Br?nsted Acid Catalyzed One-Pot Benzannulation of 2-Alkenylindoles under Aerial Oxidation: A Route to Carbazoles and Indolo[2,3- a]carbazole Alkaloids

Article abstract of DOI:10.1021/acs.orglett.8b03063

A one-pot, protecting-group-free benzannulation of 2-alkenylindoles with readily available 1,3-dicarbonyls is demonstrated to construct structurally diverse carbazoles. The use of a cheap Br?nsted acid catalyst and air as the sole oxidant exemplifies the economic viability of this protocol. The execution of four different reactions successively to generate the medicinally important indolocarbazole core is also achieved. This one-pot protecting-group-free method paved the way for the total synthesis of three medicinally important alkaloids, namely staurosporinone, arcyriaflavin A, and 7-hydroxy-K252c.

Full text of DOI:10.1021/acs.orglett.8b03063

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Brønsted Acid Catalyzed One-Pot Benzannulation of
2‑Alkenylindoles under Aerial Oxidation: A Route to Carbazoles and
Indolo[2,3‑a]carbazole Alkaloids
Shuvendu Saha, Ankush Banerjee, and Modhu Sudan Maji*
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, West Bengal, India
S
* Supporting Information
ABSTRACT: A one-pot, protecting-group-free benzannula-
tion of 2-alkenylindoles with readily available 1,3-dicarbonyls
is demonstrated to construct structurally diverse carbazoles.
The use of a cheap Brønsted acid catalyst and air as the sole
oxidant exemplifies the economic viability of this protocol.
The execution of four different reactions successively to
generate the medicinally important indolocarbazole core is
also achieved. This one-pot protecting-group-free method
paved the way for the total synthesis of three medicinally
important alkaloids, namely staurosporinone, arcyriaflavin A,
and 7-hydroxy-K252c.
indolocarbazoles9 demand a profound synthetic route to
ndolocarbazoles and carbazoles are commonly occurring
Iheterocycles present in alkaloids of therapeutic impor- access both symmetrical and even challenging unsymmetrical
tance.1,2 To date, more than 110 indolo[2,3-a]carbazole
indolo[2,3-a]carbazoles and related alkaloids.
alkaloids have been isolated from nature,3 and many of those
Alongside indolocarbazole, synthesis of carbazole, another
privileged heterocycle, primarily relied on complicated starting
materials, expensive catalysts, and longer reaction sequen-
ces.10,11 Despite merits of these methods,12 synthesis of this
heterocycle starting with simple precursors by using a cheap
and commonly available catalyst is highly attractive and
desirable. Recently, the benzannulation strategy has emerged
as one of the most powerful tools for the synthesis of
carbazoles bearing unique substitution patterns.13 In our
ongoing research interest,14 we envisioned that carbazole can
be constructed in one pot15 by annulation of 2-alkenylindoles
and appropriate 1,3-dicarbonyls using Brønsted acid catalyst
under aerial oxidation (Scheme 1).16 Advancing a step further,
are undergoing clinical trials for the treatment of cancer,
diabetic retinopathy, and Parkinson’s disease.4 In 2017,
midostaurin was approved as drug to treat patients diagnosed
with a form of blood cancer known as acute myeloid leukemia
(Figure 1).5 Synthesis of diversely functionalized indolo[2,3-
a]carbazoles was generally accomplished by Fischer indole
cyclization of functionalized cyclohexanones prepared by
tedious synthetic efforts6 or via C−C coupling using expensive
transition-metal catalysts followed by Cadogan cyclization.7,8
Limited and complicated methods for the synthesis of
Scheme 1. Working Hypothesis for the Synthesis of
Carbazoles and Indolo[2,3-a]carbazoles
Received: September 25, 2018
Figure 1. Indolocarbazoles of medical importance.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03063
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
upon extending this one-pot strategy by employing intermedi-
ately formed carbazoles bearing a 2-nitroaryl moiety at the C2-
position, valuable indolo[2,3-a]carbazoles can be synthesized
by performing an in situ Cadogan cyclization. More
importantly, on choosing the required 2-alkenylindole along
with 1,3-dicarbonyls as annulating partners, several indolo[2,3-
a]carbazole alkaloids can also be synthesized in fewer steps via
a protecting-group-free route. It is important to note that 2-
alkenylindoles have been utilized as 1,3-dienes for the [4 + 2]-
cycloaddition reactions to obtain octahydrocarbazoles.17 Here-
in, we disclose one-pot synthesis of carbazoles and
indolocarbazoles by using benzannulation protocols and their
application to the synthesis of indolocarbazole alkaloids.
