Stereochemical properties of N-benzoylated carbazole derivatives

Article abstract of DOI:10.1016/j.tet.2015.06.097

The atropisomeric properties of 2′,6′-disubstituted N-benzoylated carbazole derivatives were investigated. It was found that the bulky t-butyl and iodo groups restricted rotation about the N-C7′ and C7′-C1′ bonds to separate four stereoisomers, in which r

Full text of DOI:10.1016/j.tet.2015.06.097

Tetrahedron 71 (2015) 7046e7053
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereochemical properties of N-benzoylated carbazole derivatives
Susumu Kayama a, Hidetsugu Tabata a, Yuka Takahashi a, Norihiko Tani b,
,
Shintaro Wakamatsu a, Tetsuta Oshitari a, Hideaki Natsugari a, Hideyo Takahashi a
*
a School of Pharma Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan
b Faculty of Pharmaceutical Science, Teikyo Heisei University, 4-21-2 Nakano, Nakano-ku, Tokyo 164-8530, Japan
a r t i c l e i n f o
a b s t r a c t
The atropisomeric properties of 20,60-disubstituted N-benzoylated carbazole derivatives were in-
vestigated. It was found that the bulky t-butyl and iodo groups restricted rotation about the NeC70 and
C70eC10 bonds to separate four stereoisomers, in which rotation about the C70eC10 bond was in perfect
concert with rotation about the NeC70 bond. The relation of the rotation of the NeC70 and C70eC10 axes
was investigated by comparing the stereochemistry of variously 20,60-disubstituted N-benzoyl-carbazole
derivatives. It was suggested that the concerted rotation of the NeC70 and C70eC10 axes might occur even
in less hindered compounds.
Article history:
Received 1 June 2015
Received in revised form 26 June 2015
Accepted 28 June 2015
Available online 6 July 2015
Keywords:
Atropisomer
Gear molecule
Conformation
Stereochemistry
Carbazole
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
In the course of our study on stereochemical and physico-
chemical analyses of biologically active molecules,1 we reported the
atropisomeric properties of the indole derivatives (N-20,60-di-
substituted benzoyl-2-methylindoles) (Fig. 1(a)).2
The isolation of each enantiomer of 1 (aR and aS) with high
stereochemical stability confirmed that the rotation about the
C70eC10 axis is fully restricted by substituents at C20 and C60 to
form a twisted conformation. Recently, we have reported the
atropisomeric properties of the 20-alkyl-60-iodo-substituted N-
benzoyl-3-bromocarbazoles (Fig. 1(b)).3 Interestingly, the t-butyl-
substituted one was found to be a gear molecule,4 in which ro-
tation about the C70eC10 bond was in perfect concert with rotation
about the NeC70 bond. This unique behavior prompted us to in-
vestigate the specific stereochemical properties of variously 20-
and 60-disubstituted N-benzoyl carbazoles. In this study, adding
significant data to the preceding results, we determined the mode
of rotation about the NeC70 and C70eC10 axes utilizing 1H NMR
spectroscopy and X-ray crystallography, in combination with
calculations.
Fig. 1. (a) Atropisomers of 20,60-disubstituted N-benzoyl-2-methylindole (1). (b)
Atropisomers of 20-alkyl-60-iodo-substituted N-benzoyl-3-bromocarbazoles.
2. Results/discussion
Following the established method,3 N-benzoyl carbazole de-
rivatives (2e14) were synthesized, as shown in Scheme 1.
* Corresponding author. E-mail address: hide-tak@pharm.teikyo-u.ac.jp (H.
Takahashi).
http://dx.doi.org/10.1016/j.tet.2015.06.097
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

S. Kayama et al. / Tetrahedron 71 (2015) 7046e7053
7047
Fig. 3. X-ray crystal structure of 3.
We next examined the N-(20,40,60-trisubstituted)benzoyl-3-
bromocarbazole derivatives. For N-(20,40,60-trichloro)benzoyl-3-
bromocarbazole 4, two sets of resonance corresponding to cis and
trans conformations were observed in 1H NMR (cis:trans¼1:1.3).
Because the rotational barrier of the NeC70 axis is less than that
required for the isolation of each conformer at room temperature,
compound 4 was observed as one peak on non-chiral HPLC. It
Scheme 1. Synthesis of N-benzoylated carbazole derivatives.
1
should be noted that H NMR of N-(20,40,60-trimethyl)benzoyl-3-
bromocarbazole 5, which showed broad signals at room tempera-
ture, was observed as two sharpened sets of resonance corre-
sponding to cis and trans conformations (cis:trans¼1:1.2) at 0 ꢀC
(Fig. 4). In view of the steric bulkiness (van der Waals radius) of the
methyl (2.0 A) versus Cl (1.75 A), this appears strange. The com-
paratively higher steric hindrance of methyl versus Cl may de-
stabilize the ground states, thus lowering the interconversion
barrier. As a consequence, the peaks of the methyl derivative are
broad.
First, the conformations of compounds 2 and 3 were examined
based on the 1H NMR spectra in DMSO-d6. The aromatic protons of
the carbazole moiety of compound 2, which bears the N-4-
chlorobenzoyl group, were observed as two multiplet peaks: 2H
protons (H1 and H8) were observed at 8.18 ppm, and 6H protons
(H2, H3, H4, H5, H6, and H7) were observed at 7.37 ppm without
separation of each proton (Fig. 2(a) for 2). On the other hand, N-
(20,40,60-trichloro)benzoylated compound 3 was characterized by
a different pattern, in which H1 and H8 protons were differentiated
(Fig. 2(b) for 3). While H1 shifted to a lower field (8.66 ppm) caused
by the deshielding effect of the carbonyl group of the benzoyl
moiety, H8 shifted upfield (6.24 ppm) due to the shielding effect of
the benzene ring.
ꢀ
ꢀ
r
B
r
B
(a)
N
7'
N
7'
CH3
1'
H3C
1'
6'
O
O
6'
CH3
H3C
2'
2'
H3C
CH3
rans
c s
i
t
H5 H4
(a)
H6
H7
H3
H2
N
O
H8
H1
9.2 9.1 9.0 8.9 8.8 8.7 8.6 8.5 8.4 8.3 8.2 8.1 8.0 7.9 7.8 7.7 7.6 7.5 7.4 7.3 7.2 7.1 7.0 6.9 6.8 6.7 6.6 6.5 6.4 6.3 6.2 6.1 6.0 5.9 5.
parts per Million : Proton
H2/3/4/5/6/7
H1/8
(b)
Cl
2
8.7
8.6
8.5
8.4
8.3
8.2
8.1
8.0
7.9
7.8
7.7
7.6
7.5
7.4
7.3
7.2
7.1
7.0
6.9
6.8
6.7
6.6
6.5
6.4
6.3
6.2
parts per Million : Proton
H5 H4
(b)
H6
H3
H2
9.2 9.1 9.0 8.9 8.8 8.7 8.6 8.5 8.4 8.3 8.2 8.1 8.0 7.9 7.8 7.7 7.6 7.5 7.4 7.3 7.2 7.1 7.0 6.9 6.8 6.7 6.6 6.5 6.4 6.3 6.2 6.1 6.0 5.9 5.8
parts per Million : Proton
H7
shielded
N
H8
H1
deshielded
H8
Cl
H1
O
1
Fig. 4. H NMR (400 MHz, in CD2Cl2) spectra of compounds 5. (a) at 23 ꢀC and (b) at
0
Cl
Cl
ꢀC.
