Metal-free functionalization of N, N-dialkylanilines via temporary oxidation to N, N-dialkylaniline N-oxides and group transfer

Article abstract of DOI:10.1021/ol501813s

A simple set of protocols for the controlled elaboration of anilines is reported allowing access to a diverse array of aminophenols, aminoarylsulfonates, alkylated anilines, and aminoanilines in 29-95% yield in a single laboratory operation from easily isolable, bench-stable N,N-dialkylaniline N-oxides. The introduction of new C-O, C-C, and C-N bonds on the aromatic ring is made possible by a temporary increase in oxidation level and excision of a weak N-O bond.

Full text of DOI:10.1021/ol501813s

Letter
pubs.acs.org/OrgLett
Metal-Free Functionalization of N,N‑Dialkylanilines via Temporary
Oxidation to N,N‑Dialkylaniline N‑Oxides and Group Transfer
Robert S. Lewis,† Michael F. Wisthoff,† J. Grissmerson,† and William J. Chain*,†,‡
†Department of Chemistry, University of Hawaii at Manoa, 2545 McCarthy Mall, Honolulu, Hawaii 96822, United States
‡The University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, Hawaii 96813, United States
S
* Supporting Information
ABSTRACT: A simple set of protocols for the controlled elaboration of anilines is
reported allowing access to a diverse array of aminophenols, aminoarylsulfonates,
alkylated anilines, and aminoanilines in 29−95% yield in a single laboratory operation
from easily isolable, bench-stable N,N-dialkylaniline N-oxides. The introduction of
new C−O, C−C, and C−N bonds on the aromatic ring is made possible by a
temporary increase in oxidation level and excision of a weak N−O bond.
ngaging anilines at nitrogen and executing a group transfer
pursuit to give protected hydroxyanilines has a long history
Efrom nitrogen to carbon is an attractive method for the dating to the mid-1950s, and various pericyclic, ion-pair, and
radical-type mechanisms have been examined (Scheme 1, eq
2).4,5 A small number of carbon−carbon bond formations
utilizing these substrates have also been described over the same
time period, but substrate scope is generally limited to migrating
groups that can support an anion.6 A recent series of
investigations greatly expanded the landscape of carbon−
heteroatom bond formations in N-arylhydroxylamine rearrange-
ments, allowing access to hydroxy- and aminoanilines, as well as
cyclized products.7 These transformations are described as
concerted [3,3]-sigmatropic rearrangements and in most cases
require prolonged exposure to elevated temperature, microwave
heating, or other potentially deleterious reaction conditions.
Most of these transformations are efficient but require judicious
choice of nitrogen-protective groups and can also be sensitive to
the electronic nature of the aromatic ring.
controlled functionalization of electron-rich aromatic rings,
which are otherwise more problematic to manipulate.1 The
aniline and aminophenol substructures are embedded in many
synthetic building blocks, ligands and other catalyst frameworks,
as well as a myriad of biologically active compounds.2 Efficient
access to these structures is of value to chemists in many fields,
yet methods that allow selective and controlled elaboration of
anilines remain rare.
The all-carbon aza-Claisen rearrangement of alkylated anilines
is an inefficient process and does not provide a synthetically
useful means of aromatic functionalization (Scheme 1, eq 1).3
The introduction of weak, excisable N−O bonds into the
operative bond network affords the opportunity to exploit this
important scaffold for complexity generating reactions.4 The
rearrangement of various acylated N-arylhydroxylamines in this
We had need of several substituted anilines and sought to
overcome some of the limitations of the N-arylhydroxylamine
rearrangements and provide a single platform on which one
could execute a variety of bond formations on anilines under mild
reaction conditions at low temperature (Scheme 1, eq 3). Herein,
we describe C−O, C−C, and C−N bond formations under
exceptionally mild reaction conditions that function by virtue of
an increase in oxidation level from aniline to aniline N-oxide.