At the onset of our optimizations, first, 2.0 equiv of
ethylacetoacetate (EAA) 1a was reacted with 2a in ethyl
acetate solvent by employing 20 mol % of diphenylphosphoric
acid catalyst to generate intermediate 2,3-dialkenylindole. After
completion of the alkenylation (step 1), decalin was added,
and 6π-electrocyclization was carried out at 130 °C under air
as sole oxidant to provide carbazole 3a in 53% yield (Table 1,
Scheme 2. Scope of Electrophiles
a
Table 1. Optimization of the Reaction Conditions
a
Reaction conditions: step 1, 1 (0.40 mmol), 2a (0.20 mmol), A (25
mol %), 1.3 mL EtOAc, 110 °C; step 2, 2.7 mL of decalin, 130 °C;
b
isolated yield. 5 mol % of A used.
b
acid cat.
(mol %)
solvent
step 1/step 2
temp (°C)
step 1/step 2
yield of 3a
entry
(%)
yield). Acetylacetone also reacted well to furnish carbazole 3e
bearing a ketone functional group at the 3-position. To our
delight, unsymmetrical 1,3-diketones reacted exclusively at the
less hindered site (3f−h, 40−47% yields). Diethyl 2-
oxosuccinate furnished diester substituted carbazole 3i in
77% yield. Ethyl pyruvate also afforded carbazole 3j bearing an
ester functional group at the 4-position. Reactivity of aldehyde
over ketone was exploited to obtain carbazole 3l in 68% yield.
After successfully employing several electrophiles, the
reaction scope was further studied by varying several 2-
alkenylindoles 2b−m (Scheme 3). 2-Alkenylindoles bearing
methyl, methoxy, chloride, and bromide functional groups at
the 5-position of indole reacted efficiently to afford carbazoles
3m−p in 52−71% yields. Likewise, several functional groups
such as methyl, methoxy, fluoro, and nitro at the phenyl ring of
2-alkenylindoles were tolerated to furnish 3q−v in 50−68%
yields. 1-Naphthyl- and 2-thiophenyl-substituted 2-alkenylin-
doles were also suitable substrates (3w−x, 67−70% yields).
The alkyl group at the 2-position of the carbazole can be
incorporated, albeit in lower yield (3y, 30%). Although one of
the key highlights of this annulation strategy is that it is
protecting-group-free, if required, the N-benzyl-protected
carbazole 3z can also be synthesized in 63% yield. To show
the scalability of this method, carbazoles 3t and 3v were
synthesized on a gram scale.
After successfully executing the synthesis of several
structurally diverse carbazoles, we further explored this strategy
to the synthesis of diversified indolo[2,3-a]carbazoles 4 by
employing Cadogan cyclization. Notably, to achieve this
medicinally important indolocarbazole core structure, four
completely different reactions need to be executed sequentially
without isolating a single intermediate. For this, a nitro group
needed to be appropriately poised in the intermediate
carbazole 3 for the subsequent Cadogan cyclization, which
was achieved by using (E)-2-(2-nitrostyryl)-1H-indole as the
1
2
20
25
25
25
25
25
25
25
25
25
25
EtOAc/decalin
EtOAc/decalin
EtOAc/decalin
EtOAc/decalin
CHCl3/decalin
THF/decalin
EtOH/decalin
EtOAc/xylene
EtOAc/decalin
EtOAc/decalin
EtOAc/decalin
90/130
90/130
90/130
90/130
90/130
90/130
90/130
90/130
90/130
110/130
130/130
53
65
31
62
53
30
26
63
53
72
c
3
d
4
5
6
7
8
e
9
10
11
66
a
b
Reaction conditions: 1a (0.30 mmol), 2a (0.15 mmol). Isolated
c
d
yield. Binolphosphoric acid was used in place of A. EAA (2.5 equiv).
e
Step 2 was carried out under oxygen.
