Atropisomeric properties of 7-, 8-, and 9-membered-ring dibenzolactams: Conformation, thermal stability, and chemical reactivity

Article abstract of DOI:10.1021/jo1013383

The atropisomeric enantiomers of 7-, 8-, and 9-membered-ring dibenzolactams were separated by using chiral HPLC, and their stereochemistries were clarified by using X-ray crystallographic analysis. The atropisomers showed high stereochemical stability with the 8-membered ring being the most stable. In 7- and 8-membered dibenzolactams, highly stereoselective C7-methylation proceeded from the lower side of the ring to provide the products with a C7-methyl group in the pseudoaxial orientation, which converted to thermodynamically more stable isomers with the pseudoequatorial C7-methyl group. In 9-membered dibenzolactam, C7-methylation occurred from the opposite (upper) side of the ring to provide a thermodynamically stable product with the pseudoequatorial C7-methyl group.

Full text of DOI:10.1021/jo1013383

pubs.acs.org/joc
Atropisomeric Properties of 7-, 8-, and 9-Membered-Ring
Dibenzolactams: Conformation, Thermal Stability,
and Chemical Reactivity
Hidetsugu Tabata, Hiroyuki Suzuki, Kumi Akiba, Hideyo Takahashi, and
Hideaki Natsugari*
School of Pharmaceutical Sciences, Teikyo University, 1091-1, Midori-ku, Sagamihara,
Kanagawa 252-5195, Japan
natsu@pharm.teikyo-u.ac.jp
Received July 7, 2010
The atropisomeric enantiomers of 7-, 8-, and 9-membered-ring dibenzolactams were separated by using
chiral HPLC, and their stereochemistries were clarified by using X-ray crystallographic analysis. The
atropisomers showed high stereochemical stability with the 8-membered ring being the most stable. In
7- and 8-membered dibenzolactams, highly stereoselective C7-methylation proceeded from the lower
side of the ring to provide the products with a C7-methyl group in the pseudoaxial orientation, which
converted to thermodynamically more stable isomers with the pseudoequatorial C7-methyl group. In
9-membered dibenzolactam, C7-methylation occurred from the opposite (upper) side of the ring to
provide a thermodynamically stable product with the pseudoequatorial C7-methyl group.
Introduction
active molecules, has received considerable attention.1 In the
course of our research aimed at developing new γ-secretase
inhibitors, we have been interested in LY-411575,2 which has a
7-membered-ring dibenzolactam, a dibenzo[b,d]azepin-6-one
moiety (1) (Figure 1). The stereochemistry of 1 is of interest be-
cause, in addition to the one asymmetric center at C7, the
moiety has chirality based on the sp2-sp2 axis arising from a
biphenyl.3 Our thorough investigation of the stereochemical
and physicochemical properties of 1 revealed that it is a race-
mic compound that can be separated by chiral HPLC into the
aR- and aS-atropisomers with high stereochemical stability.4
Interestingly, methylation at C7 of 1 stereoselectively gave the
Recently, conformational analysis of medium-sized hetero-
cycles, which are found as the scaffolds of many biologically
(1) For examples, see: (a) Hassner, A.; Amit, B.; Marks, V.; Gottlieb,
H. E. J. Org. Chem. 2003, 68, 6853–6858. (b) Qadir, M.; Cobb, J.; Sheldrake,
P. W.; Whittall, N.; White, A. J. P.; Hii, K. K.; Horton, P. N.; Hursthouse,
M. B. J. Org. Chem. 2005, 70, 1545–1551. (c) Qadir, M.; Cobb, J.; Sheldrake,
P. W.; Whittall, N.; White, A. J. P.; Hii, K. K.; Horton, P. N.; Hursthouse,
M. B. J. Org. Chem. 2005, 70, 1552–1557.
(2) (a) Lanz, T. A.; Hosly, J. D.; Adams, W. J.; Merchant, K. M.
J. Pharmacol. Exp. Ther. 2004, 309, 49–55. (b) Lanz, T. A.; Fici, G. J.;
Merchant, K. M. J. Pharmacol. Exp. Ther. 2005, 312, 399–406. (c) Best, J. D.;
Jay, M. T.; Out, F.; Ma, J.; Nadin, A.; Ellis, S.; Lewis, H. D.; Pattison, C.;
Reilly, M.; Harrison, T.; Shearman, M. S.; Williamson, T. L.; Atack, R.
J. Pharmacol. Exp. Ther. 2005, 313, 902–908. (d) Wong, G. T.; Manfra, D.;
Poulet, F. M.; Zhang, Q.; Losien, H.; Bara, T.; Engstrom, L.; Pinzon-Ortiz,
M.; Fine, J. S.; Lee, H. J.; Zhang, L.; Higgins, G. A.; Parker, E. M. J. Biol.
Chem. 2004, 279, 12876–12882. (e) Cole, K. P.; Mitchell, D.; Carr, M. A.;
Stout, J. R.; Belvo, M. D. Tetrahedron: Asymmetry 2009, 20, 1262–1266.
(3) For review articles on axial chirality and atropisomerism, see:
(a) Clayden, J. Tetrahedron 2004, 60, 4335 in Tetrahedron Symposia-in-
Print on Atropisomerism (Clayden, J., Ed.) and other papers in the issue.
(b) Clayden, J.; Moran, W. J.; Edwards, P. J.; LaPlante, S. R. Angew. Chem.,
Int. Ed. 2009, 48, 6398–6401.
5984 J. Org. Chem. 2010, 75, 5984–5993
Published on Web 08/09/2010
DOI: 10.1021/jo1013383
r
2010 American Chemical Society

Tabata et al.
JOCArticle
FIGURE 1. Structures of LY-411575 and 7-, 8-, and 9-membered-
ring dibenzolactams 1-3.
SCHEME 1. Synthesis of 7-, 8-, and 9-Membered-Ring Diben-
zolactams 1-3
FIGURE 2. Separation of enantiomers of 7-, 8-, and 9-membered-
ring dibenzolactams l(a,b), 2(a,b), and 3(a,b), and X-ray crystal
structures of enantiomers 1b-R/1b-S (top), 2b-R/2b-S (middle), and
3b-R/3b-S (bottom).
methyl group at the ortho position on the benzene ring (R =
Me), which makes the molecule more rigid by introducing
steric hindrance around the biphenyl moiety. Starting from
biaryl coupling, three successive steps (i.e., hydrolysis, lac-
tam formation, and N-methylation) provided compounds
1, 2, and 3 efficiently. It is interesting to note that in the
hydrolysis, the nitrile 8(a,b) afforded the corresponding
lactam 14(a,b) directly via the carboxylic acid 11(a,b) under
hydrolysis conditions, whereas the nitriles 9(a,b) and 10(a,b)
provided the corresponding carboxylic acids 12(a,b) and
13(a,b), respectively. Thus, lactam formation with N-(3-dim-
ethylaminopropyl)-N0-ethylcarbodiimide hydrochloride (EDC)
was necessary for the 8- and 9-membered-ring compounds
15(a,b) and 16(a,b).
Separation and X-ray Crystallographic Analysis of Atropi-
somers of 7-, 8-, and 9-Membered-Ring Dibenzolactams. In
our previous communication,4 the 7-membered-ring diben-
zolactams 1(a,b) were shown to be racemic compounds,
which can be separated into atropisomeric enantiomers by
using HPLC on a chiral column (CHIRALPAK AD-H)
(Figure 2). The structures of the enantiomers have been
confirmed to be as shown in Figure 2 (top) by using X-ray
crystallographic analysis. The X-ray analysis of 1b-atropi-
somers revealed that, in addition to the chirality based on the
axis of the biphenyl moiety (a1), 1b has another axial chirality
arising from the sp2-sp2 axis of the benzene-amide bond
(a2).6 Although latent in the molecule and generally less
represented, the latter axial chirality (a2) actually exists.7
(aR*,7R*)-isomer (1: R1 = Me), which converted to the
thermodynamically stable (aS*,7R*)-atropisomer after
heating.4 Such absorbing stereochemical properties of a
7-membered-ring dibenzolactam prompted us to examine the
8- and 9-membered-ring dibenzolactams more closely. In this
paper, we deal with 7-, 8-, and 9-membered-ring dibenzolac-
tams (1-3) by comparison of the separation of the atro-
pisomers and chemical reactivity toward stereoselective
C7-methylation to elucidate the conformational properties
inherent in each ring system.
Results and Discussion
Synthesis of 7-, 8-, and 9-Membered-Ring Dibenzolactams.
The 7-, 8-, and 9-membered-ring dibenzolactams (1-3) were
prepared following the procedure used for the synthesis of
dibenzo[b,d]azepin-6-one derivatives 1 described in our pre-
vious papers4,5 (Scheme 1). Compounds 1b, 2b, and 3b have a
(4) Tabata, H.; Akiba, K.; Lee, S.; Takahashi, H.; Natsugari, H. Org.
Lett. 2008, 10, 4871–4874.
(5) Fuwa, H.; Okamura, Y.; Morohashi, Y.; Tomita, T.; Iwatsubo, T.;
Kan, T.; Fukuyama, T.; Natsugari, H. Tetrahedron Lett. 2004, 45, 2323–
2326.
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TABLE 1. Stability of the Separated Enantiomers of 7-, 8-, and 9-Membered-Ring Dibenzolactams 1-3
a
[R]D
compd
m
R
R
S
ΔGq, kJ/mol
conditions required for racemization
1a
1b
2a
2b
3a
3b
1
1
2
2
3
3
H
Me
H
Me
H
Me
-137.1
-92.0
-166.1
-163.6
-249.5
-213.7
þ131.2
þ93.7
98
122
112
37 °C, 2 hb
110 °C, 2 hb
80 °C, 3 hb
þ165.7
þ170.0
þ231.7
þ206.1
c
-
102
50 °C, 2 hb
c
-
aIn MeOH. bIn toluene. cNo change at 150 °C for 3 h in DMF.
