Regioselective Cyclization of (Indol-3-yl)pentyn-3-ols as an Approach to (Tetrahydro)carbazoles

Article abstract of DOI:10.1021/acs.orglett.8b00042

An acid-catalyzed, highly regioselective cycloisomerization as well as dehydro-cyclization of (indol-3-yl)pentyn-3-ols has been reported for the selective synthesis of tetrahydrocarbazoles and carbazoles. This process is mild and found to be very general in terms of structural diversity of substrates. Utilizing the strategy, an efficient synthetic approach for the functionalized frameworks of carbazomycins A-D has also been developed.

Full text of DOI:10.1021/acs.orglett.8b00042

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Regioselective Cyclization of (Indol-3-yl)pentyn-3-ols as an Approach
to (Tetrahydro)carbazoles
Prabhakararao Tharra and Beeraiah Baire*
Department of Chemistry, Indian Institute of Technology Madras, Chennai, Tamilnadu, India-600036
S
* Supporting Information
ABSTRACT: An acid-catalyzed, highly regioselective cyclo-
isomerization as well as dehydro-cyclization of (indol-3-
yl)pentyn-3-ols has been reported for the selective synthesis
of tetrahydrocarbazoles and carbazoles. This process is mild
and found to be very general in terms of structural diversity of
substrates. Utilizing the strategy, an efficient synthetic
approach for the functionalized frameworks of carbazomycins A−D has also been developed.
and medicinal chemistry.7 They are also key structural frame-
ropargylic alcohols are unique building blocks with the
works of many alkaloids, such as alstoscholarine and gilbertine.8
Passociation of two functional groups, i.e., alkyne and
hydroxyl.1 They undergo various useful transformations in
Despite these important properties, there is no strategy in the
literature for the simultaneous and selective synthesis of both of
these carbazole systems.
organic synthesis, utilizing either an alkyne or hydroxyl or both
of them. Chemo- and regioselective reactions of propargylic
alcohols will greatly expand their chemistry and provide access to
attractive synthetic strategies for novel functionalization.
However, development of these selective strategies is extremely
challenging, in particular the acid-mediated transformations of
propargylic alcohols due to the inherent reactivity of propargylic
alcohols (alkyne and alcohol together) as a single functional
group rather than two.
In this context, herein we disclose a strategy for the selective
generation of tetrahydrocarbazoles and carbazoles from (indol-3-
yl)pentyn-3-ols using Ag(I)9 and pTSA, respectively. This
strategy involves chemo- and regioselective intramolecular
cyclizations between indole and propagylic alcoholic units
embedded within (indol-3-yl)pentyn-3-ols under π-catalysis.10
According to our design (Scheme 1), it would be possible to
Indole and its derivatives are very important heterocyclic
compounds used in various fields such as pharmaceuticals,
materials, and agrochemicals.2 They have also been employed as
synthetic building blocks in organic synthesis. Among various
indole derivatives, carbazoles are ubiquitously found in many
natural products,3 bioactive molecules, drugs,4 and organic
materials (Figure 1).5 Many synthetic methods exist for the
generation of these tricyclic frameworks.6 Furthermore, function-
alized tetrahydrocarbazoles have been employed as anti-HPV
agents, NPY-1 antagonists, androgen receptor modulators, and
DP1 antagonists and have attracted attention in organic synthesis
Scheme 1. Design for a Regioselective Cyclization of (Indol-3-
yl)pentyn-3-ols
chemo- and regioselectively activate the alkyne present in the
propargylic alcohol unit of the (indol-3-yl)pentyn-3-ols 1 toward
the 6-exo-dig cyclizaion by employing a suitable acid catalyst. This
would result in the formation of either tetrahydrocarbazoles 2 or
carbazoles 3.
To verify our hypothesis, we started the investigation with
(indol-3-yl)pentyn-3-ol 1a. Treatment of 1a with MsOH (1.3
equiv) in CH2Cl2 at 0 °C to rt (Table 1, entry 1) resulted in an
exclusive formation of a completely aromatized 1,2-dimethylcar-
bazolederivative3ain72%yieldafter25h.Formationof3acanbe
explained via a 6-exo-dig ring closure followed by a dehydration−
aromatization cascade (see Scheme 5 for proposed mechanism).
