Metal-Free C-Arylation of Nitro Compounds with Diaryliodonium Salts

Article abstract of DOI:10.1021/acs.orglett.5b02270

An efficient, mild, and metal-free arylation of nitroalkanes with diaryliodonium salts has been developed, giving easy access to tertiary nitro compounds. The reaction proceeds in high yields without the need for excess reagents and can be extended to α-arylation of nitroesters. Nitroalkanes were selectively C-arylated in the presence of other easily arylated functional groups, such as phenols and aliphatic alcohols.

Full text of DOI:10.1021/acs.orglett.5b02270

Letter
pubs.acs.org/OrgLett
Metal-Free C‑Arylation of Nitro Compounds with Diaryliodonium
Salts
Chandan Dey,§,† Erik Lindstedt,§,† and Berit Olofsson*,†,‡
†Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
‡Stellenbosch Institute for Advanced Study (STIAS), Wallenberg Research Centre at Stellenbosch University, Marais Street,
Stellenbosch 7600, South Africa
S
* Supporting Information
ABSTRACT: An efficient, mild, and metal-free arylation of nitro-
alkanes with diaryliodonium salts has been developed, giving easy
access to tertiary nitro compounds. The reaction proceeds in high
yields without the need for excess reagents and can be extended to α-
arylation of nitroesters. Nitroalkanes were selectively C-arylated in
the presence of other easily arylated functional groups, such as
phenols and aliphatic alcohols.
arbon−carbon bond formation belongs to the fundamental
excess substrate, elevated temperature, and expensive ligands
Ctransformations in synthetic organic chemistry, and (Scheme 1b).8
Hypervalent iodine(III) compounds have recently been
efficient methods to achieve C−C bonds are of high importance.
Synthetic strategies toward complex molecules often rely on
functional groups that are compatible with a range of conditions.
Such groups can hence be introduced at an early stage and later
on be selectively transformed into other interesting functional
groups. Nitroalkanes fulfill these criteria and are often key
intermediates in total synthesis,1 due to the plethora of
derivatization possibilities (Scheme 1a).2
demonstrated as efficient reagents for a wide range of
transformations.9 Diaryliodonium salts are nontoxic, bench-
stable, and readily available electrophilic arylating reagents useful
in a range of transformations.10 Although diaryliodonium salts
have been applied in α-arylation of carbonyl compounds, the
scope remains moderate especially for acyclic systems.11 The
arylation of preformed alkali nitronates with diaryliodonium salts
was reported in the 1960s with a very limited substrate scope.12
Our research group has focused on the synthesis and
applications of diaryliodonium salts in metal-free arylations of
oxygen and nitrogen nucleophiles.13 Motivated by the ubiquitous
nature of the nitro functional group, we envisioned the use of
diaryliodonium salts in C-arylation of nitro compounds under
mild and metal-free conditions. We focused on the arylation of
secondary nitroalkanes, as tertiary nitro compounds are difficult
to access with conventional methods and can be converted to
highly useful α-tertiary amines.14 The α-arylation of nitroesters
was also targeted, and herein we present our preliminary results.
The arylation of nitrocyclopentane was optimized at room
temperature, revealing that potassium tert-butoxide in 1,2-
dimethoxyethane (DME) as solvent was most efficient.15 An
excess of diaryliodonium salt or nitroalkane was not needed, and
the reaction proceeded with high efficiency using diaryliodonium
salts with OTf, BF4, or PF6 as counterions, while OTs gave a
slightly lower yield.15 The high counterion tolerance was
pleasing, as this facilitates the synthesis of the iodonium salts.16
The optimized conditions were then applied in the arylation of
nitroalkanes 1 with various diaryliodonium salts 2 (Scheme 2).
Nitrocyclopentane was smoothly phenylated (3a), as well as
arylated with electron-deficient aryl groups to provide products
Scheme 1
The acidity of nitroalkanes parallels that of stabilized carbonyl
compounds, and they are easily functionalized with electrophiles
under basic conditions.2,3 While α-arylation of carbonyl
compounds has been studied extensively,4 the arylation of
nitroalkanes remains largely unexplored. Stoichiometric use of
heavy metal reagents based on lead5 or thallium6 generates toxic
waste, while reactions with triphenylbismuth reagents7 have poor
atom efficiency. Furthermore, the above reagents have only been
demonstrated with a limited substrate scope (Scheme 1b).
