed to warm to room temperature overnight.
After the normal workup for cuprate reactions, the crude
product was purified by distillation under reduced pressure
to give 16a (0.6843 g, 75%); bp 96–98 °C at 8 Torr. IR
To a solution of lithium dimethylcuprate (46.4 mmol) in
Et2O (125 mL) at –78 °C was added 12 (6.5361 g). The sus-
pension was stirred for 2 h at –78 °C, then for 1 h at –45 °C
and finally warmed to 0 °C for 15 min. After a standard
workup, column chromatography of the crude reaction prod-
uct gave E-3b (1.8574 g, 67%); bp 45–50 °C at 0.05 Torr.
1H NMR (C6D6) δ: 1.54 (br s, 2H, CH2D), 1.97 (d, J =
1.2 Hz, 3H, CH3), 2.39, 2.70 (2br s, 6H, 2NCH3), 5.65 (br s,
1
(neat, cm–1) νmax:1715, 1642. H NMR δ: 0.8–1.6 (m, 13H,
3CH3 + 2CH2), 2.16 (br m, 2H, CH2), 2.61 (q, J = 8 Hz, 2H,
CH2), 4.15 (q, J = 7 Hz, 2H, OCH2), 5.61 (br s, 1H, CH).
MS m/e (rel. intensity): 184 (M+, 35), 155(59), 142(75),
139(100), 127(23), 114(51). Anal. calcd. for C11H20O2: C
71.70, H 10.94; found: C 71.68, H 11.01.
2
1H, CH). H NMR (C6H6, decoupled) δ: 1.57 (90% of D,
CH2D), 1.92 (5% of D, CH2D), 5.72 (5% of D, CD). MS
m/e (rel. intensity): 129, 128, 127 (M+, d2:dl:d0, corrected,
10:71:19), 85, 84, 83 (M+ – 44, d2:dl:d0, corrected, 8:70:22).
E-3-Ethyl-2-heptenoic acid (17a) and E-3-ethyl-N,N-
dimethyl-2-heptenamide (18a)
4-Deuterio-N,N,2,3-tetramethyl-3-butenanide (E-5b)
Compound Z-3b (0.10 mL, 0.72 mmol) was lithiated ac-
cording to procedure B and the resulting dienolate was
alkylated in the normal manner with iodomethane
(0.08 mL). After a standard workup, distillation of the crude
product gave E-5b (0.0803 g, 78%); bp 40–50 °C at 0.004
To a solution of KOH (0.8695 g) in methanol–water
(15 mL, H2O–MeOH, 10:1) was added ester 16a (0.6563 g,
3.56 mmol). The reaction mixture was heated under reflux
for 5 h, extracted with diethyl ether (50 mL), acidified with
HCl, and extracted with CH2Cl2 (4 × 25 mL). The combined
CH2Cl2 extracts were dried over MgSO4, filtered, and con-
centrated under reduced pressure to give 17a (0.5091 g,
92%). Compound 17a was identified spectroscopically by IR
((neat, cm–1) νmax: 1690, 1636 (lit. value (46) νmax 1690,
1640)), then dissolved in benzene (25 mL) and treated with
1
Torr. H NMR δ: 1.26 (d, J = 7 Hz, 3H, CH3), 1.73 (s, 3H,
CH3), 2.93, 2.98 (2s, 6H, 2NCH3), 3.34 (q, J = 7 Hz, 1H,
2
CH), 4.79, 4.86 (2m, 1.3H, CHD). H NMR (C6H6) δ: 1.60
(t, J = 2.2 Hz, 10% of D), 2.93 (s, 12% of D, CD), 4.72 (s,
© 2006 NRC Canada

1406
Can. J. Chem. Vol. 84, 2006
thionyl chloride (0.9 mL) for 40 h. The excess thionyl chlo-
ride and benzene were removed under reduced pressure, the
residue dissolved in diethyl ether (25 mL), and dimethyl-