Employing TfOH and pTSA (entries 2 and 3) gave the same
Received: January 5, 2018
Figure 1. Representative examples of carbazole natural products.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00042
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Discovery and Optimization Study
Scheme 2. Scope Study for the Formation of 1-Methylene-
2,3,4,9-tetrahydro-1H-carbazol-2-ols with AgOTf
a
a
Reaction conditions: 1 (1 equiv), AgOTf (0.25 equiv), CH2Cl2, 0 °C
to rt.
reaction conditions (AgOTf (0.25 equiv), CH2Cl2, 0 °C to rt)
underwent the expected 6-exo-dig cyclization to afford the
corresponding tetrahydrocarbazoles 2b−g in excellent yields
(87−92%) in a short reaction time (25−30 min). Aryl-
propargylic alcohols 1h−j have also been successfully employed
in this transformation to generate the polycyclic products 2h−j in
excellent yields (up to 94%). Propargylic alcohols possessing
various substituents on indole ring 1k−m efficiently underwent
the transformation and afforded the functionalized tetrahydro-
carbazole derivatives 2k−m. In none of the cases we observed the
formation of carbazole derivatives (via dehydration) or products
via other competing pathways (5-exo-tet or 7-endo-dig).
Subsequently, the same (indol-3-yl)pentyn-3-ols 1b−g were
utilized for the generation of a library of structurally novel, 1,2-
disubstituted carbazole derivatives 3b−g in excellent yields
(Scheme 3). For this transformation, pTSA (0.25 equiv) in
dichloromethane at 55 °C was employed as the standard
a
b
c
Yields are after chromatographic purification. 28% of 1a 30% of 1a
d
e
40% of 1a 22% of 1a was recovered, respectively.
product 3a without any improved yield. However, an increase in
temperature to 55 °C with pTSA (1.3 equiv) accelerated the
reaction (3 h) and afforded an excellent yield (93%) of 3a. It was
found that 0.25 equiv of pTSA is highly suitable to provide 3a in
94% yield with an 8 h reaction time (Table 1, entries 5 and 6). A
further decrease in the amount of pTSA (0.15) resulted in an
incomplete conversion even after 32 h at 55 °C (entry 7). In
solvents such as ethyl acetate and acetonitrile (entries 8 and 9),
the reaction was found to be very slow. After heating for 72 h at 55
°C, only 70% and 60% of the respective conversion of 1a was
observed along with the poor yields (50% and 29%) of 3a.
Next we screened various Lewis acids to see their activation
mode toward propargylic alcohol present in 1a. Both BiCl3 and
BF3·Et2O (entries10and 11)resulted intheformation ofonly the
carbazole 3a. To our surprise, employing transition-metal-based
catalysts AgNO3, AgOTf, and Cu(OTf)2 (Table 1, entries 12−
16) resulted in the tetrahydrocarbazole 2a in excellent yields (up
to89%)viaa6-exo-digcyclizationprocess.Therewasnodetection
of any traces of the aromatized product 3a. Among the three
catalysts 0.25 equiv of AgOTf in CH2Cl2 at 0 °C (entry 14) gave
the best yield (89%) of 2a within 20 min of reaction time. It is
noteworthy that no detection of any traces of products arising
eitherfrom5-exo-tet(viahydroxylgroupdisplacement) orfrom7-
endo-dig cyclizations was observed in all the above instances.
Hence this reaction is highly chemo- (alkyne vs hydroxyl) and
regioselective (on alkyne).
Scheme 3. Scope Study for the Formation of Carbazoles with
a
pTSA
Having the optimized conditions for the formation of both
carbazoles (Table 1, entry 6) as well as tetrahydrocarbazoles
(Table 1, entry 14), we next focused on understanding the
generality of these transformations. Initially, generation of
tetrahydrocarbazoles has been investigated (Scheme 2). Various
aliphatic propargylic alcohols 1b−g upon subjection to standard
a
Reaction conditions: 1 (1 equiv), pTSA (0.25 equiv), CH2Cl2, 55 °C.