entry 1). Yield of 3a was enhanced to 65% on increasing the
catalyst loading to 25 mol % (entry 2). Employing other
Brønsted acid catalyst or increasing the EAA amount did not
provide better results (entries 3 and 4). On conducting the first
step in other solvents, the yield decreased (entries 5−7). A
similar yield was recorded when step 2 was conducted in
xylene (entry 8). Air was sufficient for the oxidative
aromatization reaction, as the yield of 3a did not improve
when the reaction was conducted under molecular oxygen
(entry 9). Finally, on increasing the temperature for the step 1,
the highest yield of 3a was obtained at 110 °C (72%, entries 10
and 11). The (E)-2-alkenyl indoles 2a was more effective as
the corresponding (Z)-isomer provided 3a in 52% yield.
With the optimized reaction conditions in hand, we first
studied the compatibility of several electrophiles. 4-Heptyl-
and 4-benzyl-substituted EAA derivatives provided carbazoles
3b and 3c in moderate yields (Scheme 2). Ethyl
benzoylacetate is also a suitable annulating partner (3d, 43%
B
DOI: 10.1021/acs.orglett.8b03063
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Organic Letters
Letter
cytomegalovirus replication inhibitor.19a Besides their own
merits, most, if not all, of the existing methods to synthesize
these alkaloids have certain limitations such as longer reaction
sequences, complicated precursors, additional protection−
deprotection steps, and use of expensive transition-metal
catalysts. To achieve the total synthesis of arcyriaflavin A, first,
saponification of the intermediate 4b by treatment with KOH
in ethanol under reflux conditions provided an anhydride
intermediate which in the presence of neat ammonium acetate
at 140 °C furnished arcyriaflavin A in 78% yield over two steps
and in 35% overall yield over three steps from 2i (Scheme
5a).19d Selective reduction of arcyriaflavin A by using LiAlH4
a
Scheme 3. Scope of 2-Alkenylindoles
Scheme 5. Total Synthesis of K252c, Arcyriaflavin A, and 7-
Hydroxy-K252c Alkaloids
a
Reaction conditions: step 1, 1 (0.40 mmol), 2 (0.20 mmol), A (25
mol %), 1.3 mL of EtOAc, 110 °C; step 2, 2.7 mL of decalin, 130 °C;
b
c
isolated yield. 15 mol % of A used. 5 mol % of A used.
annulating partner. Executing this one-pot strategy by
employing 1a as an electrophile provided the indolocarbazole
4a in 42% yield (Scheme 4). Diethyl 2-oxosuccinate and ethyl
a
Scheme 4. Scope of Indolocarbazoles
afforded alkaloid 7-hydroxy-K252c in 82% yield.20b The
synthesis of staurosporinone from arcyriaflavin A was reported
by reduction of one carbonyl group under Sn/HCl or Zn−Hg/
HCl conditions,20d,21 thus completing the synthesis of this
alkaloid in four steps from 2i in 24% overall yield. In addition
to staurosporinone, (dimethylamino)propyl quinocarbazole
also exhibits potential cytotoxicity against cancer cells.22 An
advanced intermediate 7 for the synthesis of (dimethylamino)-
propyl quinocarbazole was achieved in one pot by reduction of
3v followed by intramolecular amidation in 92% yield (Scheme
5b). Furthermore, compound 7 also resembles the core
structure present in the alkaloids calothrixin A and calothrixin
B.
To achieve the total synthesis of staurosporinone by a
second route, an attempt to brominate the benzylic hydrogen
of 3t was in vain as this resulted in ring bromination at the C6-
position. To circumvent this problem, at first the free −NH
group of 3t was sulfonaylated to furnish electron-deficient
carbazole 5 (Scheme 5c). The selective benzylic bromination
of 5 using NBS and a catalytic amount of AIBN was then
successful.18c Subsequently, nucleophilic substitution of the
benzylic bromide intermediate with ammonia followed by in
situ intramolecular amidation afforded 6 in 93% yield. Finally,
Cadogan cyclization of 6 and desulfonation completed the
a
Reaction conditions: step 1, 1 (0.40 mmol), 2i (0.20 mmol), A (5
mol %), 1.3 mL of EtOAc, 110 °C; step 2, 2.7 mL of decalin, 130 °C;
b
step 3, 0.5 mL of P(OEt)3, 180 °C; isolated yield. 25 mol % of A
c
used. 15 mol % of A used.
