Direct construction of carbazoles from 2-methyl-indole-3-carbaldehydes and enals

Article abstract of DOI:10.1039/c9gc00064j

The direct and rapid construction of carbazoles was achieved via the reaction of 2-methyl-indole-3-carbaldehydes with enals promoted by LiCl/DBU in a single operation. This mild and green reaction proceeds through a [4 + 2] cycloaddition/dehydration/oxidative aromatization cascade to generate carbazoles in good to excellent yields. The reaction features mild reaction conditions, a broad substrate scope, and excellent functional group tolerance, using O₂ (1 atm) as the sole oxidant and affording H₂O as the only by-product. More importantly, 4-fluoroquinocarbazole, a significant bioactive compound, was generated in 80% yield in only one step from the obtained carbazole.

Full text of DOI:10.1039/c9gc00064j

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DOI: 10.1039/C9GC00064J
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RSCPublishing
PAPER
Direct Construction of Carbazoles from 2-Methyl-indole-3-
carbaldehydes and Enals
Dehai Liu,a Jie Huang,a Zhenqian Fu,*a,b and Wei Huang,*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
The direct and rapid construction of carbazoles was achieved via the reaction of 2-methyl-indole-3-carbaldehydes with
enals promoted by LiCl/DBU in
a single operation. This mild and green reaction proceeds through a [4+2]
www.rsc.org/
cycloaddition/dehydration/oxidative aromatization cascade to generate carbazoles in good to excellent yields. The
reaction features mild reaction conditions, a broad substrate scope, and excellent functional group tolerance, using O2
(1atm) as the sole oxidant and affording H2O as the only byproduct. More importantly, 4-fluoroquinocarbazole, a
significant bioactive compound, was generated in 80% yield in only one step from the obtained carbazole.
(a) Some examples of carbazole-containing useful compounds
OH
Introduction
Cl
H
N
O
O
O
OH
Carbazoles, as a kind of the most privileged aza-heterocycles,
are fundamental motifs in a large number of pharmaceuticals,
alkaloild-based natural products,1 as well as organic
optoelectronic materials2 due to a wide band gap and
outstanding luminescent efficiency (Scheme 1a). For example,
Carprofen3 is a nonsteroidal anti-inflammatory pharmaceutical
used to treat joint pain and postoperative pain. Carvedilol4 is
applied in treatment of congestive heart failure and high blood
pressure. Midostaurin (Rydapt),5 as a semi-synthetic derivative
of an alkaloild Staurosporine,6 is a FDA approved drug for
treating acute myeloid leukemia, myelodysplastic syndrome
and advanced systemic mastocytosis. Furthermore, 1,2,3,5-
OMe
N
H
HN
Carvedilol
Carprofen
H
N
O
N
CN
NC
N
N
N
N
Me
O
N
MeO
MeN
R
Staurosporine
Midostaurin
R = H,
R = Bz,
4CzIPN
(b) Representive approaches for the synthesis of carbazoles
X
TM catalyst
or
tetrakis(carbazol-9-yl)-4,6-dicyanobenzene
(4CzIPN),
N
NHY
N
H
H
containing four carbazolyl units, has been demonstrated as an
excellent thermally activated delayed fluorescence material.7
Owing to the significance of carbazole compounds, the facile
and efficient synthesis of carbazoles has received continuous
attention. Numerous elegant methods have been established,8
mainly involving direct construction of the pyrrole ring moiety
through C–C and C–N bond formation,9 and direct construction
of the aromatic ring moiety though p-extension of indoles
(Scheme 1b).10 However, they often cannot avoid the use of
transition-metal catalysts, harsh conditions or multistep
X = H, halogen; Y = H, alkyl, acetyl, etc.
O
R1
R4
NO2
R1
or
+
+
2
N
R
R2
R3
N
H
Our work
(c)
O
O
H
H
LiCl/DBU
O
+
R
O2, RT
H
R
N
N
1
Ts
2
29 examples
up to 94% yield
Ts
3
Base
O2
a. Key Laboratory of Flexible Electronics & Institute of Advanced Materials, Jiangsu
National Synergetic Innovation Center for Advanced Materials, Nanjing Tech
University, 30 South Puzhu Road, Nanjing, 211816, China. E-mail:
iamwhuang@njtech.edu.cn;iamzqfu@njtech.edu.cn.
O
O
O
HO
H
H
1
R
R
- H2O
[4+2]
cycloaddition
N
b. Shaanxi Institute of Flexible Electronics (SIFE), Northwestern Polytechnical
University (NPU), 127 West Youyi Road, Xi'an, 710072, China.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
N
N
II
III
I
Ts
Ts
Ts
Figure 1 Examples of carbazole-containing useful compounds and synthetic
methods for carbazoles.