amine bubbled through the solution for 0.5 h at 0 °C. The
mixture was made basic with 10% aq. NaOH, the organic
layer separated, and the aqueous layer extracted with
CH2Cl2 (3 × 25 mL). The combined organic extracts were
dried over MgSO4, filtered, and concentrated under reduced
pressure. Distillation of the crude product gave 18a
was subjected to column chromatography (hexane – ethyl
acetate, 3:1). After a small forerun containing dialkylated
material, the one significant fraction proved to be 19b
(0.1212 g, 89%); bp 65–70 °C at 0.2 Torr. IR (neat, cm–1)
ν
max: 1646. 1H NMR (250 MHz) δ: 0.7–1.5 (m, 11H, 3CH3 +
CH2), 1.66, 1.69 (2d, J = 7 Hz, 3H, CH3 for E- and Z-19b,
respectively), 2.06, 2.46 (2m, 1H,CH for Z- and E-19b, re-
spectively), 2.92, 2.93 and 2.94, 3.02 (2× 2s, 6H, 2NCH3,
for Z- and E-19b, respectively). MS m/e (rel. intensity):
197(M+, 4), 182(100), 72(45). Anal. calcd. for C12H23NO: C
73.04, H 11.75, N 7.10; found: C 73.23, H 11.73, N 6.93.
(0.5028 g, 84%); bp 78–80 °C at 0.3 Torr. IR (neat, cm–1)
1
ν
max: 1628. H NMR δ: 0.8–1.2 (m, 6H, 2CH3), 1.3–1.6 (m,
4H, 2CH2), 2.12 (m, 2H, CH2), 2.31 (q, J = 7 Hz, 2H, CH2),
2.97, 3.01 (2s, 6H, 2NCH3), 5.74 (br s, 1H, CH). MS m/e
(rel. intensity): 183 (M+, 51), 153(32), 139(100), 72(83).
Anal. calcd. for C11H21NO: C 72.08, H 11.55, N 7.64;
found: C 71.94, H 11.33, N, 7.66.
E-3-(1,1-Dimethylethyl)-N,N-2-trimethyl-3-pentenamide
(19c)
Compound 18c (0.1160 g, 0.6328 mmol) was lithiated ac-
cording to procedure C and the resulting dienolate alkylated
with iodomethane (0.20 mL) in the normal manner. Follow-
ing a standard workup, the crude reaction mixture was sub-
jected to column chromatography (hexane – ethyl acetate,
3:1) to give only one fraction, which was shown to be 19c
(0.0940 g, 75%); bp 60–65 °C at 0.05 Torr. IR (neat, cm–1)
3-Ethyl-N,N-dimethyl-2-pentenamide (18g)
To a suspension of NaH (0.6032 g, 25.1 mmol) in benzene
(125 mL) was added diethyl 2- (dimethylamino)-2-
oxoethylphosphonate (4.92 mL, 25.0 mmol). The mixture
was stirred for 45 min and then 3-pentanone (28 mL,
26 mmol) was added. The reaction mixture was heated under
reflux for 21 h and the reaction worked up in the normal
manner. The crude product was subjected to flash chroma-
tography (ethyl acetate – hexane, 4:1) to give one fraction,
which was shown to be 18g (1.7642 g, 46%); bp 64 to 65 °C
ν
max: 1648. NMR (250 MHz) δ: 1.09 (s, 9H, 3CH3), 1.32 (d,
J = 7 Hz, 3H, CH3), 1.66 (d, J = 7 Hz, 3H, CH3), 2.93 (s,
6H, 2NCH3), 3.56 (q, J = 7 Hz, 1H, CH), 5.54 (q, J = 7 Hz,
1H, CH). MS m/e (rel. intensity): 197 (M+, 2), 182(100),
72(83). Anal. calcd. for C12H23NO: C 73.04, H 11.75, N
7.10; found: C 72.89, H 11.51, N, 7.28.