3-oxopropanoate were also found to be suitable coupling
partners, delivering indolocarbazoles 4b and 4c in good yields.
To our delight, commercially available aliphatic aldehydes also
reacted smoothly to furnish 5-alkylated indolocarbazoles 4d−f
in 40−53% yields.
Next, we applied our strategy to the total synthesis of
different indolo[2,3-a]carbazole alkaloids, namely, staurospor-
inone,18 arcyriaflavin A,19 and 7-hydroxy-K252c,20 in a
protecting-group-free and step-economical way. These natu-
rally occurring alkaloids have gained considerable attention
owing to their presence in drugs and importance in medicinal
chemistry. For example, arcyriaflavin A manifests as a human
C
DOI: 10.1021/acs.orglett.8b03063
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Sierra, J.; Sanz, M. A.; Brandwein, J. M.; de Witte, T.; Niederwieser,
D.; Appelbaum, F. R.; Medeiros, B. C.; Tallman, M. S.; Krauter, J.;
Schlenk, R. F.; Ganser, A.; Serve, H.; Ehninger, G.; Amadori, S.;
total synthesis of staurosporinone alkaloid in an improved 36%
overall yield over six steps from 2i.
In conclusion, we developed an elegant method for the
construction of polyfunctionalized carbazoles and indolo[2,3-
a]carbazoles using a benzannulation strategy employing simple
starting materials. Transition-metal-free conditions, broad
substrate scope, scalability, regioselectivity, aerial oxidation,
and readily available Brønsted acid catalyst renders this
method practical. The protecting-group-free synthesis of
staurosporinone, arcyriaflavin A, and 7-hydroxy-K252c dem-
onstrates the applicability of this method. We presume this
strategy will be fruitful for the synthesis of diversified
indolocarbazole and quinocarbazole alkaloids relevant to
medicinal chemistry.
̈
Larson, R. A.; Dohner, H. N. N. Engl. J. Med. 2017, 377, 454.
(6) (a) Bergman, J.; Pelcman, B. J. Org. Chem. 1989, 54, 824.
(b) Hu, Y.-Z.; Chen, Y.-Q. Synlett 2005, 42. (c) Kotha, S.; Saifuddin,
M.; Aswar, V. R. Org. Biomol. Chem. 2016, 14, 9868. (d) Heravi, M.
M.; Rohani, S.; Zadsirjan, V.; Zahedi, N. RSC Adv. 2017, 7, 52852.
(7) (a) Balaji, G.; Shim, W. L.; Parameswaran, M.; Valiyaveettil, S.
́
̂
Org. Lett. 2009, 11, 4450. (b) Biniek, L.; Bulut, I.; Leveque, P.; Heiser,
T.; Leclerc, N. Tetrahedron Lett. 2011, 52, 1811. (c) Chen, Q.; Zhang,
L.; Ebrahim, S.; Soliman, M.; Zhang, C.; Qiao, Q. Polymer 2013, 54,
223. (d) Kato, S.-I.; Furuya, T.; Nitani, M.; Hasebe, N.; Ie, Y.; Aso, Y.;
Yoshihara, T.; Tobita, S.; Nakamura, Y. Chem. - Eur. J. 2015, 21, 3115.
(8) (a) Cadogan, J. I. G.; Cameron-Wood, M.; Mackie, R. K.; Searle,
R. J. G. J. Chem. Soc. 1965, 4831. (b) Cadogan, J. I. G. Synthesis 1969,
11.
ASSOCIATED CONTENT
* Supporting Information
■
(9) (a) Carter, D. S.; Van Vranken, D. L. J. Org. Chem. 1999, 64,
8537. (b) Banerji, A.; Bandyopadhyay, D.; Basak, B.; Biswas, P. K.;
Banerji, J.; Chatterjee, A. Bull. Chem. Soc. Jpn. 2007, 80, 1199.
(c) Tsuchimoto, T.; Matsubayashi, H.; Kaneko, M.; Nagase, Y.;
Miyamura, T.; Shirakawa, E. J. Am. Chem. Soc. 2008, 130, 15823.
(d) Shi, Z.; Ding, S.; Cui, Y.; Jiao, N. Angew. Chem., Int. Ed. 2009, 48,
7895. (e) Yang, J.; Zhang, Q.; Zhang, W.; Yu, W. RSC Adv. 2014, 4,
13704. (f) Abe, T.; Ishikura, M. Heterocycles 2015, 90, 673.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03063.