B
DOI: 10.1021/acs.orglett.8b00042
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
conditions (Table 1, entry 6). Structurally divergent, 1,2-
dimethylcarbazoles 3k−mwere also obtained when we employed
substrates with propargylic alcohols carrying a methyl group,
against various substituted indole derivatives. The 1,2-dimethyl-
carbazoles are ubiquitously found in many bioactive carbazole
natural products such as carbazomycins A−D. Different N-
protecting groups such as n-hexyl, phenyl, and benzyl (1n−p)
were also found to be compatible under standard reaction
conditions to provide access to 1,2-dimethylcarbazoles 3n−p.
In order to delineate the mechanistic details of this process, we
performed a few control experiments (Scheme 4). When
Scheme 5. Possible Mechanism
Scheme 4. Control Experiments
via C-3 position or a 6-exo-dig-cyclization via the C-2 position of
the appended indole. These two processes will generate
corresponding iminium ions, a 2-methylenespiro[cyclopentane-
1,3′-indol]-3-ol 5a or a 1-methylene-2,3,4,9-tetrahydro-1H-
carbazol-2-ol 5a′ respectively. Rearomatization of both 5a and
5a′ (via 1,2-migration) would result in the tetrahydrocarbazole
2a. In the presence of a Brønsted acid (such as pTSA), 2a may
undergo dehydration−aromatization to yield the carbazole
derivative 3a.
Finally, to highlight the synthetic utility of our strategy, an
efficient approach to functionalized frameworks of natural
products cabazomycin A−D (Scheme 6) was undertaken.12 We
Scheme 6. An Approach to Carbazomycins A−D
tetrahydrocarbazoles 2b and 2j were treated with pTSA (0.25
equiv)indichloromethaneat55°C, thecorrespondingcarbazoles
3b and 3j were obtained in 80% and 81% respective yields after 3
h. This observation supports the intermediacy of the 1-
methylene-2,3,4,9-tetrahydro-1H-carbazol-2-ols during the for-
mation of carbazoles (Scheme 4A).
Further, to differentiate two possible pathways for the
formation of 1-methylene-2,3,4,9-tetrahydro-1H-carbazol-2-ols,
i.e., 5-exo-dig followed by 1,2-migration11 vs 6-exo-dig, we chose
an unprotected indole derivative 1q as the model substrate
(Scheme4B).When1qwastreatedwithAgOTfatrt,after30min,
an inseparable (∼1:0.15) mixture resulted of three compounds,
two diastereomeric spiro-compounds 4 vs tetrahydrocarbazole
2q in 77% yield. The same reaction when performed at rt gave a
(1:0.49) mixture of 4 vs 2q after 48 h. Further heating of this
mixture at 55 °C for 8 h resulted in only a 1:0.68 mixture. These
observations reveal that the conversion of 4 to 2q is very slow in
the presence of AgOTf. This mixture upon subjection to reaction
with pTSA, at 55 °C, gave the carbazole derivative 3q in 54% yield
after 36h. Onthe other hand, 1qupon treatment with pTSA, after
13 h at 55 °C, gave an inseparable (∼1:0.6) mixture (49%) of
three products 4 and 2q along with separable carbazole derivative
3q (34%), whereas after 36 h an exclusive formation of the
carbazole 3q resulted in 62% yield. These observations suggest
that both 5-exo-dig cyclization followed by 1,2-migration and
direct 6-exo-dig cyclization contribute to the formation of the
tetrahydrocarbazole derivatives.
chose two 1,2-dimethylcarbazole derivatives 3a and 3m as the
starting materials for this purpose. Treatment of 3a with N-
bromosuccinimide(NBS)inchloroformatrtfor4mingavethe3-
bromocarbazole 6 in 71% yield.13a Subsequent reaction of 6 with
NaOMe in the presence of CuI and DMF at 120 °C generated the
3-methoxycarbazole 7 in 87% yield, which is the N-Me-4-
deoxycarbazomycins A and B.13b Further, this two-step synthetic
strategy has alsobeenemployed forthe efficient conversion of3m
to N-Me-4-deoxycarbazomycins C and D 8 via the bromide 9. In
addition to the spectroscopic characterization, the structure of 8
was unambiguously assigned on the basis of single crystal X-ray
diffraction analysis14 (CCDC 1584984) (Scheme 6).
