Organocatalytic, oxidative, intermolecular amination and hydrazination of simple arenes at ambient temperature

Article abstract of DOI:10.1021/ol302607y

New atom-economical, environmental friendly, direct oxidative intermolecular processes of amination and hydrazination of nonprefunctionalized arenes were developed. The products were formed in a good regioselective manner under organocatalytic conditions

Full text of DOI:10.1021/ol302607y

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Organocatalytic, Oxidative, Intermolecular
Amination and Hydrazination of Simple
Arenes at Ambient Temperature
Rajarshi Samanta,† Jonathan O. Bauer,‡ Carsten Strohmann,‡ and
Andrey P. Antonchick*,†
Max-Planck-Institut fu€r Molekulare Physiologie, Abteilung Chemische Biologie,
€
Otto-Hahn-Strasse 11, 44227 Dortmund, Germany, and Technische Universitat Dortmund,
Fakultat Chemie, Anorganische Chemie, Otto-Hahn-Strasse 6, 44221 Dortmund, Germany
€
andrey.antonchick@mpi-dortmund.mpg.de
Received September 21, 2012
ABSTRACT
New atom-economical, environmental friendly, direct oxidative intermolecular processes of amination and hydrazination of nonprefunctionalized
arenes were developed. The products were formed in a good regioselective manner under organocatalytic conditions at ambient temperature.
Efficient environmentally benign methods for product
synthesis from easily available feedstock are in great
demand. Over the past decades, varieties of processes
have been developed for the coupling of prefunction-
alized building blocks in high yields and with predictable
regioselectivity.1,2 The development of direct methods of
CÀH bond functionalization provided a powerful tool for
organic synthesis. Despite the tremendous progress in
transition metal catalyzed CÀH bond functionalization,
significant challenges still remain. In order to enhance the
utility of CÀH bond functionalization, the development of
methods that proceed at ambient temperature devoid of
transition metal catalysts and metal containing oxidants
are highly desired.2 Metal-free, moreover organocatalytic
methods of direct CÀH functionalization are very bene-
ficial. The development of mild methods of oxidative
cross-coupling of nonfunctionalized arenes is highly de-
manded. Herein, we report the development of an oxida-
tive, environmentally benign method of amination and
hydrazination of nonprefunctionalized arenes at ambient
temperature under organocatalytic reaction conditions.3
Intermolecular amination of arenes is of immense inter-
est due to the prevalence of CÀN bonds in pharmaceuticals
and natural products. The catalytic methods reported so far
for intermolecular amination are based predominantly on
transition metal catalysis.4 Activated systems such as azoles
or polyfluorinated systems have been studied extensively.5
There are only a handful of examples reported in the litera-
ture for the transition metal catalyzed directed amination of
nonfunctionalized arenes.6 Synthetic strategies that afford
the direct, atom economic formation of CÀN bonds from
unactivated substrates are highly desired.
† Max-Planck-Institut f€ur Molekulare Physiologie
‡
€
Technische Universitat Dortmund
(1) For recent reviews on CÀH functionalization, see (a) Yeung,
C. S.; Dong, M. Chem. Rev. 2011, 111, 1215. (b) Cho, S. H.; Kim, J. Y.;
Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (c) Yoo, W. J.; Li,
C. J. Top. Curr. Chem. 2010, 292, 281. (d) Bouffard, J.; Itami, K. Top.
Curr. Chem. 2010, 292, 231. (e) Ashenhurst, J. A. Chem. Soc. Rev. 2010,
39, 540. (f) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (g)
Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624.
(h) Davies, H. M. L.; Bois, J. D.; Yu, J. Q. Chem. Soc. Rev. 2011, 40,
1855.
€
(2) (a) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc.
Rev. 2011, 40, 4740. (b) Klussmann, M.; Sureshkumar, D. Synthesis
2011, 353.