3
8.7
8.6
8.5
8.4
8.3
8.2
8.1
8.0
7.9
7.8
7.7
7.6
7.5
7.4
7.3
7.2
7.1
7.0
6.9
6.8
6.7
6.6
6.5
6.4
6.3
6.2
parts per Million : Proton
1
We next focused on the C20 and C60 differently substituted de-
Fig. 2. H NMR (400 MHz, in DMSO-d6) spectra of compounds 2 (a) and 3 (b) at 23 ꢀC.
rivatives 6e11. In all of these compounds, as well as in 4 and 5, two
sets of resonance corresponding to cis and trans conformations are
observed in 1H NMR (cis:trans¼1:1.2e1.3)6, although one peak is
observed on non-chiral HPLC at room temperature. It is clear that
the rotational barrier of the NeC70 axis is less than that required for
the isolation of each conformer at room temperature. Since we
succeeded in eliciting atropisomerism about the C70eC10 bond in N-
benzoyl-2-methylindole derivative 1 by introducing substituents at
C20 and C60 of benzoyl,2 we attempted separation of the atro-
pisomers of 6e11 at room temperature using chiral HPLC. Although
incomplete separation was observed for compounds 6e10, N-20-
We also succeeded in obtaining 3 as a single crystal, and its X-
ray analysis5 yielded meaningful information (Fig. 3).
The dihedral angle (f
) C60-C10-C70-O of 75.19ꢀ in compound 3
confirmed that the benzene ring is nearly orthogonal to the car-
bazole ring. It is obvious that the substituents at the 20-,60-positions
of benzoyl affects the NeC70 and C70eC10 axes to form a twisted
conformation similar to the N-benzoylated 2-methylindole de-
rivative 1.2

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S. Kayama et al. / Tetrahedron 71 (2015) 7046e7053
iodo-60-methylbenzoyl-3-bromocarbazole 113 was separated into
two peaks (CHIRALPAK IB), which means that the rotation of the
C70eC10 axis was reduced without relation to the rotation of the
NeC70 axis (Scheme 2). The atropisomers of compound 11 (11A and
11B) were successfully isolated using preparative chiral HPLC
(CHIRALPAK IB) and stereochemical stability with the activation
examined at room temperature, and we failed to isolate atro-
pisomers of 13. For compound 13, coalescence does not occur even
at 120 ꢀC in VT NMR (see the Supplementary data) and we therefore
gave up the attempt to determine the energy barrier of the in-
terconversion of cis/trans conformers of compound 13. By com-
paring the energy barrier (D
Gz) of the interconversion between cis/
free energy barrier to rotation value (
D
Gz)7 of 108 kJmolꢁ1 was
trans conformers of compounds 11e13, it is suggested that the
steric hindrance caused by alkyl substituents also reduces the ro-
tation of the NeC70 axis.
observed.3 The similar barrier height in compound 11 in compari-
son with that in N-(20-iodo-60-methylbenzoyl)-2-methylindole
(D
Gz value7 of 109 kJ molꢁ1) is likely explained by the similar ste-
Finally, surprising results were provided by compound 14. 14
was observed as two separated peaks (cis, trans) on non-chiral
HPLC, and four stereoisomers [(cis, aS), (cis, aR), (trans, aS), (trans,
aR)] were resolved on a chiral column (CHIRALPAK IB), as shown in
Scheme 3. All the isomers that can potentially result since each axis
can assume two orientations (cis/trans for the NeC70 axis, aR/aS for
the C70eC10 axis) were successfully isolated using preparative
chiral HPLC. Fortunately, the (trans, aS) isomer and (cis, aS) isomer
could be analyzed by X-ray crystallography to determine the ab-
solute stereochemistry,3 and hence the (trans, aR) isomer and (cis,
aR) isomer were determined. Using the enantiomerically pure
stereoisomer (cis, aS), the stereochemical stability was examined by
chiral HPLC analysis at 37 ꢀC in toluene after 9 days. We found that
ric or electronic effect due to the methyl group versus the aromatic
CeH. Furthermore, we performed VT NMR studies of compound 11,
which allowed us to follow the interconversion of the cis/trans
conformers (see the Supplementary data). In the VT NMR spectra of
11 in DMSO-d6, the coalescences of the signals for the cis/trans
conformers occurred at 80 ꢀC, which indicates that these con-
formers interconverted with the
D . It
Gz value of 75.8 kJ molꢁ1 8
should be noted that the possible interconversion pathways for
stereoisomers of 11 may be complicated, as shown in Scheme 2.
Although we have limited information on the ordering of priority of
the interconverting pathways, it is clear that the energy barrier of
the interconversion of the cis/trans conformers (75.8 kJ molꢁ1) is
lower than that of the interconversion of atropisomers
(108 kJ molꢁ1).
(cis, aS) was converted into (trans, aR) with a
D
Gz value7 of
102 kJ molꢁ1, and no interconversion between any other pair [i.e.,
(cis, aS)/(cis, aR), (cis, aS)/(trans, aS)] was seen. Similarly, enantio-
merically pure (trans, aS) was converted into (cis, aR) with a
D
Gz
value7 of 103 kJ molꢁ1; no interconversion between any other pair
[i.e., (trans, aS)/(trans, aR), (trans, aS)/(cis, aS)] was observed over 7
days.3 It is clear that rotation about the C70eC10 axis must be in
perfect concert with rotation about the NeC70 axis at 37 ꢀC for at
least 7 days (Scheme 3). Although such behavior has been observed
in tertiary aromatic amide systems,9 complete geared rotation
without slippage was observed here for the first time. In order to
estimate the stability of this gear system, conversion of the enan-
tiomerically pure (cis, aS) into (trans, aR) at higher temperature was
followed by analytical HPLC until the gear slipped. In previous pa-
pers on molecular gear systems, gear slippage was observed at
ambient temperature.9 However, the slippage in this system was
finally observed only after 27 h heating at 100 ꢀC.3
Scheme 2. Interconversion pathways for stereoisomers of 11e13.