FIGURE 3. Molecular shapes and dihedral angles (φ) of 7-, 8-, and 9-membered-ring dibenzolactams 1b-S, 2b-S, and 3b-S determined by
X-ray crystallographic analysis.11
The configuration of the enantiomers 1b-R and 1b-S was
shown to be (a1R,a2S) and (a1S,a2R), respectively.8,9 Taking
into consideration the fact that no diastereomers of 1(a,b) are
observed with NMR and HPLC, the latter axis (a2) is
assumed to move together like a gear, with the axis at the
biphenyl (a1) forming the stable relative configuration of
(a1R*,a2S*) in the dibenzolactam nucleus. This assumption
is also supported by the molecular modeling of 1(a,b), in
which the relative configuration of (a1R*,a2S*) is readily
built up, while that of (a1R*,a2R*) is not built up because of
the large strain.
Thus, the 8- and 9-membered-ring dibenzolactams, 2(a,b)
and 3(a,b), are also anticipated to occur in the racemic form
of the corresponding enantiomers R and S. By using HPLC
on a chiral column (CHIRALPAK AD-H and IA), the
compounds 2(a,b) and 3(a,b) were separated into the respec-
tive enantiomers (R and S), and these enantiomers were
successfully isolated by using preparative HPLC. The con-
figuration of each enantiomer was unambiguously deter-
mined with X-ray crystallographic analysis as shown in
Figure 2 (middle) for 2b and Figure 2 (bottom) for 3b, which
show the same relative configuration between the two axes
(a1 and a2) [i.e., (a1R,a2S) or (a1S,a2R)] as that of the enantio-
mers of 1.9 It was revealed that the angle of optical rotation
R (in MeOH) of the R-series of enantiomers is negative (-),
and that of the S-series of enantiomers is positive (þ) (Table 1).
Figure 3 shows the molecular shapes of 1b-S, 2b-S, and 3b-
S viewed from the chain-side of the ring. As shown in the
figure, all the molecules have E-configuration10 around the
amide bond regardless of the ring size, and each 7-, 8-, and
(6) For the axial chirality arising from the sp2-sp2 axis of the benze-
ne-amide bond, see: (a) Ikeura, Y.; Ishichi, Y.; Tanaka, T.; Fujishima, A.;
Murabayashi, M.; Kawada, M.; Ishimaru, T.; Kamo, I.; Doi, T.; Natsugari,
H. J. Med. Chem. 1998, 41, 4232–4239. (b) Natsugari, H.; Ikeura, Y.; Kamo,
I.; Ishimaru, T.; Ishichi, Y.; Fujishima, A.; Tanaka, T.; Kasahara, F.;
Kawada, M.; Doi, T. J. Med. Chem. 1999, 42, 3982–3993. (c) Albert, J. S.;
Aharony, D.; Andisik, D.; Barthlow, H.; Bernstein, P. R.; Bialecki, R. A.;
Dedinas, R.; Dembofsky, B. T.; Hill, D.; Kirkland, K.; Koether, G. M.;
Kosmider, B. J.; Ohnmacht, C.; Palmer, W.; Potts, W.; Rumsey, W.; Shen,
L.; Shenvi, A.; Sherwood, S.; Warwick, P. J.; Russell, K. J. Med. Chem. 2002,
45, 3972–3983. (d) Guile, S. D.; Bantick, J. R.; Cooper, M. E.; Donald, D. K.;
Eyssade, C.; Ingall, A. H.; Lewis, R. J.; Martin, B. P.; Mohammed, R. T.;
Potter, T. J.; Reynolds, R. H.; St-Gallay, S. A.; Wright, A. D. J. Med. Chem.
2007, 50, 254–263. (e) Welch, C. J.; Biba, M.; Pye, P.; Angelaud, R.;
Egbertson, M. J. Chromatogr. B 2008, 875, 118–121. (f) Porter, J.; Payne,
A.; Whitcombe, I.; de Candole, B.; Ford, D.; Garlish, R.; Hold, A.;
Hutchinson, B.; Trevitt, G.; Turner, J.; Edwards, C.; Watkins, C.; Davis,
J.; Stubberfield, C. Bioorg. Med. Chem. Lett. 2009, 19, 1767–1772.
(7) Atropisomeric properties of the 7-membered-ring benzolactams with-
out biphenyl moiety will be reported in due course.
(8) In this paper, to denote the compound number (suffix), the axial
chirality at a1 is used for clarity; i.e., suffix R (and R0) is used for (a1R,a2S),
and S is used for (a1S,a2R).
(9) The absolute stereochemistry was determined based on the Flack
parameter.
(10) E and Z are designated according to the IUPAC recommended rule.
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TABLE 2. C7-Methylation and Isomerization of 7-, 8-, and 9-Membered-Ring Dibenzolactams 1-3
methylation at C7
product
(stereochemistry at a1 and C7)
isomerization of the C7-methylated
product after heating in solvent
entry
substratea
yield, %
ΔGq, kJ/mol
c
1
2
3
4
5
6
1a-R
1b-R
2a-R
2b-R
3a-R
3b-R
17a-S (a1S,7R)b
17b-R (a1R,7R)
18a-R (a1R,7R)
18b-R (a1R,7R)
19a-R0 (a1R,7S)
19b-R0 (a1R,7S)
96
99
79
78
80
90
-
17b-R f 17b-R:17b-S (3:97)d,e
18a-R f 18a-R:18a-S (10:90)f,e
18b-R f no isomerizationg
113
108
;
h
-
h
-
aAll the substrates have a1R-stereochemistry. bIntermediary formation of 17a-R (alR,7R) was observed in the reaction (see main text). c17a-S is the
thermodynamically stable product and it did not isomerize at 100 °C for ca. 2 h in toluene. dReached equilibrium state at 80 °C for ca. 7 h in toluene.
eEquilibrium ratio. fReached equilibrium state at 80 °C for ca. 4 h in toluene. g18b-R did not isomerize at 150 °C for 3 h in DMF. h19a-R0 and I9b-R’ are
the thermodynamically stable products and they did not isomerize at 150 °C for 3 h in DMF.
SCHEME 2. Stereoselective Methylation at the C7-Position of 7- and 8-Membered-Ring Dibenzolactams (1 and 2) and Isomerization of
R to Sa
aNo isomerization from 18b-R to 18b-S occurred at 150 °C in DMF.
9-membered ring has a cage structure, in which the dihedral
angle (φ) of C5-C6-C7-C8 was shown to be 51.5°, 64.9°,
and 88.1°, respectively, and that of C11-C12-N1-C16 to be
43.7°, 61.8°, and 82.2°, respectively.11 It is clear that the dee-
per cage is formed in proportion to the number of the ring
system. The geometry should represent the more significan-
tly populated conformer of 1, 2, and 3 in solution.
Stereochemical Stability of Atropisomers of 7-, 8-, and
9-Membered-Ring Dibenzolactams. Next, we examined the
stereochemical stability of these separated enantiomers of
1(a,b), 2(a,b), and 3(a,b). It was revealed that all enantiomers
are relatively stable toward racemization. Table 1 shows the
activation free-energy barrier to rotation (ΔGq)12 and the
conditions (temperature, time) required for racemization of
the enantiomers in solvent. The enantiomers of 1a (R = H)
have stereochemical stability toward racemization with a
ΔGq value of 98 kJ/mol, whereas, reflecting the steric hin-
drance around the biphenyl moiety, the enantiomers of 1b
(R = Me) showed higher stereochemical stability with a ΔGq
value of 122 kJ/mol. Similarly, the enantiomers of 2b and 3b,
which have a methyl group on the benzene ring (R = Me),
are so stable that they did not interconvert at all at 150 °C in
DMF even after 3 h. It should be noted that the enantiomoer
of 2a (n = 2: 8-membered-ring lactam) has extreme stability
toward racemization (ΔGq = 112 kJ/mol) compared with
those of 1a (ΔGq = 98 kJ/mol) and 3a (ΔGq = 102 kJ/mol).
Although the reason for this difference is not apparent,
X-ray crystallographic analysis affords a clue to elucidate
the stereochemical properties of each ring system. In the
course of racemization, the cage structure should be inver-
ted. It seems reasonable that the deeper and more rigid cage
in 2 has greater resistance to the inversion of the ring system
than 1, which is confirmed by the higher ΔGq value of 112 kJ/
mol observed in 2a. Meanwhile, 3a, which has the deepest
cage, showed less stability (ΔGq = 102 kJ/mol) than 2a.
Although definitive information on this is lacking, the con-
secutive methylene chain in the 9-membered-ring system
may provide sufficient flexibility to decrease the energy barr-
ier for the conversion of the entire molecule.
Stereoselective C7-Methylation of Atropisomers of 7-, 8-,
and 9-Membered-Ring Dibenzolactams. In view of the struc-
ture of LY-411575, we next focused on the substituent effect
at the C7-position of the dibenzolactam ring on the stereo-
chemistry of the entire molecule. Thus, compounds 1-3 were
methylated (MeI/base in THF at -78 °C) to introduce an
asymmetric center at the C7-position (Table 2, Schemes 2
and 3). The results of 7- and 8-membered-ring compounds
are shown in Scheme 2 and Table 2 (entries 1-4).
(11) The numbering system in Figure 3 is that used for the X-ray crystal-
lographic analysis (CIF files in the Supporting Information).
(12) The ΔGq value was determined based on the time-dependent con-
version rate (% ee) estimated from chiral HPLC analysis of a solution of the
enantiomers after being allowed to stand at designated temperatures; see:
Petit, M.; Lapierre, A. J. B.; Curran, D. P. J. Am. Chem. Soc. 2005, 127,
14994–14995.
From the 7-membered lactam 1b-R (R = Me: a1R), two
diastereoisomers [17b-R (=7R) and 17b-R0 (=7S)] were
expected to be produced by this methylation. However, only
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Tabata et al.
