On the conformation of 8-membered ring heterocycles - Dynamic and static conformational analysis of acylated hexahydrobenzazocines

Article abstract of DOI:10.1002/ejoc.200500591

A high-field NMR analysis of several acylated hexahydrobenzazocines indicates that, surprisingly, ring methylene groups are typically diastereotopic at room temperature, as the barriers for the process of enantiomerization of the eight - membered ring are

Full text of DOI:10.1002/ejoc.200500591

FULL PAPER
DOI: 10.1002/ejoc.200500591
On the Conformation of 8-Membered Ring Heterocycles – Dynamic and Static
Conformational Analysis of Acylated Hexahydrobenzazocines
Alfred Hassner,[a] Boaz Amit,[a][‡] Vered Marks,[a] and Hugo E. Gottlieb*[a]
Keywords: Acylated benzazocines / Conformation analysis / Dynamic NMR spectroscopy / EXSY / Amide rotation
A high-field NMR analysis of several acylated hexahy-
drobenzazocines indicates that, surprisingly, ring methylene
groups are typically diastereotopic at room temperature, as
the barriers for the process of enantiomerization of the eight-
membered ring are much higher than expected. It is shown
that ring inversion is correlated (but not concerted) with rota-
tion of the amide moiety, as the carbonyl is forced out of con-
jugation with the nitrogen in the transition state. A detailed
analysis of vicinal proton-proton coupling constants, sup-
ported by molecular mechanics calculations, indicates that
these compounds exist at room temperature as a mixture of
fast-interconverting conformers of the octacycle. This is
proved by the observation of two species in the 13C NMR
spectrum of the parent compound, at temperatures below
–90 °C.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
Several years ago, we published a communication[1] not-
ing a quite unusual feature in the room temperature 1H
NMR spectra of acylated tetrahydrobenzazepines (e.g. 1):
one of the protons on the N-methylene was unusual, being
deshielded by at least 2 ppm more than the next most
deshielded aliphatic proton signals. This suggested a rather
high energy barrier between two enantiomeric species re-
sulting from a ring flip of the seven-membered ring. Sub-
sequently[2] we reported a detailed NMR study of several
such tetrahydrobenzazepines, in which we established the
ground state conformation of this class of heterocycles and
explained the reason for the very large barrier for their ring
epimerization. Specifically, the latter process is blocked by
the interaction of the aromatic ring and the acyl substitu-
ent; in order to enable this process, the acyl group has to
partially rotate out of coplanarity with the nitrogen, thus
incurring a high energetic cost. The two processes, amide
rotation and ring flip, are thus correlated (they do not occur
independently), but not concerted (i.e. two aspects of a
same conformational reorientation step). The above un-
Results and Discussion
Dynamic Transformations. Some hexahydrobenzazocines
were synthesized and the barriers for the ring-flip process
that converts the eight-membered rings of 2–4, 6 and 7 to
their enantiomeric forms determined by dynamic NMR
spectroscopy. The NMR results (NOE interactions) indeed
indicated that there was usually a major isomer in which
the carbonyl oxygen was anti to the aromatic ring and hence
syn to the N-adjacent methylene group. Specifically, we sim-
ulated the coalescence of the protons of the methylene adja-
cent to nitrogen (see Table 1 and Exp. Sect.) in the tempera-
ture-dependent 1H NMR spectra. As in the case of the
benzazepines,[2] the barriers are higher than might be ex-
pected, and they must involve partial rotation of the acyl
moiety. A hint that this is indeed the case is found in the
ring-flip barrier for the thioamide 3, which is several
kcal·mol–1 higher than for the corresponding amide 2.
In order to eliminate the possibility that ring flip and
amide rotation are concerted, we measured the barriers for
the rotation of the acyl and thioacyl moiety for 2 and 3,
respectively. The main technical difficulty in determining
this parameter is the very low concentration (2–3%), in the
1
usual H NMR deshielding was also observed in one hexa-
hydrobenzazocine (i.e. 2).[1] Since little is known about the
conformation of eight-membered rings we decided to exam-
ine the conformational behaviour of related acylated hexa-
hydrobenzazocines 2–7.