We next examined carbazoles with bulkier substituents, ethyl,
isopropyl, and t-butyl groups (compounds 12,3 13,3 143). For all
compounds, two sets of resonance corresponding to cis and trans
conformers (cis:trans¼1:1.2) were observed in the 1H NMR spectra.
Although compound 12 was observed as one peak on the non-
chiral column, it was partially separated on the chiral column
(CHIRALPAK IB) at room temperature, and hence we managed to
isolate the atropisomers (12A, 12B) with preparative HPLC. The
stereochemical stability with a
D
Gz value7 of 110 kJ molꢁ1 for 12A
and 12B may account for the increased stability of the C70eC10 axis
in 12. Examination of the VT NMR studies of compound 12 eluci-
dated that the coalescences of the cis/trans conformers of com-
pound 12 occurred at 105 ꢀC, and the barrier to the cis/trans
Scheme 3. Interconversion pathways for stereoisomers of 14.
D
Gz value of
Being interested in the process that initiates this gear system,
we performed detailed separation analysis of 6e13 on a chiral
column (CHIRALPAK IB) at 37 ꢀC and 2 ꢀC (Fig. 5). First, the
interconversion was determined to have the
81.0 kJ molꢁ1 (see the Supplementary data). On the contrary,
compound 13 was observed as one peak on all chiral columns

S. Kayama et al. / Tetrahedron 71 (2015) 7046e7053
7049
CEP-4G basis set with a Gaussian program.13 To cover all confor-
mational spaces, rotational steps of the single bonds were 15ꢀ. As
mentioned above, compounds 11e14 can rotate around the NeC70
and C70eC10 axes, which results in the energy surface shown in
Fig. 6. There were four stable conformers (M1, M2, M3, and M4),
corresponding to (trans, aR), (cis, aS), (cis, aR), and (trans, aS), re-
spectively, as shown in Scheme 2. Based on the energy barriers of
the pathways on the energy surface of compounds 11e13, it is clear
that the interconversion between conformers M1 and M2, and
between M3 and M4, is easy, which implies that the concerted
rotation of the NeC70 and C70eC10 axes should occur even in
compounds 11e13 (Scheme 2). The calculated activation barrier of
geared rotation at the RB3LYP/LanL2DZ level14 for compounds
11e13 also supports this (Fig. 6). For compound 11, the in-
terconversion between conformers M2 and M3, and between M1
and M4, seems somewhat difficult, which may result in the iso-
Fig. 5. Chromatograms of 6e13: at 37 ꢀC (upper) and at 2 ꢀC (lower).
lation of the atropisomers (11A and 11B) with a
D
Gz value of
108 kJ molꢁ1. On the contrary, the four conformers (M1, M2, M3,
and M4) should be easily interconverted into each other in com-
pounds 12 and 13 so that the stereoisomers would not be isolated.
For compound 13, the calculated results agreed with the experi-
mental results showing that the separation of stereoisomers of
compound 13 failed. However, considering that the atropisomers of
compound 12 were isolated by preparative HPLC, these calculated
results need further consideration. Based on the energy surface of
compound 14, it is clear that the interconversion between con-
formers M1 and M2, and between M3 and M4, is easy in compar-
ison with other pathways. It is important to note that all of the
energy barriers of the interconversion pathways are relatively high
in compound 14, which implies that each conformer (M1, M2, M3,
M4) should be isolated at ambient temperature. These calculated
results are consistent with the experimental results showing that
complete geared rotation without slippage was observed in com-
pound 14.
separation of compound 6, which was partially separated on the
chiral column (CHIRALPAK IB) at room temperature, was exam-
ined. While 6 was poorly resolved at 37 ꢀC, better separation of the
peaks was observed at 2 ꢀC. On the contrary, the chromatograms
of N-20-chloro-60-iodobenzoyl-3-bromocarbazole 7, N-20-bromo-
60-iodobenzoyl-3-bromocarbazole 8, N-20-iodo-60-methylbenzoyl-
3-bromocarbazole
11,
and
N-20-ethyl-60-iodobenzoyl-3-
bromocarbazole 12 broadened at lower temperature (2 ꢀC). Gen-
erally, enantiomers that are partially resolved at ambient tem-
perature can be resolved at a lower one.10 Even allowing for the
possibility that the lower column temperature reduced its effi-
ciency caused by slower adsorption-desorption kinetics, such
a significant decrease in the resolution observed in these cases
seemed unusual. In comparison with the steric bulkiness (van der
ꢀ
3 11
ꢀ
ꢀ
Waals radius) of Br (1.85 A) versus Cl (1.75 A), and van der Waals
3 10
ꢀ
volume of ethyl (38.9 A ) versus methyl (21.6 A ), it also
appeared strange that the relatively steric hindrance did not
contribute to allowing the baseline separation of the enantiomers.
As mentioned above, however, the atropisomers of 11 were iso-
3. Conclusions
lated at room temperature by preparative chiral HPLC with a
value of 108 kJ molꢁ1, and those of 12 were isolated at room
temperature with a
Gz value of 110 kJ molꢁ1, which means that
D
Gz
By introducing various substituents at the 20 and 60 positions of
N-benzoyl-carbazole derivatives, the mode of rotation about the
NeC70 and/or C70eC10 axes was investigated. Utilizing the results of
1H NMR studies and HPLC chromatography, and in silico confor-
mational analysis, the effects of the substituents on both axes were
elucidated. Although the separation of the cis/trans diastereomers
was not possible, it was revealed that the steric or electronic effects
of the substituents caused a certain barrier to rotation about the
NeC70 bond in compounds 11e13. Detailed separation analysis of
6e13 on a chiral column showed the process by which the rotation
of both the NeC70 and C70eC10 axes became slow. Although the cue
that initiates the gear system is still unclear, this study will con-
tribute to knowledge of the stereochemical properties of the 20,60-
disubstituted N-benzoylated carbazole derivatives.
D
the decrease in the resolution of chromatograms observed at 2 ꢀC
is not related to the stability of the atropisomeric properties of the
compounds. Considering all the results together, the broad chro-
matograms of 7, 8, 11, and 12 at 2 ꢀC may represent the earliest
stage of the separation of the cis/trans isomers arising from the
NeC70 axis. Meanwhile, in N-20-methyl-60-nitrobenzoyl-3-
bromocarbazole
bromocarbazole 10, the single broad peak observed at 37 ꢀC was
partly separated at
ꢀC with the appearance of the in-
9
and N-20-iodo-60-trifluoromethylbenzoyl-3-
2
terconversion plateau. Similarly, the chromatogram of N-20-iodo-
60-isopropylbenzoyl-3-bromocarbazole 13 showed four peaks that
were almost completely separated, which is similar to that of gear
compound 14 at room temperature. We assume that the sub-
stituents at the ortho positions in 9, 10, and 13 cause a half-barrier
to the rotation about the NeC70 and C70eC10 axes at the same
time. Therefore, the two peaks representing the atropisomers may
be divided into two halves, which appeared as broad peaks at
37 ꢀC, and as four partly separated peaks with the appearance of
the interconversion plateau at 2 ꢀC. The chromatograms of 6e13
may be helpful for understanding the process by which the rota-
tion of both the NeC70 and C70eC10 axes becomes slow.
