Bond rotation dynamics of enamides: The effect of the acyl group and potential for chirality transfer during 5-endo trig radical cyclizations

Article abstract of DOI:10.1021/jo200343z

Barriers to rotation of the N-alkenyl bond in a series of N-cycloalkenyl-N-benzyl acetamide derivatives have been measured in different solvents by variable-temperature NMR experiments. The barriers range from 9.7 to 14.2 kcal/mol, depending on substituents on the acetamide acyl group. Polar solvents such as chloroform and methanol increase the barrier to rotation compared to nonpolar solvents such as toluene. The barrier to rotation of "mimics" for acetamide-based radicals are estimated. The relative order of the values of k_rot for different acyl groups parallels their reported Taft E_s paramaters. For successful chirality transfer in 5-endo trig radical cyclization, it is evident that rotations would need to be significantly slower than those reported here.

Full text of DOI:10.1021/jo200343z

ARTICLE
pubs.acs.org/joc
Bond Rotation Dynamics of Enamides: The Effect of the Acyl Group
and Potential for Chirality Transfer during 5-Endo Trig Radical
Cyclizations
Andrew J. Clark,*,† Dennis P. Curran,*,‡ Joanna V. Geden,† Natalie James,† and Paul Wilson†
†Department of Chemistry, University of Warwick, Coventry, West Midlands, CV4 7AL, United Kingdom
‡Department of Chemistry, University of Pittsburgh, Pittsburgh Pennsylvania 15260, United States
S Supporting Information
b
ABSTRACT: Barriers to rotation of the N-alkenyl bond in a series of N-
cycloalkenyl-N-benzyl acetamide derivatives have been measured in different
solvents by variable-temperature NMR experiments. The barriers range from 9.7
to 14.2 kcal/mol, depending on substituents on the acetamide acyl group. Polar
solvents such as chloroform and methanol increase the barrier to rotation
compared to nonpolar solvents such as toluene. The barrier to rotation of “mimics”
for acetamide-based radicals are estimated. The relative order of the values of krot
for different acyl groups parallels their reported Taft Es paramaters. For successful
chirality transfer in 5-endo trig radical cyclization, it is evident that rotations would need to be significantly slower than those
reported here.
’ INTRODUCTION
We recently reported that N-cycloalkenyl-N-benzyl R-haloa-
cetamide derivatives 1aꢀc and the radical derived from them, 2,
are axially chiral due to restricted rotation around the CꢀN bond
of the enamide functionality (Figure 1).1 For example, a torsion
angle of 74° is observed for the N-alkenyl bond (CHCꢀNC(O))
in the X-ray crystal structure of N-cyclohexenyl-R-chloroaceta-
mide 1a (X = Cl).2 Radicals derived from homolysis of the CꢀX
bond 2 have been shown to undergo 5-endo radical cyclization to
give 3.2ꢀ6 Most 5-endo radical cyclization reactions employ R-
haloenamides as starting materials and alternate 4-exo cyclization
modes are also possible depending upon the substitution pattern
of the enamide.2ꢀ6
It is evident that radicals like 2 can only cyclize as the E-
rotamer of the amide NꢀCdO bond.2 In the Z-rotamer, the
radical cannot reach the alkene. Fortunately, enamides typically
prefer the E-rotamer,7 so their radicals are formed in a geometry
that is predisposed to cyclize. Variable temperature NMR studies
of 1aꢀc confirmed the existence of largely a single E-amide
rotamer in CDCl3 but more importantly also indicated a
relatively slow bond rotation (∼104 sꢀ1) of the N-cyclohexenyl
(enamide) bond (E,P-1f E,M-1 ΔG = 11.7ꢀ12.1 kcal molꢀ1).1
Figure 1. Rotamers of radical precursor 1aꢀc and cyclizations of
derived radical 2.