[a] Department of Chemistry, Bar-Ilan University,
Ramat-Gan 52900, Israel
E-mail: gottlieb@mail.biu.ac.il
[‡] Research carried out at the Department of Chemistry, State
University of New York,
Binghamton, NY 13901, USA
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1256–1261

On the Conformation of 8-Membered Ring Heterocycles
FULL PAPER
Table 1. Dynamic NMR-derived kinetics for ring inversion of hexa-
hydrobenzazocines.
Major rotamer
Minor rotamer
T [K]
k [s–1]
∆G†
k [s–1] ∆G†
[kcal·mol–1]
[kcal·mol–1]
2[a] 355.5
379.4
12
70
240
600
19.2
19.2
19.2
19.4
398.8
418.1
3[a] 355.5
379.4
2.5
10
35
20.3
0.5
2.5
5.5
4
37
80
150
300
600
1100
4100
12000
20000
150
350
1200
3300
6200
22.9
22.9
23.3
19.4
19.7
19.7
20.1
20.4
14.1
14.1
14.0
13.9
13.9
14.9
14.8
14.8
14.8
14.8
20.6
20.7
20.7
398.8
418.1
135
4[a] 346.3
380.7
392.1
408.3
426.3
Figure 1. Results of EXSY experiments for thioacetamide 3 (see
text and Table 2). In this graph I is the ratio of the sum of the
volume integrals of the off-diagonal peaks to those of the diagonal
peaks (see ref.[3]). As described in the text, the experiment is re-
peated for several values of the mixing time, tm, and a theoretical
curve is fitted for kobs (the sum of the forward and backward reac-
tion rates). The value of I tends asymptotically to 2 K/(K2 + 1) (the
equilibrium constant is obtained from the 1D spectrum) for large
mixing times, and if tmϾϾ1/kobs the obtained I value is not useful
in the fitting procedure.
6[b] 306.9
315.2
331.0
345.5
355.5
7[b] 306.9
315.2
331.2
346.5
355.5
[a] In C6D5Br. [b] In CDCl3.
Table 2. EXSY-derived kinetics for amide rotation of hexahy-
drobenzazocines.[a]
[b]
T
[K]
K
G0
[kcal·mol–1] [s–1]
kobs
k[c]
∆G†
equilibrium mixture, of the rotamer with the oxygen (or sul-
fur) atom positioned syn to the aromatic ring. As we ex-
plained in the previous paper in this series,[2] we find that
the most convenient way to perform this measurement is to
use the two-dimensional EXSY technique.[3] Our practice
is to repeat the EXSY experiment for several values of a
parameter called tm (mixing time), and to fit the ratio of
the integrals of the off-diagonal to the diagonal peaks to
the theoretical curve, which depends on kobs (the sum of the
[s–1]
[kcal·mol–1]
2
3
5
299.4 0.021
354.5 0.030
337.2 0.100
2.31
2.46
1.54
0.45
0.40
16.3
9.1·10–3
20.3 0.1
1.21·10–2 24.0 0.1
1.48
19.6 0.1
[a] Obtained from fitting the theoretical curve to the results of 3 to
6 values of the mixing time (see text). [b] Sum of forward and back-
wards reaction rates. [c] Major Ǟ minor.
forward and backward reaction rates) – a typical such plot turns out that the only broadening seen in the 1H spectrum,
is shown in Figure 1. The results are summarized in Table 2, even up to 400 K, is completely described by the kinetics of
and the barriers turn out to be ca. 1 kcal·mol–1 higher than the rotation of the pivalate moiety. Prof. Albrecht
the corresponding ring-flip values. The two processes are, Mannschreck (University of Regensburg, Germany), was
therefore, not concerted, but correlated; partial amide rota- able to partially separate the two enantiomers of 5 by
tion is required for the topomerization of the eight-mem- chromatography on a chiral column.[4] The (+) fraction was
bered ring, as described in detail in ref.[2] for the seven- racemised at 119.5 °C in diglyme, a process followed by po-
membered ring analogs.
larimetry at 365 nm. The barrier for racemisation was ex-
Amide 4 is similar to 2, but the extra methoxy groups tremely high: 30.3 0.1 kcal·mol–1.