JOCArticle
17b-R (a1R,7R) was obtained in 99% yield (Table 2/entry 2).13
This result indicates that the conformation defined by the
axial chiralities controlled the stereochemistry of the met-
hylation. Compound 17b-R was stable in solution at room
temperature but at elevated temperatures gradually conver-
ted to the atropisomeric diastereomer 17b-S (a1S,7R) (= the
enantiomeric form of 17b-R0). The conversion was tempera-
ture dependent. After standing in toluene at 37 °C for 2 h,
pure 17b-R was converted to a mixture of the diastereomers
(17b-R:17b-S = ca. 96:4). Similarly, after standing at 80 °C
for 2 h, the ratio was changed to ca. 42:58, and for ca. 7 h the
conversion reached equilibrium in a ratio of 3:97. The
interconversion barrier (ΔGq) between 17b-R and 17b-S
was calculated to be 113 kJ/mol. It is interesting that the
methylation of the less restricted 1a-R (R = H: a1R) pro-
vided the thermodynamically stable isomer 17a-S directly in
96% yield (Table 2/entry 1).13 However, detailed investiga-
FIGURE 4. NOE analysis of 17b-R/17b-S and 18a-R/18a-S.
1
tion of the intermediate step with TLC and H NMR re-
TABLE 3. Optical Rotation of C7-Methylated 7-, 8-, and 9-Membered-
Ring Dibenzolactams 17-19
vealed that the unstable isomer 17a-R was initially formed,
which readily isomerized to give 17a-S during workup even
at low temperature (ca. 10 °C).
C7-Methylation of the 8-membered-ring lactam 2a-R (R =
H: a1R) also proceeded highly stereoselectively to provide 18a-
R (a1R,7R) in 79% yield (Table 2/entry 3). Compound 18a-R
was shown to be more stable than the corresponding 7-mem-
bered-ring lactam 17a-R. Conversion of 18a-R into the (a1S)-
isomer 18a-S (a1S,7R) occurred at elevated temperature; e.g.,
slight isomerization occurred at 37 °C in toluene after 4 h (18a-
R:18a-S = ca. 94:6), and at 80 °C after ca. 4 h the conversion
reached equilibrium (18a-R:18a-S = ca. 10:90). The intercon-
version barrier (ΔGq) between 18a-R and 18a-S was calculated
to be 108 kJ/mol. In the more restricted 8-membered-ring
lactam 2b-R (R = Me: a1R), methylation also occurred highly
stereoselectively to provide 18b-R (Table 2/entry 4). It should
be noted that 18b-R is so stable that no isomerization of 18b-R
to 18b-S was observed even at 150 °C in DMF. Taking these
results together, it is concluded that the 8-membered-ring
lactam has a more stable conformation than the corresponding
7-membered-ring lactam.
The stereochemistry of 17b-R and -S and 18a-R and -S was
determined with NOE analysis (Figure 4). In 17b-R, NOEs
were observed between two methyl groups and between two
protons, where C7-methyl is in the pseudoaxial orientation.
On the other hand, in 17b-S, the NOEs observed were bet-
ween the C7-methyl and benzene-H and between the C7-H
and benzene-methyl, where the C7-methyl is in the pseudoe-
quatorial orientation. Similar NOEs were observed in 18a-R
and 18a-S. Thus, the stereochemistry of 17b-R and -S, 18a-R
and -S was determined to be as shown in Figure 4. It is
worthy to note that the C7-methylation products (17b-R,
18a-R, and 18b-R) have (-)-angle of optical rotation R,
whereas the isomerized compounds (17a-S, 17b-S, 18a-S,
and 18b-S) have (þ)-rotation (Table 3). These findings
would support that, by comparison with the (-)/(þ)-angle
of the enantiomers of the parent dibenzolactams (Table 1),
the structures of the products are correctly assigned.
configuration
compd
n
R
a1
C7
[R]D (MeOH)
17a-S
17b-R
17b-S
18a-R
18a-S
18b-R
19a-R0
19b-R0
0
0
0
1
1
1
2
2
H
S
R
S
R
S
R
R
R
R
R
R
R
R
R
S
þ189.3
Me
Me
H
H
Me
H
-79.3
þ116.1
-164.8
þ112.7
-158.9
-165.5
-146.1
Me
S
reaction. A plausible mechanism of the methylation of 1b-
R is illustrated in Figure 5. In the enolate form of 1b-R, the
benzene ring (A) covers the upper side of the enolate so that
the electrophile should come only from the lower side to form
17b-R. This shows that the conformation based on the axial
chiralities completely controlled the stereochemistry at the
C7-position in methylation. More noteworthy in this figure
is that the product 17b-R has a methyl group in the pseu-
doaxial orientation, which is thermodynamically unstable.
This unstable orientation resulted in the thermal atropisome-
rization from 17b-R to the thermodynamically more stable
17b-S, which has a pseudoequatorial methyl group. Stereo-
selective methylation of the 8-membered lactams (2a-R to
18a-R and 2b-R to 18b-R) and isomerization from 18a-R to
18a-S can be similarly explained. It is interesting that the
introduction of the methyl group at the C7-position of the
ring clearly lowered the ΔGq value [i.e., 122 kJ/mol (from 1b-
R to 1b-S) (Table 1) vs 113 kJ/mol (from 17b-R to 17b-S)
(Table 2)]. A similar phenomenon is observed in the 8-mem-
bered-ring lactam [112 kJ/mol (from 2a-R to 2a-S) (Table 1)
vs 108 kJ/mol (from 18a-R to 18a-S) (Table 2)]. These imply
that atropisomerism is markedly affected by the stereochemical
stability of the entire molecule, i.e., the C7-methyl reduces the
barrier by raising the ground state of the pseudoaxial conformer.
The highly stereoselective methylation observed in com-
pounds 1 and 2 is explained by a kinetically controlled
(13) In our previous work,4 C7-alkylation and isomerization of the
alkylated product were examined by using the racemate of 1(a,b), and the
same stereochemical results as described in this paper (Table 2/entries 1 and
2) were observed in the racemic form.
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FIGURE 5. A plausible mechanism of stereoselective methylation of 1b-R to 17b-R.
SCHEME 3. Stereoselective C7-Methylation of 9-Membered-
Ring Dibenzolactam (3) to 19-R0 and a Plausible Mechanism
FIGURE 6. Structure of the C7-methylation product of 9-mem-
bered-ring dibenzolactam (3): NOE analysis (for 19a-R*0) and
X-ray crystallographic analysis (for 19a-R0).
dibenzolactam covers the lower side of the enolate so that the
electrophile should come only from the upper side to form
19a-R0 and 19b-R0, stereoselectively. In addition, it is likely
that the additional flexibility in the 9-membered ring permits
immediate access to the low-energy conformation, without a
kinetic trap. The lack of thermal atropisomerization from
the products can be explained by the fact that the C7-methyl
group of 19a-R0 and 19b-R0 exists in the pseudoequatorial
orientation and thus the compounds are thermodynamically
stable.
In the case of 18b-R, since the 8-membered-ring system is
highly rigid and stable, the conformational change provided
by the C7-methyl group does not promote atropisomerization
even at elevated temperature (e.g., at 150 °C in DMF).
Interestingly, in the 9-membered-ring lactam 3(a,b), methy-
lation proceeded on a different stereochemical course from
that of the 7- and 8-membered-ring lactams (Scheme 3).
Methylation was first examined with use of racemate 3a
(R = H: a1R*), in which the sole product was obtained in
89% yield. Contrary to our expectation, however, the pro-
duct did not isomerize after heating even at 150 °C in DMF.
The structure was presumed to be (a1R*,7S*) (19a-R*0) by
using NOE analysis (Figure 6), in which the NOEs observed
between C7-H and C9-Ha (3.4%) and C7-CH3 and C8-Hc
(1.9%), and no NOE between C7-H and C8-Hd were diag-
nostic to determine the C7-methyl in the pseudoequatorial
orientation with (7S*)-configuration. From the optically
active lactam 3a-R (R = H: a1R), 19a-R0 with a (7S)-methyl
was obtained in 80% yield (Table 2/entry 5). Similarly, the
compound 3b-R (R = Me: a1R) provided 19b-R0 in 90%
yield (Table 2/entry 6). Both compounds 19a-R0 and 19b-R0
did not isomerize at elevated temperature (at 150 °C in
DMF). The angle of optical rotation R of 19a-R0 and 19b-
R0 was negative (-) (Table 3), which suggests that the axial
chirality of the parent compounds (3a-R and 3b-R: (-)-
rotation) is preserved. The stereochemistry of 19b-R0 was
unambiguously determined by using X-ray crystallographic
analysis as shown in Figure 6 to be (a1R,a2S,7S).10 These
results indicate that methylation occurred not from the lower
side but from the upper side of the 9-membered ring. It is
intriguing that in the 9-membered-ring lactams C7-methyla-
tion occurred differently from that in 7- and 8-membered-
ring systems. A plausible mechanism of this methylation is
illustrated in Scheme 3 (right side). As shown here, steric
hindrance of the benzene ring (B) of the 9-membered-ring
Conclusion
The atropisomeric enantiomers of 7-, 8-, and 9-membered-
ring dibenzolactams (1-3) were separated and isolated by
using chiral HPLC, and their stereochemistries were clarified
in X-ray crystallographic analysis. The atropisomers showed
generally high stereochemical stability, and among them the
8-membered-ring lactam is the most stable due to the deep,
rigid cage-like ring form, which creates a high barrier to
inversion of the ring system. Owing to such axial chiralities,
C7-methylation of 7-, 8-, and 9-membered-ring benzolac-
tams (1-3) proceeded highly stereoselectively in all cases. In
7- and 8-membered-ring systems, the methylation first oc-
curred from the lower side of the ring to provide the products
with the C7-methyl group in the pseudoaxial orientation,
which then isomerized at the axes by heating to form
thermodynamically more stable diastereomers with the pseu-
doequatorial C7-methyl group. It is interesting that the
conformational change at the C7-methyl group from pseu-
doaxial to pseudoequatorial affects the rate of atropisomer-
ism to lower the rotational barrier. On the other hand, in the
9-membered-ring system, C7-methylation occurred from the
upper side of the ring to provide the product with the
opposite configuration from that in 7- and 8-membered-ring
systems. Thus, 9-membered-ring dibenzolactam was shown
to possess partly different stereochemical properties from
7- and 8-membered-ring lactams. These findings may prove
to be useful for understanding the chemical behavior of the
J. Org. Chem. Vol. 75, No. 17, 2010 5989

Tabata et al.