In conclusion, we have developed highly regioselective
cyclizations of (indol-3-yl)pentyn-3-ols under Lewis as well as
Brønsted acid catalysis, for the selective synthesis of (tetrahydro)-
carbazoles. To the best of our knowledge, this is the first report on
the exploration of the reactivity of (indol-3-yl)pentyn-3-ols. This
process is mild and very general in terms of the structural novelty
of substrates. Further, this strategy has been extended to the
efficient synthesis of functionalized frameworks of carbazole
natural products, carbazomycins A−D.
Based on the above observations, we propose a possible
mechanistic pathway (Scheme 5). Initially, the Brønsted or Lewis
acid activated alkyne 1a will undergo either a 5-exo-dig-cyclization
C
DOI: 10.1021/acs.orglett.8b00042
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(6) (a) Gilchrist, T. L. Heterocyclic Chemistry; Pitman: London, 1985.
(b) Witulski, B.; Alayrac, C. Angew. Chem., Int. Ed. 2002, 41, 3281.
(c) Martínez-Esperon, M. F.; Rodríguez, D.; Castedo, L.; Saa, C. Org.
́ ́
ASSOCIATED CONTENT
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.8b00042.
■
S
Lett. 2005, 7, 2213. (d) Qiu, Y.; Kong, W.; Fu, C.; Ma, S. Org. Lett. 2012,
14, 6198. (e) Samala, S.; Mandadapu, A. K.; Saifuddin, M.; Kundu, B. J.
Org. Chem. 2013,78,6769. (f)Qiu, Y.;Zhou,J.;Fu, C.;Ma, S. Chem. -Eur.
J. 2014, 20, 14589. (g) Zheng, X.; Lv, L.; Lu, S.; Wang, W.; Li, Z. Org. Lett.
2014, 16, 5156. (h) Zhu, C.; Ma, S. Org. Lett. 2014, 16, 1542. (i) Markad,
S. B.; Argade, N. P. Org. Lett. 2014, 16, 5470. (j) Wang, L.; Li, G.; Liu, Y.
Org. Lett. 2011, 13, 3786. (k) Hashmi, A. S. K.; Yang, W.; Rominger, F.
Chem. -Eur. J. 2012, 18, 6576. (l)Qiu, Y.;Fu, C.;Zhang, X.;Ma, S. Chem. -
Eur. J. 2014, 20, 10314. (m) Wang, J.; Zhu, H.-T.; Qiu, Y.-F.; Niu, Y.;
Chen, S.; Li, Y.-X.; Liu, X.-Y.; Liang, Y.-M. Org. Lett. 2015, 17, 3186.
(n) Liddon, J. T. R.; James, M. J.; Clarke, A. K.; O’Brien, P.; Taylor, R. J.
General experimental procedures, characterization data
including copies of 1H and 13C NMR spectra (PDF)
Accession Codes
CCDC 1584984 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 Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
K.; Unsworth, W. P. Chem. - Eur. J. 2016, 22, 8777. (o) Suar
́ ́
ez, A.;Suarez-
Pantiga, S.; Nieto-Faza, O.; Sanz, R. Org. Lett. 2017, 19, 5074.
(7) (a) DiFabio, R.; Giovannini, R.; Bertani, B.; Borriello, M.; Bozzoli,
A.; Donati, D.; Falchi, A.; Ghirlanda, D.; Leslie, C. P.; Pecunioso, A.;
Rumboldt, G.; Spada, S. Bioorg. Med. Chem. Lett. 2006, 16, 1749.
(b) Gudmundsson, K. S.; Sebahar, P. R.; Richardson, L. D.; Catalano, J.
G.; Boggs, S. D.; Spaltenstein, A.; Sethna, P. B.; Brown, K. W.;Harvey, R.;
Romines, K. R. Bioorg. Med. Chem. Lett. 2009, 19, 3489. (c) Li, L.;
Beaulieu, C.; Carriere, M.-C.; Denis, D.; Greig, G.; Guay, D.; O’Neill, G.;
Zamboni, R.; Wang, Z. Bioorg. Med. Chem. Lett. 2010, 20, 7462.
