Asymmetric oxidative coupling of hydroxycarbazoles: Facile synthesis of (+)-bi-2-hydroxy-3-methylcarbazole

Article abstract of DOI:10.1016/j.bmcl.2018.02.033

Asymmetric oxidative coupling reactions of hydroxycarbazoles have been established using a chiral dinuclear vanadium complex. To demonstrate the utility of vanadium-catalyzed reactions, we have used them to synthesize (+)-bi-2-hydroxy-3-carbazole in three steps from cyclohexanone and commercially available aniline derivatives.

Full text of DOI:10.1016/j.bmcl.2018.02.033

Accepted Manuscript
Asymmetric oxidative coupling of hydroxycarbazoles: Facile synthesis of (+)-
bi-2-hydroxy-3-methylcarbazole
Makoto Sako, Akimasa Sugizaki, Shinobu Takizawa
PII:
S0960-894X(18)30135-5
https://doi.org/10.1016/j.bmcl.2018.02.033
BMCL 25629
DOI:
Reference:
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Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
29 January 2018
13 February 2018
15 February 2018
Please cite this article as: Sako, M., Sugizaki, A., Takizawa, S., Asymmetric oxidative coupling of
hydroxycarbazoles: Facile synthesis of (+)-bi-2-hydroxy-3-methylcarbazole, Bioorganic & Medicinal Chemistry
Letters (2018), doi: https://doi.org/10.1016/j.bmcl.2018.02.033
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Bioorganic & Medicinal Chemistry Letters
Asymmetric oxidative coupling of hydroxycarbazoles: Facile synthesis of (+)-bi-
2
-hydroxy-3-methylcarbazole
*
Makoto Sako, Akimasa Sugizaki, and Shinobu Takizawa
The nstitute of ꢀcientific and ndustrial Research ꢁ ꢀ R) ꢂsaka ꢃniversity, Mihogaoka, baraki-shi, ꢂsaka ꢄ67-0047, ꢅapan
th
Dedicated to Professor Dr. Dale L. Boger on the occasion of his 65 birthday.
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Asymmetric oxidative coupling reactions of hydroxycarbazoles have been established using a
chiral dinuclear vanadium complex. To demonstrate the utility of vanadium-catalyzed reactions,
we have used them to synthesize (+)-bi-2-hydroxy-3-carbazole in three steps from
cyclohexanone and commercially available aniline derivatives.
Accepted
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Enantioselective catalysis
Vanadium
Oxidative coupling
Carbazole alkaloid
Hydroxycarbazoles and bihydroxycarbazoles (Fig. 1) have
garnered considerable attention from many research groups
because they can serve as biological compounds, such as
antibiotics, antibacterial and anti-yeast agents, and free-radical
1
scavengers. So far, many efforts have been made to develop
metal-catalyzed and organocatalyzed methodologies for
2
synthesizing hydroxycarbazole derivatives. However, despite
numerous studies, there have been few reports on efficient
3
,4e
asymmetric oxidative couplings of hydroxycarbazoles.
It is
still highly desirable to explore new methods of synthesis to
enable current synthetic chemistry to capitalize on the diverse
structural
features
of
hydroxycarbazoles
and
bihydroxycarbazoles.
Fig. 1. Hydroxycarbazoles and bihydroxycarbazoles as natural
products.
In this study, we report on the highly enantioselective
coupling of hydroxycarbazoles to produce bihydroxycarbazole
derivatives. We have found that a chiral dinuclear vanadium
complex that can be used to mediate the oxidative coupling of
4
polycyclic phenols also works as a chiral catalyst for 3-
hydroxycarbazoles to produce the corresponding coupling
products with up to 80% ee. To demonstrate the utility of this
synthesis method, we have employed it for the facile preparation

