Synthesis of nitrodienes, nitrostyrenes, and nitrobiaryls through palladium-catalyzed couplings of β-nitrovinyl and o-nitroaryl thioethers

Article abstract of DOI:10.1039/c3sc50773d

A highly efficient, base-free, mild protocol for the palladium-catalyzed, copper-activated desulfitative couplings of vinyl and aryl β- nitrothioethers generates a wide variety of conjugated nitroorganics. Orthogonality to traditional Suzuki-Miyaura coupling is demonstrated, as well as synthetic utility, through reductive Cadogan cyclization, for the formation of indoles, carbazoles, and pyrroles.

Full text of DOI:10.1039/c3sc50773d

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Synthesis of nitrodienes, nitrostyrenes, and nitrobiaryls
through palladium-catalyzed couplings of b-nitrovinyl
and o-nitroaryl thioethers†
Cite this: Chem. Sci., 2013, 4, 2670
*
Gardner S. Creech and Ohyun Kwon
Received 20th March 2013
Accepted 9th April 2013
A highly efficient, base-free, mild protocol for the palladium-catalyzed, copper-activated desulfitative
couplings of vinyl and aryl b-nitrothioethers generates a wide variety of conjugated nitroorganics.
Orthogonality to traditional Suzuki–Miyaura coupling is demonstrated, as well as synthetic utility,
through reductive Cadogan cyclization, for the formation of indoles, carbazoles, and pyrroles.
DOI: 10.1039/c3sc50773d
www.rsc.org/chemicalscience
Transition metal-catalyzed cross-couplings are some of the
While designing a suitable substrate for the transition metal-
most dependable and effectual methods for forming carbon– catalyzed b-functionalization of nitroalkenes, we were drawn to
carbon bonds.1 Notwithstanding this, a great challenge remains the recently developed Liebeskind–Srogl cross-coupling of
to develop increasingly chemoselective coupling protocols that thioesters and boronic acids to form ketones.7 Whereas the
operate under mild and neutral conditions. In our burgeoning stereoselective formation of b-thioethyl nitroalkenes from a-
program investigating the reactivity of conjugated nitro- nitro ketones or via oxidation of b-thioethyl nitroalkanes has
organics,2 our endeavours were initially encumbered by the lack many precedents,8 general methods for forming b-triato or b-
of a general, systematic synthesis of 1-nitro-1,3-dienes, with a halo nitroalkenes are rare.9 In addition, vinyl suldes appear to
number of desired substrates apparently synthetically inacces- be robust functional groups—in the absence of thiophilic acti-
sible. A careful survey of the literature revealed methods that vation. Prior to this present investigation, the literature featured
rely on harsh acidic and oxidizing nitration conditions,3 the no examples of metal-catalyzed cross-couplings of vinyl thio-
Henry reaction of nitromethane with unsaturated carbonyls—a ethers,10 with the exception of the nickel-catalyzed Kumada
transformation that is severely limited in scope and efficiency,4 coupling of simple vinyl suldes.11 The use of Grignard
and the addition of zinc cuprates with 1-ethylthio-2-nitro- reagents, however, is undesirable because strongly basic
olens—a process that we found to be similarly limited in terms nucleophiles readily reduce nitro groups.12 Our hypothesis was
of the scope of both the electrophile and cuprate.5 To the best of that a highly electron-withdrawing nitro group would suffi-
our knowledge, the literature is devoid of exible and conver- ciently activate the C(sp2)–S bond for oxidative addition by
gent coupling strategies for the synthesis of conjugated nitro- palladium(0). In addition, there is a notable absence of exam-
organics, especially nitrodienes.6 Thus, we set out to assess the ples of Liebeskind–Srogl couplings of alkylthiobenzenes,
potential for a palladium-catalyzed cross-coupling reaction of a despite the multitude of known electron-poor 2-alkylthio-N-
suitably functionalized nitroalkene or nitroarene under neutral heterocycles.13 We envisaged that an ortho-nitro substituent
conditions, ideally with high chemoselectivity and a broad would similarly activate the aryl thioether for oxidative addition.
substrate scope (Scheme 1).
If successful, ready access to traditional substrates for the
Cadogan reductive cyclization would be possible, as would the
preparation of non-traditional substrates (vide infra).
Initial experiments, based on typical desultative coupling
conditions7 for the reaction of o-ethylthionitrobenzene (1a) with
(E)-1-hexenylboronic acid (2a), were moderately successful
(Table 1, entry 1).14 Gratifyingly, coupling proceeded well at
room temperature—that is, without the typical need for heat-
ing. The catalyst turnover increased upon varying the solvent
from DCM, through benzene and DMF, to methanol (entries 2–
5), with the latter resulting in an 86% isolated yield of 1-hexenyl-
2-nitrobenzene (3aa). Catalyst turnover was the limiting
factor (entries 6–8); attempts at minimizing the catalyst
loading with additional boronic acid (entry 9) or copper
Scheme 1 Desulfitative cross-coupling.