Experimental details, analytical data for all new
compounds, and NMR spectra (PDF)
̈
(10) (a) Knolker, H.-J.; Bauermeister, M. J. Chem. Soc., Chem.
AUTHOR INFORMATION
̈
Commun. 1990, 664. (b) Knolker, H.-J.; Bauermeister, M.; Pannek, J.-
■
B. Tetrahedron 1993, 49, 841. (c) Tsang, W. C. P.; Zheng, N.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560. (d) Liegault, B.;
Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou, K. J. Org. Chem. 2008,
73, 5022. (e) Jordan-Hore, J. A.; Johansson, C. C. C.; Gulias, M.;
Beck, E. M.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 16184.
(f) Stokes, B. J.; Jovanovic, B.; Dong, H.; Richert, K. J.; Riell, R. D.;
Driver, T. G. J. Org. Chem. 2009, 74, 3225. (g) Gensch, T.;
Ronnefahrt, M.; Czerwonka, R.; Jager, A.; Kataeva, O.; Bauer, I.;
Knolker, H.-J. Chem. - Eur. J. 2012, 18, 770. (h) Takamatsu, K.;
Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2014, 16, 2892.
(i) Taguchi, M.; Tokimizu, Y.; Oishi, S.; Fujii, N.; Ohno, H. Org.
Lett. 2015, 17, 6250. (j) Stepherson, J. R.; Ayala, C. E.; Tugwell, T.
H.; Henry, J. L.; Fronczek, F. R.; Kartika, R. Org. Lett. 2016, 18, 3002.
(k) Krahl, M. P.; Jager, A.; Krause, T.; Knolker, H.-J. Org. Biomol.
Chem. 2006, 4, 3215. (l) Schmidt, M.; Knolker, H.-J. Synlett 2009,
Corresponding Author
*E-mail: msm@chem.iitkgp.ac.in.
ORCID
́
Modhu Sudan Maji: 0000-0001-9647-2683
Notes
́
The authors declare no competing financial interest.
̈
̈
̈
ACKNOWLEDGMENTS
■
M.S.M. gratefully acknowledges DST/INSPIRE Faculty
Award/2013/DST/INSPIRE/04/2013/000681 and the Coun-
cil of Scientific and Industrial Research, India (Sanction No.
02(0322)/17/EMR-II), for funding. S.S. and A.B. sincerely
thank UGC, India, for fellowships.
̈
̈
̈
2421.
(11) (a) Robinson, B. Chem. Rev. 1969, 69, 227. (b) Ishikura, M.;
Yaginuma, T.; Agata, I.; Miwa, Y.; Yanada, R.; Taga, T. Synlett 1997,
214. (c) Witulski, B.; Alayrac, C. Angew. Chem., Int. Ed. 2002, 41,
3281.
REFERENCES
■
(1) (a) Chao, W.-R.; Yean, D.; Amin, K.; Green, C.; Jong, L. J. Med.
Chem. 2007, 50, 3412. (b) Janosik, T.; Wahlstrom, N.; Bergman, J.
Tetrahedron 2008, 64, 9159. (c) Wang, J.-N.; Zhang, H.-J.; Li, J.-Q.;
Ding, W.-J.; Ma, Z.-J. J. Nat. Prod. 2018, 81, 949. (d) Janosik, T.;
Rannug, A.; Rannug, U.; Wahlstrom, N.; Slatt, J.; Bergman, J. Chem.
Rev. 2018, 118, 9058.
̈
̈
(12) (a) Kataeva, O.; Krahl, M. P.; Knolker, H.-J. Org. Biomol. Chem.
̈
2005, 3, 3099. (b) Czerwonka, R.; Reddy, K. R.; Baum, E.; Knolker,
̈
̈
H.-J. Chem. Commun. 2006, 711. (c) Hesse, R.; Gruner, K. K.;
̈
Kataeva, O.; Schmidt, A. W.; Knolker, H.-J. Chem. - Eur. J. 2013, 19,
̈
(2) (a) Knolker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303.
̈
̈
14098. (d) Hesse, R.; Jager, A.; Schmidt, A. W.; Knolker, H.-J. Org.