Depending on whether cyclization (2f3) is faster than N-
alkenyl bond rotation in the radicals (E,P-2f E,M-2) then
the axial chirality of suitable enamides (E,P-1 or E,M-1)
(if separated) could be retained or transferred in 5-endo radical
cyclization reactions.8
To better contemplate the prospects of chirality transfer in
radical (2f3) or other reactions of enamides,9 a basic under-
standing of their rotation dynamics is needed. In particular, an
ability to estimate the value of krot for the radicals E,P-2f E,M-2
themselves is crucial when considering the prospects of high
levels of chirality transfer. We previously reported how the size of
the ring in which the enamide was constrained effected the
barrier to rotation. With the rate of bond rotation observed being
Received: February 28, 2011
Published: April 20, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo200343z J. Org. Chem. 2011, 76, 4546–4551
|

The Journal of Organic Chemistry
ARTICLE
Figure 3. Synthesis of enamides 4aꢀd, 6aꢀd, 7ꢀ10.
Figure 4. Expansion of the 1H NMR spectra of 6c at 183ꢀ353 K.
Figure 2. Radical precursors 4aꢀd and models for the corresponding
radicals 6aꢀd with measured ΔGq298 barrier to rotation in kcal/mol in
paranthesis.
cyclopentene , cyclododecene < cyclooctene < cyclohexene ≈
cycloheptene.1 Here we report variable temperature NMR
experiments that provide rotation barriers of a complementary
series of N-cyclohexene derived enamides in which the size of the
acyl group has been steadily increased. To estimate the barrier to
rotation in radicals such as 2, we have prepared analogues where
the bromine atom has been replaced by a hydrogen atom. These
results provide a quantitative footing for estimation of rotation
barriers that can be used to design axially chiral enamides that
could be resolved at ambient temperatures and that could
undergo onward reactions that are faster (or slower) than bond
rotations.
Figure 5. Erying plot of VT NMR data of 7 (0) and 6a (O).
The compounds were prepared by acylation with the appro-
priate acid chloride or acid bromide of the imine formed from
cyclohexanone and benzylamine, Figure 3.1 Compounds 4aꢀd
and 6aꢀd were dissolved in d8-toluene with a small amount of
tetramethylsilane for use as a chemical shift and line width
standard. 1H NMR spectra were recorded at temperature inter-
vals in the range of 183ꢀ353 K. Portions of these spectra for
compound 6c are shown in Figure 4.
Consistent with expectation as the samples were cooled,
decoalescence of the benzyl proton resonances occurred giving
rise to mutually coupled doublets as seen in our previously
reported work. This behavior is consistent with the existence of
largely a single E-amide rotamer in solution where decoales-
cences are caused by slowing of the N-cyclohexenyl bond
rotation, which reveals the diastereotopicity of the pairs of
geminal protons. Enamide 4b has an additional stereocenter,
so its rotamers are diastereomers, not enantiomers. The equilib-
rium constant for the two diastereomers 4b is about 1.
’ RESULTS AND DISCUSSION
The experiments were initiated by preparing the series of
enamides 4ꢀ61 to determine the effect of additional methyl
groups and halogen atoms attached to the acyl group on the
rotation barrier. Compounds 4aꢀc were prepared to determine
the effect of sequential replacement of H atoms with methyl
groups in the radical precursors, while compounds 6aꢀc were
prepared to determine the same effect in analogues where the
bromine atoms have been replaced by hydrogen atoms and were
studied as potential models for the reactive radicals (Figure 2).
The tri- and dihalo substrates 4d and 6d were also prepared
because these substrates have often been utilized in atom transfer
radical cyclizations (ATRC) reactions10 as well as organostan-
nane mediated radical reactions,11 where the additional halogen
substituents have been reported to facilitate cyclization. In
addition, 6d would act as a model for the radical 5d obtained
from the trichloroacetyl radical precursor 4d.
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Table 1. N-Alkenyl Bond Rotation Rates and Activation Parameters from Variable Temperature NMR Experiments
entry
comp.