4. Experimental section
4.1. General information
Materials were obtained from commercial suppliers and used
without further purification, unless otherwise noted. Melting points
were recorded on a Yanaco micro melting point apparatus and are
uncorrected. NMR spectra were recorded on a spectrometer at
600 MHz, 400 MHz for 1H NMR, and 150 MHz,100 MHz for 13C NMR.
Chemical shifts are given in parts per million (ppm) downfield from
tetramethylsilane as an internal standard, and coupling constants (J)
are reported in Hertz (Hz). Splitting patterns are abbreviated as
follows: singlet (s), doublet (d), triplet (t), quartet (q), septet (sept),
multiplet (m), and broad (br). IR spectra were recorded on a JASCO
Additionally, we carried out in silico conformational analysis12 of
11e14 to elucidate the process by which this molecular gear system
starts moving. In order to obtain the initial 3D molecular co-
ordinates of the compounds, the X-ray crystal structure of (cis, aS)
was used. Ab initio calculations were performed using the RHF/

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S. Kayama et al. / Tetrahedron 71 (2015) 7046e7053
Fig. 6. Energy surface for 11, 12, 13, and 14.
FT/IR-4200 FTIR spectrometer. High-resolution mass spectra
(HRMS) were recorded on a Shimadzu LCMS-IT-TOF mass spec-
trometer (in ESI mode). Optical rotations were determined with
a JASCO P-2200 digital polarimeter. Analytical thin-layer chroma-
tography was performed on Merck silica gel 60 F-254 plates. Col-
umn chromatography was performed using silica gel (45e60 mm,
Fuji Silysia Chemical Ltd.). High-pressure liquid chromatography
(HPLC) was performed with a Shimadzu Prominence system.
same procedure as that used for the synthesis of 2 described above
to afford the product 3 (125 mg, 0.33 mmol, 83%) as colorless
crystals. Mp 120e121 ꢀC; Rf (20% AcOEt/hexane) 0.31; 1H NMR
(400 MHz, DMSO-d6):
d
8.67 (1H, dd, J¼8.0,1.2 Hz, H1), 8.20 (1H, dd,
J¼8.0, 2.0 Hz, H5), 8.20 (1H, dd, J¼8.0, 1.2 Hz, H4), 8.02 (2H, s,
H30,H50), 7.59 (1H, dt, J¼8.0, 1.2 Hz, H2), 7.51 (1H, dt, J¼8.0, 1.2 Hz,
H3), 7.38 (1H, t, J¼8.0 Hz, H6), 7.28 (1H, dt, J¼8.0, 2.0 Hz, H7), 6.25
(1H, d, J¼8.0 Hz, H8); 13C NMR (100 MHz, DMSO-d6):
d 162.8 (C]O),
{138.5, 137.4, 136.8, 134.3, 132.4}(Ar), 129.9 (C30,C50), 128.9 (C2),
128.6 (C7), {127.0, 126.6}(Ar), 126.1 (C3), 125.3 (C6), {121.7,
120.9}(C4,C5), 117.8 (C1), 113.0 (C8); IR (KBr): 1686 cmꢁ1; HRMS
4.2. 9-(4-Chlorobenzoyl)-carbazole (2)
(ESI): m/z calcd for
C
19H10Cl3NO: 373.9901 [MþH]þ; found:
To a solution of carbazole (67 mg, 0.40 mmol) in DMF (2 mL) at
0 ꢀC under argon was added successively NaH (19.2 mg, 0.48 mmol),
373.9898.
and 4-chlorobenzoyl chloride (61 mL, 0.48 mmol). After being stirred
at 23 ꢀC for 20 h, the reaction was quenched with H2O and extracted
with AcOEt. The organic layer was washed with brine and dried over
MgSO4. After evaporation in vacuo, the residue was purified by silica
gel column chromatography (AcOEt/hexane¼1/10) to give 2 as
colorless crystals (82.1 mg, 0.27 mmol, 67%), mp 158 ꢀC; Rf (10%
4.4. 9-(2,4,6-Trichlorobenzoyl)-3-bromocarbazole (4)
2,4,6-Trichlorobenzoyl chloride (75 L, 0.48 mmol) was sub-
m
jected to reaction with 3-bromocarbazole (98 mg, 0.40 mmol) fol-
lowing the same procedure as that used for the synthesis of 2
described above to afford the product 4 (166 mg, 0.37 mmol, 92%,
cis:trans¼1:1.3) as colorless crystals. Mp 212 ꢀC; Rf (20% AcOEt/
AcOEt/hexane) 0.44; 1H NMR (400 MHz, CDCl3):
d
8.00 (2H, m), 7.67
(2H, m), 7.51 (4H, m), 7.35 (4H, m), 13C NMR (100 MHz, CDCl3):
168.5 (C]O), {139.1, 138.9, 134.1, 130.7, 129.4, 126.9, 126.2, 123.7,
hexane) 0.35; cis-4: 1H NMR (400 MHz, DMSO-d6):
d 8.64 (1H, dd,
d
120.3, 115.8}(Ar); IR (KBr): 1678 cmꢁ1; HRMS (ESI): m/z calcd for
J¼7.2, 1.2 Hz, H8), 8.51 (1H, d, J¼2.4 Hz, H4), 8.28 (1H, dd, J¼7.2,
1.2 Hz, H5), 8.03 (2H, s, H30,H50), 7.63 (1H, dt, J¼7.2, 1.2 Hz, H7), 7.53
(1H, dt, J¼7.2, 1.2 Hz, H6), 7.47 (1H, dd, J¼8.8, 2.4 Hz, H2), 6.19 (1H,
C
19H12ClNO: 306.0680 [MþH]þ; found: 306.0671.
4.3. 9-(2,4,6-Trichlorobenzoyl)-carbazole (3)
d, J¼8.8 Hz, H1); trans-4: 1H NMR (400 MHz, DMSO-d6):
d 8.58 (1H,
d, J¼8.8 Hz, H1), 8.53 (1H, d, J¼2.0 Hz, H4), 8.28 (1H, dd, J¼7.2,
1.2 Hz, H5), 8.03 (2H, s, H30,H50), 7.75 (1H, dd, J¼8.8, 2.0 Hz, H2),
7.40 (1H, dt, J¼7.2, 1.2 Hz, H6), 7.33 (1H, dt, J¼7.2, 1.2 Hz, H7), 6.25
2,4,6-Trichlorobenzoyl chloride (75
mL, 0.48 mmol) was sub-
jected to reaction with carbazole (67 mg, 0.40 mmol) following the

S. Kayama et al. / Tetrahedron 71 (2015) 7046e7053
7051
(1H, dd, J¼7.2, 1.2 Hz, H8); 13C NMR (100 MHz, DMSO-d6):
d
162.8
1686 cmꢁ1; HRMS (ESI): m/z calcd for C20H13BrClNO: 397.9942
[MþH]þ; found: 397.9933.