1
at 0.6 Torr. IR (neat, cm–1) νmax: 1630. H NMR δ: 1.05 (m,
6H, 2CH3), 2.15 (q, J = 8 Hz, 2H, CH2), 2.32 (q, J = 8 Hz,
2H, CH2), 2.98, 3.00 (2s, 6H, 2NCH3), 5.73 (br s, 1H, CH).
MS m/e (rel. intensity): 155 (M+, 57), 111(100), 72(27).
Anal. calcd.for C9H17NO: C 69.63,H 11.04, N 9.02; found:
C 69.59, H 11.13, N 9.01.
Z- and E-3-(2-Butyl)-N,N,2,5-tetramethyl-3-hexenamide
(19d)
Compound 18d (0.4405 g, 2.084 mmol) was lithiated ac-
cording to procedure C and the resulting dienolate alkylated
with iodomethane (0.30 mL) in the normal manner. Follow-
ing a standard workup, the crude reaction product was sub-
jected to preparative TLC (ethyl acetate – hexane, 1:1) to
give two fractions. The first fraction was shown to be 19d
Z- and E-3-(1-Butyl)-N,N,2-trimethyl-3-pentenamide
(19a)
Compound 18a (0.5028 g, 2.743 mmol) was lithiated ac-
cording to procedure C and the resulting dienolate was
alkylated with iodomethane (0.35 mL) in the normal manner.
Following a standard workup, the crude reaction product was
subjected to preparative TLC (ethyl acetate – hexane, 95:2) to
afford two fractions. The first fraction was shown to be 19a
(0.2254 g, 54%); bp 60–64 °C at 0.02 Torr. IR (neat, cm–1)
1
ν
max: 1643. H NMR (250 MHz) δ: 7.15 (m, 17H, 5CH3 +
CH2), 2.03 (m, 1H, CH), 2.65 (m, 1H, CH), 2.94 (m, 6H,
2NCH3), 3.25, 3.71 (m, 1H, CH). MS m/e (rel. intensity):
225 (M+, 3), 210(100), 100(23), 72(66). Anal. calcd. for
C14H27NO: C 74.61, H 12.08, N 6.21; found: C 74.61, H
11.88, N 6.01. The second fraction was found to contain
starting material 18d (0.1657 g, 38%).
(0.2925 g, 54%); bp 60–65 °C at 0.2 Torr. IR (neat, cm–1)
1
ν
max: 1645. H NMR (250 MHz) δ: 0.85–1.05 (m, 3H, CH3),
1.21 (d, J = 7 Hz, 3H, CH3), 1.32 (m, 2H, CH2), 1.61, 1.66
(2d, J = 7 Hz, 2H, CH2 from E- and Z-19a, respectively),
2.06 (m, 2H, CH2), 2.90, 2.91, 2.94, 2.97 (2 × 2s, 6H,
2NCH3 from Z- and E-19a, respectively), 3.28, 3.62 (2q, J =
7 Hz, 1H, CH from E- and Z-19a, respectively, relative area
79:21), 5.29 (q, J = 7 Hz, 2H, vinyl CH). MS m/e (rel. inten-
sity): 197 (M+, 5), 182(94), 72(100), 59(100). Anal. calcd.
for C12H23NO: C 73.04, H 11.75, N 7.10; found: C 72.83, H
11.77, N 7.36. The second fraction proved to be starting 18a
(0.1276 g, 25%).