Aniline N-oxides are conveniently generated from the corre-
sponding anilines, easily isolated and handled, and are generally
bench stable.8,9 Following an O-acylation event, group transfer
from nitrogen to carbon excises the weak N−O bond and gives an
iminium ion, and after loss of a proton, aromaticity and electron
density at nitrogen are restored. These bond formations proceed
in seconds to minutes at low temperature. The transformation of
N,N-dialkylaniline-N-oxides into oxygenated anilines was ex-
plored in the classical Boyland−Sims oxidation,10 with several
mechanistic inquiries described in the literature.11
Scheme 1. Aromatic Rearrangements Featuring N → C Group
Transfer
Received: June 23, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol501813s | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Milder, more controlled transformations in this context were
probed briefly in the past, and in these early mechanistic studies,
reaction yields varied widely (6−90%) with side products
attributed to the multiple mechanistic pathways that are available
(concerted rearrangements, ion-pair, and radical pathways).12
To our knowledge, there are only two prior examples of carbon−
carbon bond formations in this context, the reaction of N,N-
dimethylaniline-N-oxide with diketene and acetylene dicarbox-
ylates.13 In that work, spectroscopic data supported mechanisms
in which O-acylation/alkylation events are followed by
fragmentations into radical pairs, which recombined to give the
alkylated products. The alkylated products were accompanied by
several side products and thus other mechanistic possibilities
could not be excluded.14
event is followed by nonspecific decomposition via what appears
to be a deprotonation that gives an aza-xylylene.15 In the case of
p-carbonyl substitution, the acylation event is followed by
deprotonation of the N-methyl to give an iminium ion that
hydrolyzes on workup to result in the corresponding N-
methylaniline product.16
Trifluoromethanesulfonic anhydride (triflic anhydride, Tf2O)
and p-toluenesulfonyl chloride (tosyl chloride) also serve as
viable acylation/oxygenation agents (Schemes 3 and 4).7
Scheme 3. Trifluoromethanesulfonylation of N,N-
Diallkylaniline N-Oxides*
We describe efficient access to a variety of aminophenols by
sequential treatment of N,N-dialkylaniline N-oxides with
trifluoroacetic anhydride and triethylamine in dichloromethane
at −78 °C (Scheme 2). The intermediate trifluoroacetate esters
Scheme 2. Hydroxylation of N,N-Dialkylaniline N-Oxides*
*
Yields of isolated products; reactions were performed on a 1.0 mmol
a
b
scale. Reaction was performed on a 10.0 mmol scale. Reaction was
performed for 2 h at −78 °C prior to addition of triethylamine.
c
Product was isolated as a mixture of regioisomers.
*
Sequential treatment of N,N-dialkylaniline N-oxides with triflic
anhydride or tosyl chloride and triethylamine in cold dichloro-
methane gives a variety of aryl sulfonates in moderate to excellent
yields. As above, we observed the same regiochemical
preferences for functionalization and the same liabilities with
Yields of isolated products; reactions were performed on a 1.0 mmol
a
b
scale. Reaction conducted on a 10.0 mmol scale. The 2-bromo-6-
hydroxy-N,N-dimethylaniline product was detectable in the crude
product mixture but inseparable from the 2-bromo-N-methylaniline
side product.
Scheme 4. p-Toluenesulfonylation of N,N-Diallkylaniline N-
Oxides
are hydrolyzed on workup to give the phenols directly in 52−
94% yield. These conditions strongly favor ortho functionaliza-
tion, with the exception that substrates bearing a single ortho
substituent modestly favor the 4-hydroxy-N,N-dialkylaniline
product (e.g., Scheme 2, product 2b). We have not conclusively
determined the mechanism of the group transfer, and studies are
ongoing. As in the prior investigations, possibilities include
concerted [3,3]-sigmatropic rearrangements, ion-pair, and
radical pathways. In any case, we were not surprised to observe
that substrates with no open ortho or para positions (i.e., 2,4,6-
trimethyl-N,N-dimethylaniline) give no hydroxylated product.
Substrates bearing a meta substation give mixtures of ortho
hydroxylation products, favoring the less sterically encumbered
product (1.2−2:1). The reaction functions well with both
electron-donating and -withdrawing substitutents with two
notable exceptions, substrates bearing o-methyl or p-carbonyl
substituents. In the case of o-methyl substitution, the acylation
a
a
Yields of isolated products; reactions were performed on a 1.0 mmol
scale.
B
dx.doi.org/10.1021/ol501813s | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
respect to methyl and carbonyl substitution. Additionally, the
sulfonylated aniline N-oxides are more vulnerable to the
unproductive elimination reaction pathway that gives rise to N-
methylanilines. This reaction pathway dominates in substrates
bearing strong electron donors at the para position (e.g., N,N-
dimethyl-p-anisidine), but strong electron donors are tolerated at
the meta position (e.g., N,N-dimethyl-m-anisidine gives products
3h and 4b in 95% and 51% yield, respectively).