of bi-2-hydroxy-3-methylcarbazole (1) through the condensation
of cyclohexanone and commercially available aniline, followed
by
Pd(II)-catalyzed
dehydrogenative
Table 2. Substrate scope and limitations
aromatization/intramolecular C−C bond coupling and
deprotection. We used a chiral vanadium complex to mediate the
oxidative coupling of hydroxycarbazole derivatives to afford (+)-
1
with acceptable enantioselectivity (Scheme 1).
Ee
a
Entry
2, R
Temp. (°C)
Yield (%)
b
(%)
1
2
3
4
2a, 4-MeC
2b, Ph
6
H
4
30
30
30
50
50
3a, 65
3b, 55
3c, 44
3d, 20
80
80
75
65
—
2c, 4-ClC
2d, Me
6 4
H
Scheme 1. Enantioselective synthesis of bihydroxycarbazoles via
c
5
2e, Ac
3e, NR
chiral vanadium catalyzed coupling of hydroxycarbazoles.
a
b
Isolated yield. Determined by HPLC (CHIRAL ART Cellulose-SB).
No reaction.
We began the screening of reaction conditions for
enantioselective oxidative coupling using N-p-tolyl-3-
hydroxycarbazole (2a) as a model starting material, with 5 mol %
c
Considering the optimized reaction conditions, we
4
a
investigated the scope and limitations of the substrates (Table 2).
Phenyl- and 4-ClC H -substituted substrates (2b and 2c) were
(
Ra,S,S)-4 (Table 1). Among the solvents we tested (entries 1–5),
the reaction in CCl at 30 °C gave the product 3a preferentially
6
4
4
converted to the corresponding products 3b and 3c with a
moderate yield with 80% ee and 75% ee, respectively (entries 2
and 3). N-Me-3-hydroxycarbazole (2d) underwent a coupling
reaction at 50 °C to give 3d with 65% ee, but with only a 20%
yield owing to the low reactivity of 2d. The reaction of 2e, which
has an acetyl group on the nitrogen, did not proceed at all (entry
coupled at position C4 with a 65% NMR yield and 80% ee (entry
5
). A change in the ambient atmosphere from air to O decreased
2
the yield of 3a probably owing to side reactions, such as ortho-
benzoquinone formation and over-oxidative couplings of 3a
(entry 6). Although the reaction was performed at low and high
temperatures (10 °C or 50 °C), no improvement in the yields or
enantioselectivities was obtained (entries 7 and 8).
5
), thus indicating that the oxidative coupling depends greatly on
the electronic nature of the starting materials. The absolute
configuration of 3 was assigned as R by comparison with an
Table 1. Screening of reaction conditions for 3-
hydroxycarbazoles using (R ,S,S)-4
a
optical rotation of synthetic 9H,9'H-[4,4'-bicarbazole]-3,3'-diol
5
(
BACOL) (3f: R = H) by (R ,S,S)-4.
a
Since (R ,S,S)-4 proved to be effective for the oxidative
a
coupling of 3-hydroxycarbazoles 3, we focused on the
enantioselective oxidative coupling of 2-hydroxycarbazole.
Recently, Kozlowski has reported on the enantioselective
oxidative
coupling
of
N-protected-2-hydroxycarbazole
a
b
Entry Solvent
Conv. of 2a (%) Yield (%)
Ee (%)
3
derivatives, while we have investigated the coupling of N-H-2-
hydroxycarbazoles for the facile synthesis of bi-2-hydroxy-3-
methylcarbazole (1), which is isolated from the roots of Murraya
1
2
3
4
5
6
7
Toluene
1,2-Cl
CH Cl
80
94
74
87
85
>95
28
87
45
44
55
56
65
43
24
56
79
6
,7
2
C
6
H
4
74
koenigii. We synthesized the coupling precursors via a one-pot
reaction of cyclohexanone (5) and the commercially available
aniline derivative 6, with 20 mol % of Pd(OAc) and Cu(OAc)
2
2
70
2
2
8
2
(Cl CH)
2
62
(5.0 equiv) as a co-oxidant in PivOH , followed by the
deprotection of the methyl group (Scheme 2). After sequential
reactions, we obtained 2-hydroxy-3-methylcarbazole (8) in two
steps, with a 52% overall yield. Considering the coupling
CCl
CCl
CCl
CCl
4
4
4
4
80
c
d
e
79
precursor 8, we performed the initial coupling reaction of 8 using
76
3
1
5 mol % of (R ,S,S)-4 in the presence of AcOH in chloroform
a
8
69
at 0 °C. Although we obtained bi-2-hydroxy-3-methylcarbazole
1) with a 68% yield, we did not observe asymmetric induction.
(
a
1
Determined by H NMR spectroscopy using 1,3,5-trimethoxybenzene
b
as an internal standard. Determined by HPLC (CHIRAL ART
Scheme 2. Synthesis of 2-hydroxy-3-methylcarbazole (8) and an
c
d
e
Cellulose-SB). Under O
2
(balloon) instead of air. At 10 °C for 72 h. At
5
0 °C for 24 h.