Z-3-(1-Butyl)-4-methoxy-N,N,2-trimethyl-3-butenanide
(19f)
Compound 18f (0.1365 g, 0.6849 mmol) was lithiated ac-
cording to procedure C and the resulting dienolate alkylated
with iodomethane (0.15 mL) in the normal manner. Follow-
ing a standard workup, the crude reaction product was sub-
jected to flash chromatography (fine silica, ethyl acetate –
hexane, 1:1) to afford 19f (0.1234 g, 84%); bp 59–62 °C at
1
0.007 Torr. IR (neat, cm–1) νmax: 1647. H NMR (250 MHz)
δ: 0.87 (m, 3H, CH3), 1.17 (d, J = 7 Hz, 3H, CH3), 1.29 (m,
4H, 2CH2), 1.82 (m, 2H, CH2), 2.91, 2.94 (2s, 6H, 2NCH3),
3.58 (s, 3H, OCH3), 3.90 (q, J = 7 Hz, 1H, CH), 5.76 (m,
1H, CH). Irradiation of the δ 5.76 resonance resulted in a
22% integrated enhancement of the δ 1.82 resonance; irradi-
ation of the δ 1.82 resonance resulted in an 11% integrated
enhancement in the δ 5.76 signal. MS m/e (rel. intensity):
Z- and E-3-(2-Butyl)-N,N,-2-trimethyl-3-pentenamide
(19b)
Compound 18b (0.1260 g, 0.6784 mmol) was lithiated ac-
cording to procedure C and the resulting dienolate was
alkylated with iodomethane (0.15 mL) in the normal manner.
Following a standard workup, the crude reaction product
© 2006 NRC Canada

Green et al.
1407
213 (M+, 26), 198(27), 141(100), 99(62). Anal. calcd. for
C13H23NO: C 67.57, H 10.87, N 6.57; found: C 67.68, H
10.76, N 6.63.
diastereomers (0.2480 g, 95%); bp 89–94° at 0.02 Torr. IR
1
(neat, cm–1) νmax: 1646. H NMR (250 MHz) δ: 0.87, 0.89
(2s, 9H, 3CH3), 1.03, 1.15 (2d, J = 7 Hz, 3H, CH3), 1.26 (d,
J = 7 Hz, 3H, CH3), 1.4–2.1 (m, 5H, 2CH2 + CH), 2.23 (q,
J = 7 Hz, 1H, CH), 2.93, 3.06 and 2.95, 2.97 (4s, 6H,
2NCH3), 3.32, 3.37 (2q, J = 7 Hz, 1H, CH), 5.45, 5.73 (2dd,
J = 7, 7 Hz, 1H, CH). MS m/e (rel. intensity): 251 (M+, 9),
236(33), 194(100), 101(25), 72(136). Anal. calcd. for
C16H29NO: C 76.44, H 11.63, N 5.57; found: C 76.36, H
11.72, N 5.48.
Z- and E-3-Ethyl-N,N,3-trimethyl-3-pentenamide (19g)
Compound 18g (0.1220 g, 0.7858 mmol) was lithiated ac-
cording to procedure C and the resulting dienolate alkylated
with iodomethane (0.20 mL) in the normal manner. Follow-
ing standard workup, column chromatography (hexane –
ethyl acetate, 5:2) afforded one fraction, which was shown to
be 19g (0.1057 g, 80%); bp 58–62 °C at 0.2 Torr. IR
1
(neat, cm–1) νmax: 1645. H NMR (250 MHz) δ: 0.96 (t, J =
N,N-Dimethyl-2-[trans-5-(1,1-dimethylethyl)-6-methyl-1-
cyclohexenyl]propanamide (34)
8 Hz, 3H, CH3), 1.18, 1.21 (2d, J = 7 Hz, 3H, CH3 for Z-
and E-19g, respectively), 1.62, 1.67 (2d, J = 7, 3H, CH3 for
E- and Z-19g, respectively), 2.10 (q, J = 8 Hz, 2H, CH2),
2.96 (m, 6H, 2NCH3), 3.29, 3.64 (2q, J = 7 Hz, 1H, CH for
E- and Z-19g, respectively, relative area 79:21), 5.27 (q, J =
7 Hz, 1H, CH). MS m/e (rel. intensity): 169 (M+, 4),
154(100), 74(69), 72(89). Anal. calcd. for C10H19NO: C
70.96, H 11.31, H 8.28; found: C 70.86, H 10.89, N 8.63.