R group
CH2Brb
CH(Me)Brc
krot 298 Ka (sꢀ1
)
ΔH‡a(kcal/mol)
ΔSqa(cal/molK)
ΔGq a (kcal/mol)
298
1
2
4a
4b
4.39 ꢁ 104
4.55 ꢁ 103
4.55 ꢁ 103
1.06 ꢁ 103
2.52 ꢁ 102
2.51 ꢁ 105
7.46 ꢁ 104
1.80 ꢁ 104
6.66 ꢁ 103
6.43 ꢁ 103
7.45 ꢁ 104
4.89 ꢁ 105
2.29 ꢁ 104
7.9
7.9
ꢀ10.9
ꢀ13.9
ꢀ13.9
ꢀ6.6
2.0
11.1
12.0
12.0
13.3
14.2
10.1
10.9
11.7
12.2
12.3
10.8
9.7
7.9
3
4c
4d
6a
6b
6c
6d
7
C(Me)2Br
CCl3
11.3
14.8
9.2
4
5
Me
ꢀ2.9
ꢀ14.7
ꢀ10.6
ꢀ7.4
0.9
6
Et
6.4
7
i-Pr
8.5
8
CHCl2
t-Bu
10.0
12.5
7.5
9
10
11
12
8
CHdCH2
C6H5
CH2Ph
ꢀ11.1
ꢀ12.2
ꢀ12.4
9
6.0
10
7.8
11.5
a Estimated errors krot 298 K ( 13%, ΔHq = ( 0.3 kcal/mol, ΔSq = ( 1.0 cal/(mol K), ΔGq298 = ( 0.2 kcal/mol, these are in-line with related work.7
b Values taken from ref 1. c The rotamers are diastereomers, so forward and reverse rates were determined.
Figure 6. Radical precursors 7ꢀ10 with measured ΔG‡ barrier to
298
Figure 7. X-ray crystal structure of one diastereomer of 4b.
rotation in kcal/mol in paranthesis.
Using the WINDNMR 7.1 line-shape analysis program12 to
analyze the benzyl peaks of 4aꢀd and 6aꢀd, we determined the
rotational rate constant krot at each temperature T. The standard
Erying plots for the 6a and 7 are shown in Figure 5. The
activation enthalpies and entropies were calculated in the stan-
dard way and are shown in Table 1. The benzylic protons were
well resolved from other resonances in every case, so these were
made the focal points of the line shape analyses.
4cf6c δΔGq298 = 1.6 kcal/mol). A greater difference was observed
upon comparison of the trichloracetyl derivative 4d with the dichlo-
roacetyl “radical model” 6d, (4df6d δΔGq = 2.0 kcal/mol).
298
Thus, a drop of ΔGq298 between 1.0 and 2.0 kcal/mol correlates to a
5ꢀ26 times increase in the krot 298Kvalueongoingfromtheradical
presursors to the “radical models”.
Arguably a better model for the sp2 hybridized radicals 5bꢀc
are the vinyl 8 and the aryl 9 derivatives containing an sp2 carbon
center where the radical would be situated, Figure 6.13 While
The 400 MHz NMR spectra of 4aꢀc and 6aꢀc at room
temperature were simple, and peak broadening and decoales-
cence were observed upon cooling. It can be seen from compar-
ing 6aꢀc in Table 1 that the sequential addition of methyl groups
the barrier for rotation of “sp2 radical model” 8 (ΔGq
=
=
298
10.8 kcal/mol) is similar to the “sp3 radical model” 6b (ΔGq
298
10.9 kcal/mol) the measured barriers for 6c (ΔGq298 = 11.7 kcal/mol)
298
imparts a steady increase of 0.8 kcal/mol in the ΔGq values
and the benzoyl derivative 9 (ΔGq = 9.7 kcal/mol) were
298
(6af6b δΔGq298 =0.8kcal/mol,6bf6c δΔGq298 = 0.8 kcal/mol).
For completeness, we prepared the pivaloyl analogue 7 and
298
significantly different. The decreased value for the benzoyl analog
9 is consistent with related observations in anilides.14 The phenyl
ring of 9 is likely twisted out of the plane of the CdO in the
ground state and can twist even more as the CꢀN bond rotates.