̈
(b) Schmidt, A. W.; Reddy, K. R.; Knolker, H.-J. Chem. Rev. 2012,
Biomol. Chem. 2014, 12, 3866. (e) Kutz, S. K.; Schmidt, A. W.;
̈
112, 3193. (c) Bauer, I.; Knolker, H.-J. Top. Curr. Chem. 2011, 309,
203. (d) Roy, J.; Jana, A. K.; Mal, D. Tetrahedron 2012, 68, 6099.
̈
Knolker, H.-J. Synthesis 2017, 49, 275.
(13) (a) Ozaki, K.; Zhang, H.; Ito, H.; Lei, A.; Itami, K. Chem. Sci.
2013, 4, 3416. (b) Wu, J.-Q.; Yang, Z.; Zhang, S.-S.; Jiang, C.-Y.; Li,
Q.; Huang, Z.-S.; Wang, H. ACS Catal. 2015, 5, 6453. (c) Poudel, T.
N.; Lee, Y. R. Chem. Sci. 2015, 6, 7028. (d) Verma, A. K.; Danodia, A.
K.; Saunthwal, R. K.; Patel, M.; Choudhary, D. Org. Lett. 2015, 17,
3658. (e) Raji Reddy, C.; Rani Valleti, R.; Dilipkumar, U. Chem. - Eur.
J. 2016, 22, 2501. (f) Rathore, K. S.; Lad, B. S.; Chennamsetti, H.;
Katukojvala, S. Chem. Commun. 2016, 52, 5812. (g) Fan, X.; Yu, L.-Z.;
Wei, Y.; Shi, M. Org. Lett. 2017, 19, 4476. (h) Wang, H.; Wang, Z.;
Wang, Y.-L.; Zhou, R.-R.; Wu, G.-C.; Yin, S.-Y.; Yan, X.; Wang, B.
Org. Lett. 2017, 19, 6140. (i) Gu, Y.; Huang, W.; Chen, S.; Wang, X.
Org. Lett. 2018, 20, 4285. (j) Poudel, T. N.; Karanjit, S.; Khanal, H.
D.; Tamargo, R. J. I.; Lee, Y. R. Org. Lett. 2018, 20, 5648.
̈
̈
(e) Knolker, H.-J.; Frohner, W.; Reddy, K. R. Eur. J. Org. Chem. 2003,
740.
́
́
(3) (a) Sanchez, C.; Mendez, C.; Salas, J. A. Nat. Prod. Rep. 2006,
́
23, 1007. (b) Sanchez, C.; Salas, A. P.; Brana, A. F.; Palomino, M.;
̃
Pineda-Lucena, A.; Carbajo, R. J.; Mendez, C.; Moris, F.; Salas, J. A.
Chem. Commun. 2009, 4118.
́
(4) (a) Parkinson Study Group. Neurology 2004, 62, 330.
́
́
(b) Sanchez, C.; Mendez, C.; Salas, J. A. J. Ind. Microbiol. Biotechnol.
2006, 33, 560. (c) Butler, S. M. Nat. Prod. Rep. 2008, 25, 475.
(5) (a) Gallogly, M. M.; Lazarus, H. M.; Cooper, B. W. Ther. Adv.
Hematol. 2017, 8, 245. (b) Stone, R. M.; Mandrekar, S. J.; Sanford, B.
L.; Laumann, K.; Geyer, S.; Bloomfield, C. D.; Thiede, C.; Prior, T.
̈
W.; Dohner, K.; Marcucci, G.; Lo-Coco, F.; Klisovic, R. B.; Wei, A.;
D
DOI: 10.1021/acs.orglett.8b03063
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(14) (a) Sahu, S.; Banerjee, A.; Maji, M. S. Org. Lett. 2017, 19, 464.
(b) Banerjee, A.; Sahu, S.; Maji, M. S. Adv. Synth. Catal. 2017, 359,
1860.
́
(15) (a) Hayashi, Y. Chem. Sci. 2016, 7, 866. (b) Gonzalez, J. F.;
́
Rocchi, D.; Tejero, T.; Merino, P.; Menendez, J. C. J. Org. Chem.
2017, 82, 7492.
(16) (a) Laha, J. K.; Dayal, N. Org. Lett. 2015, 17, 4742. (b) Chen,
S.; Li, Y.; Ni, P.; Huang, H.; Deng, G.-J. Org. Lett. 2016, 18, 5384.