(C]O for trans), 162.7 (C]O for cis), {138.8, 137.7, 137.6, 137.3, 137.1,
135.8, 134.0,133.9, 129.7, 128.8,126.3, 125.5,118.5, 117.9}(Ar), {131.4,
132.3, 123.0, 129.9}(C30 ꢂ2, C50 ꢂ2), 131.1 (C2 for cis), 129.4 (C7 for
cis), 125.8 (C6 for cis), 124.5 (C4 for cis), 121.6 (C5 for cis), 117.8 (C8
for cis), 114.9 (C1 for cis), 131.4 (C2 for trans), 129.2 (C7 for trans),
125.5 (C6 for trans), 123.8 (C4 for trans), 122.3 (C5 for trans), 119.5
(C1 for trans), 113.0 (C8 for trans); IR (KBr): 1693 cmꢁ1; HRMS (ESI):
m/z calcd for C19H9BrCl3NO: 451.9006 [MþH]þ; found: 451.9004.
4.7. 9-(2-Chloro-6-iodobenzoyl)-3-bromocarbazole (7)
2-Chloro-6-iodobenzoyl chloride (180.5 mg, 0.6 mmol) was
subjected to reaction with 3-bromocarbazole (73.8 mg, 0.3 mmol)
following the same procedure as that used for the synthesis of 5
described above to afford the product 7 (135.7 mg, 0.27 mmol, 89%,
cis:trans¼1:1.3) as white solids. Mp 122e123 ꢀC; Rf (10% AcOEt/
4.5. 9-(2,4,6-Trimethylbenzoyl)-3-bromocarbazole (5)
hexane) 0.29; cis-7: 1H NMR (400 MHz, DMSO-d6):
d 8.67 (1H, d,
J¼7.6 Hz, H8), 8.50 (1H, d, J¼2.4 Hz, H4), 8.28 (1H, d, J¼7.6 Hz, H5),
8.02 (1H, d, J¼7.6 Hz, H50), 7.76 (1H, m, H30), 7.63 (1H, t, J¼7.6 Hz,
H7), 7.52 (1H, t, J¼7.6 Hz, H6), 7.41 (2H, m, H2, H40), 5.96 (1H, d,
To a solution of 3-bromocarbazole (73.8 mg, 0.3 mmol) in THF
(2 mL) KHMDS (1.8 mL in 0.5 M solution of toluene, 0.9 mmol) was
added and stirred at room temperature for 30 min. 2,4,6-
trimethylbenzoyl chloride (109.6 mg 0.6 mmol) in THF (2 mL)
was added to the mixture at 0 ꢀC. After stirring for 20 h at room
temperature, the reaction was quenched with H2O and extracted
with AcOEt. The organic layer was washed with brine and dried
over MgSO4. After evaporation in vacuo, the residue was purified by
silica gel column chromatography (AcOEt/hexane¼1/10) to give 5
(93.6 mg, 0.24 mmol, 80%, cis:trans¼1:1.3 at 0 ꢀC) as white solids.
Mp 131.5 ꢀC; Rf (10% AcOEt/hexane) 0.43; cis-5: 1H NMR (600 MHz,
J¼8.8 Hz, H1); trans-7: 1H NMR (400 MHz, DMSO-d6):
d 8.61 (1H, d,
J¼8.8 Hz, H1), 8.52 (1H, d, J¼2.0 Hz, H4), 8.28 (1H, d, J¼7.6 Hz, H5),
8.02 (1H, d, J¼7.6 Hz, H50), 7.76 (2H, m, H30, H2), 7.41 (2H, m, H6,
H40), 7.24 (1H, t, J¼7.6 Hz, H7), 6.04 (1H, d, J¼7.6 Hz, H8); 13C NMR
(100 MHz, DMSO-d6)
d 166.2 (C]O for trans), 166.1 (C]O for cis),
{140.7, 140.6, 139.1, 137.6, 137.4, 136.0, 129.1, 129.0, 126.0, 125.8,
125.4, 118.3, 117.9}(Ar), {134.2, 134.1, 130.7, 125.2}(C40 ꢂ2 for cis and
trans, C2 for cis, C6 for trans), 138.9 (C50 for cis), 130.5 (C30 for cis),
129.6 (C7 for cis), 124.4 (C4 for cis), 121.5 (C5 for cis), 117.7 (C8 for
cis), 115.1 (C1 for cis), 131.3 (C2 for trans), 128.8 (C7 for trans), 123.7
(C4 for trans), 122.1 (C5 for trans), 119.6 (C1 for trans), 113.3 (C8 for
CD2Cl2 at 0 ꢀC):
d
8.85 (1H, d, J¼5.6 Hz, H8), 8.11 (1H, s, H4), 8.00
(1H, d, J¼5.6 Hz, H5), 7.60 (1H, t, J¼5.6 Hz, H7), 7.48 (1H, t, J¼5.6 Hz,
H6), 7.17 (1H, d, J¼6.0 Hz, H2), 7.01 (2H, s, H30,H50), 5.94 (1H, d,
J¼6.0 Hz, H1), 2.40 (3H, s, CH3), 2.09 (6H, s, CH3 ꢂ2); trans-5: 1H
trans); IR (KBr) 1674 cmꢁ1
C
; HRMS (ESI): m/z calcd for
19H10BrClINO: 509.8752 [MþH]þ; found: 509.8767.