(3) For the results of our group on CÀH functionalization, see: (a)
Antonchick, A. P.; Samanta, R.; Kulikov, K.; Lategahn, J. Angew.
Chem., Int. Ed. 2011, 50, 8605. (b) Samanta, R.; Lategahn, J.; Antonchick,
A. P. Chem. Commun. 2012, 48, 3194. (c) Samanta, R.; Kulikov, K.;
Strohmann, C.; Antonchick, A. P. Synthesis 2012, 44, 2325. (d) Samanta,
R.; Antonchick, A. P. Angew. Chem., Int. Ed. 2011, 50, 5217.
(4) For recent reviews, see: (a) Zhang, M.; Zhang, A. Q. Synthesis 2012,
44, 1. (b) Matsuda, N.; Hirano, K.;Satoh, T.;Miura, M.Synthesis 2012, 44,
1792. (c) Zhang, M. Synthesis 2011, 3408. (d) Barker, T. J.; Jarvo, E. R.
Synthesis 2011, 3954. (e) Samanta, R.; Antonchick, A. P. Synlett 2012, 23,
809. (f) Zalatan, D. N.; Du Bois, J. Top. Curr. Chem. 2010, 292, 347.
(g) Stokes, B. J.; Driver, T. G. Eur. J. Org. Chem. 2011, 4071.
r
10.1021/ol302607y
XXXX American Chemical Society

Recently, we developed an intermolecular, metal-free,
direct oxidative method of CÀN bond formation via cross-
coupling of nonprefunctionalized arenes mediated by a
hypervalent iodine7 reagent.3a The products were ob-
tained regioselectively at ambient temperature. Neverthe-
less, electron-poor arenes were not reactive under the
developed reaction conditions. Simultaneously, Chang
et al.8a and DeBoef et al.8b reported similar transformation
using the same reagent. Interestingly, conducting the reac-
tion at higher temperature allowed functionalization of
electron poor arenes. The application of higher tempera-
ture required increased amounts of reagent due to low
thermostability of (diacetoxy)iodobenzene and resulted
in nonregioselective formation of aminated products.
Inspired by the possibilty of functionalization of CÀH
bonds under metal-free conditions via cross-amination,
we were motivated to develop mild organocatalytic
conditions.9 We envisaged that application of nitrenium
Table 1. Optimization of the Organocatalytic Cross Aminationa
entry
ArI (mol %)
PhI (20)
solvent time [h] yield [%]b
o:pc
1
CHCl3
6
62
71
50
82
76
62
76
69
93
50
62
nd
5:1
3:1
2
4-MeC6H4I (20) CHCl3
4
3
4-FC6H4I (20)
3 (10)
CHCl3
CHCl3
CH2Cl2
CCl4
7
4:1
4
3
2.5:1
3:1
5
3 (10)
3.5
3.5
3.5
2
6
3 (10)
3:1
7
3 (10)
DCE
6:1
8d
9e
10d,f
11d,g
3 (10)
DCE
DCE
6:1
3 (10)
7
3.5:1
5:1
3 (10)
DCE
4
3 (10)
DCE
4
6:1
12d,h 3 (10)
DCE
3
nd
(5) (a) Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A. Org.
Lett. 2009, 11, 1607. (b) Wang, Q.; Schreiber, S. L. Org. Lett. 2009, 11,
5178. (c) Cho, S. H.; Kim, J. Y.; Lee, S. Y.; Chang, S. Angew. Chem., Int.
Ed. 2009, 48, 9127. (d) Kim, J. Y.; Cho, S. H.; Joseph, J.; Chang, S.