So it can get out of the way relatively easier than corresponding
sp3 groups. On the other hand the vinyl compound 8, while it
looks less hindered than 9, is conjugated s-cis, so in order to twist
this group out of the way during CꢀN bond rotation this
conjugation must be broken. Finally, we measured the barrier
to rotation of the benzylic derivative 10. This was found to be
found a similar increase (6cf7 δΔGq = 0.6 kcal/mol). A
similar but marginally larger trend was observed in the bromide
series 4aꢀc (4af4b δΔGq298 = 0.9 kcal/mol, 4bf4c δΔGq
=
298
1.3 kcal/mol). More importantly, when comparing the bro-
mides 4aꢀc with their “radical models” 6aꢀc where we have
replaced the bromine atom with a hydrogen atom a decrease of
between 1.0 and 1.6 kcal/mol in the ΔGq value is observed
298
(4af6a δΔGq298 = 1.0 kcal/mol, 4bf6b δΔGq298 = 1.1 kcal/mol,
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Table 2. N-Alkenyl Bond Rotation Rates and Activation Parameters from Variable Temperature NMR Experiments for 4a and 4c
in Different Solvents
compound
solvent
krot 298 Ka (sꢀ1
)
ΔHqa (kcal/mol)
ΔSqa (cal/mol K)
ΔGq a (kcal/mol)
298
4a
4a
4a
4c
4c
4c
4c
d8-tolueneb
CD3ODb
4.54 ꢁ 103
1.96 ꢁ 103
1.58 ꢁ 103
1.06 ꢁ 103
326.1
8.1
8.2
ꢀ10.0
ꢀ11.3
ꢀ10.6
ꢀ6.6
ꢀ4.3
4.2
11.1
11.6
11.7
13.3
14.0
14.2
14.2
b
CDCl3
8.5
d8-toluene
CD3OD
CDCl3
11.3
12.7
15.4
12.5
251.4
CD3NO2
245.3
ꢀ5.7
a Estimated errors krot 298 K ( 13%, ΔHq = (0.3 kcal/mol, ΔSq= (1.0 cal/(mol K), ΔGq298 = (0.2 kcal/mol, these are in-line with related work.7
b Value taken from ref 1.
greater than the primary bromide 4a and similar to the isopropyl
derivative 6c.
increases the rate of rotation only between 5 and 26 times.
Unfortunately, for radical mimic 6a this corresponds to the rate
of CꢀN bond rotation being approximately 25 times faster than
cyclization at room temperature indicating that while chirality
transfer in radicals such as 5a is not practical, transfer from radical
5d should occur, but be relatively low. For successful chirality
transfer in 5-endo cyclizations, it is evident that rotations would
need to be significantly slower than those reported here.
It was possible to solve the X-ray structure for 4b. The
torsional angle of the key N-alkenyl bond for one of the isomers
is 84°, this is similar to that observed for anilides1,15 and is slightly
larger than the reported value of 74° for the primary chlorine
analogue 1a1 and significantly larger than the 2-tetralone deriva-
tive 11 (56°), Figure 7.2 Unlike the 2-tetralone derivative 11,
where the amide nitrogen exhibited partial sp3 hybridization with
the sum of bond angles to nitrogen being 356.9° and the torsion
angle of the amide CꢀN bond being around 152.0°, for 4b the
amide nitrogen shows sp2 character as expected (with the sum of
bond angles to nitrogen being 359.9° and the torsion angle of the
amide CꢀN bond 179.1°).
’ EXPERIMENTAL SECTION
N-Cyclohex-1-enyl-N-benzyl-2-bromopropionamide (4a).