NMR (600 MHz, CD2Cl2 at 0 ꢀC):
d
8.76 (1H, d, J¼6.0 Hz, H1), 8.23
(1H, s, H4), 7.95 (1H, d, J¼5.2 Hz, H5), 7.60 (1H, d, J¼6.0 Hz, H2), 7.29
4.8. 9-(2-Bromo-6-iodobenzoyl)-3-bromocarbazole (8)
(1H, t, J¼5.2 Hz, H6), 7.09 (1H, t, J¼5.2 Hz, H7), 7.01 (2H, s, H30,H50),
6.09 (1H, d, J¼5.2 Hz, H8), 2.40 (3H, s, CH3), 2.09 (6H, s, CH3 ꢂ2); 13
C
2-Bromo-6-iodobenzoyl chloride (207.2 mg, 0.6 mmol) was
subjected to reaction with 3-bromocarbazole (73.8 mg, 0.3 mmol)
following the same procedure as that used for the synthesis of 5
described above to afford the product 8 (127.5 mg, 0.23 mmol, 77%,
cis:trans¼1:1.3) as white solids. Mp 124 ꢀC; Rf (10% AcOEt/hexane)
NMR (150 MHz, CD2Cl2 at 0 ꢀC):
d 169.2 (C]O for trans), 169.1 (C]O
for cis), {139.6, 139.5, 138.5, 137.3, 136.9, 135.8, 133.4, 133.3, 133.2,
127.8, 127.4, 124.6, 124.2, 116.5, 115.8}(Ar), 128.8 (C2 for cis), 128.1
(C30, C50 for cis), 127.7 (C7 for cis), 123.8 (C6 for cis),122.0 (C4 for cis),
118.9 (C5 for cis), 117.0 (C8 for cis), 114.4 (C1 for cis), 20.4 (CH3 for
cis), 17.9 (CH3 ꢂ2 for cis), 129.5 (C2 for trans), 128.1 (C30, C50 for
trans), 127.0 (C7 for trans), 123.0 (C6 for trans), 121.5 (C4 for trans),
119.4 (C5 for trans), 118.5 (C1 for trans), 112.9 (C8 for trans), 20.4
(CH3 for trans), 17.9 (CH3 ꢂ2 for trans); IR (KBr) 1682 cmꢁ1; HRMS
0.40; cis-8: 1H NMR (400 MHz, DMSO-d6):
d
8.70 (1H, d, J¼8.0 Hz,
H8), 8.50 (1H, d, J¼2.0 Hz, H4), 8.28 (1H, dd, J¼8.0, 1.6 Hz, H5), 8.05
(1H, d, J¼7.6 Hz, H50), 7.89 (1H, d, J¼7.6 Hz, H30), 7.63 (1H, dt, J¼8.0,
1.6 Hz, H7), 7.52 (1H, t, J¼8.0 Hz, H6), 7.35 (2H, m, H2, H40), 5.96 (1H,
d, J¼8.8 Hz, H1); trans-8: 1H NMR (400 MHz, DMSO-d6):
d 8.61 (1H,
(ESI): m/z calcd for
392.0658.
C
22H18BrNO: 392.0645 [MþH]þ; found:
d, J¼8.8 Hz, H1), 8.52 (1H, d, J¼2.0 Hz, H4), 8.26 (1H, dd, J¼8.0,
1.2 Hz, H5), 8.05 (1H, d, J¼7.6 Hz, H50), 7.89 (1H, d, J¼7.6 Hz, H30),
7.50 (1H, dd, J¼8.8, 2.0 Hz, H2), 7.35 (2H, m, H6, H40), 7.24 (1H, dt,
J¼8.0, 1.2 Hz, H7), 6.04 (1H, d, J¼8.0 Hz, H8); 13C NMR (100 MHz,
4.6. 9-(2-Chloro-6-methylbenzoyl)-3-bromocarbazole (6)
DMSO-d6):
d 167.1 (C]O for trans), 166.9 (C]O for cis), {142.5,
2-Chloro-6-methylbenzoyl chloride (113.4 mg, 0.6 mmol) was
subjected to reaction with 3-bromocarbazole (73.8 mg, 0.3 mmol)
following the same procedure as that used for the synthesis of 5
described above to afford the product 6 (104.4 mg, 0.26 mmol, 87%,
cis:trans¼1:1.2) as white solids. Mp 113 ꢀC; Rf (10% AcOEt/hexane)
142.3, 139.1, 137.6, 137.4, 136.0, 129.6,129.1, 126.0,125.5, 119.5, 119.5,
118.3, 117.6}(Ar), {134.3, 134.3, 130.6, 125.2}(C40 ꢂ2 for cis and trans,
C2 for cis, C6 for trans), 139.3 (C50 for cis), 133.6 (C30 for cis), 129.0
(C7 for cis), 125.8 (C6 for cis), 124.3 (C4 for cis), 121.5 (C5 for cis),
117.9 (C8 for cis), 115.2 (C1 for cis), 95.2 (C60 for cis), 139.3 (C50 for
trans), 133.5 (C30 for trans), 131.3 (C2 for trans), 128.8 (C7 for trans),
123.7 (C4 for trans), 122.1 (C5 for trans), 119.7 (C1 for trans), 113.4
(C8 for trans), 95.2 (C60 for trans); IR (KBr) 1678 cmꢁ1; HRMS (ESI):
m/z calcd for C19H10Br2INO: 553.8247 [MþH]þ; found: 553.8227.
0.35; cis-6: 1H NMR (400 MHz, DMSO-d6):
d
8.69 (1H, d, J¼8.0 Hz,
H8), 8.48 (1H, d, J¼2.4 Hz, H4), 8.27 (1H, d, J¼8.0 Hz, H5), 7.59 (2H,
m, H7, H30), 7.48 (3H, m, H6, H50, H40), 7.33 (1H, m, H2), 5.89 (1H, d,
J¼8.4 Hz, H1), 2.17 (3H, s, CH3); trans-6: 1H NMR (400 MHz, DMSO-
d6):
d
8.63 (1H, d, J¼8.8 Hz, H1), 8.51 (1H, d, J¼2.0 Hz, H4), 8.24 (1H,
d, J¼8.0 Hz, H5), 7.73 (1H, dd, J¼8.8, 2.0 Hz, H2), 7.59 (1H, m, H30),
7.48 (2H, m, H50, H40), 7.33 (1H, m, H6), 7.19 (1H, t, J¼8.0 Hz, H7),
5.97 (1H, d, J¼8.0 Hz, H8), 2.17 (3H, s, CH3); 13C NMR (100 MHz,
4.9. 9-(2-Methyl-6-nitrobenzoyl)-3-bromocarbazole (9)
2-Methyl-6-nitrobenzoyl chloride (119.8 mg, 0.6 mmol) was
subjected to reaction with 3-bromocarbazole (73.8 mg, 0.3 mmol)
following the same procedure as that used for the synthesis of 5
described above to afford the product 9 (55.2 mg, 0.13 mmol, 45%,
cis:trans¼1:1.3) as yellow solids. Mp 169 ꢀC; Rf (33% AcOEt/hexane)
DMSO-d6):
d 166.4 (C]O for trans), 166.3 (C]O for cis), {139.0,
137.6,137.5,137.4,136.3,135.8,135.7,129.0,128.9,125.7,125.3,118.0,
117.4}(Ar), {130.5, 130.5, 128.1, 128.1}(C40 ꢂ2, C50 ꢂ2), 132.6 (C30 for
cis), 131.2 (C2 for cis), 129.5 (C7 for cis), 125.8 (C6 for cis), 124.3 (C4
for cis), 121.4 (C5 for cis),117.7 (C8 for cis),115.0 (C1 for cis), 19.1 (CH3
for cis), 132.6 (C30 for trans), 131.2 (C2 for trans), 128.7 (C7 for trans),
125.0 (C6 for trans), 123.7 (C4 for trans), 122.1 (C5 for trans), 119.5
(C1 for trans), 113.1 (C8 for trans), 19.1 (CH3 for trans); IR (KBr)
0.40; cis-9: 1H NMR (400 MHz, DMSO-d6):
d
8.65 (1H, d, J¼8.0 Hz,
H8), 8.50 (1H, s, H4), 8.28 (1H, m, H5), 8.27 (1H, m, H50), 7.90 (1H, m,
H30), 7.84 (1H, m, H40), 7.64 (1H, t, J¼8.0 Hz, H7), 7.52 (1H, t,
J¼8.0 Hz, H6), 7.33 (1H, m, H2), 6.05 (1H, d, J¼8.8 Hz, H1), 2.09 (3H,

7052
S. Kayama et al. / Tetrahedron 71 (2015) 7046e7053
s, CH3); trans-9: 1H NMR (400 MHz, DMSO-d6):
d
8.60 (1H, d,
of Science. H.T. is grateful for financial support from the Astellas
Foundation for Research on Metabolic Disorders (2013), Uehara
Memorial Foundation (2014), and MEXT-Supported 53.6 Program
for the Strategic Research Foundation at Private Universities
(2013d2017). H.T. thanks Dr. Motoko Hayashi and her co-workers
at Daicel Corporation for informative discussions on chiral HPLC
spectra.