Angew. Chem., Int. Ed. 2010, 49, 9899. (e) Kawano, T.; Hirano, K.;
Satoh, T.; Miura, M. J. Am. Chem. Soc. 2010, 132, 6900. (f) Zhao, H.;
Wang, M.; Su, W.; Hong, M. Adv. Synth. Catal. 2010, 352, 1301. (g)
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R.; Jin, K.; Wang, X.; Duan, C. Org. Biomol. Chem. 2012, 10, 3715. For
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Froehr, T.; Sindlinger, C. P.; Kloeckner, U.; Finkbeiner, P.;
Nachtsheim, B. J. Org. Lett. 2011, 13, 3754. (m) Lamani, M.; Prabhu,
K. R. J. Org. Chem. 2011, 76, 7938. (n) Wertz, S.; Kodama, S.; Studer, A.
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128, 9048. (b) Ng, K.-H.; Chan, A. S. C.; Yu, W.-Y. J. Am. Chem. Soc.
2010, 132, 12862. (c) Xiao, B.; Gong, T.-J.; Xu, J.; Liu, Z.-J.; Liu, L.
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Mei, T.-S.; Chan, K. S. L.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 7652. (f)
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a Conditions: 1a (1 equiv), anisole (10 equiv), ArI, AcOOH (2.2
equiv), trifluoroacetic acid (5 equiv) in solvent (0.2 M). b Isolated yields.
c Ratio measured by 1H NMR d Anisole (2 equiv) was used. e Reaction
conducted at 0 °C. f CF3CO2H used (2.5 equiv). g AcOOH used (3 equiv).
h Without CF3CO2H. Bz = benzoyl group, DCE = 1,2 dichloroethane,
nd = not determined.
cations stabilized by a heteroatom could provide an
access to cross-amination.10,11 The stabilized nitrenium
ions could be obtained under catalytic conditions using
aryliodide as catalyst. The reactive iodine(III) species
would be generated by in situ oxidation of aryl iodide
with peracetic acid.12,13 Herein, we describe the realiza-
tion of CÀH bond functionalization of arenes under
organocatalytic conditions.
We began our studies using N-methoxybenzamide (1a)
as amination reagent for the functionalization of anisole
(Table 1). A variety of aryl iodides were screened in
presence of peracetic and trifluoroacetic acid in order to
obtain the desired product (2a) in good yield and regio-
selectivity (Table 1, entries 1À4). The application of sub-
stoichiometric amounts of iodobenzene provided the tar-
get product in 62% yield with the major ortho regioisomer
over the corresponding para regioisomer in 5:1 ratio
(Table 1, entry 1). Electron rich 4-iodotoluene provided a
slightly better yield compared to iodobenzene, whereas
(7) For reviews on iodine (III), see: (a) Ochiai, M. Chem. Rec. 2007, 7,
12. (b) Zhdankin, V. V. ARKIVOC 2009, No. i, 1. (c) Uyanik, M.;
Ishihara, K. Chem. Commun. 2009, 2086. (d) Tohma, H.; Kita, Y. Adv.
Synth. Catal. 2004, 346, 111. (e) Dohi, T.; Ito, M.; Yamaoka, N.;
Morimoto, K.; Fujioka, H.; Kita, Y. Tetrahedron 2009, 65, 10797. (f)
Wirth, T. Angew. Chem., Int. Ed. 2005, 44, 3656. (g) Brand, J. P.;
ꢀ
Gonzalez, D. F.; Nicolai, S.; Waser, J. Chem. Commun. 2011, 47, 102.
(h) Silva, L. F., Jr.; Olofsson, B. Nat. Prod. Rep. 2011, 28, 1722. (i)
Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299. (j) Quideau, S.;
Pouysegu, L.; Deffieux, D. Synlett 2008, 467. (k) Ciufolini, M. A.;
Braun, N. A.; Canesi, S.; Ousmer, M.; Chang, J.; Chai, D. Synthesis
2007, 3759.
(8) (a) Kim, H. J.; Kim, J.; Cho, S. H.; Chang, S. J. Am. Chem. Soc.
2011, 133, 16382. (b) Kantak, A. A.; Potavathri, S.; Barham, R. A.;
Romano, K. M.; DeBoef, B. L. J. Am. Chem. Soc. 2011, 133, 19960.