The literature procedure3a was followed using benzylamine (1.07 g,
10 mmol), cyclohexanone (2.94 g, 10 mmol), bromoacetyl bromide
(2.20 g, 11.0 mmol) and triethylamine (2.97 g 30 mmol) to give the
product 4a (925 mg, 30%).3a Spectroscopic data (1H NMR and 13C
NMR) was consistent with previously reported results. Rf (3:1 pet ether:
EtOAc) 0.6; υmax (film)/cmꢀ1 2934, 1646; δH (CDCl3, 400 MHz) 7.28
(5H, m), 5.50 (1H, s), 4.62 (2H, br s), 3.95 (2H, s), 2.07 (4H, m), 1.69
(2H, m), 1.40 (2H, m); δC (100 MHz, CDCl3) 166.1, 137.8, 137.4,
129.2, 128.7, 128.4, 127.4, 49.8, 41.9, 27.4, 25.3, 24.7, 21.4; m/z (ESI)
330 ([M]þNa); [Found: ([M]þNa) 330.0464, C15H18BrNO requires
([M]þNa) 330.0469].
General procedure for the formation of compounds 4bꢀd, 6aꢀd,
7ꢀ10: Cyclohexanone (1 equiv) and benzylamine (1 equiv) were added
to dry toluene at room temperature. The reaction mixture was heated at
reflux, using DeanꢀStark apparatus, overnight. The crude reaction
mixture was allowed to cool to room temperature, then cooled further
to 0 °C, before addition of the appropriate acyl halide (1 equiv), followed
by diethylaniline (1 equiv). The reaction was allowed to reach room
temperature and stirred for 4 h. The reaction mixture was washed with 2
M HCl. The organic layer was dried over MgSO4, filtered and
concentrated in vacuo to yield a crude product purified via flash
chromatography using 3:1 pet ether/EtOAc. For compounds 7 and 8,
the enamide alkene quaternary carbon and the aromatic quaternary
carbon are coincident in the 13C NMR spectra. For 4c, the gem dimethyl
group exhibits a very broad 13C NMR resonance.
We briefly explored the effect of solvent on the rotation barrier
of both enamide 4c and 4a (Table 2). Radical cyclizations of related
enamides have been mediated by organostannane reagents11 and
with copper complexes under ATRC conditions.10 The former
reactions tend to be carried out in nonpolar solvents (such as
cyclohexane, toluene or benzene) while the latter tend to be carried
out in polar solvents (such as dichloromethane, acetonitrile or
methanol). The data shows that in general more polar solvents
increase the barrier to rotation, although this difference is slight
(0.5ꢀ0.9 ( 0.2 kcal/mol) and there seems to be no correlation with
dielectric constant ε, dipole moment μ, or viscosity η. Focusing on
the solvents used in Bu3SnH (toluene) and in ATRC (chlorinated,
alcohol) reactions, the trend with 4c was identical with 4a, namely
ΔGq = toluene < MeOH ≈ CDCl3. This corresponds to a
298
decrease in the rate of CꢀN bond rotation upon changing the
solvent from d8-toluene to CDCl3 of approximately 2.9 and 4.2
times for 4a and 4c.
’ CONCLUSIONS
A range of radical precursors 4aꢀd, radical “mimics” 6aꢀd,
and 8 have been prepared to measure the rate of bond rotation
around their CꢀN bonds. The relative order of rotation parallels
the size of the acyl substituents and their reported Taft Es
parameters,16 notably 6a (0.00) < 6b (0.07) < 4a (0.27) < 6c
(0.47) < 4b (0.93) < 6d (1.54) ≈ 7 (1.54) < 4c (1.77)17 < 4d
(2.06). For efficient chirality transfer to occur in 5-endo trig
cyclizations, the rate of CꢀN bond rotation must be significantly
slower than the rate of cyclization (1 ꢁ 104 sꢀ1). Increased steric
hindrance at the acyl center lowers the rate of rotation as
expected (4a = 43900 sꢀ1, 4b = 9000 sꢀ1, 4c = 1060 sꢀ1, 4d =
252 sꢀ1) but more importantly replacing the large halogen atom
with a hydrogen atom to ‘mimic’ the radical interemediates 5aꢀd
N-Cyclohex-1-enyl-N-benzyl-2-bromopropionamide (4b).