Compound 18g (0.4156 g, 268 mmol) was lithiated
according to procedure C and alkylated at –78 °C with
iodomethane (0.4 mL). After allowing the reaction to warm
overnight to RT, a standard workup was performed and the
crude reaction product was subjected to preparative TLC
(ethyl acetate – hexane, 5:2) to yield 19g (0.3213 g, 71%) as
the only isolated fraction. Integration of the δ 3.29 and δ 3.64
Compound 33 (0.198 g, 0.808 mmol) was lithiated ac-
cording to procedure C and the resulting dienolate alkylated
with iodomethane (0.10 mL) in the normal manner. Follow-
ing a standard workup, the crude reaction product was sub-
jected to flash chromatography (fine silica, hexane – ethyl
acetate, 9:2) to give one major fraction, which contained 34
as a pair of diastereomers (0.1670 g, 82%); bp 90–95 °C at
1
0.02 Torr. IR (neat, cm–1)
νmax
: 1646. H NMR : 0.84 (s,
δ
9H, 3CH3), 0.9–2.3 (m, 12H, 2CH3 + 2CH2 + 2CH), 2.93,
2.97 (2s, 6H, 2NCH3), 3.1–3.6 (m, 1H, CH), 5.34, 5.58
(2br s, 1H, CH). MS m/e (rel. intensity): 251 (M+, 12),
236(39), 194(100), 101(38), 72(147). Anal. calcd. for
C16H29NO: C 76.44, H 11.63, N, 5.57; found: C 76.21, H
11.50, N 5.64.
1
resonances in the H NMR spectrum established the ratio of
E-19g:Z-19g as 92:8.
trans-6-Deuterio-5-(1,1-dimethylethyl)-1-cyclohexenyl-
N,N-dimethylpropanamide (36)
Z-N,N-Dimethyl-3-hexenamide (23)
Compound Z-35 (0.1666 g, 0.743 mmol) was lithiated ac-
cording to procedure C and the resulting dienolate alkylated
with iodomethane (0.15 mL) in the normal manner. Follow-
ing standard workup, the crude product was subjected to
flash chromatography (fine silica, hexane – ethyl acetate,
4:1) to afford one fraction, which contained 36 as a pair of
diastereomers (0.1667 g, 95%); bp 90–95 °C at 2 Torr. IR
Compound 23 was prepared by the method reported by
Baldwin and co-workers (16j) in 35% yield based on methyl
sorbate; bp 46–48 °C at 2 Torr.
Z-N,N,-2-Trimethyl-3-hexenamide (24)
Compound 23 (0.1394 g, 0.987 mmol) was lithiated ac-
cording to procedure A and the resulting dienolate alkylated
with iodomethane (0.20 mL) in the normal manner. Follow-
ing a standard workup, column chromatography (hexane –
ethyl acetate, 5:2) of the crude product gave, after a forerun
that contained a trace amount of dialkylated material, com-
pound 24 (0.1281 g, 84%); bp 75–80 °C at 2.0 Torr. IR
1
(neat, cm–1) νmax: 1646. H NMR (250 MHz) δ: 0.87 (s, 9H,
3CH3), 1.22 (d, J = 7 Hz, 3H, CH3), 1.0–1.35 (partially ob-
scured m, 1H, CH), 1.65–2.2 (m, 5H, CH2 + 3CH), 2.95,
2.96, 2.97, 2.98 (4s, 6H, 2NCH3), 3.18 (m, 1H, CH), 5.47
2
(m, 1H, CH). H NMR δ: 1.92 (s, approx. 89% of D), 3.07
(s, approx. 8% of D), 5.49 (s, approx. 3% of D). MS m/e
(rel. intensity): 239, 238, 237 (M+, d2:d1:d0, corrected,
5:93:22), 238 (M+, 36), 223(38), 181(100), 167(35),
100(40), 72(173).