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synthesis. Therefore, further development of simple and established, several bases and solvents were then investigated,
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DOI: 10.1039/C9GC00064J
efficient strategies for the construction of carbazoles is highly wherein DBU and THF proving to be the best choices,
desirable. In particular, an ideal synthetic route would be respectively (see SI for details). To our delight, the product
transition metal-free, start from simple and readily available yield was considerably increased when the reaction was
raw materials, use green and mild reaction conditions, involve performed under O2 (entry 12). Using a mixed solvent
a single operation, and show excellent tolerance of various (THF/CH3CN = 1:1, v/v) further increased the product yield
reactive functional groups for further derivatizations.
(entry 13). Furthermore, adding t-BuOH improved the product
[4+2] cycloaddition has been proven as one of the most yield up to 82% (entry 14). Without DBU, the desired product
powerful and reliable strategies for the construction of a series 3a was not observed (entry 15).
of structurally diverse six-membered rings from simple raw
materials.11 Furthermore, although molecular oxygen (O2) is an
Table 1. Optimization of reaction conditionsa
ideal oxidant, the direct use of O2 as a sole oxidant remains a
O
O
H
DBU, LiCl
t-BuOH
critical challenge in academia and industry.12 As part of our
ongoing interest in the synthesis of carbo- and heterocycles,10j,
H
O
+
R
H
THF/CH3CN
O2, 30 °C
R
13
N
we envisaged a novel strategy for the synthesis of highly
N
Ts
Ts
functionalized carbazoles might be achieved via the reaction of
1
2a
3
2-methyl-indole-3-carbaldehydes and enals in
a single
operation (Scheme 1c). In fact, this strategy presents some
apparent challenges, including (i) achieving the difficulty [4+2]
cycloaddition of in situ-generated dienolate I with enals; (ii)
ensuring all processes, including [4+2] cycloaddition,
dehydration and aerobic oxidative aromatization, successively
accomplished under identical conditions; (iii) retaining the
highly reactive formyl moiety under basic and oxidative
conditions. Herein, we present the successful development of
a mild and green synthetic route to carbazoles based on the
reaction of 2-methyl-indole-3-carbaldehydes and enals
promoted by inexpensive Lewis acid LiCl and DBU in a single
operation. Notably, this transition metal-free strategy avoids
problematic heavy-metal residues, which should substantially
promote its potential use in the preparation of
pharmaceuticals and materials. More importantly, the formyl
group in the obtained carbazoles can undergo subsequent
derivatizations. Recently, the group of Wan14 described an
efficient method for the construction of polyfunctionalized
benzaldehydes on the basis of [4+2] annulation of linear
dienals and tertiary enaminones.
Entrya
Base
Lewis acid
solvent
Yield(%)b
1
2
3
4
5
6
7
8
9
10
11
12c
13c d
14c e
15c e
Several bases
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
-
-
Cu(OTf)2
Zn(OTf)2
Sc(OTf)2
Mg(OTf)2
FeCl3
ZnCl2
LiCl
LiF
LiBr
NaCl
LiCl
THF
THF
THF
THF
THF
THF
THF
THF
THF
n.d.
<10
<10
<10
<10
n.d.
n.d.
63
30
57
<10
75
79
THF
THF
THF
LiCl
LiCl
LiCl
THF/CH3CN
THF/CH3CN
THF/CH3CN
82
n.d.
a
Reaction conditions: cinnamaldehyde 1a (1.5 equiv), 2a (0.1 mmol),
base (2.0 equiv), Lewis acid (0.2 or 3.0 equiv), solvent (1.0 mL), 30 C,
24 h. [b] Yields of products isolated after column chromatography. [c]
Under an O2 balloon. [d] THF/CH3CN=1:1. [e] 100 µL of t-BuOH was
added. n.d. = not detected.
Results and discussion
With acceptable optimized conditions in hand (Table 1,
entry 14), we then evaluated the reaction scope for enal
substrates using 2a as a model substrate (Table 2). Enals
bearing various substituents with diverse electronic and steric
properties on the β-aryl ring, reacted smoothly to generate the
corresponding carbazole-3-carbaldehydes 3a–3k in good to
excellent yields. Gratifyingly, CHO, ester, CN, NO2, and halide
groups were well tolerated. Enals bearing β-2-naphthyl or
heteroaromatic rings (such as 2-furyl or 2-thienyl rings) also
reacted efficiently (3l–n). Notably, a β-alkyl enal also gave
desired product 3o, albeit in a lower yield. Pleasingly, β-
carbazolyl and fluorenyl enals were suitable substrates,
generating products 3i and 3j in good yields, respectively.
Notably, no reaction occurred when N-Ts was replaced with N-
Me for substrates 2.
