Microwave-assisted synthesis of 3-nitroindoles from N-aryl enamines via intramolecular arene-alkene coupling

Article abstract of DOI:10.1021/ol303314x

A variety of N-aryl β-nitroenamines were effectively transformed into 3-nitroindoles in good yields and with complete regioselectivity via a rapid microwave (μW) assisted intramolecular arene-alkene coupling reaction. This report further demonstrates the versatility of this method by constructing 3-carboalkoxy-and 3-cyanoindoles. Optimization data, substrate scope, and applications are discussed.

Full text of DOI:10.1021/ol303314x

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Microwave-Assisted Synthesis of
3‑Nitroindoles from N‑Aryl Enamines
via Intramolecular AreneꢀAlkene
Coupling
Huy H. Nguyen and Mark J. Kurth*
Department of Chemistry, University of California, One Shields Avenue, Davis,
California 95616, United States
mjkurth@ucdavis.edu
Received December 3, 2012
ABSTRACT
A variety of N-aryl β-nitroenamines were effectively transformed into 3-nitroindoles in good yields and with complete regioselectivity via a rapid
microwave (μW) assisted intramolecular areneꢀalkene coupling reaction. This report further demonstrates the versatility of this method by
constructing 3-carboalkoxy- and 3-cyanoindoles. Optimization data, substrate scope, and applications are discussed.
The indole scaffold, a ubiquitous core structure
present in numerous natural products and synthetic
pharmaceuticals, has been found to present antitumor,
anticancer, antimicrobial, antibacterial, and anti-inflam-
matory activities,1 and dozens of methods for the
construction of indoles have been developed.2 Belonging
to this privileged heterocyclic class, substituted nitroin-
doles are versatile intermediates in the synthesis of
important biologically active molecules. For example,
3-nitroindoles are useful precursors in the syntheses of
the novel antidiabetic agent N-(1H-indol-3-yl)-guanidine3
(1) as well as the cruciferous phytoalexins isocyalexin A (2)
and rapalexin A (3) (naturally occurring isocyanide and
(1) (a) Wu, S.; Wang, L.; Guo, W.; Liu, X.; Liu, J.; Wei, X.; Fang, B.
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isothiocyanate indoles, respectively; see Figure 1).4
A
3-nitroindole is also the key building block in the synthe-
sis of a 3-acylamino-2-aminopropionic acid derivative
(4),5 which has proven to be a potent ligand for the
glycine coagonist site on the N-methyl-D-aspartate
(NMDA) receptor involvedin memoryand developmental
processes.
ꢀ
Nazare, M.; Schneider, C.; Lindenschmidt, A.; Will, D. W. Angew.
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10.1021/ol303314x
XXXX American Chemical Society

is particularly interesting, as it represents an effective route
to substituted indoles from o-chloroanilines and ketones.2k
Driver et al. reported a route to3-nitroindoles from β-nitro
styryl azides by Rh2(II)-catalyzed nitro-group migration,9
which is an effective method, but it is somewhat limited by
its use of the expensive Rh2(esp)2 catalyst as well as the
multiple synthetic steps required to prepare the precursor
nitro styryl azides. 3-Nitroindoles prepared by this method
were unfunctionalized at the 2-position. To the best of our
knowledge, there has been only one report of a substituted
3-nitroindole synthesized by CꢀH activation cyclization
(a modest yield of 62% was reported).10
Building on our recently reported multicomponent
method for indole synthesis utilizing coupled palladium-
catalyzed coupling reactions,11 we believed an appropriate
methodology could be developed to construct substituted
3-nitroindoles. Herein, we report the versatile palladium-
catalyzed cyclization of N-aryl β-nitroenamines as a route
to functionalized 3-nitroindoles, a method also applicable
(vide infra) to the synthesis of indoles bearing other
electron-withdrawing groups (ꢀCO2R/ꢀCN) at C3.
Since its first introduction in the mid-1980s, microwave
(μW) irradiation has been widely employed as an effective
reaction acceleration protocol, resulting in rapid, clean,
and high-yielding transformations.12 Indeed, there is am-
ple literature precedent proving microwave irradiation can
mediate, for example, the Heck reaction.13 It is also well
established that elevated pressure also assists a Pd-
mediated coupling reaction by accelerating oxidative
addition and improving the catalyst lifetime and turnover
by enhancing ligand associationꢀdissociation.14
Figure 1. Bioactive compounds containing indole scaffold.