(neat, cm–1) νmax: 1643. H NMR (250 MHz) δ: 1.00 (t, J =
1
8 Hz, 3H, CH3), 1.81 (d, J = 7 Hz, 3H, CH3), 2.10 (m, 2H,
CH2), 2.94, 3.01 (2s, 6H, 2NCH3), 3.61 (qd, J = 7, 7 Hz, 1H,
CH), 5.04 (m, 2H, 2CH2); a signal at δ 3.33 (qd, m, CH for
E-24) was barely perceptible and E-24 was therefore esti-
mated to be present to the extent of 5%. MS m/e (rel. inten-
sity): 155 (M+, 16), 140(22), 83(100). Anal. calcd. for
C9H17NO: C 69.63, H 11.04, N 9.02; found: C 69.63, H
11.16, N 9.08.
N,N-Dimethyl-2-[trans-3-(1,1-dimethylethyl)-6-methyl-1-
cyclohexenyl]propanamide (38) and N,N-dimethyl-2-[5-
(1,1-dimethylethyl)-2-inethyl-1-cyclohexenyl]propanamide (39)
Compound Z-37 (0.1442 g, 0.607 mmol) was lithiated ac-
cording to procedure C and the resulting dienolate alkylated
with iodomethane (0.15 mL) in the normal manner. Follow-
ing a standard workup, the reaction product was subjected to
column chromatography (hexane – ethyl acetate, 5:1) to give
one fraction. The contents of this fraction were shown by
N,N-Dimethyl-2-[cis-5-(1,1-dimethylethyl)-6-methyl-1-
cyclohexenyl]propanamide (32)
Compound 31 (0.2468 g, 1.04 mmol) was lithiated ac-
cording to procedure C and the resulting dienolate alkylated
with iodomethane (0.18 mL) in the normal manner. Follow-
ing a standard workup, the crude product was subjected to
column chromatography (hexane – ethyl acetate, 4:1) to give
one fraction, which was shown to contain 32 as a pair of
1
GC and H NMR spectroscopy to be a roughly 1:1 mixture
of 38 and 39 (0.1328 g, 87%); bp 89–94 °C at 0.05 Torr. IR
1
(neat, cm–1) νmax: 1648. H NMR (250 MHz) δ: 0.83, 0.83
(2s, 9H, 3CH3), 1.0–2.3 (m, 12 protons of 38 and 13 protons
of 39, 2CH3 + 2CH2 + 2CH of 38 and 2CH3 + 3CH2 + CH
© 2006 NRC Canada

1408
Can. J. Chem. Vol. 84, 2006
of 39), includes 1.65 (s, CH3 of 39), 2.9–3.0 (m, 6H,
2NCH3), 3.17, 3.3, 3.57 (q, J = 7 Hz, q, J = 7 Hz and m, 1H,
CH), 5.33, 5.57 (2s, 1 proton of 38, CH). MS m/e (rel. inten-
sity): 251 (M+, 12), 236(52), 194(100), 180(52), 101(36),
84(20), 72(171). Anal. calcd. for C16H29NO: C 76.44, H
11.63, N 5.57; found: C 76.56, H 11.75, N 5.56.
to column chromatography (hexane – ethyl acetate, 1:1) to
afford one fraction, which contained 46 as a pair of
diastereomers (0.1562 g, 92%); bp 85–90 °C at 0.2 Torr. IR
(neat, cm–1) νmax: 1644. 1H NMR δ: 0.87 (s, 9H, 3CH3), 1.0–
1.35 (partially obscured m, 1H, CH), 1.6–2.2 (m, 6H, 2CH2
+ 2CH), 2.95, 2.96, 2.97, 2.98 (4s, 6H, 2NCH3), 3.18 (m,
1H, CH), 5.47 (m, 0.65H, CD). 2H NMR (decoupled) δ: 1.72
(9% of D), 2.28 (26% of D), 3.60 (65% of D). MS m/e (rel.
intensity): 239, 238, 237 (M+, d2:d1:d0, corrected, 8:27:65),
237 (M+, 27), 222(26), 181(100), 166(31), 101(50), 72(38).