JOCArticle
related medium-sized ring systems and for future drug design
of biologically active compounds.
(1.57 g, 5.8 mmol) were treated to afford 10a as a brown oil (1.1
g, 80%): 1H MMR (400 MHz, CDCl3) δ 1.77 (td, J = 7.3, 7.5
Hz, 2H), 2.16 (t, J = 7.3 Hz, 2H), 2.66-2.80 (m, 2H), 3.47 (br,
2H), 6.76 (d, J = 7.8 Hz, 1H), 6.80 (t, J = 7.5 Hz, 1H), 6.99 (dd,
Experimental Section
J = 1.4, 7.5 Hz, 1H), 7.16-4.22 (m, 2H), 7.28-7.36 (m, 3H); 13
C
2-(20-Aminobiphenyl-2-yl)acetonitrile (8a): To a stirred mix-
ture of 2-bromoaniline (4a) (1.79 g, 10.4 mmol), triethylamine
(5.8 mL, 41.6 mmol), Pd(OAc)2 (117 mg, 0.52 mmol), 2-(dicyclo-
hexylphosphine)biphenyl (729 mg, 2.1 mmol), and dioxane (21
mL) was added pinacolborane (3.8 mL, 26 mmol) dropwise at
25 °C under argon. The mixture was stirred for 1 h at 80 °C,
cooled to room temperature, and treated successively with H2O
(7.0 mL), 2-iodophenylacetonitrile (5) (1.70 g, 7.0 mmol) in
NMR (100 MHz, CDCl3) δ 16.7, 26.3, 32.1, 115.1, 118.2, 119.4,
126.3, 127.0, 128.0, 128.6, 129.5, 130.0, 130.5, 138.4, 138.8,
143.5; IR (neat) 3373, 2361, 1616, 1481 cm-1; HRMS (ESI) m/
z calcd for C16H16N2 237.1386 (M þ Hþ), found 237.1400.
4-(20-Amino-60-methylbiphenyl-2-yl)butanenitrile (10b): Ac-
cording to a similar procedure as described for the preparation
of 8a, 2-bromo-3-methylaniline (614 mg, 3.3 mmol) and 2-io-
dophenylbutanenitrile 7 (600 mg, 2.2 mmol) were treated to
afford 10b as a brown oil (482 mg, 87%): 1H MMR (400 MHz,
CDCl3) δ 1.75-1.83 (m, 2H), 1.91 (s, 3H), 2.20 (dd, J = 6.8, 7.0
Hz, 2H), 2.46-2.60 (m, 2H), 3.34 (br, 2H), 6.62 (m, 1H), 6.70 (m,
1H), 7.08 (dd, J = 7.5, 7.8 Hz, 1H), 7.11-7.15 (m, 1H),
7.30-7.35 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 16.8, 20.4,
25.9, 32.1, 112.6, 119.5, 119.9, 126.0, 127.4, 127.9, 128.1, 129.7,
130.4, 136.6, 137.2, 138.9, 143.7; IR (neat) 3373, 2361, 1612,
1464 cm-1; HRMS (ESI) m/z calcd for C17H18N2 251.1543 (M þ
Hþ), found 251.1540.
dioxane (7.0 mL), and Ba(OH)2 8H2O (9.8 g, 31 mmol). The
3
mixture was heated at 100 °C for 1 h, cooled to room tempera-
ture, and filtered through Celite. To the filtrate was added brine
(20 mL), and the mixture was extracted with dichloromethane.
The extract was dried and concentrated. The residue was
purified by column chromatography (silica gel, hexane/ethyl
acetate = 8/1) to afford 8a as a pale yellow oil (1.44 g, 99%): 1H
NMR (400 MHz, CDCl3) δ 3.47 (br, 2H), 3.54 (d, J = 18.8 Hz,
1H), 3.73 (d, J = 18.8 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.84
(dd, J = 7.3, 7.6 Hz, 1H), 7.01 (d, J = 6.4 Hz, 1H), 7.14-7.30
(m, 2H), 7.40-7.46 (m, 2H), 7.60-7.62 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 21.5, 115.3, 118.2, 118.7, 124.9, 128.5, 128.5,
129.2, 129.4, 129.9, 130.6, 138.1, 143.3; IR (neat) 3366, 2249,
1618, 1483 cm-1; HRMS (EI) m/z calcd for C14H12N2 208.1000
(Mþ), found 208.0991.
3-(20-Aminobiphenyl-2-yl)propanoic acid (12a): A mixture of
9a (130 mg, 0.59 mmol), sodium hydroxide (234 mg, 5.9 mmol),
H2O (2.0 mL), and EtOH (4.0 mL) was stirred for 8 h at 100 °C.
After being cooled to room temperature, the mixture was
concentrated. The concentrate was acidified with 1 N HCl and
extracted with ethyl acetate. The extract was dried and concen-
trated to afford 12a as pale yellow crystals (116 mg, 82%): mp
107-108 °C; 1H MMR (400 MHz, CDCl3) δ 2.39-2.52 (m, 2H),
2.73-2.789 (m, 2H), 5.21 (br, 2H), 6.75 (d, J = 7.8 Hz, 1H), 6.80
(t, J = 7.3 Hz, 1H), 7.00 (dd, J = 1.4, 7.5 Hz, 1H), 7.15-7.20 (m,
2H), 7.25-7.32 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 28.2,
34.7, 115.3, 118.3, 126.6, 126.8, 128.0, 128.5, 129.2, 130.0, 130.4,
138.3, 138.9, 143.3, 178.2; IR (KBr) 3378, 1714 cm-1; HRMS
(ESI) m/z calcd for C15H15NO2 242.1176 (M þ Hþ), found
242.1172. Similarly, carboxylic acids, 12b, 13a, and 13b were
prepared from the corresponding nitriles, 9b, 10a, and 10b,
respectively.
2-(20-Amino-60-methylbiphenyl-2-yl)acetonitrile (8b): Com-
pound 5 (1.64 g, 6.75 mmol) was treated according to a similar
procedure as described for the preparation of 8a with use of
2-bromo-3-methylaniline (4b) (1.88 g, 10.1 mmol) in place of 4a
to afford 8b as brown crystals (1.44 g, 96%): mp 62-64 °C; 1H
NMR (400 MHz, CDCl3) δ 1.92 (s, 3H), 3.33 (br, 2H), 3.43 (d,
J = 18.8 Hz, 1H), 3.56 (d, J = 18.8 Hz, 1H), 6.63 (dd, J = 0.6,
7.81 Hz, 1H), 6.72 (d, J = 7.3 Hz, 1H), 7.11 (t, J = 7.7 Hz, 1H),
7.20-7.22 (m, 1H), 7.43-7.46 (m, 2H), 7.63-7.65 (m, 1H); 13
C
NMR (100 MHz, CDCl3) δ 20.2, 21.1, 112.7, 117.8, 120.1, 124.3,
128.4, 128.6, 128.8, 128.9, 129.4, 130.5, 136.6, 136.9, 143.4; IR
(KBr) 3383, 2251, 1614, 1464 cm-1; HRMS (EI) m/z calcd for
C15H14N2 222.1157 (Mþ), found 222.1149.
3-(20-Amino-60-methylbiphenyl-2-yl)propanoic acid (12b): brown
1
crystals (76%), mp 132-134 °C; H MMR (400 MHz, CDCl3)
3-(200-Aminobiphenyl-2-yl)propanenitrile (9a): According to a
similar procedure as described for the preparation of 8a, 2-bro-
moaniline 4a (1.41 g, 8.2 mmol) and 2-iodophenylpropanenitrile
6 (1.42 g, 5.58 mmol) were treated to afford 9a as brown crystals
(1.19 g, 97%): mp 46-48 °C; 1H MMR (400 MHz, CDCl3)
δ 2.48-2.47 (m, 2H), 2.79-2.85 (m, 2H), 3.48 (br, 2H), 6.75-
6.83 (m, 2H), 6.99 (d, J = 7.3 Hz, 1H), 7.17-7.25 (m, 2H),
7.35-7.37 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 18.2, 29.2,
115.2, 118.3, 119.3, 125.8, 127.7, 128.3, 128.8, 129.6, 129.9,
130.6, 137.0, 138.3, 143.5; IR (KBr) 3371, 2361, 1616, 1483
cm-1; HRMS (ESI) m/z calcd for C15H14N2 223.1230 (M þ H)þ,
found 223.1217.
δ 1.92 (s, 3H), 2.40-2.55 (m, 2H), 2.65-2.75 (m, 2H), 4.28 (br,
2H), 6.62 (d, J = 7.8 Hz, 1H), 6.71 (d, J = 7.3 Hz, 1H), 7.06-7.12
(m, 2H), 7.30-7.39 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 20.3,
28.1, 34.3, 112.9, 120.2, 126.4, 127.3, 127.9, 128.0, 129.4, 130.3,
136.7, 137.1, 138.9, 143.4, 178.0; IR (KBr) 3372, 1714 cm-1
;
HRMS (ESI) m/z calcd for C16H17NO2 256.1332 (M þ Hþ),
found 256.1314.
4-(20-Aminobiphenyl-2-yl)butanoic acid (13a): brown oil
(76%); 1H MMR (400 MHz, CDCl3) δ 1.71-1.81 (m, 2H),
2.20 (t, J = 7.5 Hz, 2H), 2.45-2.62 (m, 2H), 4.41 (br, 2H), 6.77
(dd, J = 0.7, 8.0 Hz, 1H), 6.81 (dd, J = 1.2, 7.5 Hz, 1H), 7.01
(dd, J = 1.4, 7.5 Hz, 1H), 7.13-7.20 (m, 2H), 7.23-7.32 (m,
3H); 13C NMR (100 MHz, CDCl3) δ 25.7, 32.2, 33.4, 115.3,
118.4, 126.5, 127.0, 127.8, 128.3, 129.4, 130.2, 130.3, 138.2,
140.1, 143.1, 178.4; IR (neat) 3379, 1706 cm-1; HRMS (ESI)
m/z calcd for C16H17NO2 256.1332 (M þ Hþ), found 256.1330.