Palladium-catalyzed methodology has mainly focused on
arylation of nitromethane and primary nitroalkanes and requires
Received: August 5, 2015
© XXXX American Chemical Society
A
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Letter
efficient recovery of the resulting iodoarene.15 Nitroalkanes with
longer carbon chains were employed to provide products 3x−
3ac. Importantly, acyclic products containing a pyridyl moiety
could be obtained both by arylation with a pyridyl moiety (3z)
and by arylation of a pyridyl-substituted nitroalkane (3aa and
3ab). Selective C-arylation was observed with 5-nitro-2-heptanol
to reach 3ac (vide infra).
a
Scheme 2. C-Arylation of Nitroalkanes
Pd-catalyzed arylations of nitromethane and primary nitro-
alkanes use 2−10 equiv of nitroalkane.8a−d Under our optimized
conditions, the arylation of 1-nitropropane resulted in a mixture
of mono- and diarylated products. To our delight, monoarylation
proceeded well in the presence of excess nitropropane, delivering
compound 4 in up to 76% yield (Scheme 3).
Scheme 3. Monoarylation of 1-Nitropropane
α,α-Disubstituted α-amino acids are important structural
motifs present in many natural products and antibiotics,18 and
the α-arylation of α-amino acid derivatives introduces new
structural motifs that can affect the binding mode to proteins and
receptors.19 We envisioned a complementary method to access
such compounds via α-arylation of nitroesters,8e the products of
which are easily reduced to the corresponding α-amino acids.19a,b
Upon arylation of 2-nitroester 5 under the optimized
conditions, only trace amounts of product 6 was obtained with
recovery of starting material 5 (Scheme 4). Reoptimization of the
reaction with this less reactive nucleophile revealed that α-
arylated product 6a could be obtained in good yield with cesium
carbonate in toluene at reflux.15 Upon exploring the scope of the
a
Reaction conditions: 1 (0.2−0.5 mmol) and t-BuOK were stirred in
anhydrous DME (1−2 mL) for 10 min at rt before addition of 2 and
b
c
anhydrous DME (0.5−1 mL). BF4 as counterion 1H NMR yield with
1,4-dimethoxybenzene as internal standard. 5 mmol scale. Based on
recovered 1.
d
e
a
Scheme 4. α-Arylation of Nitroesters
3b−d. Importantly, halide-substituted diaryliodonium salts easily
underwent the reaction, delivering the products 3e,f in high
yields. Halide substituents can be used for further trans-
formations, and such products can be difficult to access via
metal-catalyzed arylations.
Electron-donating groups on the diaryliodonium salts were
well tolerated, yielding 3g−j. Anisyl-substituted product 3j could
be obtained despite its instability.5b,15 To our delight, transfer of a
pyridyl group could be accomplished to furnish 3k in high yield.
This is important, as pyridyl moieties are omnipresent in
biologically interesting molecules.17 Steric hindrance in the
ortho-position of the aryl group hampered the reaction, and
dimesityliodonium triflate gave only traces of product. While an
ortho-tolyl group could only be transferred to reach product 3l
with difficulty, the corresponding ortho-fluoride substituted
product 3m was obtained in excellent yield. Nitroalkanes with
varying ring sizes were compatible with this transformation, and
both the six- and seven-membered phenylated products 3n,o
were isolated in comparable yields to 3a. Various diaryliodonium
salts were applied to these nitroalkanes, delivering products 3p−s
in high yield, including pyridyl-substituted products 3r and 3s.