make the aromatic ring more electron-rich, and therefore,
In conclusion, it should be understood that the ring-flip
the conjugation of the latter with the amide nitrogen is re- process, which eventually converts a compound into its en-
pressed. In such cases, the barrier for amide rotation is ex- antiomer, must involve a transition state in which the amide
pected to be higher, and we notice a parallel slight increase and the aromatic moieties are essentially coplanar. If C-7 is
in the barrier for ring flip (ca.19.7 instead of 19.2 unsubstituted, this is accommodated by a partial rotation
kcal·mol–1). In compounds 6, in which one additional atom of the acyl unit out of resonance, without quite reaching
of the eight-membered ring is sp2- rather than sp3-hybrid- the transition state for amide rotation. For 5, the 7-methyl
ised, and 7, in which an oxygen substitutes a methylene, the substituent blocks the pathway followed by the other acyl-
ring is more flexible and the barrier for the ring-flip process ated benzazocines, and, while amide rotation occurs with
is considerably reduced (to 14.0 and 14.8 kcal·mol–1, respec- its expected energy barrier, enantiomerization is a very
tively).
high-energy process.
Pivalate 5 belongs to a class of its own. We are able to
Ground-State Structure. Room temperature NMR spec-
measure the kinetics of amide rotation (Table 2), but it troscopic data for compounds 2–7 is presented in Table 3,
Eur. J. Org. Chem. 2006, 1256–1261
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1257

A. Hassner, B. Amit, V. Marks, H. E. Gottlieb
FULL PAPER
Table 4 and Table 5. Lack of proton signal overlap in the Table 4. JHH values for 2–7.[a]
spectrum of thioacetamide 3 allowed us to do a full analysis
JHH
2
3
4
5
6
7
of H-H coupling constants for this material. Since the spec-
tral features of the other compounds in the series, and espe-
cially JHH, when measurable (Table 4), are very similar, we
conclude that, unless otherwise noted, we can speak in ge- 2β,3α
neral about the whole family of these amides.
2α,2β
2α,3α
2α,3β
13.5
3
8.5
8
3
15
1
10
11
1
14
4
6.5
10
3
12
4
13.3
3.1
8.0
8.1
2.8
15.4
0.8
9.9
9.7
1.0
14.7
4.2
6.6
9.8
4.2
13.7
4.3
4.2
12.7
4.2
13.7
7.3
1.5
7.5
1.2
7.5
13
3
8
8
3
15
1
10
10
1
14.5
4.5
6.5
10
4
14
4
13.2
2.5
5.9
10.2
2.2
15.2
1.0
10.0
10.0
0.5
12.5
4.5
6.5
10.0
4.5
12.8
4.5
3.4
12.8
4.6
13.4
13
3
11
3
3
13
13.5
3
6
10
2
14.5
1
10
9.5
1
14.5
4
11.5
3
3.5
11.5
2β,3β
3α,3β
3α,4α
3α,4β
1
Table 3. H NMR chemical shifts for 2–7.
3β,4α
12
3
15
6
H
2[a]
3[a]
4[a,d]
5[a,e]
6[b]
7[c]
3β,4β
4α,4β
4α,5α
4α,5β
4β,5α
4β,5β
5α,5β
5α,6α
5α,6β
5β,6α
5β,6β
6α,6β
7,8
2α
2β
3α
3β
4α
4β
5α
5β
6α
6β
7
8
9
10
4.76
2.76
1.39
1.69
1.55
1.35
1.50
1.88
2.64
2.64
7.27
7.29
7.31
7.10
1.76
5.63
3.12
1.94
1.49
1.69
1.33
1.87
1.55
2.48
2.65
7.29
7.35
7.31
7.07
2.18
4.73
2.69
1.43
1.66
1.58
1.29
1.54
1.81
2.26
3.06
4.72
2.48
1.77
1.54
1.65
0.96
1.68
1.62
2.67
2.73
4.65
3.10
1.78
1.45
1.94
1.81
2.81
3.36
4.74
2.61
1.94
1.65
1.50
1.69
4.06
4.27
12
6
13
4
12.5
4
13
4
4
[a]
13
8.1
7.5
7.6
7.2
7.20
7.13
7.32
7.12
7
1
7
7.5
1
7.5
0.5
7.5
7.5
1.5
7.5
1.5
7.5
7.03
6.98
7,9
8,9
8,10
9,10
6.81
6.84
1.82
7.8
CH3CO
(CH3)3CO
7
8.5
0.96
0.98
0.97
[a] Cannot be measured due to the close proximity of the chemical
shifts of these protons.
