Substituent-Guided Palladium-Ene Reaction for the Synthesis of Carbazoles and Cyclopenta[ b]indoles

Article abstract of DOI:10.1021/acs.orglett.9b00410

An efficient palladium-catalyzed intramolecular Trost-Oppolzer type Alder-ene strategy was developed for the synthesis of carbazoles and cyclopenta[b]indoles from easily accessible(3-allyl-1H-indol-2-yl)methyl acetates. This strategy was extended for the synthesis of naphthalenes and dibenzobenzofurans as well. In addition, a short synthesis of antibacterial and antifungal natural product glycozoline and its analogues was also achieved.

Full text of DOI:10.1021/acs.orglett.9b00410

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Substituent-Guided Palladium-Ene Reaction for the Synthesis of
Carbazoles and Cyclopenta[b]indoles
Sonu Yadav, Raju Hazra, Animesh Singh, and S. S. V. Ramasastry*
Organic Synthesis and Catalysis Lab, Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER)
Mohali, Sector 81, Manauli PO, S. A. S. Nagar, Punjab 140306, India
S
* Supporting Information
ABSTRACT: An efficient palladium-catalyzed intramolecular
Trost−Oppolzer type Alder-ene strategy was developed for
the synthesis of carbazoles and cyclopenta[b]indoles from
easily accessible(3-allyl-1H-indol-2-yl)methyl acetates. This
strategy was extended for the synthesis of naphthalenes and
dibenzobenzofurans as well. In addition, a short synthesis of
antibacterial and antifungal natural product glycozoline and its analogues was also achieved.
arbazoles are an important class of nitrogen-containing
Cheterocycles, which are frequently encountered in several
bioactive compounds.1 In addition, carbazoles exhibit interest-
ing properties for application as optoelectronic materials and
conducting polymers.2 Recently, carbazole-based synthetic
dyes have been developed3 and carbazole derivatives also
have been employed as ligands for sensing applications.4 A few
representative carbazole natural products, medicinally impor-
tant compounds, and some optoelectronic materials are
depicted in Figure 1.5
observation made during the evaluation of substrate scope led
to the discovery of a new method for the synthesis of
cyclopenta[b]indoles H.
Scheme 1. Hypothesis and the Present Work: Substitution-
Dependent Alder-Ene Reaction for the Synthesis of
Benzenoids and Cyclopentanoids
We commenced this study with the synthesis of carbazoles
(Scheme 1). It was postulated that the allyl acetate A under the
influence of an appropriate palladium complex could form the
(π-allyl)palladium species B. An intramolecular ene-type
reaction of the appropriately positioned olefin followed by
deprotonation could then generate dihydrocarbazoles D,
which, presumably via aerobic oxidation or in the presence
of a suitable oxidizing agent, afford carbazoles and other
related benzenoids. Thus, this hypothesis combines the
electrophilic features of the Tsuji−Trost reaction9 and the
Figure 1. A few important carbazoles.
Due to their various applications, numerous methods for the
synthesis of functionalized carbazoles have been developed,
which include the classical Borsche−Drechsel cyclization6 and
the Graebe−Ullmann synthesis,7 to mention only a few among
many other outstanding approaches.8 Despite these advance-
ments, the development of modular and efficient approaches
for the synthesis of carbazoles is of considerable interest.
Herein, we wish to report a general and practical strategy for
the synthesis of carbazoles E from easily accessible (3-allyl-1H-
indol-2-yl)methyl acetates A (Scheme 1). A serendipitous
Received: January 31, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00410
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
nucleophilic features of the ene reaction.10 To our knowledge,
this strategy also represents the first palladium-ene reaction-
based approach for the synthesis of carbazoles.
With the intention to validate the hypothesis proposed in
Scheme 1, the indolyl acetate 1a was chosen as the model
substrate (Table 1).11 Various combinations of metal catalysts
(ii) the overall reaction can be perceived to be a one-pot
sequential Tsuji−Trost reaction, Alder-ene reaction, and an
oxidative aromatization, all of them being promoted by the
same catalyst in one pot.
To evaluate the scope and generality of the method, the
optimized conditions were applied to a variety of substrates
possessing diverse steric and electronic features (Scheme 2). A
a b
,
Table 1. Optimization of the Reaction Parameters
Scheme 2. Substrate Scope for 1,3-Disubstituted Carbazoles
a b
,
3
c
entry
catalyst (10 mol %)
solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
t (h)
yield (%)
d
1
Pd(PPh3)4
Pd2(dba)3
Pd(OAc)2
[Ir(cod)Cl]2
Ni(cod)2
Pd(PPh3)2Cl2
[PdCl(allyl)]2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
72
72
72
72
72
72
72
26
72
72
72
24
36
18
29
−
−
20
33
−
d
2
3
4
d
5
d
6
−
7
8
9
15
74
52
−
69
83
45
85
66
1,2-DCE
DMF
d
10
11
CH3CN
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
e
12
f
13
14
PdCl2
PdCl2
PdCl2
g
h
15
a
Reaction conditions: See the Supporting Information for details.
