You are on page 1of 4

SYNTHESIS0039-78 1 437-210X

Georg Thieme Verlag Stuttgart New York


2015, 47, 21252128
paper

Syn thesis

2125

Paper

Y. Takahashi et al.

Isolation of Atropisomers of N-Benzoylated Pyrroles and Imidazoles


X

Shintaro Wakamatsu
Hidetsugu Tabata

N
7'

Tetsuta Oshitari

1'

Hideaki Natsugari

Hideyo Takahashi*

Abstract The stereochemistry of N-benzoylated pyrroles and imidazoles was studied. 2,6-Disubstituted 1-benzoypyrroles and 1-benzoylimidazoles were shown to have an atropisomeric property and their
stable atropisomers were isolated.

7'

1'

6'

6'

X = CH, N
atropisomers

MeO

OMe

CO2H

HO2C
N

6'

1'

O
Cl

7'

7'
1'

6'

2'

O
Cl

2'

aS

Key words amides, atropisomerism, chirality, heterocycles, pyrroles

In the course of our researches on axial chirality and its


relationship to biological activities,1 we identified an atropisomeric property in 2,6-disubstituted derivatives of indometacin (N-benzoylated 2-methylindoles) (Figure 1).2
The isolation of stereochemically stable aR- and aS-enantiomers of the indometacin derivative 1 confirmed that rotation about the C7C1 axis is completely restricted by substituents at C2 and C6. These successful results prompted
us to investigate 2,6-disubstituted N-benzoylcarbazole derivatives 2.3 As expected, the presence of bulky substituents
at the 2- and 6-positions restricted the rotation around the
C7C1 bond, permitting the isolation of stereochemically
stable enantiomers of 2. Interestingly, bulkier substituents
(tert-butyl and iodo) restricted rotation about both the C7
C1 and NC7 bonds, generating separate stereoisomers.3
We also found that the compound was a gear molecule in
which rotation about the C7C1 bond was in perfect concert with that about the NC7 bond at room temperature.3
In this context, we next focused our attention on pyrrole and imidazole. We expected that the unsubstituted
five-membered heterocyclic moiety would be too small to
restrict rotation about the C7C1 axis. However, contrary
to our expectation, highly stable atropisomers of 2,6disubstituted N-benzoylpyrrole and N-benzoylimidazole
could be separated. Here, we report that small five-mem-

2'

Faculty of Pharma Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan
hide-tak@pharm.teikyo-u.ac.jp

Received: 03.03.2015
Accepted after revision: 16.03.2015
Published online: 22.04.2015
DOI: 10.1055/s-0034-1380537; Art ID: ss-2015-f0134-op

t-Bu

t-Bu

aR

Br

Br

N
1'

O
X

7'

6'

6'

7'
1'
2'

2'

O
X

Figure 1 Stereoisomers of [1-(2-chloro-6-iodobenzoyl)-5-methoxy-2methyl-1H-indol-3-yl]acetic acid (1) and various 2,6-disubstituted Nbenzoylcarbazole derivatives 2

bered heterocyclic moieties are capable of inducing atropisomeric properties in the corresponding 2,6-disubstituted N-benzoyl derivatives.
Various N-benzoylated pyrrole (3) and imidazole (4) derivatives were synthesized by the established method (Table 1).
First, 1-(2-chloro-6-iodobenzoyl)-1H-pyrrole (3a) was
characterized by means of 1H NMR spectroscopy with chloroform-d1 as a solvent. The four aromatic CH protons of
pyrrole appeared as four broad peaks. In particular, the
downfield shift of H5 ( = 7.65 ppm) in 3a suggests a deshielding effect of the carbonyl group of the benzoyl moiety.

Georg Thieme Verlag Stuttgart New York Synthesis 2015, 47, 21252128

Downloaded by: IP-Proxy Albert-Ludwigs-Universitt Freiburg, Albert-Ludwigs-Universitt Freiburg. Copyrighted material.