The scope could be extended to also include C−C bond
formation with acyclic nitroalkanes. These compounds under-
went the arylation smoothly with both electron-withdrawing and
-donating diaryliodonium salts, delivering products 3t−ac in
good to excellent yields. Phenylation of 2-nitropropane furnished
the product 3t in high yield, but the volatility of 3t lowered the
isolated yield. The synthesis of 3v could easily be scaled up, with
a
Reaction conditions: 5 (0.2 mmol) and Cs2CO3 were stirred in
anhydrous toluene (1 mL) for 10 min at rt before addition of 2 and
anhydrous toluene (0.5 mL). The resulting mixture was stirred for 1 h
at rt followed by 6 h at 110 °C. BF4 as counterion. Reaction time 16
h.
b
c
reaction, electronically and sterically different iodonium salts
were employed under the optimized reaction conditions,
affording α-arylated nitroesters 6. Again, electron-withdrawing
as well as electron-donating aryl groups could be transferred
(6b−f). The synthesis of α-anisyl nitroester 6e was accomplished
in good yield upon prolonged reaction time. Also this arylation
B
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proved sensitive to ortho-substituents on the aryl group, and
reaction with dimesityliodonium triflate only afforded trace
amounts of product. Pleasingly, transfer of an ortho-fluorophenyl
group to nitroester 6f was achieved in 73% yield, and a pyridyl
moiety was easily incorporated to reach product 6g.
Competition experiments were performed to investigate the
compatibility of the reaction with other functional groups. As
mentioned above, selective C-arylation to 3ac was observed with
5-nitro-2-heptanol (Scheme 5a), despite the known reactivity of
The use of unsymmetric diaryliodonium salts (Ar1 ≠ Ar2) is
desirable, due to their straightforward synthesis and the
possibility to use an inexpensive aryl iodide as a “dummy”
ligand. High chemoselectivity, i.e. selective transfer of Ar1 over
Ar2, is necessary to ensure high yields of the desired products and
to avoid isolation problems. We have recently reported a detailed
study on chemoselectivity trends for arylations of N-, O-, and C-
centered nucleophiles under metal-free conditions.20 Based on
those results, electron-rich or ortho-substituted aryl moieties
could be good dummy groups for the C-arylation of nitroalkanes.
As expected, the more electron-deficient aryl group was
transferred to nitrocyclopentane, delivering products 3b and 3c
with moderate to excellent selectively (Table 1, entries 1−2).
Scheme 5. Competition Experiments
a
1H NMR yield with internal standard.
aliphatic alcohols at room temperature.13c The addition of a
benzylic alcohol to the reaction was well tolerated, delivering
product 3a in good yield (Scheme 5b).13d
Table 1. Chemoselectivity Trends
To our delight, even a phenol remained untouched under the
reaction conditions (Scheme 5c), although phenols are excellent
substrates in arylations with diaryliodonium salts.13e In all cases,
no O-arylation byproducts were detected. These features allow
for late stage C-arylation of relevant nitro compounds.
Arylations with diaryliodonium salts under metal-free
conditions can either proceed via an SET mechanism24 or by
formation of a T-shaped intermediate followed by ligand
coupling between the nucleophile and the equatorial aryl
ligand.20,25 The arylation of nitroalkanes proved to be insensitive
to the radical trap 1,1-diphenylethylene (DPE), and an aryne
intermediate seems unlikely, as regioisomeric mixtures of
products were not observed.15We therefore propose a ligand-
coupling mechanism similar to that proposed for α-arylation of
carbonyl compounds.25c Scheme 6 depicts product formation via
Scheme 6. Proposed Mechanism
a
b
Conditions according to Schemes 2, 4. Ratio of arylated products
c
(Ar1 vs Ar2) in the crude reaction mixture. Isolated yield of major
d
e
two different T-shaped intermediates that could be in fast
equilibrium, with product formation to 3 either by normal ligand
coupling (A) or via a [2,3]-rearrangement (B).
product. Isolated as a mixture. 1H NMR yield with internal standard.
The anisyl moiety proved to be a good dummy ligand for
chemoselective transfer of a pyridyl group (6g, entry 3). The
observed sensitivity to ortho-substituents could be exploited with
aryl(mesityl)iodonium salts, selectively providing products 3a
and 6a (entries 4,5). This dummy group could also be employed
in transfer of other aryl groups.15 This chemoselectivity is
opposite to the commonly encountered “ortho-effect”21 and has
been termed an “anti-ortho effect”.20 We subsequently set out to
compare the electronic and steric effects using an anisyl(o-
tolyl)iodonium salt, which resulted in preferential transfer of the
more electron-rich aryl group to give 3j (entry 6). This is a
unique example of the “anti-ortho effect” overriding the electronic
effect in a metal-free arylation with diaryliodonium salts.22,23
In conclusion, we have demonstrated an efficient, straightfor-
ward, and metal-free approach for the C-arylation of nitroalkanes
and nitroesters. The reaction entails equimolar amounts of
reagents, gives high yields, and can be easily up-scaled with
recovery of the formed iodoarene. Electron-rich and -deficient
iodonium salts are equally compatible, and the reaction proceeds
smoothly with cyclic as well as acyclic nitroalkanes. The
arylations can be chemoselectively performed using either an
anisyl or a mesityl dummy group and provides a strong “anti-
ortho effect” that overrides the electronic preference.