Scheme 6. Amination of N,N-Dimethylanline N-Oxide (1a)
Importantly, the elevated reactivity of N,N-dialkylaniline N-
oxides allows facile carbon−carbon bond formation under
exceptionally mild reaction conditions: O-acylation events that
give C−C π-systems in their wake result in efficient and clean N
→ C group transfer, and following rearrangement, a decarbox-
ylation gives the final alkylated products. Ethyl malonyl
chloride,17 a substrate that will present a π-system by virtue of
its existence predominantly as an enol tautomer, functions
successfully in this context (Scheme 5). We have noted the same
of carbon−heteroatom and carbon−carbon bonds onto the
aromatic ring in the absence of metals, Lewis acids, or other
exotic reagents. Our future efforts are directed toward unraveling
the mechanistic details of these reactions, expanding the scope of
new bond forming reactions of aniline-N-oxides, and the
application of these methods to natural product synthesis.
These studies will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
Scheme 5. Alkylation of N,N-Dialkylaniline N-Oxides with
Ethyl Malonyl Chloride*
S
Experimental details and spectral data for compounds 1−6. This
material is available free of charge via the Internet at http://pubs.
acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: chain@hawaii.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Institutes of Health
(R01CA163287), the University of Hawaii, and the Achievement
Rewards for College Scientists Foundation (R.S.L.) are gratefully
acknowledged. We thank W. Yoshida (UH) for assistance with
NMR data collection, and we thank Dr. W. Niemczura (UH) and
Dr. J. Greaves (UC Irvine Mass Spectrometry Facility) for
accurate mass measurements.
REFERENCES
*
■
Yields of isolated products; reactions were performed on a 1.0 mmol
(1) (a) Arora, A. In Aromatic Organic Chemistry; Discovery Publishing
House: India, 2008. (b) Hepworth, J. D.; Waring, D. R.; Waring, J. M. In
Aromatic Chemistry; Royal Society of Chemistry: Cambridge, 2002. (c)
Taylor, R. Electrophilic Aromatic Substitution; Wiley: New York, 1990.
(d) Katritzky, A. R.; Taylor, R. Electrophilic Substitution of Hetero-
cycles: Quantitative Aspects. In Advances in Heterocyclic Chemistry;
Academic Press: New York, 1990; Vol. 47. (e) Taylor, R. In
Comprehensive Chemical Kinetics; Bamford, C. H., Tipper, C. F. H.,
Eds.; Elsevier: New York, 1972; Vol. 13, pp 1−406.
(2) (a) Boyd, G. V. In Science of Synthesis: Methods of Molecular
Transformations (Houben-Weyl); Scheumann, E., Ed.; Thieme: Stuttgart,
2002; Vol. 11, pp 481−492. (b) Gelman, D. S.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2003, 42, 5993−5996. (c) Andersen, K. K.; Bray, D. D.;
Chumpradit, S.; Clark, M. E.; Habgood, G. J.; Hubbard, C. D.; Young, K.
a
b
scale. Reaction was performed on a 10.0 mmol scale. Product was
isolated as a mixture of regioisomers.
regiochemical preferences as in the above carbon−heteroatom
bond formations and the same liability with respect to
demethylation to give N-methylanilines. Moreover, the
carbon−carbon bond formation event appears to be quite facile,
occurring at low temperature in a matter of minutes; the slowest
event of the reaction sequence appears to be the decarboxylation.
The reaction functions well for both electron-donating and
-withdrawing substitutents, and C-alkylated products are
obtained cleanly in 29−67% yield.
Methods for the direct amination of anilines are exceptionally
rare.7 We have successfully executed a group transfer to give a
new C−N bond using N,N-dialkylaniline N-oxides and phenyl
isocyanate as a nitrogen source (Scheme 6), which to our
knowledge is only the second example of the introduction of a
new C−N bond on an aromatic ring utilizing an aniline N-
oxide.13b,18 Studies to increase the efficiency of this trans-
formation are ongoing.
́
M. J. Org. Chem. 1991, 56, 6508−6516. (d) Levai, A. Heterocycles 2008,
75, 2155−2185. (e) Carta, A.; Piras, S.; Loriga, G.; Paglietti, G. Mini-Rev.
Med. Chem. 2006, 6, 1179−1200. (f) Sato, N. In Science of Synthesis;
Yamamoto, Y., Ed.; Thieme: Stuttgart, 2004; Vol. 16, pp 751−844.
(3) For examples of the aza-Claisen rearrangement and aza-aromatic
Claisen rearrangement, see: (a) Marcinkiewicz, S.; Green, J.; Mamalis, P.
Tetrahedron 1961, 14, 208−222. (b) Hill, R. K.; Gilman, N. W.