J¼8.8 Hz, H1), 8.54 (1H, s, H4), 8.28 (1H, m, H5), 8.27 (1H, m, H50),
7.90 (1H, m, H30), 7.84 (1H, m, H40), 7.75 (1H, d, J¼8.8 Hz, H2), 7.33
(1H, m, H6), 7.17 (1H, t, J¼8.4 Hz, H7), 6.10 (1H, d, J¼8.4 Hz, H8), 2.09
(3H, s, CH3); 13C NMR (100 MHz, DMSO-d6):
d 165.8 (C]O for trans),
165.7 (C]O for cis), {145.8, 139.1, 137.6, 137.3, 137.3, 136.0, 131.5,
131.4, 129.0, 128.5, 125.7, 125.2, 118.0, 117.5}(Ar), 138.4 (C30 for cis),
132.3 (C40 for cis), 130.5 (C2 for cis), 129.6 (C7 for cis), 125.8 (C6 for
cis), 124.3 (C4 for cis), 123.8 (C50 for cis), 121.5 (C5 for cis), 117.5 (C8
for cis),114.9 (C1 for cis),18.5 (CH3 for cis),138.4 (C30 for trans),132.3
(C40 for trans), 131.2 (C2 for trans), 128.9 (C7 for trans), 125.1 (C6 for
trans), 123.8 (C50 for trans), 123.7 (C4 for trans), 122.2 (C5 for trans),
119.4 (C1 for trans), 113.0 (C8 for trans), 18.5 (CH3 for trans); IR (KBr)
1678 cmꢁ1; HRMS (ESI): m/z calcd for C20H13BrN2O3: 409.0182
[MþH]þ; found: 409.0165.
Supplementary data
Supplementary data (1H and 13C NMR spectra of all compounds,
the VT NMR studies, details of computational studies, and XRD
crystallography files) associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2015.06.097.
References and notes
4.10. 9-(2-Iodo-6-trifluoromethyl)-3-bromocarbazole (10)
1. For representative articles on axial chirality, see: (a) Clayden, J. Tetrahedron
Symposia-in-print on Atropisomerism, 2004, Vol. 60, p 4335; (b) Clayden, J.;
Moran, W. J.; Edwards, P. J.; Laplante, S. R. Angew. Chem., Int. Ed. 2009, 48,
63989e66401; (c) Zask, A.; Murphy, J.; Ellestad, G. A. Chirality 2013, 25,
265e274; (d) Laplante, S. R.; Fader, L. D.; Fandrick, K. R.; Fandrick, D. R.; Hucke,
O.; Kemper, R.; Miller, S. P. F.; Edwards, P. J. J. Med. Chem. 2011, 54, 7005e7022;
(e) 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, 3982e3993;
(f) Lee, S.; Kamide, T.; Tabata, H.; Takahashi, H.; Shiro, M.; Natsugari, H. Bioorg.
Med. Chem. 2008, 16, 9519e9523; (g) Tabata, H.; Akiba, S.; Lee, H.; Takahashi, H.;
Natsugari, H. Org. Lett. 2008, 10, 4871e4874; (h) Tabata, H.; Nakagomi, J.;
Morizono, D.; Oshitari, T.; Takahashi, H.; Natsugari, H. Angew. Chem., Int. Ed.
2011, 50, 3075e3079; (i) Tabata, H.; Wada, N.; Takada, Y.; Oshitari, T.; Takahashi,
H.; Natsugari, H. J. Org. Chem. 2011, 76, 5123e5131; (j) Tabata, H.; Wada, N.;
Takada, Y.; Nakagomi, J.; Miike, T.; Shirahase, H.; OShitari, T.; Takahashi, H.;
Natsugari, H. Chem.dEur. J. 2012, 18, 1572e1576; (k) Tabata, H.; Yoneda, T.;
Oshitari, T.; Takahashi, H.; Natsugari, H. J. Org. Chem. 2013, 78, 6264e6270; (l)
Yoneda, T.; Tabata, H.; Tasaka, T.; Oshitari, T.; Takahashi, H.; Natsugari, H. J. Med.
Chem. 2015, 58, 3268e3273.
2. (a) Takahashi, H.; Wakamatsu, S.; Tabata, H.; Oshitari, T.; Harada, A.; Inoue, K.;
Natsugari, H. Org. Lett. 2011, 13, 760e763; (b) Wakamatsu, S.; Takahashi, Y.;
Oshitari, T.; Tani, N.; Azumaya, I.; Katsumoto, Y.; Tanaka, T.; Hosoi, S.; Natsugari,
H.; Takahashi, H. Chem.dEur. J. 2013, 19, 7056e7063.
3. (a) Tabata, H.; Kayama, S.; Takahashi, Y.; Tani, N.; Wakamatsu, S.; Tasaka, T.;
Oshitari, T.; Natsugari, H.; Takahashi, H. Org. Lett. 2014, 16, 1514e1517; (b)
Kayama, S.; Tani, N.; Takahashi, Y.; Tabata, H.; Wakamatsu, S.; Oshitari, T.;
Natsugari, H.; Takahashi, H. Chem. Pharm. Bull. 2014, 62, 836e838.
4. For a representative articles on gear molecule, see: (a) Iwamura, H.; Mislow, K.
Acc. Chem. Res. 1988, 21, 175e182; (b) Stevens, A. M.; Richards, C. J. Tetrahedron
Lett. 1997, 38, 7805e7808; (c) Setaka, W.; Nirengi, T.; Kabuto, C.; Kira, M. J. Am.