The functional group tolerance toward aliphatic alcohols and
phenols is excellent, despite the well-known, high reactivity of
alcohols with diaryliodonium salts under mild conditions. The
C
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X. Angew. Chem., Int. Ed. 2013, 52, 10245−10249. Enantioselective α-
arylations: (e) Bigot, A.; Williamson, A. E.; Gaunt, M. J. J. Am. Chem. Soc.
2011, 133, 13778−13781. (f) Harvey, J. S.; Simonovich, S. P.; Jamison,
C. R.; MacMillan, D. W. C. J. Am. Chem. Soc. 2011, 133, 13782−13785.
(g) Allen, A. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2011, 133, 4260−
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5516−5519. (i) Ochiai, M.; Kitagawa, Y.; Takayama, N.; Takaoka, Y.;
Shiro, M. J. Am. Chem. Soc. 1999, 121, 9233−9234.
reaction is proposed to proceed by a ligand-coupling pathway via
two possible intermediates.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02270.
(12) (a) Park, K. P.; Clapp, L. B. J. Org. Chem. 1964, 29, 2108−2108.
(b) Kornblum, N.; Taylor, H. J. J. Org. Chem. 1963, 28, 1424−1425.
(c) Singh, P. R.; Khanna, R. K. Tetrahedron Lett. 1982, 23, 5355−5358.
(13) (a) Tinnis, F.; Stridfeldt, E.; Lundberg, H.; Adolfsson, H.;
Olofsson, B. Org. Lett. 2015, 17, 2688−2691. (b) Ghosh, R.; Stridfeldt,
E.; Olofsson, B. Chem. - Eur. J. 2014, 20, 8888−8892. (c) Ghosh, R.;
Lindstedt, E.; Jalalian, N.; Olofsson, B. ChemistryOpen 2014, 3, 54−57.
(d) Lindstedt, E.; Ghosh, R.; Olofsson, B. Org. Lett. 2013, 15, 6070−
6073. (e) Jalalian, N.; Petersen, T. B.; Olofsson, B. Chem. - Eur. J. 2012,
18, 14140−14149.
Experimental details and spectral data for novel
compounds; NMR spectra of all products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: berit.olofsson@su.se.
Author Contributions
§C. D. and E. L. contributed equally.
Notes
(14) Clayden, J.; Donnard, M.; Lefranc, J.; Tetlow, D. J. Chem.
Commun. 2011, 47, 4624−4639.
(15) See the Supporting Information for details.
The authors declare no competing financial interest.
(16) The diaryliodonium salts were synthesized according to:
(a) Bielawski, M.; Malmgren, J.; Pardo, L. M.; Wikmark, Y.; Olofsson,
B. ChemistryOpen 2014, 3, 19−22. (b) Bielawski, M.; Aili, D.; Olofsson,
B. J. Org. Chem. 2008, 73, 4602−4607. (c) Zhu, M.; Jalalian, N.;
Olofsson, B. Synlett 2008, 2008, 592−596. (d) Bielawski, M.; Olofsson,
B. Chem. Commun. 2007, 2521−2523.
ACKNOWLEDGMENTS
Carl Trygger’s Foundation (13:338; 14:359) is gratefully
acknowledged for financial support.
■
(17) Pyridine and its derivatives are commonly found in nature, in
agricultural products, and in pharmaceuticals. New methods to access
pyridyl containing molecules are therefore in high demand. See:
Baumann, M.; Baxendale, I. R. Beilstein J. Org. Chem. 2013, 9, 2265−
2319.
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