Anal. calcd. for C15H27NO: C 75.90, H 11.46, N 5.90;
found: C 76.02, H 11.72, N 6.38.
cis-2-Deuterio-5-(1,1-dimethylethyl)cyclohexanone (44)
To a solution of LDA (13 mmol) in THF (65 mL) at
–78 °C was added 3-(1,1-dimethylethyl)cyclohexanone
(0.9988 g, 6.48 mmol) in a minimum amount of THF
(-5 mL). The solution was stirred for 1 h at –78 °C. In a
separate flask, D2O (0.25 mL) was added to a stirred solu-
tion of trifluoroacetic anhydride (0.92 mL, 13 mmol) at
–78 °C and the solution allowed to warm to RT. The con-
tents of the latter flask were then added to the former flask,
the mixture was stirred at –78 °C for 10 min, and MgSO4
added. After warming to RT, the mixture was filtered
through Celite and concentrated under reduced pressure.
Distillation of the crude reaction product gave 44 (0.4614 g,
46%); bp 96–98 °C at 10 Torr. MS m/e (rel. intensity): 155,
154, 153 (M+, d2:dl:d0 = 10:40:50).
Material on deposit
The experimental procedures and spectral data for the
preparation of 14b–14d, 15b–15d, 16b–16f, 17b–17f, 18b–
18f, (diethylamino)-2-oxoethylphosphonate, the precursors
to 31, 33, 35, and 37, and the minimized structures, final
Cartesian coordinates, and energies for the calculated transi-
tion states for senecioamide deprotonation (47, 49, and 50)
have been deposited as Supplementary material.6
Acknowledgements
Z- and E-(cis-2-Deuterio-5-(1,1-dimethylethyl)cyclo-
hexylidene]-N,N-dimethylacetamide (Z- and E-45)
We are grateful to the Natural Sciences and Engineering
Research Council of Canada (NSERC) for support of our
synthetic programs. JRG was a NSERC 1967 Fellowship
awardee. We also wish to thank James Gauld for assistance
with the DFT calculations on the deprotonation transition
states.
N,N-Dimethyltrimethylsilylacetamide (0.9543 g, 5.99 mmol)
was lithiated according to procedure A. To a –78 °C solution
of the resulting enolate was added 44 (0.9301 g, 5.99 mmol)
in a minimum amount of THF (-3 mL). The reaction mix-
ture was stirred for 3 h at –78 °C, warmed to RT, and two
drops of water and MgSO4 were added. After filtration
through Celite and concentration of the filtrate under re-
duced pressure, the crude reaction product was subjected to
flash chromatography (fine silica, hexane–Et2O, 2:1). Four
fractions were isolated. The first fraction contained starting
material 44 (0.0530 g, 6%). The second fraction proved to
be E-45 (6.2084 g, 27% including fraction No. 3, see com-
pound Z-35) contaminated with a small amount (4%) of Z-
45. The third fraction was a 34:66 mixture of E-45 and Z-45
(0.2084 g). The final fraction was shown to contain Z-45
(0.3805 g, 52% including fraction Nos. 2 and 3); bp 85–
90 °C at 0.1 Torr. IR (neat, cm–1) νmax: 1628. 1H NMR
(250 MHz) δ: 0.87 (s, 9H, 3CH3), 1.0–1.3 (m, 2H, CH2),
1.65–2.1 (m, 4.5H, CH2 + 2CH + CD), 2.30 (d, J = 13 Hz,
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2
5.68 (s, 1H, CH). H NMR (C6D6, decoupled) δ: 1.60 (55%
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