[a] At 297 2 K in CDCl3. [b] At 210 2 K in CDCl3. [c] At
250 2 K in CDCl3. [d] 7-OMe and 8-OMe: δ = 3.69 and 3.86 ppm,
respectively. [e] 7-Me and 10-Me: δ = 2.30 and 2.20 ppm, respec-
tively.
weaker NOE interaction than the other three (gauche) pairs.
The coupling constants in Table 4 are unexpected. Most The cross-peaks detected in a NOESY spectrum show here
often, adjacent methylenes in a chain tend to be staggered. too that the 5–6 methylene pair is conventional; for the
This reflects itself in one large vicinal interaction (an anti other adjacent methylenes, however, all vicinal NOE inter-
relationship, ca. 12 Hz) and three smaller ones (gauche rela- actions are strong. Furthermore, one expects that only the
tionships, ca. 4 Hz). The Table reveals that, except for the two pseudoaxial protons in a 1,3 relationship should be
5–6 methylene pair, two coupling constants are larger (but close in space (less than 3.5 Å) – therefore, if an NOE inter-
usually Ͻ12 Hz) and two are smaller. This is also reflected action is detected between 2α and 4α, there should not be
in NOE interactions: in the typical staggered arrangement, one between 2β and 4β, or vice versa. For 3, both pairs of
the two protons in the anti relationship show a significantly protons show significant NOE cross-peaks [as a matter of
Table 5. 13C NMR chemical shifts for 2–7.
C
2[a]
2[a,b]
3[a]
4[a,c]
5[a,d]
6[e]
6[b,e]
7[e]
2
3
4
5
50.00
26.22
26.34
31.33
53.75
58.45
25.33
25.99
31.02
50.31
26.48
26.28
29.95
53.17
26.19
28.41
26.36
49.90
49.57
53.50
26.28[f]
27.27[f]
31.27
22.54[f]
23.68[f]
40.83
26.06[f]
27.79[f]
75.80
39.69
6
7
8
9
10
11
12
30.78
30.90
129.96
30.23
23.96
27.05
201.38
131.05[g]
130.20[g]
134.45
128.94
141.68
137.26
200.20
131.21[g]
129.57[g]
135.56
128.05
142.92
136.43
130.28
128.33
128.78
127.49
141.86
141.28
170.43
22.47
130.49
129.28
128.10
125.06
143.49
139.17
201.06[h]
33.86[h]
147.26
152.60
110.37
122.78
135.64
134.96
170.71
22.32
134.24
129.87
128.16
132.57
142.24
139.30
130.53
124.99
130.10
123.04
139.00
155.35
CH3CO
CH3CO
(CH3)3CCO
(CH3)3CCO
(CH3)3CCO
177.17
41.37
29.23
178.40
42.22
29.38
178.18
40.22
27.86
177.30
40.73
28.75
[a] In CDCl3 at 297 2 K. [b] Minor amide rotamer. [c] 7-OMe and 8-OMe: δ = 60.97 and 55.63, respectively. [d] 7-Me and 10-Me: δ =
19.38 and 18.11, respectively. [e] In CD2Cl2 at 200 2 K. [f] Chemical shifts with the same superscript within a column may be inter-
changed. [g] Chemical shifts with the same superscript within a column may be interchanged. [h] CH3CS moiety.
1258
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Eur. J. Org. Chem. 2006, 1256–1261

On the Conformation of 8-Membered Ring Heterocycles
FULL PAPER
Table 6. Calculated vs. experimental vicinal coupling constants for amide 2.
Calculated (MM3)
Experimental
A
B
60% A
H–C–C–H
dihedral angle 3JHH
dihedral angle
3JHH
3JHH
3JHH
2α
2α
2β
2β
3α
3α
3β
3β
4α
4α
4β
4β
5α
5α
5β
5β
3α
3β
3α
3β
4α
4β
4α
4β
5α
5β
5α
5β
6α
6β
6α
6β
88
48
179
88
94
152
22
93
54
62
188
52
51
64
167
52
2.2
4.5
12.5
1.8
0.4
10.3
10.1
0.5
4.1
2.6
12.7
4.5
4.8
2.3
12.6
4.6
62
177
54
61
90
25
155
90
60
175
54
60
75
40
169
65
2.4
12.5
3.6
3.1
0.4
9.6
10.9
0.3
4.2
13.0
4.0
3.0
1.0
6.8
12.8
1.0
2.3
7.7
8.9
2.3
0.4
10.0
10.4
0.4
4.1
6.8
9.2
3.9
3.3
4.1
12.7
3.2
3
8.5
8
3
1
10
11
1
4
6.5
10
3
4
4
12.5
4
relative energy
0.00
0.32 kcal·mol–1
definition, in the tables, protons labeled “α” are positioned
on the same side of the plane of the aromatic ring as the benzazocines exist as a mixture of rapidly interconverting
amide (or thioamide) moiety].