Yield (70%); Cream solid mp 86ꢀ87 °C; Rf (3:1 pet ether/EtOAc) 0.8;
υmax (film)/cmꢀ1 2922, 1651; δH (CDCl3, 400 MHz) 7.20 (5H, m),
5.48 (1H, m), 4.75ꢀ4.50 (3H, m), 2.16 (1H, m), 2.00 (3H, m), 1.79
(3H, d, J 6.8 Hz), 1.64 (2H, m), 1.53 (2H, m); δC (100 MHz, CDCl3)
169.7, 138.0, 137.8, 129.4, 129.0, 128.7, 128.7, 50.4, 39.9, 28.4, 25.1, 23.1,
22.7, 21.7; m/z (ESI) 344.1 ([M]þNa) 322.1 [M]þ; [Found:
([M]þNa) 344.0620, C16H20BrNO requires ([M]þNa) 344.0626];
[Found: C, 59.6; H, 6.2; N, 4.4. C16H20BrNO requires C, 59.6; H,
6.3; N, 4.35].
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N-Cyclohex-1-enyl-N-benzyl-2-bromo-2-methylpropio-
namide (4c)1. Yield (69%); clear oil; Rf (3:1 pet ether/EtOAc) 0.80;
υmax (film)/cmꢀ1 2931, 2859, 1630, 1495, 1449, 1390, 1364, 1257,
1171, 1107, 920, 726, 697; δH (300 MHz CDCl3) 7.21 (5H, m), 5.53
(1H, m), 4.90 (1H app br s), 4.19 (1H, app br s), 2.12 (2H, br s), 1.96
(8H, app br s), 1.63 (2H, m), 1.47 (2H, m); δC (75.5 MHz, CDCl3)
170.2, 137.4 (x 2), 129.3 (broad), 128.2, 128.0, 126.9, 58.2, 52.2, 34.0
(broad), 27.8, 24.4, 22.4, 21.0; m/z (ESI) 358 ([M]þNa) 336; [Found:
([M]þNa), 358.0777, C17H22BrNO requires ([M]þNa), 358.0782];
[Found: C, 60.7; H, 6.7; N, 4.1. C17H22BrNO requires C, 60.7; H, 6.6;
N, 4.2].
(1H, br s), 4.67 (2H, s), 2.06ꢀ1.92 (4H, m), 1.68ꢀ1.48 (4H, m); δC
(75.5 MHz CDCl3) 165.2, 137.9 (x 2), 136.6, 128.7, 128.6 (x 2), 128.3,
128.2, 127.1, 49.8, 28.7, 24.7, 22.7, 21.5; m/z (ESI) 264 ([M]þNa) 242
[M]þ; [Found: ([M]þNa) 264.1359, C16H19NNaO requires
264.1364].
N-Cyclohex-1-enyl-N-benzamide (9).20 Yield (32%); Dark
yellow oil; Rf (3:1 pet ether/EtOAc) 0.54; υmax (film)/cmꢀ1 3061,
3029, 2929, 2858, 2837, 1632, 1576, 1495, 1446, 1436, 1388; δH (300
MHz, CDCl3) 7.44ꢀ7.40 (2H, m), 7.29ꢀ7.15 (8H, m), 5.18 (1H, br t, J
3.5 Hz), 4.73 (2H, s), 1.84ꢀ1.66 (4H, m), 1.40ꢀ1.19 (4H, m); δC (75.5
MHz CDCl3) 170.6, 139.0, 138.1, 137.3, 129.7, 128.6, 128.4, 128.2,
127.9, 127.6, 127.3, 50.7, 28.9, 24.8, 22.6, 21.4; m/z (ESI) 314
([M]þNa), 292 [M]þ; [Found: [M]þ 292.1696, C20H22NO requires
292.1701]; [Found: ([M]þNa) 314.1515, C20H2NNaO requires
314.1521]; [Found: C, 81.9; H, 7.3; N, 4.5, C20H21NO requires C,
82.4; H, 7.3; N, 4.8].
N-Cyclohex-1-enyl-N-benzyltrichloroacetamide (4d)18.