(9) For selected application of iodine (III) in formation of CÀN
bonds, see: (a) Dohi, T.; Maruyama, A.; Minamitsuji, Y.; Takenaga, N.;
Kita, Y. Chem. Commun. 2007, 1224. (b) Farid, U.; Wirth, T. Angew.
Chem., Int. Ed. 2012, 51, 3462. (c) Wardrop, D. J.; Bowen, E. G.;
Forslund, R. E.; Sussman, A. D.; Weerasekera, S. L. J. Am. Chem. Soc.
2010, 132, 1188. (d) Lovick, H. M.; Michael, F. E. J. Am. Chem. Soc.
(11) For selected reports on transfomations of stabilized nitrenium
ions, see: (a) Wardrop, D. J.; Bowen, E. G. Org. Lett. 2011, 13, 2376. (b)
Bowen, E. G.; Wardrop, D. J. Org. Lett. 2010, 12, 5330. (c) Murata, K.;
Tsukamoto, M.; Sakamoto, T.; Saito, S.; Kikugawa, Y. Synthesis 2008,
32. (d) Nagashima, A.; Sakamoto, T.; Kikugawa, Y. Heterocycles 2007,
74, 273. (e) Kikugawa, Y.; Nagashima, A.; Sakamoto, T.; Miyazawa, E.;
Shiiya, M. J. Org. Chem. 2003, 68, 6739. (f) Wardrop, D. J.; Basak, A.
Org. Lett. 2001, 3, 1053. (g) Kikugawa, Y.; Shimada, M.; Matsumoto,
K. Heterocycles 1994, 37, 293. (h) Kikugawa, Y.; Kawase, M. Chem.
Lett. 1990, 581. (i) Kikugawa, Y.; Kawase, M. J. Am. Chem. Soc. 1984,
106, 5728. (j) Glover, S. A.; Goosen, A.; McCleland, C. W.; Schoonraad,
J. L. J. Chem. Soc., Perkin Trans. 1 1984, 2255. (k) Wardrop, D. J.;
Bowen, E. G.; Forslund, R. E.; Sussman, A. D.; Weerasekera, S. L.
J. Am. Chem. Soc. 2010, 132, 1188. (l) Krasnova, L. B.; Hili, R. M.;
Chernoloz, O. V.; Yudin, A. K. ARKIVOC 2005, No. iv, 26. (m)
Zibinsky, M.; Stewart, T.; Surya Prakash, G. K.; Kuznetsov, M. A.
Eur. J. Org. Chem. 2009, 21, 3635.
~
2010, 132, 1249. (e) Souto, J. A.; Zian, D.; Muniz, K. J. Am. Chem. Soc.
€
ꢀ
2012, 134, 7242. (f) Roben, C.; Souto, J. A.; Gonzalez, Y.; Lishchynskyi,
~
A.; Muniz, K. Angew. Chem., Int. Ed. 2011, 50, 9478. (g) Yoshimura, A.;
Middleton, K. R.; Zhu, C.; Nemykin, V. N.; Zhdankin, V. V. Angew.
Chem., Int. Ed. 2012, 51, 8059.
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Chem. 2001, 36, 167.
B
Org. Lett., Vol. XX, No. XX, XXXX

electron poor iodoarenes such as 4-fluoroiodobenzene led
to formation of 2a in lower yield (Table 1, entries 2, 3). To
our delight, we found that iodoarene 312 catalyzed the
intermolecular amination at lower catalyst loading, result-
ing in shorter reaction time and better yield of 2a (Table 1,
entry 4). It is notable that successful intermolecular trans-
formations using catalyst 3 have never been described to
the best of our knowledge. Afterward, various solvents
were tested (Table 1, entries 4À7). We could increase the
regioselectivity of 2a toward ortho over para in 6:1 ratio by
optimization of the solvent (Table 1, entry 7). Notably, use
of THF, MeCN, MeNO2, MeOH was not successful.