The synthetic utility of 3-nitroindoles creates a demand
for reliable and versatile routes to these heterocycles from
inexpensive precursors. Classic indole nitration methods,
utilizing strongly acidic conditions,6a nitrous acid,6b or
benzoyl nitrate6c (generated in situ from benzoyl chloride
and silver nitrate), can be effective, but their harsh condi-
tions generally result in low functional group tolerance,
low yield, and/or lack of regioselectivity.6
Experimentally, we observed that the benzoyl nitrate
method leads to the formation of significant quantities of
tarry side products, reducing the reaction yield and com-
plicating purification. This method also requires stoichio-
metric silver nitrate, which creates heavy metal waste
disposal issues. These shortcomings, in conjunction with
the inherent limitations of direct nitration, prompted our
investigation into more effective routes to 3-nitroindoles.
In the past several years, the emergence of numerous
methods for indole synthesis utilizing organometallic cat-
alyzed cross-coupling or metal-free oxidative coupling
CꢀN/CꢀC bond formation has attracted considerable
Our initial studies focused on the intramolecular areneꢀ
alkene coupling of enamine 5a [(Z)-2-bromo-N-(1-nitro-
prop-1-en-2-yl)aniline; Table 1], which is available from
the condensation of o-bromoaniline with 1-nitropropan-2-
one.15 This o-bromoaniline-based enamine was chosen as a
model substrate since bromoarenes are known to undergo
palladium cross-coupling reaction faster than, for exam-
ple, chloroarenes; in addition, o-bromoaniline derivatives
are more readily available than iodoanilines. As illustrated
in Table 1, we began by assessing the catalytic activities of
various sources of palladium(0) (entries 1ꢀ3).
attention.2jꢀm,7,8 In that context, Nazare’s methodology
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While Pd2(dba)3/DPPF/Cs2CO3/toluene/130 °C/48 h
(Table 1, entry 1) and Pd(PPh3)4/CuI/Et3N/toluene/
130 °C/18 h (entry 2) systems did not promote product
formation, 5 mol % Pd(PPh3)4/Et3N/pyridine/140 °C/48 h
(entry 3) did effect the desired transformation. However,
(8) For the cyclization of o-haloanilino enamines, see: (a) Kasahara,
A.; Izumi, T.; Murakami, S.; Yanai, H.; Takatori, M. Bull. Chem. Soc.
Jpn. 1986, 59, 927–8. (b) Sakamoto, T.; Nagano, T.; Kondo, Y.;
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Wilson, C. Tetrahedron Lett. 1993, 34, 8365–8. (d) Chen, L.-C.; Yang, S.-
C.; Wang, H.-M. Synthesis 1995, 385–6. (e) Blache, Y.; Sinibaldi-Troin,
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Chapat, J.-P. J. Org. Chem. 1997, 62, 8553–6. (f) Edmonson, S. D.;
Mastracchio, A.; Parmee, E. R. Org. Lett. 2000, 2, 1109–12. (g) Dajka-
Halasz, B.; Monsieurs, K.; Elias, O.; Karolyhazy, L.; Tapolcsanyi, P.;
Maes, B. U. W.; Riedl, Z.; Hajos, G.; Dommisse, R. A.; Lemiere,
G. L. F.; Kosmrlj, J.; Matyus, P. Tetrahedron 2004, 60, 2283–91. (h)
Maruyama, J.; Yamashita, H.; Watanabe, T.; Arai, S.; Nishida, A.
Tetrahedron 2009, 65, 1327–35. (i) Yamazaki, K.; Nakamura, Y.;
Kondo, Y. J. Org. Chem. 2003, 68, 6011–19. (j) Yamazaki, K.; Kondo,
Y. J. Comb. Chem. 2002, 4, 191–2. (k) Yamazaki, K.; Kondo, Y. Chem.
Commun. 2002, 210–1.
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4702–5.
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(11) Knapp, J. M.; Zhu, J. S.; Tantillo, D. J.; Kurth, M. J. Angew.
Chem., Int. Ed. 2012, 51, 10588–91.
(12) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron
2001, 57, 9225–83.
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66.
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2087–88.