Yuka Takahashi

2126

Paper

Y. Takahashi et al.

Table 1 Synthesis of N-Benzoylated Pyrrole and Imidazole Derivativesa


4

X
NaH

N
H

DMF

COCl
Y

3
2

103 kJ/mol),3 the increased stability of 3d with pyrrole is


surprising. It is noteworthy that the simple pyrrole moiety
provides a sufficient effect to reduce rotation about the
C7C1 axis in 3d.

G = 110 kJ/mol
N

Y
3ad
4ad

7'

1'

t-Bu

t-Bu
2'

2'

I
X

Yield (%)

3a

CH

Cl

56

3b

CH

Br

55

3c

CH

Me

77

3d

CH

t-Bu

50

4a

Cl

84

4b

Br

80

4c

Me

61

4d

t-Bu

76

Reaction conditions: pyrrole or imidazole (0.8 mmol), NaH (1.2 mmol),


2,6-disubstituted benzoyl chloride (1.2 mmol), DMF (4 mL), 23 C.

The fact that the CH protons of the symmetric pyrrole ring


were observed as four separate peaks implies the presence
of axial chirality. Similar resonances were observed in the
1
H NMR spectra of 1-(2-bromo-6-iodobenzoyl)-1H-pyrrole
(3b) and 1-(2-bromo-6-methylbenzoyl)-1H-pyrrole (3c).
We therefore attempted to resolve compounds 3ac into
enantiomers by using chiral HPLC (Chiralpak IB). Although
neither compound 3a nor compound 3b was separable at
22 C, both compounds were partly separable at 2 C. Compound 3c was poorly resolved at both 22 C and 2 C. The
fact that the atropisomers could not be separated at room
temperature implies that the energy barrier between the
atropisomers of 3ac is low and that these compounds
therefore exist in achiral forms at room temperature.
However, the four aromatic protons of pyrrole in the 1(2-tert-butyl-6-iodobenzoyl)-1H-pyrrole (3d) were observed as separated sharp peaks, suggesting that an atropisomeric property should exist. As we expected, separation
of 3d on a chiral column (Chiralpak IB) provided a good result (Scheme 1). By preparative chiral HPLC, we succeeded
in isolating two atropisomers of 3d with opposite []D values. Isomer 3d-A (which had the shorter retention time in
HPLC) was obtained in 99% ee and had an []D23 of +90.1 (c
0.20, MeOH), whereas 3d-B (which had the longer retention time in HPLC) was obtained in 98% ee and had an []D23
of 86.9 (c 0.19, MeOH). The activation free-energy barrier
to rotation (G) for 3d-A and 3d-B was calculated to be 110
kJ/mol (Scheme 1; see also the Supporting Information);4
racemization occurred after storage for two hours at 80 C
in toluene. Considering that the atropisomers of the bulkier
carbazole derivative 2 show a lower stability (G = 102

7'

1'

6'

6'

N
O
I

3d

Scheme 1 Stability of the atropisomers of 1-(2-tert-butyl-6-iodobenzoyl)-1H-pyrrole (3d)

To estimate the effect of the five-membered ring on rotation about the C7C1 and NC7 axes of the N-benzoylated derivatives, we next examined the imidazole derivatives
4ad. Although N-acylimidazoles are generally considered
to be mild acylating agents,5 the 2,6-disubstituted N-benzoylimidazoles showed adequate stability at room temperature. In the 1H NMR spectra (CDCl3) of 1-(2-chloro-6-iodobenzoyl)-1H-imidazole (4a), 1-(2-bromo-6-iodobenzoyl)1H-imidazole (4b), and 1-(2-iodo-6-methylbenzoyl)-1Himidazole (4c), the three aromatic CH protons of the imidazole moiety appeared as broad, undifferentiated peaks. After close examination with various types of chiral column,
no separation of stereoisomers of 4ac could be achieved at
room temperature. Unlike 4ac, the tert-butyl-substituted
analogue 4d showed two sets of resonances corresponding
to E- and Z-conformations in the 1H NMR spectrum (Z/E =
1:1.7) (Scheme 2).6 Although dissymmetric imidazole derivatives theoretically exist as mixtures of E/Z-amide rotamers, among compounds 4ad, only 4d appeared as a diastereomeric mixture in its 1H NMR spectrum. Because the
rotational barrier about the NC7 axis is less than that required for isolation of the two conformers at 23 C, compound 4d appeared as a single peak on nonchiral HPLC.
However, 4d could be separated into two peaks when analyzed on a chiral column (Chiralpak IB) at 23 C, showing
that rotation about the C7C1 axis was restricted, as in the
case of 3d (Scheme 1). Enantiomers of compound 4d with
opposite []D values were successfully isolated by means of
preparative chiral HPLC. Isomer 4d-A (with the shorter retention time in HPLC) was obtained in 97% ee and had an
[]D21 value of 70.7 (c 0.15, CHCl3), whereas isomer 4d-B
(with the longer retention time in HPLC) was obtained in
97% ee and had an []D21 value of +72.3 (c 0.14, CHCl3). The
stereochemical stability corresponded to a G value of
101kJ/mol (see Supporting Information).
On the basis of the above results, it is clear that small
five-membered heterocyclic moieties are capable of inducing atropisomeric properties in their 2,6-disubstituted Nbenzoyl derivatives. We consider that the barrier to rotation
about the C7C1 axis is provided by the coplanar struc-