oxidative coupling of 8
In summary, we have performed enantioselective oxidative
coupling of hydroxycarbazole derivatives using chiral vanadium
complexes. By using the proposed protocol, we have
demonstrated the short step asymmetric synthesis of bi-2-
hydroxy-3-methylcarbazole, but with up to 21% ee owing to
ready racemization.
Table 3. Screening of reaction conditions in an enantioselective
oxidative coupling of 8 using chiral mononuclear vanadium
complexes
Acknowledgments
The work was supported by JSPS KAKENHI Grant Numbers
JP16K08163 (C), JP16H01152 (Middle Molecular Strategy), and
JP17H05373 (Coordination Asymmetry). The Ministry of
Education, Culture, Sports, Science and Technology (MEXT),
Japan Society for the Promotion of Science (JSPS), the CREST
project of Japan Science and Technology Corporation (JST), and
JST Advance Catalytic Transformation Program for Carbon
Utilization (ACT-C) Grant Number JPMJCR12YK. We
acknowledge the technical staff of the Comprehensive Analysis
Center of ISIR, Osaka University (Japan).
a
b
Entry V cat.
Conv. of 8 (%)
Yield (%)
Ee (%)
Rac
15
1
2
3
4
5
(S)-9
>95
64
59
43
63
78
44
70
(S)-10
(R
a
,S)-11
93
18
(S
(R
(R
a
,S)-11
>95
90
9
a
,S)-12
21
6
a
,S)-13
>95
16
References and notes
a
1
Determined by H NMR spectroscopy using 1,3,5-trimethoxybenzene
b
1. (a) Moody, C. J. Synlett 1994, 681. (b) Tasler, S.; Bringmann, G.
Chem. Rec. 2002, 2, 113. (c) Wang, Y.-S.; He, H.-P.; Shen, Y.-M.;
Hong, X.; Hao, X.-J. J. Nat. Prod. 2003, 66, 416.
as an internal standard. Determined by HPLC (DAICEL CHRALPAK
IA).
2
.
(a) Knölker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303. (b)
Knölker, H.-J. Chem. Lett. 2009, 38, 8. (c) Roy, J.; Jana, A. K.;
Mal, D. Tetrahedron 2012, 68, 6099. (d) Brütting, C.; Fritsche, R.
F.; Kutz, S. K.; Böger, C.; Schmidt, A. W.; Kataeva, O.; Knölker,
H.-J. Chem. Eur. J. 2018, 24, 458.
3
4
.
.
Kang, H.; Lee, Y. E.; Reddy, P. V. G.; Dey, S.; Allen, S. E.;
Niederer, K. A.; Sung, P.; Hewitt, K.; Torruellas, C.; Herling, M.
R.; Kozlowski, M. C. Org, Lett. 2017, 19, 5505.
Selected reviews and reports on the chiral vanadium catalysis, see:
During screening of the vanadium complexes, we found that
mononuclear vanadium complexes also promoted the present
reaction. The results obtained using chiral mononuclear
vanadium complexes are shown in Table 3. Using 30 mol % of
(
a) Takizawa, S, Chem. Pharm. Bull. 2009, 57, 1179. (b)
Takizawa, S.; Gröger, H.; Sasai, H. Chem. Eur. J. 2015, 21, 8992.
c) Sako, M.; Takizawa, S.; Yoshida, Y.; Sasai, H. Tetrahedron:
(
Asymmetry 2015, 26, 613. (d) Sako, M.; Takeuchi, Y.; Tsujihara,
T.; Kodera, J.; Kawano, T.; Takizawa, S.; Sasai, H. J. Am. Chem.
Soc. 2016, 138, 11481. (e) Sako, M.; Ichinose, K.; Takizawa, S.;
Sasai, H. Chem. Asian J. 2017, 12, 1305.
Dubois, M.-A.; Grandbois, A.; Collins, S. K.; Schmitzer, A. R. J.
Mol. Recognit. 2011, 24, 288.
(S)-9 led to 1 with a 59% yield, but it was in the form of a
racemic mixture (entry 1). The vanadium catalyst (S)-10, which
bears bulky tert-butyl groups, showed an asymmetric induction
with 15% ee (entry 2). The use of other mononuclear vanadium
complexes that possess a chiral binaphthyl backbone 11–13
resulted in the formation of 1 in moderate yields with ca. 20%
ees (entries 3–6). Further investigation of the reaction conditions
5
.
6. Ito, C.; Thoyama, Y.; Omura, M.; Kajiura, I.; Furukawa, H. Chem.
Pharm. Bull. 1993, 41, 2096.
7
.
(a) Knölker, H.-J.; Goesmann, H.; Hofmann, C. Synlett 1996, 737.
b) Dhara, K.; Mandal, T.; Das, J.; Dash, J. Angew. Chem. Int. Ed.
015, 54, 15831. and ref. 2c
(
2
(vanadium catalysts, reaction solvents, and temperature; see
supplementary material) revealed no improvement in the
enantioselectivity. One reason responsible for the low
enantioselectivity is the low rotation barrier of the aryl–aryl bond
that leads to the racemization of the coupling product 1. To
demonstrate the easy racemization of 1, we performed an optical
resolution of 1 (>95% ee) with chiral high performance liquid
chromatography, using a preparative DAICEL CHIRALPAK IC
column. After the separation, followed by the removal of the
solvent using a rotary evaporator at room temperature, the
enantioselectivity had decreased to ca. 80% ee from an optically
pure form in a few minutes. The enantioselectivity of 1 dropped
further to less than 20% after 3 days at room temperature in the
solution. Thus, the coupling product 1 was found to be easily
8
.
Wen, L.; Tang, L.; Yang, Y.; Zha, Z.; Wang, Z. Org. Lett. 2016,
18, 1278.
9. The easy racemization of 1 is probably due to less configurational
stability of Aryl-Aryl bond, see ref 2d.
Supplementary Material
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
9
racemized in a solution even at room temperature.

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Asymmetric oxidative coupling of hydroxycarbazoles:
Facile synthesis of (+)-bi-2-hydroxy-3-
methylcarbazole
Makoto Sako, Akimasa Sugizaki, Shinobu Takizawa*