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Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Condition Optimization: Synthesis of 6a from 5aa
Scheme 1. Synthesis of β-Nitroenamines 5 from o-Bromoani-
lines and R-Nitroketones
t
time yieldb
entry
catalyst
base
solvent (°C) (h)
(%)
1c
2c
3c
4d
5d
6d
7d
8d
9d
Pd2(dba)3/DPPF
Pd(PPh3)4/CuI
Pd(PPh3)4
Cs2CO3 toluene 130 48
0
Et3N
Et3N
Et3N
Et3N
toluene 130 18
pyridine 140 48
pyridine 140 1.5
0
25
57
81
81
82
48
83
83
Pd(PPh3)4
Pd(PPh3)4
DMF
140 1.5
140 1.5
140 1.5
140 1.5
140 1.5
140 1.5
Pd(PPh3)4
DIPEA DMF
Pd(OAc)2/P(o-tol)3
Et3N
DMF
DMF
DMF
DMF
were obtained only as the Z-isomers, which presumably is
a consequence of hydrogen bonding between the NH group
and an oxygen on the nitro moiety.17
Pd(OAc)2/P(n-Bu)3 Et3N
Pd(OAc)2/P(t-Bu)3 Et3N
10d Pd(OAc)2/tBuXPhos Et3N
Under our optimized conditions, enamines 5aꢀk were
successfully transformed into the corresponding 3-nitroin-
doles (6aꢀk) in moderate to good yields (Scheme 2).
Substrates with electron-donating or -neutral substituents
were converted to the desired indoles in higher yields than
those with electron-withdrawing groups. Microwave heat-
ing providedbetter indole yieldsthanconventional oilbath
heating (6b,e). The presence of an electron-donating
5-OMe group in substrates 5d and 5h lowered the yields
a Optimal reaction condition: 5a (1 equiv), Pd(PPh3)4 (5 mol %),
Et3N (5 equiv), DMF (0.1 M), μW at 140 °C, 90 min. b Isolated
yields. c Conventional oil bath heating. d Microwave irradiated.
dba = dibenzylideneacetone, DPPF = 1,10-bis(diphenylphosphanyl)-
ferrocene. DIPEA = N,N-diisopropylethylamine. tBuXPhos = 2-di-
tert-butylphosphino-20,40,60-triisopropylbiphenyl.
the interconversion proceeded slowly and in low yield
(25%) under conventional oil bath heating conditions.
Under microwave irradiation at the same bulk tempera-
ture, the transformation went to completion in 90 min and
in significantly improved yield (57%; entry 4). As illu-
strated in Table 1/entry 5, switching to DMF, another
highly polarizable solvent that, like pyridine, responds well
to microwave irradiation, further improved the 3-nitroin-
dole yield (57f81%). Finally, DIPEA and Et3N were both
similarly effective, affording product 6a in 81% yield
(Table 1, entries 5 and 6). A combination of Pd(OAc)2
(4 mol %) and PPh3 (8 mol %) gave the same results as
Pd(PPh3)4 (5 mol %). We also screened more active
σ-donor monodentate phosphine ligands (entries 7ꢀ10);
while P(o-tol)3, P(t-Bu)3, and tBuXPhos gave slightly higher
yields, these ligands were not utilized in this work due to
their air sensitivity and higher costs compared to Pd(PPh3)4.
With optimized conditions for 5a f 6a in hand (Table 1),
we set out to more generally explore methodology for
converting o-bromoanilines and R-nitroketones into the
requisite 2-bromo-N-(1-nitroprop-1-en-2-yl)- and 2-bromo-
N-(2-nitro-1-arylvinyl)aniline derivatives (5aꢀk; Scheme 1).
These enamine substrates were synthesized in 30ꢀ88% yield
by an acid-catalyzed condensation reaction between com-
mercially available o-bromoanilines and R-nitroketones, in
turn available by the C-acylation of nitromethane with N-
acylimidazoles15 [prepared in situ by the reaction of car-
boxylic acids with 1,10-carbonyldiimidazole (CDI) or acid
chlorides with imidazole (Scheme 1)].16 Substrates 5aꢀk
Scheme 2. Examples of Substituted 3-Nitroindolesa
a Optimal reaction condition: 5 (1 equiv), Pd(PPh3)4 (5 mol %), Et3N
(5 equiv), DMF (0.1 M), μW at 140 °C, 90 min. Isolated yields. Products
characterized by 1H, 13C NMR, IR, and HRMS. bOil bath heating yields.
(16) Staab, H. A. Angew. Chem., Int. Ed. 1962, 1, 351–67.
(17) Casarrubios, L.; Perez, J. A.; Brookhart, M.; Templeton, J. L. J.
Org. Chem. 1996, 61, 8358–59.
Org. Lett., Vol. XX, No. XX, XXXX
C

of the corresponding indoles. Aryl enamines (5eꢀg) led to
slightly higher indole yields than did aliphatic enamines.
Substitution at C4 (see 6k) is also tolerated, but the yield is
diminished (42% vs 81% for 6a).