Department of Chemistry and Biochemistry, University of California, 607 Charles
E. Young Drive East, Los Angeles, CA 90095-1569, USA. E-mail: ohyun@chem.ucla.
edu; Fax: +1 310-206-3722; Tel: +1 310-267-4954
† Electronic supplementary information (ESI) available: Experimental details and
spectral data of new compounds. DOI: 10.1039/c3sc50773d
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Table 1 Optimization of the coupling for the least-reactive thioether
Table 2 Cross-couplings of the o-nitroaryl thioether 1a with aryl and vinyl
boronic acids
Pd(PPh3)4
[mol%]
CuTC
[equiv.]
2a
[equiv.]
Isolated
yield [%]
Isolated
Entry
Solvent
Entry
1
RB(OH)2
Product
yield [%]a
1
2
3
4
5
6
7
8
20
20
20
20
20
5
10
15
10
10
10
20
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
3.0
4.5
1.5
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
6.0
3.0
3.0
1.5
THF
38
48
53
63
86
23
60
67
55
64
64
79
CH2Cl2
Benzene
DMF
99
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
2
96b
9
10
11
12
3
4
5
6
94b
99
88
91
thiophenecarboxylate (CuTC: entries 10 and 11) did not result in
exhaustive conversion. Finally, decreasing the content of
boronic acid decreased the isolated yield, albeit to only a small
extent (entry 12).
Next, we employed o-ethylthionitrobenzene (1a) for the
synthesis of various o-nitrobiaryls and o-nitrostyrenes (Table 2).
Desultative cross-coupling with phenylboronic acid resulted in
quantitative conversion to the o-nitrobiaryl 3ab (entry 1).
Couplings with both 4-chlorophenylboronic acid and 3-bromo-
phenylboronic acid proceeded with equally high efficiency to
yield the biaryl halides 3ac and 3ad, respectively (entries 2 and 3).
These results are particularly striking because these aryl halides
are typical substrates for Suzuki–Miyaura cross-couplings,
demonstrating the orthogonal reactivity of aryl suldes with
aromatic halides under base-free cuprous activation. In addi-
tion, both electron-rich 2,3-methylenedioxyphenylboronic acid
and electron-poor 3-triuoromethylphenylboronic acid under-
went cross-couplings in excellent yields (entries 4 and 5,
respectively). The presence of free phenolic protons did not
interfere with the transformation, as evidenced by a notable
isolated yield (91%) of the biaryl 3ag (entry 6).
7
8
86
99
9
53
83
10
Isolated yield. b No protodehalogenation or halide-coupling observed.
a
In addition to arylboronic acids, vinylboronic acids were also
suitable partners for the coupling reaction. Both (E)-hexenyl-
boronic acid (2a) and (E)-b-styrenylboronic acid (2h) underwent
smooth couplings to form their expected nitrostyrenes (entries proceeded rapidly at room temperature, with complete conver-
and 8, respectively). a-Styrenylboronic acid underwent sion observed at a lower catalyst loading (10 mol%). The cross-
7
coupling, with diminished efficiency, to form the gem-diary- couplings of both electron-rich and -poor arylboronic acids
lethene 3ai (entry 9). Finally, cyclohexenylboronic acid was also proceeded with very high yields (entries 1–5). Heteroarylboronic
compatible with the coupling protocol (entry 10). Therefore, a acids were tolerated as well, as evidenced by the smooth
wide variety of boronic acids are suitable for the desultative coupling of 3-pyridylboronic acid in 94% yield, although mild
couplings of o-ethylthionitrobenzene, generating both o-nitro- heating was required in this case to ensure full conversion
biaryls and o-nitrostyrenes in excellent yields.
(entry 6). An ortho-substituted phenylboronic acid underwent
To further expand the scope of compatible sp2-hybridized cross-coupling with relatively moderate efficiency, presumably
thioether coupling partners, we explored the couplings of the b- due to greater steric hindrance (entry 7).
nitrovinyl thioethers 1b–d with both aryl and vinylboronic acids
Cross-couplings of vinyl thioethers with vinylboronic acids
(Table 3). Desultative coupling of the vinyl thioethers provided corresponding 1-nitro-1,3-dienes in good to excellent
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Table 3 Cross-couplings of the b-nitrovinyl thioethers 1b–d with various boronic
Table 3 (Contd. )
acids
Isolated
Isolated
Entry Thioether
15
RB(OH)2
Product
yield [%]a
Entry Thioether
1
RB(OH)2
Product
yield [%]a
94d
84c
99
16
1d
2
1b
1b
1b
1b
1b
90
99
99
96
94
a
b
Isolated yield.