Georg Thieme Verlag Stuttgart New York Synthesis 2015, 47, 21252128

Downloaded by: IP-Proxy Albert-Ludwigs-Universitt Freiburg, Albert-Ludwigs-Universitt Freiburg. Copyrighted material.

Syn thesis

2127

tures in 3d and 4d. In other words, because the NC7 bond


in N-benzoylated pyrroles and imidazoles is expected to
have a double-bond amide character,7 the carbonyl group
has a tendency to be coplanar with the unsubstituted pyrrole or imidazole moiety. Furthermore, steric hindrance by
the 2- and 6-substituents causes the benzene ring to be
orthogonal to the coplanar carbonyl group and pyrrole or
imidazole moiety. Consequently, the C7C1 axis is frozen
to provide atropisomeric properties in compounds 3d and
4d.
N

NC7' rotation

7'
1'

O
t-Bu

Paper

Y. Takahashi et al.

t-Bu

(fast)

6'

2'

N
7'

O
I

C7'C1' rotation
(very slow)

IR (ATR): 1697 cm1.


H NMR (600 MHz, CDCl3): = 7.77 (dd, J = 8.4, 1.2 Hz, 1 H, H3), 7.67
(m, 1 H, H5), 7.57 (dd, J = 7.8, 1.2 Hz, 1 H, H5), 7.10 (dd, J = 8.4, 7.8 Hz,
1 H, H4), 6.44 (m, 1 H, H2), 6.40 (m, 1 H, H3), 6.23 (m, 1 H, H4), 1.29
[s, 9 H, C(CH3)3].
13
C NMR (150 MHz, CDCl3): = 169.3 (C=O), {150.5, 137.9, 137.4,
131.1, 127.5, 121.8, 118.9, 114.5, 113.8, 95.9} (Ar), 37.0 [C(CH3)3], 31.6
[C(CH3)3].

(Z, aS)

(E, aS)

NaH (60% in oil; 47.4 mg, 1.2 mmol) was added to a solution of pyrrole (53.6 mg, 0.8 mmol) in DMF (4 mL) at 0 C under argon, and the
mixture was stirred for 10 min. A soln of 2-tert-butyl-6-iodobenzoyl
chloride (387.1 mg, 1.2 mmol) in THF (2 mL) was added, and the mixture was stirred at 23 C for 3 h. The reaction was quenched with icewater (20 mL) and the mixture was extracted with EtOAc (3 20 mL).
The organic layer was dried (MgSO4) and concentrated in vacuo, and
the residue was purified by column chromatography [silica gel, EtOAchexane (1:12)] to give a white solid; yield: 142 mg (50%, 0.40
mmol); mp 95 C.
1

1'

2'

6'

N-(2-tert-Butyl-6-iodobenzoyl)-1H-pyrrole (3d); Typical Procedure

C7'C1' rotation
(very slow)

HRMS (ESI): m/z [M + H]+ calcd for C15H17INO: 354.0365; found:


354.0349.
1-(2-Chloro-6-iodobenzoyl)-1H-pyrrole (3a)

N
N
7'

NC7' rotation

t-Bu
1'

O
I
(E, aR)

6'

IR (ATR): 1685 cm1.