(d) Miller, C. P.; Bhaket, P.; Muthukaman, N.; Lyttle, C. R.; Shomali, M.;
Gallacher, K.; Slocum, C.; Hattersley, G. Bioorg. Med. Chem. Lett. 2010,
20, 7516.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: beeru@iitm.ac.in.
ORCID
Beeraiah Baire: 0000-0001-8810-1620
Notes
The authors declare no competing financial interest.
(8) (a) Cai, X. H.; Du, Z. Z.; Luo, X. D. Org. Lett. 2007, 9, 1817.
(b) Gerfaud, T.; Xie, C.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2011,
50, 3954. (c) Miranda, E. C.; Blechert, S. Tetrahedron Lett. 1982, 23,
5395. (d) Jiricek, J.; Blechert, S. J. Am. Chem. Soc. 2004, 126, 3534.
(9) For reactions of Ag(I) activated indole tethered alkynes: (a) James,
M. J.; Cuthbertson, J. D.; O’Brien, P.; Taylor, R. J. K.; Unsworth, W. P.
Angew. Chem., Int. Ed. 2015, 54, 7640. (b) Clarke, A. K.; James, M. J.;
O’Brien, P.; Taylor, R. J. K.; Unsworth, W. P. Angew. Chem., Int. Ed. 2016,
55, 13798. (c) Liddon, J. T. R.; Clarke, A. K.; Taylor, R. J. K.; Unsworth,
W. P. Org. Lett. 2016, 18, 6328. (d) Gupta, S.; Koley, D.; Ravikumar, K.;
Kundu, B. J. Org. Chem. 2013, 78, 8624.
ACKNOWLEDGMENTS
■
WethanktheIndianInstituteofTechnologyMadras, Chennaifor
the infrastructural facility. We thank SERB-INDIA for financial
support through the EMR/2016/000041 grant. T.P.R. thanks
CSIR, New Delhi for the SRF fellowship and IIT Madras for a
predoctoral fellowship. We thank Technical Officer: Mr.
Ramkumar for single crystal X-ray analysis. Dedicated to the
memory of Prof. Late Adusumilli Srikrishna.
́
(10) For π-acid catalysis with alkynes: (a) Alvarez-Corral, M.; Munoz-
̃
REFERENCES
■
Dorado, M.; Rodríguez-García, I. Chem. Rev. 2008, 108, 3174. (b) Blanc,
A.; Tenbrink, K.; Weibel, J.-M.; Pale, P. J. Org. Chem. 2009, 74, 4360.
(c) Ren, H.; Luo, Y.; Ye, S.; Wu, J. Org. Lett. 2011, 13, 2552. (d) Xu, T.;
Liu, G. Org. Lett. 2012, 14, 5416. (e) Verma, A. K.; Kotla, S. K. R.;
Choudhary, D.; Patel, M.; Tiwari, R. K. J. Org. Chem. 2013, 78, 4386.
(f) Fang, G.; Bi, X. Chem. Soc. Rev. 2015, 44, 8124. (g) Karmakar, S.; Das,
P.; Ray, D.; Ghosh, S.; Chattopadhyay, S. K. Org. Lett. 2016, 18, 5200.
(h)Han, D.;Chen, J.;He,Q.;Fan,R. Org.Lett. 2016,18,4690. (i)Kumar,
P.; Aggarwal, T.; Verma, A. K. J. Org. Chem. 2017, 82, 6388. (j) Santhi, J.;
Baire, B. Chem. Select. 2017, 2, 4338. (k) Gandhi, S.; Tharra, P.; Baire, B.
Chem. Select. 2017, 2, 1058. (l) Gandhi, S.; Baire, B. Chem. Select. 2017, 2,
3964.
(1) (a) Tsuji, J.; Mandai, T. Angew. Chem. 1995, 107, 2830; Angew.
Chem., Int. Ed. Engl. 1996, 34, 2589. (b) Alexakis, A. Pure Appl. Chem.
1992, 64, 387. (c) Miyake, Y.; Uemura, S.; Nishibayashi, Y.
ChemCatChem 2009, 1, 342. (d) Bauer, E. B. Synthesis 2012, 44, 1131.
(e) Furstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410.