eight-member ring conformers by taking 13C spectra of par-
We were able to confirm the assumption that the acylated
All these results strongly suggest that the room tempera- ent compound 2, at low temperatures, in CDCl2F as a sol-
ture NMR spectrum actually reflects two or more fastly vent (see Figure 3). Below –70 °C, several of the lines
equilibrating conformers (for each of the amide rotamers). broaden considerably and eventually split into two unequal
In order to explore this possibility, we performed molecular peaks in a 2.8:1 ratio (δ = 22.56 and 19.81 for the acetyl
mechanics calculations for amide 2. We used the GMMX
subroutine of PCModel,[5] which performs a random search
for low-lying conformers. We then optimized the geometries
and the energies of the latter with the MM3 force field.
It turns out that two different conformations of the eight-
membered ring are found, with an energy difference of 0.32
kcal·mol–1 (see Table 6). While in both conformers the ni-
trogen atom and carbons 2, 5 and 6 are roughly coplanar,
in conformer “A” C-3 is below this plane (on the α-side of
the molecule) and C-4 is above it (on the β-side), while in
conformer “B” the orientations of the latter two carbons
are reversed (see Figure 2). Furthermore, if we calculate
3
weighted averages of the JHH values predicted for the two
conformers, using weights of 0.6 and 0.4 for A and B,
respectively, the results closely mimic the experimental val-
ues of the vicinal coupling constants. These estimates of
∆G0 are in good agreement, as K = 0.6:0.4 = 1.5 corre-
sponds, at room temperature, to an energy difference of 0.24
kcal·mol–1.
Figure 3. 13C spectra of N-acetylbenzazocine (2), in CDCl2F as a
solvent. As can be seen, several of the lines broaden considerably
at low temperatures. Significantly, the signal for the CH3 of the
acetyl moiety at ca. δ = 22 splits into two unequal peaks corre-
sponding to the two conformational isomers of the eight-membered
Figure 2. Calculated conformations for N-acetylbenzazocine (2).
ring (see text and Figure 2).
Eur. J. Org. Chem. 2006, 1256–1261
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1259

A. Hassner, B. Amit, V. Marks, H. E. Gottlieb
FULL PAPER
the extraction was saponified with NaOH (40 g) in H2O (100 mL)
and EtOH (200 mL). The basic solution was washed with Et2O,
acidified with concd. HCl and the yellow precipitate was washed
with H2O and dried under high vacuum. The crude 5-(2Ј,3Ј-dimeth-
oxyphenyl)pentadienoic acid (19 g, 81 mmol, 90%) was used with-
out purification in the next step. This acid (10 g, 43 mmol) was
dissolved in AcOH (200 mL) with the addition of 10% Pd/C (1 g)
and the mixture hydrogenated overnight at 25 psi. After filtration
and evaporation an oily product was left. Distillation gave pure 5-
(2Ј,3Ј-dimethoxyphenyl)pentanoic acid (9 g, 38 mmol, 88%; b.p.
161–164 °C at 0.2 Torr). This acid (27 g, 113 mmol) was mechani-
cally stirred with of polyphosphoric acid (PPA, 550 g) for 40 h at
40 °C; the obtained mass was treated with ice water, and extracted
with CH2Cl2 (300 mL). The organic solvent was dried (Na2SO4)
and evaporated, and the residue recrystallized from petroleum ether
to yield 6,7-dimethoxybenzosuberone (16 g, 73 mmol, 65%; m.p.
47 °C). This ketone (11 g, 50 mmol) was dissolved in concd. HCl
(180 mL), the solution was cooled and NaN3 (4.9 g, 75 mmol) was
added in small portions, so as to keep the temp. below 8 °C. The
reaction mixture was then stirred for 90 h at room temp, poured
into H2O (500 mL) and extracted with CHCl3 (2×200 mL). After
the organic solvent was dried (Na2SO4) and evaporated, the residue
was shown by TLC to consist of a mixture of two isomeric lactams.