(c) Chen, S.; Li, Y.; Ni, P.; Yang, B.; Huang, H.; Deng, G.-J. J. Org.
Chem. 2017, 82, 2935. (d) Kong, A.; Han, X.; Lu, X. Org. Lett. 2006,
8, 1339. (e) Park, I.-K.; Suh, S.-E.; Lim, B.-Y.; Cho, C.-G. Org. Lett.
̀
2009, 11, 5454. (f) Hussain, M.; Toguem, S.-M. T.; Ahmad, R.; Tung,
D. T.; Knepper, I.; Villinger, A.; Langer, P. Tetrahedron 2011, 67,
5304. (g) Humne, V.; Dangat, Y.; Vanka, K.; Lokhande, P. Org.
Biomol. Chem. 2014, 12, 4832.
(17) (a) Ren, J.-W.; Zhou, Z.-F.; Xiao, J.-A.; Chen, X.-Q.; Yang, H.
Eur. J. Org. Chem. 2016, 1264. (b) Zheng, C.; Lu, Y.; Zhang, J.; Chen,
X.; Chai, Z.; Ma, W.; Zhao, G. Chem. - Eur. J. 2010, 16, 5853.
(c) Tian, X.; Hofmann, N.; Melchiorre, P. Angew. Chem., Int. Ed.
2014, 53, 2997.
(18) (a) Moody, C. J.; Rahimtoola, K. F. J. Org. Chem. 1992, 57,
2105. (b) Wada, Y.; Nagasaki, H.; Tokuda, M.; Orito, K. J. Org. Chem.
2007, 72, 2008. (c) Rajeshwaran, G. G.; Mohanakrishnan, A. K. Org.
Lett. 2011, 13, 1418. (d) Fox, J. C.; Gilligan, R. E.; Pitts, A. K.;
Bennett, H. R.; Gaunt, M. J. Chem. Sci. 2016, 7, 2706.
(19) (a) Slater, M. J.; Cockerill, S.; Baxter, R.; Bonser, R. W.; Gohil,
K.; Gowrie, C.; Robinson, J. E.; Littler, E.; Parry, N.; Randall, R.;
Snowden, W. Bioorg. Med. Chem. 1999, 7, 1067. (b) Bergman, J.;
Koch, E.; Pelcman, B. J. Chem. Soc., Perkin Trans. 2000, 1, 2609.
(c) Alonso, D.; Caballero, E.; Medarde, M.; Tome, F. Tetrahedron
Lett. 2005, 46, 4839. (d) Torney, P.; Shirsat, R.; Tilve, S. Synlett 2014,
25, 2121. (e) Borrero, N. V.; DeRatt, L. G.; Barbosa, L. F.; Abboud,
K. A.; Aponick, A. Org. Lett. 2015, 17, 1754. (f) Lee, S.; Kim, K.-H.;
Cheon, C.-H. Org. Lett. 2017, 19, 2785. (g) Men, Y.; Hu, Z.; Dong, J.;
Xu, X.; Tang, B. Org. Lett. 2018, 20, 5348.
(20) (a) Fabre, S.; Prudhomme, M. Bioorg. Med. Chem. Lett. 1992, 2,
449. (b) Harris, W.; Hill, C. H.; Keech, E.; Malsher, P. Tetrahedron
Lett. 1993, 34, 8361. (c) Howard-Jones, A. R.; Walsh, C. T. J. Am.
Chem. Soc. 2006, 128, 12289. (d) Yu, X.; Yang, A.; Lin, W.; Li, S.-M.
Tetrahedron Lett. 2012, 53, 6861.
(21) Reddy, G. M.; Chen, S.-Y.; Uang, B.-J. Synthesis 2003, 497.
(22) Muthu Ramalingam, B.; Dhatchana Moorthy, N.; Chowdhury,
S. R.; Mageshwaran, T.; Vellaichamy, E.; Saha, S.; Ganesan, K.;
Rajesh, B. N.; Iqbal, S.; Majumder, H. K.; Gunasekaran, K.; Siva, R.;
Mohanakrishnan, A. K. J. Med. Chem. 2018, 61, 1285.
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DOI: 10.1021/acs.orglett.8b03063
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