4-(20-Amino-60-methylbiphenyl-2-yl)butanoic acid (13b): pale
yellow crystals (98%), mp 67-69 °C; 1H MMR (400 MHz,
CDCl3) δ 1.80 (m, 2H), 1.92 (s, 3H), 2.24 (t, J = 7.5 Hz, 2H),
2.37-2.49 (m, 2H), 4.80 (br, 2H), 6.62 (d, J = 8.0 Hz, 1H), 6.70
3-(20-Amino-60-methylbiphenyl-2-yl)propanenitrile (9b): Ac-
cording to a similar procedure as described for the preparation
of 8a, 2-bromo-3-methylaniline 4b (721 mg, 3.9 mmol) and
2-iodophenylpropanenitrile 6 (669 mg, 2.6 mmol) were treated
to afford 9b as brown crystals (545 mg, 89%): mp 76-78 °C; 1H
MMR (400 MHz, CDCl3) δ 1.91 (s, 3H), 2.42-2.53 (m, 2H),
2.66-2.80 (m, 2H), 3.36 (br, 2H), 6.62 (d, J = 7.8 Hz, 1H), 6.71
(d, J = 7.3 Hz, 1H), 7.07-7.17 (m, 2H), 7.36-7.44 (m, 3H); 13
C
NMR (100 MHz, CDCl3) δ 17.9, 20.3, 29.2, 112.7, 119.4, 120.0,
125.5, 128.2, 1278.3, 129.9, 130.4, 136.5, 137.0, 137.2, 143.7; IR
(KBr) 3375, 2243, 1612, 1464 cm-1; HRMS (ESI) m/z calcd for
C16H16N2 237.1386 (M þ Hþ), found 237.1374.
(d, J = 7.3 Hz, 1H), 7.04-7.12 (m, 2H), 7.27-7.36 (m, 3H); 13
C
NMR (100 MHz, CDCl3) δ 20.3, 25.1, 32.0, 33.4, 112.6, 120.0,
126.5, 126.9, 127.7, 127.8, 129.4, 130.1, 136.7, 136.9, 140.0,
143.4, 178.3; IR (KBr) 3378, 1707 cm-1; HRMS (ESI) m/z calcd
for C17H19NO2 270.1489 (M þ Hþ), found 270.1479.
4-(20-Aminobiphenyl-2-yl)butanenitrile (10a): According to a
similar procedure as described for the preparation of 8a, 2-bro-
moaniline (1.48 g, 8.6 mmol) and 2-iodophenylbutanenitrile 7
5H,7H-Dibenzo[b,d]azepin-6-one (14a): To a solution of 8a
(339 mg, 1.63 mmol) in methanol (10 mL) was added sodium
5990 J. Org. Chem. Vol. 75, No. 17, 2010

Tabata et al.
JOCArticle
hydroxide (652 mg, 16.3 mmol) in H2O (5 mL), then the mixture
was heated at 90 °C for 8 h. After being cooled to room tem-
perature, the mixture was treated with saturated aqueous NaH-
CO3 and extracted with ethyl acetate. The organic layer was
washed successively with 1 N HCl and saturated aqueous NH4-
Cl, dried, and concentrated. The concentrate was purified by
column chromatography (silica gel, hexane/ethyl acetate = 4/1)
to afford 14a as colorless crystals (223 mg, 65%), mp 114-
(ESI) m/z calcd for C17H17NO 252.1383 (M þ Hþ), found
252.1366.
5-Methyl-5H,7H-dibenzo[b,d]azepin-6-one (1a): To a stirred
solution of 14a (104.6 mg, 0.5 mmol) in DMF (5 mL) at 0 °C
under argon was added sodium hydride (60% in oil) (30 mg, 0.75
mmol). The mixture was stirred for 30 min at 25 °C, cooled to
0 °C, and treated with MeI (0.16 mL, 2.5 mmol). After the
mixture was stirred for 1 h at 25 °C, water and ethyl acetate were
added to the mixture. The organic layer was separated, washed
with brine, dried, and concentrated. The concentrate was pur-
ified by column chromatography (silica gel, hexane/ethyl acet-
ate = 5/1) to afford 1a as colorless crystals (104.4 mg, 94%), mp
156-157 °C; 1H NMR (400 MHz, CDCl3) δ 3.32 (s, 3H), 3.42 (d,
J = 12.7 Hz, 1H), 3.58 (d, J = 12.7 Hz, 1H), 7.28-7.46 (m, 6H),
7.57-7.59 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 36.1, 42.1,
122.4, 125.1, 127.5, 127.7, 127.9, 128.3, 128.5, 129.9, 133.7,
135.4, 136.2, 141.7, 171.5; IR (KBr) 2995, 1651 cm-1; HRMS
(EI) m/z calcd for C15H13NO 223.0997 (Mþ), found 223.0998.
Similarly, N-methylation of dibenzolactams 14b, 15a, 15b, 16a,
and 16b afforded N-methyl derivatives 1b, 2a, 2b, 3a, and 3b,
respectively.
1
116 °C: H NMR (400 MHz, CDCl3) δ 3.46 (d, J = 11.7 Hz,
1H), 3.57 (d, J = 11.7 Hz, 1H), 7.11 (dd, J = 7.8, 8.1 Hz, 1H),
7.29 (td, J = 1.2, 7.8 Hz, 1H), 7.35-7.44 (m, 4H), 7.55-7.59 (m,
1H), 7.65 (dd, J = 7.6, 7.8 Hz, 1H), 8.28 (br, 1H); 13C NMR (100
MHz, CDCl3) δ 41.8, 121.8, 125.0, 127.7, 128.4, 128.6, 128.7,
130.0, 132.0, 134.1, 135.7, 136.4, 173.1; IR (KBr) 3063, 1695
cm-1; HRMS (EI) m/z calcd for C14H11ON 209.0841 (Mþ),
found 209.0838.
1-Methyl-5H,7H-dibenzo[b,d]azepin-6-one (14b): According
to a similar procedure as described for the preparation of 14a,
compound 8b (274 mg, 1.23 mmol) was treated to afford 14b as
colorless crystals (170 mg, 62%), mp 155-158 °C: 1H NMR (400
MHz, CDCl3) δ 2.44 (s, 3H), 3.43 (d, J = 12.5 Hz, 1H), 3.47 (dd,
J = 1.7, 12.5 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 7.6
Hz, 1H), 7.25 (dd, J = 7.6, 9.5 Hz, 1H), 7.31-7.45 (m, 4H), 8.05
(br, 1H); 13C NMR (100 MHz, CDCl3) δ 21.8, 41.5, 119.3, 126.1,
127.5, 127.7, 127.8, 128.2, 130.4, 131.2, 134.2, 135.4, 136.4,
137.0, 173.9; IR (KBr) 3065, 1670 cm-1; HRMS (EI) m/z calcd
for C15H13ON 223.0997 (Mþ), found 223.1006.
5H,7H,8H-Dibenzo[b,d]azocin-6-one (15a): To a solution of
12a (597 mg, 2.47 mmol) in CH2Cl2 (80 mL) under argon were
added triethylamine (1.0 mL, 7.4 mmol) and EDC (1.42 g, 7.42
mmol). After being stirred for 23 h at 25 °C, the mixture was
washed successively with saturated aqueous NaHCO3, 1 N HCl,
and saturated aqueous NH4Cl, dried, and concentrated. The
concentrate was purified by column chromatography (silica gel,
hexane/ethyl acetate = 3/1) to afford 15a as colorless crystals
(373 mg, 68%), mp 215-217 °C: 1H MMR (400 MHz, CDCl3) δ
2.56-2.64 (m, 1H), 2.90 (m, 3H), 6.99 (br, 1H), 7.13-7.15 (m,
1H), 7.19-7.37 (m, 5H), 7.38-7.43 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 29.6, 34.4, 126.3, 126.8, 127.8, 128.3, 128.5,
129.5, 130.4, 135.5, 138.0, 138.5, 140.8, 174.3; IR (KBr) 3055,
2947, 1653, 1394 cm-1; HRMS (ESI) m/z calcd for C15H13NO
224.1070 (M þ Hþ), found 224.1060. Similarly, dibenzolactams,
15b, 16a, and 16b were prepared from the corresponding
carboxylic acids, 12b, 13a, and 13b, respectively.
1,5-Dimethyl-5H,7H-dibenzo[b,d]azepin-6-one (1b): colorless
crystals (93%), mp 137-139 °C; 1H NMR (400 MHz, CDCl3) δ
2.40 (s, 3H), 3.26 (s, 3H), 3.40 (d, J = 12.5 Hz, 1H), 3.47 (d, J =
12.5 Hz, 1H), 7.19 (d, J = 7.8 Hz, 2H), 7.29-7.40 (m, 4H), 7.47
(d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 22.0, 36.0,
42.0, 119.9, 125.9, 127.3, 127.6, 127.9, 128.2, 130.0, 132.8, 133.8,
136.6, 136.8, 142.4, 172.3; IR (KBr) 2982, 1668 cm-1; HRMS
(EI) m/z calcd for C16H15ON 237.1154 (Mþ), found 237.1156.
5-Methyl-5H,7H,8H-dibenzo[b,d]azocin-6-one (2a): colorless
crystals (99%), mp 96-97 °C; 1H MMR (400 MHz, CDCl3) δ
2.48-2.54 (m, 1H), 2.61-2.69 (m, 1H), 2.81-2.88 (m, 1H),
2.94-3.02 (m, 1H), 2.95 (s, 3H), 7.09-7.11 (m, 1H), 7.21-7.36
(m, 5H), 7.39-7.47 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
30.4, 34.0, 35.9, 125.9, 126.6, 128.0, 128.3, 129.0, 129.5, 130.4,
130.4, 138.0, 138.1, 141.0, 142.8, 172.7; IR (KBr) 3051, 2970,
1655, 1450 cm-1; HRMS (ESI) m/z calcd for C16H15NO
238.1226 (M þ Hþ), found 238.1210.