The first band to elute from a silica gel column (CHCl3) was crys-
tallized from MeOH to yield 7,8-dimethoxy-3,4,5,6-tetraahydro-1-
benzazocin-2(1H)-one (7 g, 30 mmol, 41%, m.p. 183–184 °C);
C13H17NO3 (235) calcd. C 66.36, H 7.28, N 5.95; found C 66.41,
H 7.30, N 5.95. This lactam (7 g, 30 mmol) was added in small
portions to a slurry of LiAlH4 (4 g, 105 mmol) in anhydrous ether
(250 mL). The mixture was refluxed for 40 h, after which the excess
hydride was decomposed with Na2SO4·10H2O. The solids were ex-
tracted with boiling ethyl acetate(2×250 mL); the combined or-
ganic phases were evaporated to dryness, and the resulting oil puri-
fied by distillation to yield 7,8-dimethoxy-1,2,3,4,5,6-hexahydro-1-
benzazocine (5 g, 23 mmol, 77%; b. p. 161–164 °C at 0.2 Torr). This
amine (5 g) was dissolved in a mixture of benzene (40 mL), acetic
anhydride (40 mL) and triethylamine (5 mL) and stirred overnight
at room temp. Ether (400 mL) was then added, and the red solution
was extracted with 1  HCl until the washings were colourless, then
washed with satd. NaCl and ammonia. The organic layer was dried
(Na2SO4), then all volatile components were evaporated. The re-
sulting red oil was treated with charcoal in boiling ligroin. The now
colourless oil treated with ether/petroleum ether at 0 °C to yield
crystalline 4, (4 g, 15 mmol, 65%; m.p. 85–86 °C). C15H21NO3
(263) calcd. C 68.41, H 8.04, N 5.32; found C 68.43, H 8.10, N
5.31. HRMS: m/z calcd. 263.1521; found 263.1517.
methyl group of the major and minor isomers, respectively,
at –112.5 °C; ∆G0 = 0.33 kcal·mol–1). From a lineshape
analysis at –92.4 °C, we obtain a major Ǟ minor rate con-
stant of 150 s–1, corresponding to an activation barrier of
8.6 kcal·mol–1.
Conclusion
We are able to identify three different dynamic processes
in the title compounds. In ascending order of energies, the
first (∆G‡ = 8.6 kcalmol–1 for parent amide 2) involves a
fast interconversion between two distinct conformers of the
eight-membered ring, which differ in ground state energy
by ca. 0.3 kcal·mol–1. The next process (∆G‡ = 19.2
kcalmol–1) is the enantiomerization of the heterocyclic ring,
which is correlated, but not concerted with the highest-en-
ergy process, amide rotation (∆G‡ = 20.3 kcalmol–1).
Experimental Section
Molecular Mechanics Calculations: Initial ground state conforma-
tions were obtained with PCModel;[5] the structures were optimized
with the MMX force field included in this package, which is based
on Allinger’s MM2. More accurate calculations were then per-
formed with the MM3 force field (versions 1994 and 1996).
NMR Spectroscopy: NMR spectra were run at 600.1 (1H) and 150.9
MHz (13C) on a Bruker DMX-600 instrument. Probe temperatures
were measured with a calibrated digital thermometer; we estimate
temperatures to be accurate to 0.5 K. Peak assignments in Table 3
and Table 5 were unambiguously determined with the aid of two-
dimensional techniques such as COSY, HMQC and HMBC. NOE
interactions were detected in NOESY spectra. NMR lineshape
analyses were performed using computer programs based on the
equations of Alexander[6] for the case of two spin-coupled exchang-
ing protons (in the ring-flip process, see text) or of Sutherland[7]
for the case of two exchanging singlets. For more details on the
EXSY technique (2D-NMR Exchange Spectroscopy), used to de-
termine the rates of amide (or thioamide) rotation, see ref.[3]
.
Synthesis of Hexahydrobenzazocines
1-Acetyl-1,2,3,4,5,6-hexahydro-1-benzazocine (2) has been reported
in the literature.[8] For this study, we prepared it starting from
benzosuberone, via a Schmidt rearrangement followed by LAH re-
duction and acylation. C13H17NO (203) calcd. C 76.81, H 8.43;
found C 76.77, H 8.47.