Tetrahedron Lett. 1967, 8, 1421−1423. (c) Walters, M. A.; McDonough,
C. S.; Brown, P. S.; Hoem, A. B. Tetrahedron Lett. 1991, 32, 179−182.
(d) Beholz, L. G.; Stille, J. R. J. Org. Chem. 1993, 58, 5095−5100. For
recent reviews of the aza-Claisen rearrangement, see: (e) Nubbemeyer,
The elevated reactivity of N,N-dialkylaniline N-oxides
facilitates clean, efficient, controlled, and scalable introduction
C
dx.doi.org/10.1021/ol501813s | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
U. In Natural Products Synthesis II; Mulzer, J., Ed.; Springer: Berlin,
2005; Vol. 244, pp 149−213. (f) Majumdar, K. C.; Bhattacharyya, T.;
Chattopadhyay, B.; Sinha, B. Synthesis 2009, 2117−2142. For a recent
example of an acid-mediated aza-Claisen rearrangement under excep-
tionally mild reaction conditions, see: (g) Maity, P.; Pemberton, R. P.;
Tantillo, D. J.; Tambar, U. K. J. Am. Chem. Soc. 2013, 135, 16380−
16383.
(4) (a) Bassoli, A.; Di Gregorio, G.; Galliani, G.; Riboldi, M.; Rindone,
B.; Tollari, S.; Chioccara, F. Bull. Chim. Soc. Fr. 1988, 293−297.
(b) Pereira, M.; Manuela, A.; Santos, P. P. In Chemistry of
Hydroxylamines, Oximes and Hydroxamic Acids, Part 1; Rappoport, Z.,
Liebman, J. F., Eds.; John Wiley and Sons: Chichester, 2009. (c) Luo, Y.-
R. In Comprehensive Handbook of Chemical Bond Energies; CRC Press
and Taylor & Francis Group: Boca Raton, 2007; p 353. For a recent
review of the chemistry of hydroxylamines, see:. (d) Tabolin, A. A.; Ioffe,
S. L. Chem. Rev. 2014, 114, 5426−5476.
(16) This oxidation−elimination pathway is a known strategy for the
demethylation of amines and is active to a small extent in all the
reactions we describe here. For previous examples, see: (a) Mechaca, R.;
Martinez, V.; Rodriguez, A.; Rodriguez, N.; Flores, M.; Gallego, P.;
Manzanares, I.; Cuevas, C. J. Org. Chem. 2003, 68, 8859−8866.
(b) Periasamy, M.; Jayakumar, K. N.; Bharathi, P. J. Org. Chem. 2000, 65,
3548−3550. The demethylation reaction may also proceed by a
Polonovski reaction; see: (c) Grierson, D. Org. React. 1990, 39, 85−295.
(d) Cave, A.; Kan-Fan, C.; Potier, P.; Le Men, J. Tetrahedron 1967, 23,
4681−4689.
(17) (a) Niwayama, S.; Cho, H.; Lin, C. Tetrahedron Lett. 2008, 49,
4434−4436. (b) Shimada, N.; Stewart, C.; Bow, W. F.; Jolit, A.; Wong,
K.; Zhou, Z.; Tius, M. A. Angew. Chem., Int. Ed. 2012, 51, 5727−5729.
(18) The aniline N-oxides can act as a Lewis base catalyst in a
dimerization of the isocyanate, but this reaction can be suppressed by the
slow addition of the isocyanate to the aniline N-oxide. The dimerization
of isocyanates to give carbodiimides has been reported for other Lewis
base catalysts such as phosphines and phosphine oxides. For examples,
see: (a) Monagle, J. J.; Campbell, T. W.; McShane, H. F., Jr. J. Am. Chem.
Soc. 1962, 84, 4288−4295. (b) Blair, J. S.; Smith, G. E. P. J. Am. Chem.
Soc. 1934, 56, 907−910. (c) Raiford, L. C.; Freyermuth, H. B. J. Org.
Chem. 1943, 8, 230−238. (d) Campbell, T. W.; Monagle, J. J. J. Am.
Chem. Soc. 1962, 84, 3673−3677.
(5) (a) Horner, L.; Steppan, H. Justus Liebigs Ann. Chem. 1957, 606,
24−47. (b) Oae, S.; Sakurai, T.; Kimura, H.; Kozuka, S. Chem. Lett.
1974, 671−674. (c) Gutschke, D.; Heesing, A.; Heuschkel, U.
Tetrahedron Lett. 1979, 20, 1363−1364.
(6) (a) Coates, R. M.; Said, I. M. J. Am. Chem. Soc. 1977, 99, 2355−
2357. (b) Blechert, S. Tetrahedron Lett. 1984, 25, 1547−1550. (c) Endo,
Y.; Hizatate, S.; Shudo, K. Tetrahedron Lett. 1991, 32, 2803−2806.