1,5-Dimethyl-5H,7H,8H-dibenzo[b,d]azocin-6-one (2b): col-
orless crystals (89%), mp 130-132 °C; H MMR (400 MHz,
1
CDCl3) δ 2.13 (s, 3H), 2.47-2.56 (m, 2H), 2.60-2.70 (m, 1H),
2.83-2.91 (m, 1H), 2.88 (s, 3H), 7.05-7.06 (m, 1H), 7.13 (d, J =
7.6 Hz, 1H), 7.23-7.35 (m, 5H); 13C NMR (100 MHz, CDCl3) δ
20.6, 29.8, 34.3, 35.7, 123.5, 126.5, 128.1, 128.5, 128.8, 129.7,
130.4, 136.8, 137.6, 138.3, 140.0, 143.1, 172.5; IR (KBr) 2941,
1649, 1466 cm-1; HRMS (ESI) m/z calcd for C17H17NO
252.1383 (M þ Hþ), found 252.1380.
1-Methyl-5H,7H,8H-dibenzo[b,d]azocin-6-one (15b): color-
less crystals (64%), mp 216-218 °C; 1H NMR (400 MHz,
CDCl3) δ 2.15 (s, 3H), 2.50-2.73 (m, 3H), 2.76-2.86 (m, 1H),
6.70 (br, 1H), 7.05-7.08 (m, 2H), 7.25-7.30 (m, 5H); 13C NMR
(100 MHz, CDCl3) 20.8, 29.4, 34.4, 124.2, 126.7, 128.0, 128.2,
129.2, 129.8, 135.8, 137.1, 137.5, 138.3, 140.2, 174.5; IR (KBr)
3182, 3055, 1657, 1446 cm-1; HRMS (ESI) m/z calcd for
C16H15NO 238.1226 (M þ Hþ), found 238.1207.
5-Methyl-5H,7H,8H,9H-dibenzo[b,d]azonin-6-one (3a): col-
1
orless crystals (96%), mp 128-130 °C; H MMR (400 MHz,
CDCl3) δ 2.48-2.54 (m, 1H), 2.61-2.69 (m, 1H), 2.81-2.88 (m,
1H), 2.94-3.02 (m, 1H), 2.95 (s, 3H), 7.09-7.11 (m, 1H),
7.21-7.36 (m, 5H), 7.39-7.47 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 28.3, 34.4, 34.9, 36.8, 125.3, 127.3, 128.0, 128.2, 128.6,
129.1, 129.7, 129.8, 137.5, 140.4, 142.8, 143.1, 172.7; IR (KBr)
2932, 1653, 1446 cm-1; HRMS (ESI) m/z calcd for C17H17NO
252.1383 (M þ Hþ), found 252.1381.
5H,7H,8H,9H-Dibenzo[b,d]azonin-6-one (16a): colorless
crystals (75%), mp 174-177 °C; 1H MMR (400 MHz, CDCl3)
δ 1.87-2.22 (m, 5H), 2.73 (dd, J = 1.7, 5.8 Hz, 1H), 6.58 (br,
1H), 6.97 (d, J = 7.3 Hz, 1H), 7.19-7.24 (m, 2H), 7.30-7.38 (m,
3H), 7.42-7.46 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 28.3,
33.8, 34.1, 126.1, 127.8, 128.4, 128.6, 128.7, 128.9, 129.4, 129.9,
136.0, 138.4, 140.1, 176.1; IR (KBr) 3260, 2930, 1630, 1452
cm-1; HRMS (ESI) m/z calcd for C16H15NO 260.1046 (M þ
Naþ), found 260.1041.
1,5-Dimethyl-5H,7H,8H,9H-dibenzo[b,d]azonin-6-one (3b):
colorless crystals (93%), mp 160-162 °C; 1H MMR (400
MHz, CDCl3) δ 1.88-1.97 (m, 2H), 2.01-2.09 (m, 3H þ 2H),
2.13-2.20 (m, 1H), 2.69-2.74 (m, 1H), 2.83 (s, 3H), 6.95 (d, J =
7.3 Hz, 1H), 7.14-7.21 (m, 2H), 7.25-7.37 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 20.4, 28.3, 34.1, 34.7, 36.7, 124.5, 125.8,
127.9, 128.5, 128.6, 129.3, 129.9, 136.4, 137.8, 140.1, 141.3,
143.2, 173.6; IR (KBr) 2930, 1651, 1444 cm-1; HRMS (ESI)
m/z calcd for C18H19NO 266.1539 (M þ Hþ), found 266.1537.
Separation of Enantiomers by Using Chiral HPLC. Atropi-
somers of 1,5-dimethyl-5H,7H-dibenzo[b,d]azepin-6-one (1b-R
and 1b-S): CHIRALPAK AD-H (1.0 cm φ ꢀ 25 cm); eluent,
1-Methyl-5H,7H,8H,9H-dibenzo[b,d]azonin-6-one (16b): col-
orless crystals (81%), mp 216-219 °C; H MMR (400 MHz,
CDCl3) δ 1.82-2.15 (m, 5H), 2.06 (s, 3H), 2.73 (dd, J = 3.9, 13.1
Hz, 1H), 6.61 (br, 1H), 6.88 (d, J = 7.3 Hz, 1H), 7.14-7.35 (m,
6H); 13C NMR (100 MHz, CDCl3) δ 20.5, 28.4, 33.6, 33.8, 126.1,
126.6, 127.5, 128.1, 128.4, 129.7, 130.1, 136.1, 137.4, 137.4, 139.7,
142.5, 176.2;IR(KBr) 3177, 3055, 2932, 1660, 1442cm-1; HRMS
1
J. Org. Chem. Vol. 75, No. 17, 2010 5991

Tabata et al.
JOCArticle
hexane:2-propanol (9:1); flow rate, 3.0 mL/min; temperature,
5,7-Dimethyl-5H,7H-dibenzo[b,d]azepin-6-one (17a-S): To a
solution of 1a-R (13.4 mg, 0.06 mmol) in THF (0.3 mL) at
-78 °C under argon was added KHMDS (0.5 M in toluene) (0.6 mL,
0.3 mmol). The mixture was stirred for 10 min and treated with
MeI (19 μL, 0.3 mmol). After being stirred for 1 h at -78 °C, the
mixture was gradually warmed to 0 °C, to which was added
saturated aqueous NH4Cl. The mixture was extracted with
diethyl ether, the extract was dried, and the solvent was evapo-
rated. The residue was purified by column chromatography
(silica gel, hexane/ethyl acetate = 6/1) to afford 17a-S (13.7 mg,
96%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.60 (d,
J = 6.8 Hz, 3H), 3.33 (s, 3H), 3.44 (q, J = 6.8 Hz, 1H), 7.29-
7.47 (m, 6H), 7.56-7.59 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 12.3, 36.1, 39.6, 122.2, 123.3, 125.0, 126.9, 127.9 128.3, 128.5,
129.7, 133.9, 136.5, 139.3, 141.5, 172.9; IR (neat) 2980, 1665
cm-1; HRMS (ESI) m/z calcd for C16H15NO 238.1232 (M þ
Hþ), found 238.1248. [R]23D þ189.3 (c 0.29, MeOH). Monitor-
22 °C; detection, 254 nm. Former peak (1b-R): retention time =
D
14.4 min; [R]21 -92.0 (c 0.3, MeOH). Latter peak (1b-S):
D
retention time = 21.7 min; [R]21 þ93.7 (c 0.3, MeOH). The
absolute stereochemistry of 1b-R and 1b-S was determined by
the single-crystal X-ray analysis as described below. The crystal
structures determined by the X-ray analysis are shown in
Figure 2 (top). Similarly, atropisomers of 1a, 2a, 2b, 3a, and
3b were separated with chiral HPLC.
Atropisomers of 5-methyl-5H,7H-dibenzo[b,d]azepin-6-one
(1a-R and 1a-S): Separation of 1a into its atropisomers was
carried out by preparative HPLC with CHIRALPAK AD-H
(1.0 cm φ ꢀ 25 cm) under detection at 254 nm. Elution with a
mixture of hexane:2-propanol (9:1) at a flow rate of 2.0 mL/min
at 22 °C gave 1a-S and 1a-R. Fomer peak (1a-R): retention
time = 12.9 min; [R]21D -137.1 (c 0.3, MeOH). Latter peak (1a-S):
retention time = 16.7 min; [R]21 þ131.2 (c 0.3, MeOH). The
D
1
absolute stereochemistry of the separated atropisomers of 1a
was assigned by comparison with the retention time and the
(-)/(þ)-angle of optical rotation R of 1b-R and 1b-S.
ing of the intermediate step of the reaction with TLC and H
NMR revealed that the unstable isomer 17a-R was initially
formed, which readily isomerized to give 17a-S during workup.
1,5,7-Trimethyl-5H,7H-dibenzo[b,d]azepin-6-one (17b-R): Ac-
cording to a similar procedure as described for the C7-methyla-
tion of 1a-R, compound 1b-R (19.2 mg, 0.081 mmol) was treated
to afford 17b-R (20.2 mg, 99%) as colorless crystals, mp 97-
102 °C: 1H NMR (400 MHz, CDCl3) δ 0.88 (d, J = 7.6 Hz, 3H),
2.39(s, 3H),3.29(s, 3H), 3.97(q,J= 7.6 Hz, 1H), 7.16 (dd, J=7.3,
8.1 Hz, 2H), 7.26-7.34 (m, 4H), 7.43-7.45 (m, 1H); 13CNMR(100
MHz, CDCl3) δ 13.5, 22.2, 37.2, 51.0, 119.8, 126.1, 127.7, 127.8,
128.0, 128.6, 131.0, 133.1, 133.2, 136.4, 141.2, 141.4, 175.1; IR
(KBr) 2930, 1651 cm-1; HRMS (EI) m/z calcd for C17H17ON
251.1310 (Mþ), found 251.1306; [R]23D -79.3 (c 0.15, MeOH).