N

(fast)
2'

Colorless crystals; yield: 74 mg (56%, 0.22 mmol); mp 122 C.

6'

7'
1'

2'

O
t-Bu

(Z, aR)

Scheme 2 Interconversion path for stereoisomers of 4d

In summary, highly stable atropisomers of 1-(2-tertbutyl-6-iodobenzoyl)-1H-pyrrole (3d) and -imidazole (4d)


were isolated. In these compounds, the carbonyl group is
believed to be coplanar with the plane of the pyrrole or imidazole moiety, thereby inducing the unexpected atropisomeric properties.

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 JEOL-ECA600 spectrometer
at 600 MHz for 1H NMR and at 150 MHz for 13C NMR. Chemical shifts
are reported relative to TMS as an internal standard. IR spectra were
recorded on a JASCO FT/IR-4200 FT-IR spectrometer. High-resolution
mass spectra were recorded on a Shimadzu LCMS-IT-TOF mass spectrometer operated in the ESI mode. Optical rotations were determined with a JASCO P-2200 digital polarimeter. Analytical TLC was
performed on Merck silica gel 60 F-254 plates. Column chromatography was performed on silica gel (4560 m; Fuji Silysia Chemical
Ltd.). HPLC was performed with a Shimadzu Prominence system.

H NMR (600 MHz, CDCl3): = 7.80 (d, J = 8.4 Hz, 1 H, H3), 7.65 (br s,
1 H, H5), 7.47 (d, J = 7.8 Hz, 1 H, H5), 7.14 (dd, J = 7.8, 8.4 Hz, 1 H, H4),
6.52 (br s, 1 H, H2), 6.43 (br s, 1 H, H3), 6.29 (br s, 1 H, H4).
13

C NMR (150 MHz, CDCl3): = 164.9 (C=O), {139.5, 137.7, 132.2,


131.7, 129.5, 120.9, 118.9, 114.8, 114.5, 92.9} (Ar).

HRMS (ESI): m/z [M + H]+ calcd for C11H8ClINO: 331.9319; found:


331.9334.
1-(2-Bromo-6-iodobenzoyl)-1H-pyrrole (3b)
Colorless crystals; yield: 82 mg (55%, 0.22 mmol); mp 125 C.
IR (ATR): 1682 cm1.
1

H NMR (600 MHz, CDCl3): = 7.85 (d, J = 8.4 Hz, 1 H, H3), 7.65 (m, 2
H, H5, H5), 7.06 (dd, J = 8.4, 8.4 Hz, 1 H, H4), 6.52 (br s, 1 H, H2), 6.44
(br s, 1 H, H3), 6.30 (br s, 1 H, H4).

13

C NMR (150 MHz, CDCl3): = 165.6 (C=O), {141.3, 138.2, 132.6,


132.5, 121.0, 119.7, 118.9, 114.9, 114.5, 92.9} (Ar).

HRMS (ESI): m/z [M + H]+ calcd for C11H8BrINO: 375.8842; found:


375.8828.
1-(2-Iodo-6-methylbenzoyl)-1H-pyrrole (3c)
Colorless crystals; yield: 192 mg (77%, 0.62 mmol); mp 102 C.
IR (ATR): 1686 cm1.
1

H NMR (600 MHz, CDCl3): = 7.71 (d, J = 8.4 Hz, 1 H, H5), 7.66 (br s,
1 H, H5), 7.26 (d, J = 7.8 Hz, 1 H, H3), 7.09 (dd, J = 8.4, 7.8 Hz, 1 H, H4),
6.49 (br s, 1 H, H2), 6.42 (br s, 1 H, H3), 6.26 (br s, 1 H, H4), 2.28 (s, 3 H,
CH3).
13
C NMR (150 MHz, CDCl3): = 167.7 (C=O), {140.3, 137.3, 136.6,
131.3, 130.0, 121.2, 118.8, 114.5, 114.2, 92.5} (Ar), 20.0 (CH3).