Unless mentioned otherwise, all the reactions were performed at 80
b
c
d
°C. Isolated yields after column chromatography. 1a remained as
e
such even at 100 °C. 1a remained as such at rt−40 °C; a 1:1 mixture
of 2a and 3a was observed at 60 °C and 1a was obtained in 73% yield
f
at 100 °C. 5 mol % PdCl2 was employed; 35% of 2a was also isolated.
a
g
h
Reaction conditions: See Supporting Information for details.
Chromatographic yields.
20 mol % PdCl2 was employed. Reaction with 1a′ possessing OBoc
b
group instead of OAc.
and solvents were evaluated, and the key results are
summarized in Table 1. While the Pd(0) catalysts were
unsuccessful, Pd(OAc)2 straightaway provided 3a, although in
poor yield (entries 1−3). The structure of 3a was readily
deduced from the spectroscopic data and was eventually
confirmed by X-ray diffraction analysis (CCDC 1590634).12
Our efforts to enhance the efficiency of the reaction with Ir-
or Ni-catalysts were not encouraging (Table 1, entries 4 and
5). Then, we turned our attention to Pd(II) catalysts. Among
them, PdCl2-promoted reaction generated 3a in good yield
(entry 8). A brief solvent screening was undertaken from
where 1,4-dioxane was realized to be optimal for the
conversion of 1a to 3a (entries 12). Whereas a 5 mol %
loading of PdCl2 lowered the conversion, the reaction with a
higher catalyst loading (20 mol %) required less time for
completion, but did not offer any significant improvement in
the yield (entries 13 and 14). Interestingly, the reaction of 1a′
(1a with OBoc group instead of OAc) under the best yielding
conditions afforded 3a in 66% yield (entry 15).
wide range of 1,3-disubstituted carbazoles possessing electron-
donating and -withdrawing arenes, and heteroarenes at R1,
could be accessed in good yields (3b−3h). Even carbazoles
substituted with bromo- and chloro-functionalities (such as 3i
and 3j) could be conveniently prepared. These compounds are
amenable for further synthetic elaborations; thereby, complex
carbazole derivatives can be rapidly assembled.13
This method can be extended for the synthesis of
monosubstituted carbazoles as well (Scheme 3). For example,
unsubstituted indolyl acetates 1k−1m, under the prototypical
conditions, furnished the respective carbazoles 3k−3m in good
Scheme 3. Synthesis of 3-Substituted Carbazoles and the
Total Synthesis of the Natural Product Glycozoline
Thus, 10 mol % of the cheap and readily available palladium
chloride in a less toxic and environmentally benign dioxane
medium were realized to be optimal for the transformation of
1a to 3a. Some other salient features of this method include
the following: (i) unlike many Pd-catalyzed reactions, this
reaction does not require any additives, reoxidants, bases, etc.;
B
DOI: 10.1021/acs.orglett.9b00410
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Organic Letters
Letter
yields, thereby enhancing the scope of the present method.
Further treatment of 3k−3m with TBAF generated NH-
carbazoles 4k−4m in excellent yields.8c Among them, 4m is
the antibiotic and antifungal natural product glycozoline.5a The
other analogues of glycozoline (4k and 4l) are known to have
prominent biological activity profiles.14
Scheme 5. Unexpected Formation of Cyclopenta[b]indole
10a and a Plausible Mechanistic Rationale
After successfully establishing a new method for the facile
synthesis of carbazoles, we considered extending this concept
to the synthesis of other prominent benzenoids. Accordingly, a
variety of ε,ω-unsaturated acetates (5 and 6) were prepared
and subjected to the optimized conditions (Scheme 4). An
Scheme 4. Synthesis of Naphthalenes (7) and
Dibenzofurans (8)
a b c
, ,
Scheme 6. Substrate Scope for Cyclopenta[b]indoles 10
interesting range of 1,3-disubstituted naphthalenes (7a and
7b) and dibenzofurans (8a and 8b) were achieved in an
efficient manner. It is worth mentioning that naphthalenes15
and benzofuranoids16 are the primary molecular architectures
of many bioactive compounds and drug candidates and find
important applications in materials chemistry as well.17
Next, as part of our efforts to evaluate the scope of the
palladium-ene process, we made an interesting observation.
When the acetate 9a having no substitution at the vinylic
position was subjected to the prototypical conditions described
in Scheme 2, the cyclopenta[b]indole 10a was isolated in 53%
yield (Scheme 5). In addition, the 2-benzyl-3-vinyl-N-
tosylindole 11a was also isolated in 28% yield.