Thermal isomerization of 17b-R to aS-1,5,7-trimethyl-5H,7H-
dibenzo[b,d]azepin-6-one (17b-S): A solution of 17b-R (17.1 mg,
0.068 mmol) in toluene (1.8 mL) under argon was heated at
110 °C for 30 min with stirring. The solvent was evaporated to
afford an oily residue of a mixture of 17b-R and 17b-S in a ratio
of 3:97, from which 17b-S was obtained as colorless crystals
(16.5 mg, 96%), mp 154-156 °C: 1H NMR (400 MHz, CDCl3) δ
1.56 (d, J = 6.8 Hz, 3H), 2.41 (s, 3H), 3.26 (s, 3H), 3.46 (q, J =
6.8 Hz, 1H), 7.18 (d, J = 7.8 Hz, 2H), 7.26-7.34 (m, 2H),
7.38-7.46 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 11.9, 22.0,
36.1, 39.6, 119.7, 123.1, 125.4, 127.7, 127.8, 128.2, 128.9, 129.8,
Atropisomers of 1,5-dimethyl-5H,7H,8H-dibenzo[b,d]azocin-
6-one (2b-R and 2b-S): CHIRALPAK IA (1.0 cm φ ꢀ 25 cm);
eluent, hexane:2-propanol (19:1); flow rate, 1.0 mL/min; tem-
perature, 28 °C; detection, 254 nm. Former peak (2b-R): reten-
tion time = 44.6 min; [R]22D -163.5 (c 0.4, MeOH). Latter peak
(2b-S): retention time = 55.3 min; [R]22D þ170.0 (c 0.4, MeOH).
The absolute stereochemistry of 2b-R and 2b-S was determined
by the single-crystal X-ray analysis as described below. The
crystal structures determined by the X-ray analysis are shown in
Figure 2 (middle).
Atropisomers of 5-methyl-5H,7H,8H-dibenzo[b,d]azocin-6-
one (2a-R and 2a-S): CHIRALPAK IA (1.0 cm φ ꢀ 25 cm);
eluent, hexane:2-propanol (19:1); flow rate, 1.0 mL/min; tem-
perature, 28 °C; detection, 254 nm. Former peak (2a-R): reten-
tion time = 52.5 min; [R]23D -166.1 (c 0.37, MeOH). Latter peak
(2a-S): retention time = 64.3 min; [R]23D þ165.7 (c 0.37, MeOH).
The absolute stereochemistry of the separated atropisomers of
2a was assigned by comparison with the retention time and the
(-)/(þ)-angle of optical rotation R of 2b-R and 2b-S.
Atropisomers of 1,5-dimethyl-5H,7H,8H,9H-dibenzo[b,d]azo-
nin-6-one (3b-S and 3b-R): CHIRALPAK IA (1.0 cm φ ꢀ 25 cm);
eluent, hexane:EtOH (97:3); flow rate, 1.5 mL/min; tempera-
ture, 27 °C; detection, 254 nm. Fomer peak (3b-S): retention
133.0, 136.4, 140.6, 142.2, 173.7; IR (KBr) 2938, 1668 cm-1
;
time = 39.0 min; [R]22 þ 206.1 (c 0.21, MeOH). Latter peak
HRMS (ESI) m/z calcd for C17H17NO 252.1383 (M þ Hþ),
D
22
(3b-R): retention time = 44.5 min; [R]D -213.7 (c 0.195,
found 252.1385; [R]23D þ116.1 (c 0.15, MeOH).
MeOH). The absolute stereochemistry of 3b-S and 3b-R was
determined by the single-crystal X-ray analysis as described
below. The crystal structures determined by the X-ray analysis
are shown in Figure 2 (bottom).
5,7-Dimethyl-5H,7H,8H-dibenzo[b,d]azocin-6-one (18a-R): Ac-
cording to a similar procedure as described for the C7-methylation
of 1a-R, compound 2a-R (27.0 mg, 0.11 mmol) was treated to
afford 18a-R(23.0 mg, 79%) as colorless crystals, mp 120-122 °C:
1H NMR (400 MHz, CDCl3) δ 1.15 (d, J = 7.3 Hz, 3H), 1.98 (dd,
J = 10.7, 13.4 Hz, 1H), 2.71 (dd, J = 9.5, 13.4 Hz, 1H), 2.93 (s,
3H), 3.09-3.19 (m, 1H), 7.25-7.35 (m, 6H), 7.41 (td, J = 1.5, 7.6
Hz, 1H), 7.46 (td, J = 1.7, 7.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 18.5, 38.5, 39.8, 45.3, 126.8, 126.9, 127.5, 127.9, 128.2,
128.5, 128.9, 129.5, 138.4, 138.8, 140.3, 142.0, 174.6; IR (KBr)
2924, 1635, 1444 cm-1; HRMS (ESI) m/z calcd for C17H17NO
Atropisomers of 5-methyl-5H,7H,8H,9H-dibenzo[b,d]azonin-
6-one (3a-S and 3a-R): CHIRALPAK IA (1.0 cm φ ꢀ 25 cm);
eluent, hexane:2-propanol (100:1); flow rate, 2.5 mL/min; tem-
perature, 27 °C; detection, 254 nm. Former peak (3a-S): reten-
tion time = 53.8 min; [R]22 þ231.7 (c 0.215, MeOH). Latter
D
peak (3a-R): retention time = 64.9 min; [R]22 -249.5 (c 0.215,
D
MeOH). The absolute stereochemistry of the separated atropi-
somers of 3a was assigned by comparison with the retention time
and the (-)/(þ)-angle of optical rotation R of 3b-S and 3b-R.
Thermal stability of the atropisomers of 1a, 1b, 2a, 2b, 3a, and 3b
(Table 1): A solution of the enantiomers of 7-, 8-, and 9-membered-
ring dibenzolactams (1a, 1b, 2a, 2b, 3a, and 3b) in toluene (or
DMF) was heated at the designated temperature (Table 1), and the
time-dependent conversion rate (% ee) was estimated from chiral
HPLC analysis. The figures of the conversion rate are included in
the Supporting Information. The activation free-energy barrier to
rotation (ΔGq) was determined based on the conversion rate. The
calculation was carried out according to the procedure reported by
Curran et al.12
252.1383 (M þ Hþ), found 252.1392; [R]23 -164.8 (c 0.15,
D
MeOH).
Thermal isomerization of 18a-R to aS-1,5-dimethyl-5H,7H,-
8H-dibenzo[b,d]azocin-6-one (18a-S): A solution of 18a-R (14.3
mg, 0.057 mmol) in toluene (1.4 mL) under argon was heated at
110 °C for 3 h with stirring. The solvent was evaporated to afford
an oily residue of a mixture of 18a-R and 18a-S in a ratio of
10:90, from which 18a-S was obtained as colorless crystals (12.9
mg, 90%), mp 141-142 °C: 1H NMR (400 MHz, CDCl3) δ 1.16
(d, J = 6.6 Hz, 3H), 2.52 (dd, J = 9.3, 14.9 Hz, 1H), 2.84-2.92
(m, 1H), 2.95 (s, 3H), 3.10 (dd, J = 9.0, 14.9 Hz, 1H), 7.06-7.08
(m, 1H), 7.14-7.16 (m, 1H), 7.22-7.52 (m, 6H); 13C NMR
5992 J. Org. Chem. Vol. 75, No. 17, 2010

Tabata et al.
JOCArticle
˚
(100 MHz, CDCl3) δ 18.7, 35.8, 36.4, 41.7, 126.3, 126.7, 128.1,
128.4, 129.2, 130.4, 130.7, 131.0, 137.9, 138.2, 141.5, 142.7,
175.4; IR (KBr) 2928, 1664, 1442 cm-1; HRMS (ESI) m/z calcd
c = 18.7160(3) A, R = 90°, β = 90°, γ = 90°, T = 173 K, Z = 4,
V= 1242.24(4) A , Dcalc =1.269gcm-3, μ(CuKR) = 6.206 cm-1
,
000 = 504.00, GOF = 0.715, Rint = 0.045, R1 = 0.0320, wR2 =
3
˚
F
for C17H17NO 252.1383 (M þ Hþ), found 252.1389; [R]22
0.0808, Flack = 0.2(3). The CIF file of the crystal data for 1b-S is
available in the Supporting Information of our preceding paper.4
Crystal data of 1b-R: C16H15ON, mp 137-139 °C, Mr =
D
þ112.7 (c 0.15, MeOH).
1,5,7-Trimethyl-5H,7H,8H-dibenzo[b,d]azocin-6-one (18b-R):
According to a similar procedure as described for the C7-met-
hylation of 2a-R, compound 2b-R (18.6 mg, 0.074 mmol) was
treated to afford 18b-R (15.3 mg, 78%) as colorless crystals, mp
142-145 °C: 1H NMR (400 MHz, CDCl3) δ 1.07 (d, J = 7.3 Hz,
3H), 1.88 (dd, J = 10.2, 13.1 Hz, 1H), 2.13 (s, 3H), 2.71 (dd, J =
9.5, 13.1 Hz, 1H), 2.89 (s, 3H), 3.02-3.11 (m, 1H), 7.17 (dd, J =
0.7, 7.5 Hz, 1H), 7.21-7.36 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ 18.4, 20.5, 38.4, 39.2, 45.7, 125.1, 126.4, 127.6, 128.35,
128.37, 128.4, 129.6, 136.6, 136.9, 138.9, 139.2, 142.0, 174.5; IR
(KBr) 2966, 1639, 1458 cm-1; HRMS (ESI) m/z calcd for C18-
˚
237.30, Cu KR (λ = 1.54187 A), orthorhombic, P212121, colorless
prism 0.50 ꢀ 0.50 ꢀ 0.40 mm3, crystal dimensions a = 8.04577(15)
˚
˚
˚
A, b = 8.25270(15) A, c = 18.7170(3) A, R = 90°, β = 90°, γ =
90°, T = 173 K, Z = 4, V = 1242.80(4) A , Dcalc = 1.268 g cm-3
,
=
3
˚
μ(Cu KR) = 6.204 cm-1, F000 = 504.00, GOF = 1.228, Rint
0.025, R1 = 0.0290, wR2 = 0.0683, Flack parameter = -0.3(3).