Yield (20%); dark yellow oil; Rf (3:1 pet ether/EtOAc) 0.78; υmax
(film)/cmꢀ1 3032, 2928, 2859, 1665, 1496, 1438, 1389, 1246, 1175, 848,
808, 697; δH (300 MHz CDCl3) 7.34ꢀ7.28 (5H, m), 5.59 (1H, m), 5.05
(1H, br d, J 13.0 Hz), 4.26 (1H, br s), 2.22 (2H, br), 2.01 (2H, br),
1.68ꢀ1.51 (4H, br); δC (75 MHz CDCl3) 178.7, 142.0, 128.8, 128.4,
128.3, 127.7, 74.6, 53.3, 27.5, 24.6, 22.4, 21.1; m/z (ESI) 354 ([M]þNa);
m/z [Found: ([M]þNa) 354.0193, C15H16Cl3NNaO requires
354.0195].
N-Cyclohex-1-enyl-N-benzyl-2-phenylacetamide (10).
Yield 23%; Off-white solid mp 146ꢀ147 °C; Rf (3:1 pet ether/EtOAc)
0.56; υmax (film)/cmꢀ1 3028, 2937, 1632, 1581, 1451, 1427, 1399, 1248,
1166, 1026, 702; δH (300 MHz, CDCl3) 7.33ꢀ7.19 (10H, m), 5.29 (1H,
br s), 4.61 (2H, s), 3.70 (2H, s), 2.03ꢀ1.86 (4H, m), 1.67ꢀ1.49 (4H,
m); δC (75.5 MHz CDCl3) 170.6, 138.3, 138.2, 136.3, 129.2, 129.0,
128.9, 128.5, 128.3, 127.3, 126.7, 49.7, 41.0, 28.3, 24.9, 22.9, 21.6; m/z
(ESI) 328 ([M]þNa); 306 [M]þ; [Found: ([M]þNa) 328.1672,
C21H23NNaO requires 328.1677]; [Found: C, 82.4; H, 7.5; N, 4.5,
C21H23NO requires C, 82.6; H, 7.6; N, 4.6].
N-Cyclohex-1-enyl-N-benzylacetamide (6a).3a Yield (33%);
Pale yellow oil; Rf (3:1 pet ether/EtOAc) 0.6; υmax (film)/cmꢀ1 2928,
1644; δH (CDCl3, 300 MHz) 7.22 (5H, m), 5.37 (1H, m), 4.60 (2H,s),
2.06 (3H,s), 1.95 (4H,m), 1.62 (2H, m), 1.49 (2H, m); δC (CDCl3, 75.5
MHz) 170.0, 138.9, 138.1, 128.7, 128.2, 128.1, 127.1, 49.4, 28.0, 24.7,
22.7, 21.6, 21.5; m/z (ESI) 252 ([M]þNa), 231 [M]þ; [Found:
([M]þNa) 252.1359, C15H19NO requires ([M]þNa) 252.1364].
N-Cyclohex-1-enyl-N-benzylpropionamide (6b). Yield
(20%); Cream solid mp 72ꢀ73 °C; Rf (3:1 pet ether/EtOAc) 0.6; υmax
(film)/cmꢀ1 2935, 1634; δH (CDCl3, 300 MHz) 7.28 (5H, m), 5.38,
(1H, s), 4.60 (2H, s), 2.33 (2H, q, J 7.5 Hz), 2.00 (4H, m), 1.64 (2H, m)
1.53 (2H, m), 1.12 (3H, t, J 7.5 Hz); δC (CDCl3, 75.5 MHz) 173.4,
138.4, 138.3, 128.7, 128.2, 128.0, 127.0, 49.6, 28.2, 26.8, 24.8, 22.8, 21.5,
10.1; m/z (ESI) 266 ([M]þNa); [Found: ([M]þNa) 266.1515,
C16H21NO requires ([M]þNa) 266.1521].
’ ASSOCIATED CONTENT
S
Supporting Information. Contains VT NMR experi-
b
1
ments, rotational data, Eyring plots and copies of H NMR
and 13C NMR spectra spectra for 4aꢀd, 6aꢀd, 7ꢀ10 and X-ray
data for 4b. This material is available free of charge via the
Internet at http://pubs.acs.org.