7,10-Dimethyl-1-pivaloyl-1,2,3,4,5,6-hexahydro-1-benzazocine (5):
6,9-Dimethylbenzosuberone[10] (19 g, 93 mmol, prepared from 2,5-
dimethylbenzaldehyde in a sequence of reactions similar to the one
in the previous paragraph), NH2OH·HCl (14 g, 201 mmol), pyri-
dine (200 mL) and EtOH (100 mL) were refluxed for 25 h. The sol-
vents were then evaporated and the residue was dissolved in ether/
water. The organic layer was washed with satd. citric acid, then
satd. NaCl and evaporated to yield an oil, which was triturated
with petroleum ether to give crude 6,9-dimethylbenzosuberone ox-
ime (10 g, 46 mmol, 49%, as an amorphous white powder) which
was used without purification in the next step. The oxime (9 g,
41 mmol) and PPA (200 g) were stirred for 15 min at 130 °C; after
cooling and treatment with ice water(1 L), the mixture was ex-
tracted with CHCl3 (2×200 mL). The organic layer was washed
with H2O, dried and evaporated, and the residue was shown by
1-Thioacetyl-1,2,3,4,5,6-hexahydro-1-benzazocine (3) was prepared
by the reaction of 2 (0.2 g, 1.2 mmol) with an equivalent amount
of 2,4-bis(p-methoxyphenyl)-1,3-dithiaphosphetane 2,4-disulfide
(Lawesson’s reagent) in HMPA (2 mL), for 9 h at 85 °C, according
to the established procedure.[9] 3 (0.1 g, 0.5 mmol, 47%) was puri-
fied by column chromatography (silica gel, 1:1 ether/pentane) and
obtained as pale yellow crystals; m.p. 75–78 °C. HRMS: m/z calcd.
for [C13H17NS+H]+ 220.1159; found 220.1159.
1-Acetyl-7,8-dimethoxy-1,2,3,4,5,6-hexahydro-1-benzazocine (4): A
mixture of 2,3-dimethoxybenzaldehyde (15 g, 90 mmol) and of
methyl crotonate (18 g, 180 mmol) was added dropwise to a cooled
suspension of potassium tert-butoxide (30 g, 267 mmol) in tert-bu-
tyl alcohol (250 mL, temp. kept below 20 °C), and the reaction mix-
ture was stirred overnight at room temp. The reaction mixture was TLC to consist of a mixture of two isomeric lactams. The first band
acidified (AcOH) and extracted with CHCl3. The oily residue of to elute from a silica gel column (CHCl3) was crystallized from
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1256–1261

On the Conformation of 8-Membered Ring Heterocycles
FULL PAPER
CH2Cl2/petroleum ether to yield 7,10-dimethyl-3,4,5,6-tetraahydro-
1-benzazocin-2(1H)-one (6 g, 27 mmol, 66%, m.p. 162 °C). This lac-
tam (4 g, 18 mmol) was added in small portions to a slurry of Li-
AlH4 (3 g, 79 mmol) in anhydrous ether (200 mL). The mixture was
refluxed for 40 h, and workup as described above yielded 7,10-di-
methyl-1,2,3,4,5,6-hexahydro-1-benzazocine (b.p. 77–80 °C at
0.03 Torr). C13H19N (189) calcd. C 82.48, H 10.12, N 7.34; found
C 82.39, H 10.12, N 7.39. To a solution of this amine (2.3 g,
12 mmol) in anhydrous benzene (50 mL), pivaloyl chloride (1.2 g,
10 mmol) was added while stirring, and a precipitate formed imme-
diately. Triethylamine (2 mL) was then added and the mixture was
stirred for 24 h at room temp. 300 mL of ether was then added,
and the solution was washed with satd. NaCl, 1 N HCl and again
satd. NaCl. The organic layer was dried (Na2SO4), and evaporated,
resulting in a red oil, which was treated with charcoal in boiling
ligroin. On evaporation of the solvent and cooling, crystals of 5
were formed (2 g, 7 mmol, 58%), m.p. 42 °C. C18H27NO (273)
calcd. C 79.07, H 9.95, N 5.12; found C 79.03, H 9.96, N 5.11.
HRMS: m/z calcd. 273.1779; found 273.1780. From Prof. Albrecht
with 2  HCl and H2O. The residue of the organic phase was puri-
fied by column chromatography (silica gel, CHCl3). The resulting
oil solidified on trituration with ether and was recrystallized from
CH2Cl2/ether to give 6 (1.2 g, 4.6 mmol, 85%, m.p. 120–121 °C),
C16H21NO2 (259) calcd. C 74.13, H 8.10; found C 74.12, H 8.14.