HRMS (ESI): m/z [M + H]+ calcd for C12H11INO: 311.9867; found:


311.9880.

Georg Thieme Verlag Stuttgart New York Synthesis 2015, 47, 21252128

Downloaded by: IP-Proxy Albert-Ludwigs-Universitt Freiburg, Albert-Ludwigs-Universitt Freiburg. Copyrighted material.

Syn thesis

2128

Syn thesis

Paper

Y. Takahashi et al.

1-(2-Chloro-6-iodobenzoyl)-1H-imidazole (4a)
White solid; yield: 112 mg (84%, 0.34 mmol); mp 93 C.

HRMS (ESI): m/z [M + H]+ calcd for C14H16IN2O: 355.0306; found:


355.0302.

IR (ATR): 1714 cm1.

13

C NMR (150 MHz, CDCl3): = 163.4 (C=O), {138.2, 138.0, 137.4,


133.2, 131.8, 131.5, 129.8, 116.6, 92.5} (Ar).
HRMS (ESI): m/z [M + H]+ calcd for C10H7ClIN2O: 332.9292; found:
332.9286.

Acknowledgment
This work was supported in part by a Grant-in-Aid for Scientific Research (C) (24590020) from the Japan Society for the Promotion of
Science. H.T. is grateful for financial support from the Astellas Foundation for Research on Metabolic Disorders (2013) and the MEXTSupported 53.6 Program for the Strategic Research Foundation at Private Universities (20132017).

1-(2-Bromo-6-iodobenzoyl)-1H-imidazole (4b)
White solid; yield: 121 mg (80%, 0.32 mmol); mp 110 C.
IR (ATR): 1720 cm1.
1

H NMR (600 MHz, CDCl3): = 8.206.90 (br s, 3 H, H2, H4, H5) 7.88
(d, J = 7.2 Hz, 1 H, H3), 7.68 (d, J = 8.4 Hz, 1 H, H5), 7.13 (dd, J = 8.4,
7.2 Hz, 1 H, H4).
13
C NMR (150 MHz, CDCl3): = 164.2 (C=O), {140.0, 138.5, 137.5,
133.3, 132.9, 131.7, 119.7, 116.6, 92.5} (Ar).

HRMS (ESI): m/z [M + H]+ calcd for C10H7BrIN2O: 376.8785; found:


376.8781.
1-(2-Iodo-6-methylbenzoyl)-1H-imidazole (4c)
Yellow oil; yield: 76 mg (61%, 0.24 mmol).
IR (ATR): 1719 cm1.
1

H NMR (600 MHz, CDCl3): = 7.807.10 (br s, 3 H, H2, H4, H5), 7.75
(d, J = 8.4 Hz, 1 H, H5), 7.30 (d, J = 7.2 Hz, 1 H, H3), 7.15 (dd, J = 7.2,
8.4 Hz, 1 H, H4), 2.28 (s, 3 H, CH3).
13

C NMR (150 MHz, CDCl3): = 166.2 (C=O), {138.9, 137.9, 137.4,


136.9, 132.2, 131.6, 130.4, 116.6, 91.9,} (Ar), 19.9 (CH3).

HRMS (ESI): m/z [M + H]+ calcd for C11H10IN2O: 312.9833; found:


312.9832.
1-(2-tert-Butyl-6-iodobenzoyl)-1H-imidazole (4d)
Colorless crystals; yield: 108 mg (76%, 0.30 mmol); mp 95 C.
IR (ATR): 1716 cm1.
1

H NMR (600 MHz, CDCl3): (Z isomer) = 8.52 (br s, 1 H, H2), 7.80 (m,
1 H, H3), 7.60 (m, 1 H, H5), 7.17 (m, 1 H, H4), 7.06 (br s, 1 H, H4),
6.65 (br s, 1 H, H5), 1.30 [s, 9 H, C(CH3)3]; (E isomer) = 7.80 (m, 2 H,
H2, H3), 7.60 (m, 1 H, H5), 7.40 (br s, 1 H, H4), 7.17 (m, 2 H, H5, H4),
1.29 [s, 9 H, C(CH3)3].
13
C NMR (150 MHz, CDCl3): [(Z isomer) = 168.2 (C=O), {150.6, 138.5,
137.6, 136.6, 131.7, 131.4, 127.6, 118.2, 95.0} (Ar), 36.9 [C(CH3)3], 31.7
[C(CH3)3]; (E isomer) = 167.7 (C=O), {150.9, 137.6, 137.6, 136.6,
131.9, 131.8, 127.7, 116.0, 95.4} (Ar), 36.9 [C(CH3)3], 31.7 [C(CH3)3].