The formation of 10a and 11a can be explained as depicted
in Scheme 5. The reaction presumably commences with a Pd-
catalyzed isomerization of the unactivated terminal olefin18
followed by the oxidative addition, to form J.19 Although the
mechanism leading to the formation of 11a from J is not
established at this stage, it can be surmised that the reductive
elimination of J to 11a is promoted by the presence of an
adventitious amount of water.20 While an intramolecular
palladium ene reaction of J generates K,19 which undergoes α-
elimination to afford 10a′ (a regioisomer of 10a), a γ′-
elimination of K provides neutral but unstable intermediate
10a′′. Finally, the double bond isomerization of 10a′ or a
[1,5]-sigmatropic hydrogen shift of 10a′′ affords 10a.21
Having realized the significance of the aforementioned
observation, we commenced to optimize various parameters
influencing the reaction (see the Supporting Information for
details). During the screening, it was realized that the
selectivity toward the formation of 10a could be significantly
enhanced in the acetonitrile medium, in which case 10a was
isolated in 72% yield. Under these conditions, a wide range of
1,2-disubstituted cyclopenta-fused indoles were synthesized in
a highly regioselective manner (Scheme 6, 10a−10i).22 It is
evident that electronically distinct arenes, and heteroarenes,
a
Reaction conditions: See the Supporting Information for details.
b
c
Isolated yields after column chromatography. About 12−15% of 11
d
was also isolated in each case. Reaction with 9a′ (9a with OBoc
group instead of OAc).
were well-tolerated at R1. The presence of chloro- and bromo-
functionalities (10h and 10i) on the arene moiety presents the
opportunity for further elaborations. The significance of
cyclopenta[b]indoles as the primary molecular architectures
in several bioactive molecules and their relevance in medicinal
C
DOI: 10.1021/acs.orglett.9b00410
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Organic Letters
Letter
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chemistry as well as in materials science makes the present
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standard conditions furnished the cyclopetannulated indole
14a, via the intermediacy of 13a. It is interesting to note that
Pd-catalyzed twofold olefin isomerizations are known,18b,24 but
not under such straightforward conditions as reported herein.
In summary, we presented a divergent approach for the
synthesis of a variety of carbazoles, naphthalenes, dibenzofur-
ans, and cyclopenta[b]indoles from easily accessible (3-allyl-
1H-indol-2-yl)methyl acetates. Interesting substitution de-
pendence on the product distribution was realized. Based on
the mechanistic considerations, this phenomenon was
efficiently crafted to yield the product of choice. The
methodologies described herein have been realized to be
practical and scalable25 and demonstrated great potential for
the synthesis of new heterocycles. We are currently involved in
extending these strategies toward the total synthesis of
complex carbazole and indole-based natural products, and
the results will be communicated in due course.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00410.
Experimental procedures and spectral data for all new
compounds (1H NMR, 13C NMR) (PDF)
Accession Codes
CCDC 1590634 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
̈
2018, 20, 4796. (l) Kaufmann, J.; Jackel, E.; Haak, E. Angew. Chem.,
Int. Ed. 2018, 57, 5908. (m) Bal, A.; Maiti, S.; Mal, P. J. Org. Chem.
2018, 83, 11278. (n) Mandal, T.; Chakraborti, G.; Karmakar, S.;
Dash, J. Org. Lett. 2018, 20, 4759. (o) Men, Y.; Hu, Z.; Dong, J.; Xu,
X.; Tang, B. Org. Lett. 2018, 20, 5348.
AUTHOR INFORMATION
(9) (a) Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett.
1965, 6, 4387. (b) Trost, B. M.; Fullerton, T. J. J. Am. Chem. Soc.
1973, 95, 292.
(10) (a) For seminal works on the Pd-catalyzed ene-type reaction,
see: Trost, B. M.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781.
(b) Oppolzer, W. Pure Appl. Chem. 1988, 60, 39.
■
Corresponding Author
*E-mail: ramsastry@iisermohali.ac.in.
ORCID
S. S. V. Ramasastry: 0000-0001-5814-9092
Notes
(11) See the Supporting Information for the synthesis of 1a and its
analogues.
(12) (a) The structure of 3a was also confirmed by comparing the
data of structurally related compounds. See: Witulski, B.; Alayrac, C.
Angew. Chem., Int. Ed. 2002, 41, 3281. (b) James, M. J.; Clubley, R. E.;
Palate, K. Y.; Procter, T. J.; Wyton, A. C.; O’Brien, P.; Taylor, R. J. K.;
Unsworth, W. P. Org. Lett. 2015, 17, 4372.
(13) (a) Jacquemard, U.; Routier, S.; Tatibouet, A.; Kluza, J.; Laine,
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(b) Huang, Y.; Guo, Z.; Song, H.; Liu, Y.; Wang, Q. Chem. Commun.
2018, 54, 7143.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
IISER Mohali is acknowledged for funding and for the NMR,
mass and departmental X-ray facilities. S.S.V.R. thanks DST for
the Swarnajayanti fellowship and SERB for the Core Research
Grant (CRG/2018/000016). S.Y., R.H., and A.S. thank IISER
Mohali for research fellowships.
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Pharm. Bull. 1985, 33, 4132. (b) Momin, A. A.; Urmode, T. D.;
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E
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