N-Cyclohex-1-enyl-N-benzyl-2-methylpropionamide (6c).
Yield (18%); Pale yellow solid mp 78ꢀ80 °C; Rf (3:1 pet ether/EtOAc)
0.8; υmax (film)/cmꢀ1 2929, 1634; δH (CDCl3, 400 MHz) 7.24 (5H,
m), 5.40 (1H, s), 4.59 (2H, s), 2.81 (1H, sept, J 6.7 Hz), 1.99 (4H, m),
1.68 (2H, m), 1.52 (2H, m), 1.12 (6H, d, J 6.5 Hz); δC (CDCl3, 75.5
MHz) 177.0, 138.6, 138.5, 128.7, 128.2, 127.5, 127.0, 49.7, 31.4 (broad),
28.8, 24.7, 22.9, 21.5, 20.2; m/z (ESI) 280.2 ([M]þNa) 258.1 [M]þ;
[Found: ([M]þNa) 280.1672, C17H23NO requires ([M]þNa)
280.1677].
’ AUTHOR INFORMATION
Corresponding Author
*a.j.clark@warwick.ac.uk; curran@pitt.edu.
’ ACKNOWLEDGMENT
We thank the National Science Foundation and the Engineer-
ing and Physical Science Research Council for funding this work.
The Oxford Diffraction Gemini XRD system was obtained
through the Science City Advanced Materials project: Creating
and Characterizing Advanced Materials, with support from
Advantage West Midlands (AWM) and in part funded by the
European Regional Development Fund (EDRF).
N-Cyclohex-1-enyl-N-benzyldichloroacetamide (6d).18
Yield (31%); Off-white solid mp 41ꢀ42 °C; Rf (3:1 pet ether/EtOAc)
0.67; υmax (film)/cmꢀ1 3030, 2927, 1673, 1495, 1440, 1403, 1210, 1177,
1078, 922, 803, 744, 670; δH (300 MHz CDCl3) 7.34ꢀ7.24 (5H, m),
6.39 (1H, s), 5.53 (1H, br m), 4.65 (2H, br s), 2.06 (4H, m), 1.74ꢀ1.52
(4H, m); δC (75 MHz CDCl3) 163.8, 136.9, 136.5, 130.4, 128.8, 128.5,
127.7, 64.1, 50.4, 27.9, 24.7, 22.5, 21.2; m/z (ESI) 320 ([M]þNa); m/z
[Found: ([M]þNa) 320.0579, C15H17Cl2NNaO requires 320.0585].
N-Cyclohex-1-enyl-N-benzyl-2-dimethylpropionamide (7).
Yield (6%); Yellow oil; Rf (3:1 pet ether/EtOAc) 0.9; υmax (film)/cmꢀ1
2928, 1625; δH (CDCl3, 400 MHz) 7.23 (5H, m), 5.28 (1H, m), 4.42 (2H,
br s), 2.07 (4H, m), 1.67 (2H, m), 1.54 (2H, m), 1.25 (9H, s); δC (CDCl3,
75.5 MHz) 178.0, 138.7 (x 2), 128.4, 128.2, 128.1, 126.8, 51.7, 40.9, 29.3,
28.4, 24.6, 22.6, 21.3; m/z (ESI) 294.2 ([M]þNa) 272.2 [M]þ; [Found:
([M]þNa) 294.1828, C18H25NO requires ([M]þNa) 294.1834].
N-Cyclohex-1-enyl-N-benzylprop-2-enamide (8).19 Yield
(46%); Yellow oil; Rf (3:1 pet ether/EtOAc) 0.41; υmax (film)/cmꢀ1
2926, 1648, 1408, 1350, 1236, 1138, 1079, 980, 698; δH (300 MHz,
CDCl3) 7.29ꢀ7.18 (5H, m), 6.54ꢀ6,45 (1H, dd, J 17.0, 9.7 Hz),
6.42ꢀ6.35 (1H, dd, J 17.0, 2.8), 5.63ꢀ5.59 (1H, dd, J 9.7, 2.8), 5.39
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