(d) Uchida, T.; Endo, Y.; Hizatate, S.; Shudo, K. Chem. Pharm. Bull.
1994, 42, 419−421. (e) Endo, Y.; Uchida, T.; Hizatate, S.; Shudo, K.
Synthesis 1994, 1096−1105. (f) Almeida, P. S.; Prabhakar, S.; Lobo, A.
M.; Marcelo-Curto, M. J. Tetrahedron Lett. 1991, 32, 2671−2674.
(g) Lobo, A. M.; Prabhakar, S. Pure Appl. Chem. 1997, 69, 547−552.
(h) Santos, P. F.; Almeida, P. S.; Lobo, A. M.; Prabhakar, S. Heterocycles
2001, 55, 1029−1043. (i) Mao, Z.; Baldwin, S. W. Org. Lett. 2004, 6,
2425−2428.
(7) (a) Porzelle, A.; Woodrow, M. D.; Tomkinson, N. C. O. Org. Lett.
2010, 12, 812−815. (b) Porzelle, A.; Cooper, W. J.; Woodrow, M. D.;
Tomkinson, N. C. O. Synlett 2010, 2471−2473. (c) Porzelle, A.;
Woodrow, M. D.; Tomkinson, N. C. O. Org. Lett. 2010, 12, 1492−1495.
(d) Porzelle, A.; Woodrow, M. D.; Tomkinson, N. C. O. Eur. J. Org.
Chem. 2008, 5135−5143. See also: (e) Ram, R. N.; Soni, V. K. J. Org.
Chem. 2013, 78, 11935−11947.
(8) See the Supporting Information for details.
(9) Substrates with benzylic or allylic substitution at nitrogen readily
undergo [1,2]- and [2,3]-Meisenheimer rearrangements; see: (a) Mei-
senheimer, J. Ber. 1919, 52B, 1667−1677. (b) Meisenheimer, J.;
Greeske, H.; Willmersdorf, A. Ber. 1922, 55B, 513−532. (c) Kleinsch-
midt, R. F.; Cope, A. C. J. Am. Chem. Soc. 1944, 66, 1929−1933.
(d) Pine, S. H. Org. React. 1970, 18, 403−464. (e) Oae, S.; Ogino, K.
Heterocycles 1977, 6, 583−675. (f) Hoffmann, R. W. Angew. Chem., Int.
Ed. 1979, 18, 563−572. (g) Bruckner, R. In Comprehensive Organic
̈
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York,
́
1991; Vol. 6, pp 873−908. (h) Marko, I. E. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York,
1991; Vol. 3, pp 913−974. (i) Albini, A. Synthesis 1993, 263−277.
(j) Sweeney, J. B. Chem. Soc. Rev. 2009, 38, 1027−1038.
(10) (a) Behrman, E. J. Org. React. 1988, 35, 421−511. (b) Behrman, E.
J. Beilstein J. Org. Chem. 2006, 2 (22).
(11) (a) Behrman, E. J. J. Org. Chem. 1992, 57, 2266−2270.
(b) Edward, J. T.; Whiting, J. Can. J. Chem. 1971, 49, 3502−3514.
(12) (a) Huisgen, R.; Bayerlin, F.; Hegkamp, W. Chem. Ber. 1959, 92,
3223−3241. (b) Oae, S.; Asai, N.; Fujimori, K. Bull. Chem. Soc. Jpn.
1979, 52, 2409−2412. (c) Oae, S.; Kitao, T.; Kitaoka, Y. J. Am. Chem.
Soc. 1962, 84, 3366−3369. (d) Oae, S.; Ogino, K. Heterocycles 1977, 6,
583−675.
(13) (a) Taylor, G. A. J. Chem. Soc., Perkin Trans. 1 1979, 376−378.
(b) Sheradsky, T.; Nov, E. J. Chem. Soc., Perkin Trans 1 1983, 527−529.
(14) The arylation of aniline N-oxides under the influence of
trifluoromethanesulfonic acid in benzene has also been described
(presumably via intermediacy of dicationic intermediates). See: Shudo,
K.; Ohta, T.; Endo, Y.; Okamoto, T. Tetrahedron Lett. 1977, 18, 105−
108.
(15) Wojciechowski, K. Eur. J. Org. Chem. 2001, 3587−3605.
D
dx.doi.org/10.1021/ol501813s | Org. Lett. XXXX, XXX, XXX−XXX