Scheme 4. Extending the Scope of Reactiona
In the case of heterocyclic (40-thiazole, 5iꢀj) enamines,
the yields were slightly lower, which could be due to
poisoning of the catalyst. A chloro substituent on the aryl
part of the enamine (5c,g) is tolerated in this transforma-
tion. We did not observe the formation of intermolecular
coupling products with chloro-substituted aryl enamines.
We also verified that this reaction does not involve the
formation of soluble palladium nanoparticles as the cata-
lytically active species by adding Hg(0); this poisoning test
on substrate 5b was negative.18 Finally, microwave irradia-
tion provided such clean reaction mixtures that the isola-
tion/purification protocol consisted of subjecting the crude
reaction mixture to silica gel chromatography without the
need for an aqueous workup.
With these encouraging results in hand, we decided to
further probe the reaction scope by employing other
enamine substrates bearing electron-withdrawing substi-
tuents, such as cyano or carboalkoxy groups. N-Arylena-
mine carboxylate and N-arylaminoacrylonitrile substrates
were obtained in good yields from the acid catalyzed
condensation of o-bromoanilines with β-ketoesters or
3-oxo-3-aryl-propionitrile, respectively (Scheme 3).
a Reaction condition: 7 (1 equiv), Pd(PPh3)4 (5 mol %), Et3N
(3 equiv), DMF (0.1 M), μW at 140 °C, 50 min. Isolated yields. Products
characterized by 1H, 13C NMR, IR, and HRMS.
(8e,f) in excellent yield and modest catalyst loading. We note
that 3-cyanation methods20 on preformed indoles utilize
stoichiometric amounts of toxic cyanating agents.
Finally, we note that the aryl chloride moieties in 6c/g
and 8e/f can be exploited in subsequent synthetic modifi-
cation. For example, SuzukiꢀMiyaura cross-coupling re-
actions can enable further diversification.21
In summary, we have developed a rapid and effective
microwave mediated route to 3-nitroindoles from N-aryl
β-nitroenamines by a palladium-catalyzed intramolecular
areneꢀalkene coupling reaction. This method utilizes cataly-
tic amounts of relatively inexpensive Pd(PPh3)4.Theenamines
required for this transformation are readily available in one
synthetic step from commercially available o-bromoanilines.
This technology accesses indoles with functionalization at the
2-position, accommodating alkyl, aryl, or heterocyclic sub-
stituents. Substrate studies establish that the chemistry re-
ported here affords good functional group tolerance and can
also provide access to 3-carboalkoxy- and 3-cyanoindoles.
Scheme 3. Preparation of N-Aryl Enamine Carboxylates and
3-Arylaminoacrylonitriles
Acknowledgment. We thank the National Institutes of
Health(GM089153and DK072517) for generousfinancial
support of this work. H.H.N. thanks Dr. John M. Knapp
(UC Davis; Kurth Group) for helpful discussions. We also
thank Ms. Kelli M. Farber (UC Davis; Kurth Group) for
assistance in the collection of HRMS data.
Employing these enamines in our optimized reaction
delivered the desired3-carboalkoxy indoles and 3-cyanoin-
doles (Scheme 4) with a shorter irradiation time. Our yields
of 3-carboalkoxy indoles were comparable to similar ex-
amples synthesized by the CꢀH activation method re-
ported by Glorius et al.19 With our o-bromoaniline
protocol, we did not observe any nonselective formation of
regioisomers, an issue with the Glorius method. N-Arylami-
noacrylonitriles were rapidly converted to 3-cyanoindoles
Supporting Information Available. Full experimental
details and characterization data (1H NMR, 13C NMR,
IR, HRMS, and mp) of all novel compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) A Hg(0) poisoning test was performed according to: Weddle,
K. S.; Aiken, J. D.; Finke, R. G. J. Am. Chem. Soc. 1998, 120, 5653–66.
€
(19) Neumann, J. J.; Rakshit, S.; Droge, T.; Wurtz, S.; Glorius, F.
Chem.;Eur. J. 2011, 17, 7298–303.
(20) (a) Peng, J.; Zhao, J.; Hu, Z.; Liang, D.; Huang, J.; Zhu, Q. Org.
Lett. 2012, 14, 4966–9. (b) Yang, Y.; Zhang, Y.; Wang, J. Org. Lett.
2011, 13, 5608–11. (c) Subba Reddy, B. V.; Begum, Z.; Jayasudhan
Reddy, Y.; Yadav, J. S. Tetrahedron Lett. 2010, 51, 3334–36.
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(21) Kudo, M.; Perseghini, G.; Fu, C. Angew. Chem., Int. Ed. 2006,
45, 1282–84.
The authors declare no competing financial interest.
D
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