HRMS: m/z calcd. 259.1573; found 259.1560.
1-Pivaloyl-2,3,4,5-tetrahydro-6H-1,6-benzoxazocine (7): The known
2,3,4,5-tetrahydro-6H-1,6-benzoxazocine[12] (2.48 g, 14.5 mmol)
was treated with pivaloyl chloride (1.56 g, 12.9 mmol) as described
in the previous paragraph. The resulting oil solidified on standing
and was purified by a double recrystallization from hexane to yield
7 (2.5 g, 10.1 mmol, 78%, m.p. 108–109 °C), C15H21NO2 (247)
calcd. C 72.84, H 8.56, N 5.66; found C 72.88, H 8.58, N 5.65.
HRMS: m/z calcd. 247.1572; found 247.1595.
Supporting Information (see footnote on the first page of this arti-
cle): 13C NMR spectrum of 1-thioacetyl-1,2,3,4,5,6-hexahydro-1-
benzazocine (3) in CDCl3.
Mannschreck (University of Regensburg, vide supra) we learnt that
[1] A. Hassner, B. Amit, Tetrahedron Lett. 1977, 18, 3203–3206.
[2] A. Hassner, B. Amit, V. Marks, H. E. Gottlieb, J. Org. Chem.
2003, 68, 6853–6858.
16.5
for the pure (–)-enantiomer the m.p. is 46–50 °C, and [α]
–133 5.
=
365
[3] C. L. Perrin, T. J. Dwyer, Chem. Rev. 1990, 90, 935–967.
[4] We are grateful to Prof. Mannschreck (University of Regens-
burg, Germany) for providing us with these data.
[5] PCMODEL version 7.50.00, Serena Software, Bloomington,
Indiana, USA.
[6] S. Alexander, J. Chem. Phys. 1962, 37, 967–974.
[7] I. O. Sutherland, in: Annual Reports in NMR Spectroscopy, vol.
4 (Eds.: E. F. Mooney), Academic Press, London, 1971, p. 80.
[8] Y. Ishihara, T. Tanaka, G. Goto, J. Chem. Soc., Perkin Trans.
1 1992, 3401–3406.
1-Pivaloyl-2,3,4,5-tetrahydro-1-benzazocin-6(1H)-one
known
1,2,3,4,5,6-hexahydro-1-benzazocin-6-ol[11]
(6):
The
(1.77 g,
10 mmol) was added to a solution of pivaloyl chloride (1.44 g,
12 mmol) in benzene (60 mL) at room temp. After 2 min, a precipi-
tate started to appear, and triethylamine (1.5 g) was added to the
solution, which was then stirred for a further 40 min. Ether was
added (200 mL) and the organic the mixture was washed with di-
lute citric acid and then H2O. The residue from the organic layer
was recrystallized from petroleum ether to yield of 1-pivaloyl-
1,2,3,4,5,6-hexahydro-1-benzazocin-6-ol (1.7 g, 7 mmol, 70%); m.p.
186–188 °C, C16H23NO2 (261) calcd. C 73.56, H 8.81; found C
73.48, H 8.87. This alcohol (1.4 g, 5.4 mmol) was dissolved in pyri-
dine (20 mL) and added to CrO3/pyridine reagent [prepared by
slowly adding CrO3 (1.7 g) to pyridine (30 mL) at 0 °C; it took
about 30 min until the orange complex was formed]. The alcohol
solution was added with cooling so as to keep the temp. below
15 °C, and the final mixture was stirred overnight at room temp. It
was then diluted with CHCl3, filtered through Celite and washed
[9] S. Scheibye, B. S. Pedersen, S.-O. Lawesson, Bull. Soc. Chim.
Belg. 1978, 87, 229–238.
[10] T. Watanabe, I. Kawamoto, N. Soma, Chem. Pharm. Bull.
1970, 18, 2087–2093.
[11] G. R. Proctor, I. W. Ross, J. Chem. Soc., Perkin Trans. 1 1972,
885–889.
[12] D. Misiti, V. Rimatori, F. Gatta, J. Heterocycl. Chem. 1973, 10,
689–696.
Received: August 3, 2005
Published Online: December 27, 2005
Eur. J. Org. Chem. 2006, 1256–1261
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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