We selected the reaction of cinnamaldehyde 1a and readily
available 2-methyl-1-tosyl-1H-indole-3-carbaldehyde 2a15 as
the model reaction for optimizing conditions. The key results
of reaction optimization were summarized in Table 1. Initial
reaction attempts were unsuccessful, with no desired product
afforded when several bases (including DBU, DBN, K2CO3, t-
BuONa and Et3N) were employed in THF at room temperature
(entry 1). Several Lewis acids, including Cu(OTf)2, Zn(OTf)2,
Sc(OTf)3, Mg(OTf)2, FeCl3 and ZnCl2 were then investigated,
affording no product or < 10% yield of carbazole 3a (entries 2–
7). Inexpensive LiCl16 is a weak Lewis acid known to activate
cinnamaldehyde 1a. Furthermore, lithium cations can stabilize
oxygen anions. We envisaged that these synergetic effects
might help the reaction to proceed. Pleasingly, when LiCl was
added, desired carbazole 3a was generated in 62% yield (entry
8). Replacing LiCl with LiF, LiBr, and NaCl led to a decreased
product yield (entries 9–11). With a proper Lewis acid
2 | J. Name., 2012, 00, 1-3
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Table 2. Reaction Scopea
Subsequent transformations of the obtainedVcieawrAbrtaiczleoOlen-li3ne-
carbaldehydes were performed, as shown in Scheme 2 and
Table 4. Selective reduction of the nitro moiety of carbazoles 3
DOI: 10.1039/C9GC00064J
O
O
H
DBU, LiCl
t-BuOH
H
O
+
Table 3. Reaction Scopea
R
H
R
THF/CH3CN
O2, 30 °C
N
N
Ts
O
Ts
O
1
H
DBU, LiCl
t-BuOH
2a
3
H
R1
O
R1
R
+
H
THF/CH3CN
O2, 30 °C
R
N
N
3a
X = H: ; 82% yield
Ts
O
Ts
1
2
3
3b
X = CN: ; 58% yield
H
3c [b]
X = CO2Me:
3d
;
55% yield
X = Cl: ; 70% yield
O
X
3e
X = OMe: ; 75% yield
N
3r
X = F: ; 94% yield
3s
X = Cl: ; 83% yield
X
H
3f
X = Me: ; 79% yield
Ts
3t
X = Br: ; 86% yield
3u
X = Me: ; 89% yield
O
H
O
H
N
O
N
H
Ts
O
H
N
N
N
O
MeO
Cl
X
Ts
O2N
Ts
3h
Ts
H
3g
; 90% yield
O
; 77% yield
O
3i
; 68% yield
X
N
N
N
N
O
H
Ts
Ts
H
H
3w
X = Cl:
; 81% yield
3x
X = Br: ; 82% yield
3v
X = Br: ; 42% yield
F
N
N
N
O
H
O2N
O
O
Ts
Ts
3k
Ts
Cl
X
F
H
H
3l
; 73% yield
3j
; 52% yield
O
; 62% yield
O
Ph
Br
Ph
N
N
N
O
O2N
Ts
Ts
Ts
H
O
H
H
3y
X= F:
X= Cl:
; 67% yield
3ab
3ac
; 62% yield
; 76% yield
3z
; 73% yield
3aa
X= Me:
; 86% yield
N
N
S
N
Ts
Ts
Ts
a
Reaction conditions: 1 (1.5 equiv), cinnamaldehyde 2a (0.1 mmol), DBU
3n
; 64% yield
3m
; 62% yield
3o
; 40% yield
(2.0 equiv), LiCl (3.0 equiv), t-BuOH (100 µL), THF/CH3CN=1:1 (1.0 mL), 30 C,
O2, 24 h. Yields (after SiO2 chromatography purification) were based on 2.
O
O
H
H
using Zn/AcOH, followed by intramolecular cyclizationn and
detosylation, efficiently delivered quinocarbazoles 4a–4c in
good yields. Furthermore, as analogues of alkaloid calothrixin
B, quinocarbazoles 4 show a wide range of promising biological
activities.17 More importantly, 4-fluoroquinocarbazole 4c has
been demonstrated to exhibit potent cytotoxicity against the
NCI-H460 cell line (GI50 =1 nM), and deserves further study.
Notably, the previously reported synthesis of 4c from 2-
methyl-1-(phenylsulfonyl)-1H-indole-3-carbaldehyde required
eight steps. 17 In constrast, using our strategy, 4c was elegantly
constructed in only one step (80% yield) from generated
carbazole 3j, and in only two steps from 2a (50% overall yield).