Reaction was performed under reux.
c
Stereochemistry determined through NOESY-NMR spectroscopic
3
d
analysis (see the ESI†). Diastereoisomeric ratio was not determined.
4
yields in short order (Table 3, entries 8–12). Application of the
desultative cross-coupling protocol to the acyclic b-nitrovinyl
thioethers 1c and 1d also proved successful (entries 13–16), but,
conspicuously, with the loss of the stereochemical integrity of
the nitroalkene.15 Despite isomerization, we isolated the nitro-
dienes 3cc, 3cj, and 3dm each as a single diastereoisomer,
presumably due to sufficient steric bias toward one of the two b-
substituents. Notwithstanding, the b-nitrovinyl thioethers
underwent facile desultative couplings with aryl and vinyl-
boronic acids, with exemplary yields, under mild conditions at
room temperature.
5
6b
7
1b
81
o-Nitrostyrenes and o-nitrobiaryl compounds are traditional
substrates for Cadogan reductive cyclizations to form indoles
and carbazoles (Scheme 2a);16 this lesser-utilized process for
indole formation is comparable with the Leimgruber–Batcho
indole synthesis, but without the need to prepare b-dimethyla-
mino-2-nitrostyrenes or dinitrostyrenes prior to reduction.17
Although the Cadogan reductive cyclization has been applied
only sparingly in organic synthesis, it has been used widely in
the synthesis of polycarbazole and heteroacene electronic
materials.18,19 With ready access to traditional o-nitrostyrene
substrates, we treated 3aa with triethyl phosphite to obtain the
8
9
1b
1b
86
99
10
1b
84
11
12
1b
1b
82
68
13
14
90c
90c
1c
Scheme 2 Cadogan reductive cyclization.
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indole 4a in 76% yield.20,21 “Inverted” substrates, such as b-
nitrostyrene, have previously provided Cadogan products in
only a few isolated instances,22 yet here we found that the b-
nitrostyrene 3bc is a viable substrate for reductive cyclization,
generating the indole 4b (Scheme 2b). The corresponding non-
arene reductive Cadogan cyclizations, to generate pyrroles, have
not been disclosed previously, perhaps due in part to the lack of
reliable methods for forming 1-nitro-1,3-dienes. We found that
nitrodienes, such as 3bh, are amenable to Cadogan conditions,
in this case realizing the pyrrole 5 in good yield (Scheme 2c).
The cross-couplings of b-ethylthionitroolens and o-ethyl-
thionitrobenzenes described herein provide rapid access to
functionalized nitrodienes, nitrostyrenes, and nitrobiaryls, all
of which are readily converted into valuable N-heteroaromatics.
To fully delineate the inherent power of orthogonal cross-
coupling protocols, we prepared the o-ethylthionitrobenzene
substrate 6 featuring an aryl bromide handle for Suzuki–
Miyaura cross-coupling (Scheme 3). Under the desultative
coupling conditions, substrate 6 reacted with both phenyl-
boronic acid (2b) and hexenylboronic acid (2a) to generate the
biaryl 7a and the nitrostyrene 7b, respectively. In each case,
neither coupling nor protodebromination occurred at the aryl
bromide. Subsequently, we subjected the aryl bromides 7a and
7b to Suzuki–Miyaura cross-couplings with the crossed boronic
acids. Finally, we subjected the nitroarenes 8a and 8b to
Cadogan reductive cyclizations to generate the functionalized
carbazole 9a and the 2,6-disubstituted indole 9b, respectively.
Accordingly, chemoselective, orthogonal cross-coupling proto-
cols can be used in tandem to rapidly generate substituted
aromatic N-heterocycles.
Acknowledgements
Financial support from the NSF (CHE7096481) is gratefully
acknowledged.
Notes and references
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In summary, we have developed a general protocol for the
coupling of b-nitrovinyl and o-nitroaryl thioethers with boronic
acids under chemoselective, mild, base-free conditions. The
reaction typically proceeds with high efficiency, generating
nitrodienes, nitrostyrenes, and nitrobiaryls of high synthetic
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Scheme 3 Orthogonal cross-couplings and Cadogan cyclizations. 20 mol%
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RB(OH)2, toluene–EtOH–H2O, reflux; c P(OEt)3, reflux.
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2674 | Chem. Sci., 2013, 4, 2670–2674
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