̈
́
(f) Chinchilla, R.; Najera, C. Chem. Soc. Rev. 2011, 40, 5084. (g) Alcaide,
B.; Almendros, P.; Quirs, M. T.; Lopez, R.; Menndez, M. I.; Sochacka-
́
Cwikła, A. J. Am. Chem. Soc. 2013, 135, 898. (h) Huang, W.; Zheng, P.;
Zhang, Z.; Liu, R.; Chen, Z.; Zhou, X. J. Org. Chem. 2008, 73, 6845.
(i) Huang, W.; Hong, L.; Zheng, P.; Liu, R.; Zhou, X. Tetrahedron 2009,
65, 3603. (j) Meyer, K. H.; Schuster, K. Ber. Dtsch. Chem. Ges. B 1922, 55,
819. (k) Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429.
(l) Engel, D. A.; Dudley, G. B. Org. Biomol. Chem. 2009, 7, 4149.
(2) (a) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48,
9608. (b) Ishikura, M.; Abe, T.; Choshi, T.; Hibino, S. Nat. Prod. Rep.
2013, 30, 694. (c)Ito, C.;Itoigawa, M.;Sato, A.;Hasan, C. M.;Rashid, M.
A.; Tokuda, H.; Mukainaka, T.; Nishino, H.; Furukawa, H. J. Nat. Prod.
2004, 67, 1488.
(11) (a) Corkey, B. K.; Heller, S. T.; Wang, Y.-M.; Toste, F. D.
Tetrahedron 2013, 69, 5640. (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.
(12) (a) Knolker, H.-J.; Schlechtingen, G. J. Chem. Soc., Perkin Trans. 1
̈
1997, 1, 349. (b) Chowdhury, B. K.; Jha, S. Synth. Commun. 2001, 31,
1559. (c) Ca, N. D.; Sassi, G.; Catellani, M. Adv. Synth. Catal. 2008, 350,
2179. (d) Moody, C. J.; Shah, P. J. Chem. Soc., Perkin Trans. 1 1989, 1,
2463. (e) Markad, S. B.; Argade, N. P. Org. Lett. 2014, 16, 5470.
(13) (a) Braiek, M. B.; Aloui, F.; Moussa, S.; Tounsi, M.; Marrot, J.;
Hassine, B. B. Tetrahedron Lett. 2013, 54, 5421. (b) Hensel, T.;
Trpcevski, D.; Lind, C.; Grosjean, R.; Hammershøj, P.; Nielsen, C. B.;
Nannestad, T. B.; Nielsen, B. E.; Magnussen, M. S.; Minaev, B.;
Baryshnikov, G. V.; Pittelkow, M. Chem. - Eur. J. 2013, 19, 17097.
(14) Further details are given in the table on p 36 of the Supporting
Information.
(3) (a) Knolker, H.-J. Synlett 1992, 1992, 371. (b) Knolker, H.-J.;
̈
̈
Reddy, K. R. Chem. Rev. 2002, 102, 4303. (c) Schmidt, A. W.; Reddy, K.
R.; Knolker, H.-J. Chem. Rev. 2012, 112, 3193.
̈
(4) (a) Lemster, T.; Pindur, U.; Lenglet, G.; Depauw, S.; Dassi, C.;
David-Cordonnier, M.-H. Eur. J. Med. Chem. 2009, 44, 3235. (b)Barta, T.
E.; Barabasz, A. F.; Foley, B. E.; Geng, L.; Hall, S. E.; Hanson, G. J.; Jenks,
M.; Ma, W.; Rice, J. W.; Veal, J. Bioorg. Med. Chem. Lett. 2009, 19, 3078.
(c) Gu, W.; Wang, S. Eur. J. Med. Chem. 2010, 45, 4692.
(5) (a) Adhikari, R. M.; Neckers, D. C.; Shah, B. K. J. Org. Chem. 2009,
74, 3341. (b) Tsvelikhovsky, D.; Buchwald, S. L. J. Am. Chem. Soc. 2011,
133, 14228. (c) Kato, S.; Yamada, Y.; Hiyoshi, H.; Umezu, K.; Nakamura,
Y. J. Org. Chem. 2015, 80, 9076.
D
DOI: 10.1021/acs.orglett.8b00042
Org. Lett. XXXX, XXX, XXX−XXX