Furthermore, treating 3i with 2,6-dimethyl benzylamine and
N
N
Et
Et
N
Ts
Ts
3p
; 88% yield
3q
; 74% yield
a
Reaction conditions: 1 (1.5 equiv), cinnamaldehyde 2a (0.1 mmol), DBU
(2.0 equiv), LiCl (3.0 equiv), t-BuOH (100 µL), THF/CH3CN=1:1 (1.0 mL), 30 C,
O2, 24 h. Yields (after SiO2 chromatography purification) were based on 2.
We then investigated the generality of 2-methyl-3-formyl
indoles 2 using β-carbazolyl enal 1x as a model substrate under
the optimized conditions. The reactions proceeded smoothly
with a range of substituents at the 4，5 and 6 positions on the
indole ring, leading to the formation of diverse biscarbazoles
(3r–x) in good to excellent yields. Other enals were also
employed to evaluate the generality of 2-methyl-3-formyl
indoles 2, leading to similar results (3y–ac) to β-carbazolyl enal
1x. N-tosyl 2-methyl 3-acetyl indole cannot give the desired
carbazole. Notably, CHO, NO2, F, Cl, and Br groups in the
obtained carbazoles 3 significantly increased the possibility of
further synthetic transformations.
NaBH3CN, followed by
a P(OEt)3-promoted cyclization,
benzylation, and detosylation afforded product 5 which can be
converted into K-252c18 (staurosporinone) 6 using a known
process. 19
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Table 4. Synthetic transformations. a
in only one step using pesent strategy. Further eVxiepwloArrtaictleioOnnlionef
this catalytic process is underway in our laboratory.
DOI: 10.1039/C9GC00064J
O
X
N
X
H
Zn/AcOH
Y
N
H
Y
Acknowledgements
N
O2N
N
4
Ts
3
We acknowledge financial support by National Natural Science
Foundation of China (21602105), National Key R&D Program of
China (2017YFA0204704), Natural Science Foundation of
Jiangsu Province (BK20171460) and National Key Basic
Research Program of China (973) (2015CB932200). We thank Y.
Guo in this group for reproducing the reactions of 3a, 3j, and
3s.
F
N
N
F
N
N
N
H
H
H
4b
4a
; 77% yield
4c
; 88% yield
; 80% yield
a
Reaction conditions: 3 (0.1 mmol), Zn (20 equiv.), AcOH (3.0 mL),
reflux, overnight.
Notes and references
1
For selected reviews, see: (a) A. W. Schmidt, K. R. Reddy, H. J.
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N
O
F
O
H
H
2 steps
8 steps
N
H
4c
N
N
2
Potent cytotoxicity
against NCI-H460 cell
line (GI50 = 1 nM)
50% yield
SO2Ph
Ts
25% yield
2a
Lit.
Our method
O
H
i. NaBH3CN, 2,6-
dimethyl benzylamine
HN
N
3
4
5
ii. P(OEt)3
N
O2N
iii. BnBr
Ts
R. B. Innis, F. M. A. Correa, S. H. Snyder, Life Sci. 1979,
2255.
,
N
H
iv. K2CO3/MeOH
3i
Bn
5
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T. Meyer, D. G. Gilliland, J. D. Griffin, Cancer Cell. 2002, 1,
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H
O
N
6
7
8
H. Uoyama, K. Goushi, K. Shizu, H. Nomura, C. Adachi, Nature
2012, 492, 234.
N
HN
H
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K-252c
Scheme 2. Synthetic transformations.
Conclusions
In summary, we have successfully developed a mild and green
method for the construction of carbazoles on the basis of the
reaction of 2-methyl-indole-3-carbaldehydes and enals
promoted by Lewis acid LiCl and DBU in a single operation.
Notably, this transition metal-free strategy features mild and
green reaction conditions, a broad substrate scope, and
excellent functional group tolerance, using O2 as the sole
oxidant and giving H2O as the only byproduct. More
importantly, the obtained carbazoles were suitable for further
derivatization. The important bioactive 4-fluoroquinocarbazole
4c was constructed from the obtained carbazole in 80% yield
9
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Green Chemistry
Page 6 of 6
ARTICLE
Journal Name
Graphic Abstract
View Article Online
DOI: 10.1039/C9GC00064J
O
O
O
N
H
H
LiCl/DBU
One step
80% yield
R'
H
R'
+
R
1 atm O2
F
N
N
Ts
R
N
30 °C
H
Ts
29 examples
Potent cytotoxicity
against NCI-H460 cell
line (GI50 = 1 nM)
up to 94% yield
Mild and green conditions
Excellent functional group tolerance A broad substrate scope
Direct construction of carbazoles
The direct and rapid construction of carbazoles was achieved
based on the reaction of 2-methyl-indole-3-carbaldehydes and
enals promoted by Lewis acid LiCl and DBU in a single operation.
6 | J. Name., 2012, 00, 1-3
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