Chem. Soc. 2008, 130, 15762e15763; (d) Sciebura, J.; Skowronek, P.; Gawronski,
J. Angew. Chem., Int. Ed. 2009, 48, 7069e7072; (e) Kao, C.-Y.; Hsu, Y.-T.; Lu, H.-F.;
Chao, I.; Huang, S.-L.; Lin, Y.-C.; Sun, W.-T.; Yang, J. S. J. Org. Chem. 2011, 76,
5782e5792; (f) Kelly, T. R. Acc. Chem. Res. 2001, 34, 514e522; (g) Bartoli, G.;
Bosco, M.; Lunazzi, L.; Macciantellli, D. Tetrahedron 1994, 50, 2561e2570.
5. CCDC 1059748 contains the supplementary crystallographic data for this paper.
This data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
2-Iodo-6-trifluoromethylbenzoyl chloride (200.7 mg, 0.6 mmol)
was subjected to reaction with 3-bromocarbazole (73.8 mg,
0.3 mmol) following the same procedure as that used for the syn-
thesis of 5 described above to afford the product 10 (111.7 mg,
0.21 mmol, 68%, cis:trans¼1:1.3) as colorless crystals. Mp 125 ꢀC; Rf
(10% AcOEt/hexane) 0.20; cis-10: 1H NMR (400 MHz, CDCl3):
d 8.83
(1H, dd, J¼7.6, 1.2 Hz, H8), 8.15 (1H, d, J¼7.6 Hz, H30), 8.09 (1H, d,
J¼2.4 Hz, H4), 7.94 (1H, dd, J¼7.6, 1.2 Hz, H5), 7.92 (1H, d, J¼7.6 Hz,
H50), 7.61 (1H, dt, J¼7.6, 1.2 Hz, H7), 7.48 (1H, dt, J¼7.6, 1.2 Hz, H6),
7.43 (1H, t, J¼7.6 Hz, H40), 7.17 (1H, d, J¼9.2, Hz, H2), 5.84 (1H, d,
J¼9.2 Hz, H1); trans-10: 1H NMR (400 MHz, CDCl3):
d 8.72 (1H, d,
J¼8.4 Hz, H1), 8.15 (1H, d, J¼7.6 Hz, H30), 8.12 (1H, d, J¼2.4 Hz, H4),
7.93 (1H, dd, J¼7.6, 1.2 Hz, H5), 7.92 (1H, d, J¼7.6 Hz, H50), 7.67 (1H,
dd, J¼8.4, 2.4 Hz, H2), 7.43 (1H, t, J¼7.6 Hz H40), 7.31 (1H, dt, J¼7.6,
1.2 Hz, H6), 7.10 (1H, dt, J¼7.6,1.2 Hz, H7), 5.99 (1H, dd, J¼7.6, 1.2 Hz,
H8); 13C NMR (100 MHz, CDCl3):
d 166.0 (C]O for trans),165.8 (C]O
for cis), {139.8, 139.5, 137.9, 137.7, 136.2, 129.7, 129.3, 129.3, 128.5,
126.1, 117.5}(Ar), 143.7 (C30 for cis), 131.6 (C40 for cis), 129.8 (C2 for
cis), 129.0 (C7 for cis), 127.0 (C50 for cis), 125.4 (C6 for cis), 123.4 (C4
for cis),120.6 (C5 for trans),118.4 (C8 for trans),114.9 (C1 for cis), 94.8
(C20 for cis), 143.7 (C30 for trans), 131.6 (C40 for trans), 130.9 (C2 for
trans), 127.8 (C7 for trans), 127.0 (C50 for trans), 124.4 (C6 for trans),
122.5 (C4 for trans),119.7 (C5 for trans),119.7 (C1 for trans),113.6 (C8
for trans), 94.8 (C20 for trans); IR (KBr) 1678 cmꢁ1; HRMS (ESI): m/z
calcd for C20H10BrF3INO: 543.9015 [MþH]þ; found: 543.9002.
4.11. 2-Iodo-6-trifluoromethylbenzoic acid
6. As to the rotational barrier of the compounds 6e10 was estimated about
To a solution of 2-trifluoromethylbenzoic acid (571 mg, 3 mmol)
in DMF (15 mL) at room temperature was added successively
Pd(OAc)2 (33.7 mg, 0.15 mmol), iodobenzenediacetate (1.450 g,
4.5 mmol), and iodine (571.2 mg, 4.5 mmol). After being stirred at
100 ꢀC for 24 h, the reaction was diluted with AcOEt and washed
with dil. HCl. The organic layer was washed with brine and dried
over MgSO4. After evaporation in vacuo, the residue was purified by
silica gel column chromatography (AcOEt/hexane¼1/2) to give 2-
iodo-6-trifluoromethylbenzoic acid (560.2 mg, 1.77 mmol, 59%) as
colorless crystals. Mp 155 ꢀC; Rf (50% AcOEt/hexane) 0.33; 1H NMR
70e80 kJ molꢁ1
.
7. For the determination of
J. Am. Chem. Soc. 2005, 127, 14994e14995.
8. For the determination of
Gz values by VT NMR, see: Boiadjiev, S. E.; Lightner,
D
Gz values, see: Petit, M.; Lapierre, A. J. B.; Curran, D. P.
D
D. A. Tetrahedron 2002, 58, 7411e7421.
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(400 MHz, CD3OD):
d
8.14 (1H, d, J¼8.0 Hz, H3), 7.72 (1H, d,
J¼8.0 Hz, H5), 7.30 (1H, t, J¼8.0 Hz, H4); 13C NMR (100 MHz,
CD3OD):
d 169.0 (C]O), 143.1 (C3), 139.5 (C1), 130.3 (C4), {127.7,
127.4 (C6)}, {125.6,125.5 (C5)}, 92.7 (C2); IR (KBr) 1713 cmꢁ1; HRMS
(ESI): m/z calcd for C8H4F3IO2: 314.9135 [MꢁH]ꢁ; found: 314.9118.
10. Diaz, J. E.; Vanthuyne, N.; Rispaud, H.; Roussel, C.; Vega, D.; Orelli, L. R. J. Org.
Chem. 2015, 80, 1689e1695.
Acknowledgements
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This work was supported in part by a Grant-in-Aid for Scientific
Research (C) (24590020) from the Japan Society for the Promotion

S. Kayama et al. / Tetrahedron 71 (2015) 7046e7053
7053
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14. In all DFT calculations, we optimized geometries with tight convergence cri-
teria and fine grids for numerical integration. We also reassessed all geometries
and energies about conformers of compound 14 (t-Bu, I), and therefore the
values of activation energies differ from values we previously reported.