References
(1) For representative review articles on axial chirality, see:
(a) Clayden, J. Tetrahedron 2004, 60, 4335. (b) Clayden, J.;
Moran, W. J.; Edwards, P. J.; LaPlante, S. R. Angew. Chem. Int. Ed.
2009, 48, 6398. (c) Zask, A.; Murphy, J.; Ellestad, G. A. Chirality
2013, 25, 265. (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, 7005. (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, 3982.
(f) Lee, S.; Kamide, T.; Tabata, H.; Takahashi, H.; Shiro, M.;
Natsugari, H. Bioorg. Med. Chem. 2008, 16, 9519. (g) Tabata, H.;
Akiba, K.; Lee, S.; Takahashi, H.; Natsugari, H. Org. Lett. 2008, 10,
4871. (h) Tabata, H.; Nakagomi, J.; Morizono, D.; Oshitari, T.;
Takahashi, H.; Natsugari, H. Angew. Chem. Int. Ed. 2011, 50,
3075. (i) Tabata, H.; Wada, N.; Takada, Y.; Oshitari, T.; Takahashi,
H.; Natsugari, H. J. Org. Chem. 2011, 76, 5123. (j) Tabata, H.;
Wada, N.; Takada, Y.; Nakagomi, J.; Miike, T.; Shirahase, H.;
Oshitari, T.; Takahashi, H.; Natsugari, H. Chem. Eur. J. 2012, 18,
1572. (k) Tabata, H.; Yoneda, T.; Oshitari, T.; Takahashi, H.;
Natsugari, H. J. Org. Chem. 2013, 78, 6264.
(2) (a) Takahashi, H.; Wakamatsu, S.; Tabata, H.; Oshitari, T.;
Harada, A.; Inoue, K.; Natsugari, H. Org. Lett. 2011, 13, 760.
(b) Wakamatsu, S.; Takahashi, Y.; Oshitari, T.; Tani, N.; Azumaya,
I.; Katsumoto, Y.; Tanaka, T.; Hosoi, S.; Natsugari, H.; Takahashi,
H. Chem. Eur. J. 2013, 19, 7056.
(3) Tabata, H.; Kayama, S.; Takahashi, Y.; Tani, N.; Wakamatsu, S.;
Tasaka, T.; Oshitari, T.; Natsugari, H.; Takahashi, H. Org. Lett.
2014, 16, 1514.
(4) For measurements of the G values, see:Petit, M.; Lapierre, A. J.
B.; Curran, D. P. J. Am. Chem. Soc. 2005, 127, 14994.
(5) Staab, H. A. Angew. Chem., Int. Ed. Engl. 1962, 1, 351.
(6) See the Supporting Information (CH-COSY-, and HH-COSY-NMR
spectra) for the determination of the E/Z-conformations.
(7) (a) Stewart, W. E.; Siddall, T. H. III. Chem. Rev. 1970, 70, 517.
(b) Matsuo, T.; Shosenji, H. J. Chem. Soc. D 1969, 501.

Georg Thieme Verlag Stuttgart New York Synthesis 2015, 47, 21252128

Downloaded by: IP-Proxy Albert-Ludwigs-Universitt Freiburg, Albert-Ludwigs-Universitt Freiburg. Copyrighted material.

1
H NMR (600 MHz, CDCl3): = 8.007.30 (br s, 3 H, H2, H4, H5) 7.85
(d, J = 8.4 Hz, 1 H, H3), 7.52 (d, J = 7.8 Hz, 1 H, H5), 7.22 (dd, J = 8.4,
7.8 Hz, 1 H, H4).