The CIF file of the crystal data for 1b-R is available in the
Supporting Information of our preceding paper.4
Crystal data of 2b-S: C17H17ON, mp 130-132 °C, Mr =
˚
251.33, Cu KR (λ = 1.54187 A), tetragonal, P41, colorless prism
3
H19NO 288.1359 (M þ Naþ), found 288.1361; [R]23 -158.9
˚
0.70 ꢀ 0.60 ꢀ 0.50 mm , crystal dimensions a = 10.00744(18) A,
D
˚
c = 13.5007(3) A, R = 90°, β = 90°, γ = 90°, T = 173 K, Z = 4,
(c 0.11, MeOH). Compound 18b-R did not isomerize at 150 °C
for 3 h in DMF.
V = 1352.08(4) A , Dcalc = 1.235 g cm-3, μ(Cu KR) = 5.972
3
˚
cm-1, F000 = 536.00, GOF = 1.278, Rint = 0.027, R1 = 0.0264,
5,7-Dimethyl-5H,7H,8H,9H-dibenzo[b,d]azonin-6-one (19a-
R*0): To a solution of diisopropylamine (0.2 mL, 1.51 mmol)
in THF (1.5 mL) at -78 °C under argon was added n-BuLi (1.58 M
in hexane) (0.96 mL, 1.51 mmol). After being stirred for 10 min, the
mixture was treated with 3a (75.9 mg, 0.30 mmol), stirred for
10 min, and treated with MeI (94 μL, 1.51 mmol). After being
stirred for 2.5 h at -78 °C, the mixture was treated with satu-
rated aqueous NH4Cl, then extracted with ethyl acetate. The
extract was dried, and the solvent was evaporated. The residue
was purified by column chromatography (silica gel, hexane/
ethyl acetate = 3/1) to afford 19a-R*0 (71 mg, 89%) as colorless
crystals, mp 165-167 °C: 1H NMR (400 MHz, CDCl3) δ 1.05 (d,
J = 6.6 Hz, 3H), 1.63-1.67 (m, 1H), 1.79-1.88 (m, 1H),
2.28-2.33 (m, 1H), 2.28-2.33 (m, 1H), 2.66 (ddd, J = 1.9,
5.8, 6.1 Hz, 1H), 2.78 (s, 3H), 7.04 (dd, J = 1.2, 1.4 Hz, 1H),
wR2 = 0.0615, Flack parameter = -0.1(2).
Crystal data of 2b-R: C17H17ON, mp 130-132 °C, Mr =
˚
251.33, Cu KR (λ = 1.54187 A), tetragonal, P43, colorless prism
3
˚
0.30 ꢀ 0.30 ꢀ 0.10 mm , crystal dimensions a = 10.00645(18) A,
˚
c = 13.4991(3) A, R = 90°, β = 90°, γ = 90°, T = 173 K, Z = 4,
V = 1351.65(4) A , Dcalc = 1.235 g cm-3, μ(Cu KR) = 5.974
3
˚
cm-1, F000 = 536.00, GOF = 1.020, Rint = 0.040, R1 = 0.0404,
wR2 = 0.1002, Flack parameter =0.3(4).
Crystal data of 3b-S: C18H19ON, mp 160-162 °C, Mr =
˚
265.35, Cu KR (λ = 1.54187 A), orthorhombic, P212121, color-
less prism 0.40 ꢀ 0.35 ꢀ 0.20 mm3, crystal dimensions a =
˚
˚
˚
8.85223(16) A, b = 11.3388(2) A, c = 14.4403(3) A, R = 90°,
3
˚
β = 90°, γ = 90°, T = 173 K, Z = 4, V = 1449.43(5) A , Dcalc
=
1.216 g cm-3, μ(Cu KR) = 5.823 cm-1, F000 = 568.00, GOF =
0.966, Rint = 0.025, R1 = 0.0381, wR2 = 0.1091, Flack
parameter = -0.2(3).
7.15-7.21 (m, 2H), 7.28-7.35 (m, 3H), 7.40-7.48 (m, 2H); 13
C
NMR (100 MHz, CDCl3) δ 20.4, 34.0, 36.8, 36.9, 38.2, 125.3,
127.6, 127.9, 128.2, 128.6, 129.1, 129.7, 129.8, 137.5, 140.4,
142.1, 142.9, 176.6; IR (KBr) 2935, 1657, 1477 cm-1; HRMS
(ESI) m/z calcd for C18H19NO 266.1539 (M þ Hþ), found
266.1533. Compound 19a-R*0 did not isomerize at 150 °C for
3 h in DMF. The NOE experiment of 19a-R*0 is described in
Figure 6 to reveal that the relative stereochemistry is (a1R*,
a2S*,7S*). Similarly, C7-methylation of the atropisomer 3a-R
(25.7 mg, 0.102 mmol) afforded optically active compound 19a-
R0 (a1R,a2S,7S) (21.7 mg, 80%), mp 157-159 °C: [R]23D -165.5
Crystal data of 3b-R: C18H19ON, mp 160-162 °C, Mr =
˚
265.35, Cu KR (λ = 1.54187 A), orthorhombic, P212121, color-
less prism 0.40 ꢀ 0.40 ꢀ 0.15 mm3, crystal dimensions a =
˚
˚
˚
8.8513(3) A, b = 11.3404(3) A, c = 14.4414(5) A, R = 90°,
3
˚
β = 90°, γ = 90°, T = 173 K, Z = 4, V = 1449.58(8) A , Dcalc
=
1.216 g cm-3, μ(Cu KR) = 5.822 cm-1, F000 = 568.00, GOF =
0.862, Rint = 0.047, R1 = 0.0344, wR2 = 0.0752, Flack para-
meter = -0.0(3).
Crystal data of 19a-R0: C18H19ON, mp 157-159 °C, Mr =
1
(c 0.15, MeOH); H NMR and 13C NMR were identical with
˚
265.35, Cu KR (λ = 1.54187 A), orthorhombic, P212121, color-
less prism 0.25 ꢀ 0.20 ꢀ 0.10 mm3, crystal dimensions a =
those of 19a-R*0. The crystal structure of 19a-R0 determined by
the X-ray analysis is shown in Figure 6, and the crystal data are
described below.
˚
˚
˚
8.62372(16) A, b = 11.6285(2) A, c = 14.8609(3) A, R = 90°,
3
˚
β = 90°, γ = 90°, T = 173 K, Z = 4, V = 1490.27(5) A , Dcalc
=
1.183 g cm-3, μ(Cu KR) = 5.663 cm-1, F000 = 568.00, GOF =
0.994, Rint = 0.037, R1 = 0.0429, wR2 = 0.0992, Flack
parameter =0.0(5). The CIF files of the crystal data for 2b-S,
2b-R, 3b-S, 3b-R, and 19a-R0 are available in the Supporting
Information.
1,5,7-Trimethyl-5H,7H,8H,9H-dibenzo[b,d]azonin-6-one (19b-R0):
According to a similar procedure as described for the C7-
methylation of 3a-R, compound 3b-R (7.4 mg, 0.03 mmol)
was treated to afford 19b-R0 (7.0 mg, 90%) as colorless crystals,
mp 154-156 °C: 1H NMR (400 MHz, CDCl3) δ 1.02 (d, J = 6.8
Hz, 3H), 1.59-1.64 (m, 1H), 1.77-1.86 (m, 1H), 2.05 (s, 3H),
2.05-2.12 (m, 1H), 2.21-2.28 (m, 1H), 2.66 (ddd, J = 1.9, 5.8,
13.4 Hz, 1H), 2.78 (s, 3H), 6.96 (d, J = 7.5 Hz, 1H), 7.13 (d, J =
7.8 Hz, 1H), 7.18 (td, J = 1.4, 7.3 Hz, 1H), 7.22-7.36 (m, 4H);
13C NMR (100 MHz, CDCl3) δ 20.4, 29.9, 33.8, 36.7, 38.0,
124.8, 125.7, 128.0, 128.6, 129.2, 129.9, 136.4, 137.8, 140.0,
141.2, 143.0, 176.7; IR (KBr) 2934, 1660, 1464 cm-1; HRMS
(ESI) m/z calcd for C19H21NO 280.1696 (M þ Hþ), found
Acknowledgment. We thank Sagami Chemical Research
Center for X-ray analysis. This work was supported in part
by a Grant-in-Aid for Scientific Research (C) (21590124) and
a Grant-in-Aid for Young Scientists (B) (21790025) from the
Japan Society for the Promotion of Sciences.
280.1682; [R]22 -146.1 (c 0.11, MeOH). Compound 19b-R0
Supporting Information Available: General experimental
procedure, spectral data for all compounds, figures of thermal
isomerization rate of enantiomers of 1a, 1b, 2a, 3a, 17b-R, and
18a-R, and X-ray crystal data (CIF) for 2b-R, 2b-S, 3b-R, 3b-S,
and 19b-R0. This material is available free of charge via the
Internet at http://pubs.acs.org.
D
did not isomerize at 150 °C for 3 h in DMF.
Single-Crystal X-ray Analysis. Crystal data of 1b-S: C16H15-
˚
ON, mp 137-139 °C, Mr = 237.30, Cu KR (λ = 1.54187 A),
orthorhombic, P212121, colorless prism 0.30 ꢀ 0.30 ꢀ 0.20 mm3,
˚
crystal dimensions a = 8.04449(15) A, b = 8.25073(15) A,
˚
J. Org. Chem. Vol. 75, No. 17, 2010 5993