Gratifyingly, substantial decrease of arene amount to
2 equiv led to the desired product in impressive yield
(69%) with the same regioselectivity (Table 1, entry 8).
When the reaction was performed at 0 °C, 2a was obtained
with a better yield (93%) but regioselectivity was reduced
(Table 1, entry 9). Decrease of trifluoroacetic acid amount
or increase of peracetic acid amount provided the product
in lower yield (Table 1, entries 10, 11). The formation of the
desired product was not observed in absence of trifluo-
roacetic acid (Table 1, entry 12). With exception of trifluo-
roacetic acid, utilization of other additives such as triflic
acid, boron trifluoride, trimethylsilyl triflate did not pro-
vide the desired product.
After optimizing the method for the organocatalytic,
oxidative intermolecular amination at ambient tempera-
ture, we focused on the exploration of the scope and
generality of the method. At first, benzene and monosub-
stituted benzene derivatives were examined (Scheme 1,
products 2bÀ2g). We were pleased to find that simple
benzene also can be aminated in this process with 86%
yield (Scheme 1, product 2b). Even electron poor arenes
like chlorobenzene, fluorobenzene were functionalized
using this developed mild method with modest yield
and para-regioselectivity (Scheme 1, product 2c, 2d). The
application of electron-rich arenes led to a yield of up
to 93% (Scheme 1, product 2e). Notably, replacement of
the methyl group to pivaloyl at the oxygen atom of phenol
led to a switch in regioselectivity of amination (Table 1,
entry 8 and Scheme 1, product 2g). Polysubstituted ben-
zene derivatives smoothly react giving desired products in
59À96% yield (Scheme 1, products 2hÀ2l). Afterward,
having in hand a wide range of aminated arenes with
N-methoxy benzamide, we tested various amination re-
agents (Scheme 1, products 2mÀ2r). In general, we found
that the presence of substituents with different electronic
and steric properties did not have exceptional effect on
Scheme 1. Scope of Amination of Arenes
Reaction conditions: 1a (1 equiv), arene (20 equiv), 3 (10 mol %),
AcOOH (2.2 equiv), CF3CO2H (5 equiv), in DCE (0.2 M). Yields are given
for isolated products after column chromatography. Newly formed bonds
are shown in bold. aArene (2 equiv) used. bThe minor regioisomeric position
is labeled with the respective carbon atom number. Ratio of regioisomeric
products was measured by weight of isolated product.
the formation of intermolecular CÀN bonds. Finally, the
developed organocatalytic protocol allows functional-
ization of arenes by amino acid derivatives in modest
yield (Scheme 1, product 2r). It is notable that only products
of monoamination were selectively obtained under the
developed reaction conditions. The obtained N-methoxy-
N-phenylbenzamide derivatives 2 represent a common scaf-
fold for bioactive compounds and useful products for the
synthesis of nitrogen-containing derivatives (see the Sup-
porting Information for details).
After successful development of the intermolecular ami-
nation process, we looked for organocatalytic hydrazination
of nonprefunctionalized arenes. Notably, intermolecular
cross-coupling of hydrazine derivatives and nonprefunc-
tionalized arenes had not been reported earlier to the
best of our knowledge. We were pleased to find that in
an initial test reaction under the developed organocatalytic
conditions, the N-(1,3-dioxoisoindolin-2-yl)acetamide (4)
reacted smoothly with benzene to give the cross hydra-
zinated product at ambient temperature in 92% yield
(Scheme 2, product 5a). Afterward, we focused on inves-
tigation of the generality of the discovered organocatalytic
cross-hydrazination. Cross hydrazination worked uninter-
ruptedly with monosubstituted benzenes in good to ex-
cellent yields (Scheme 2, product 5bÀ5l). The sterically
bulky reagent 4 forced the para selectivity during organo-
catalytic hydrazination. The yield and regioselectivity of
para-isomers were increased from fluorobenzene to iodo-
benzene (Scheme 2, products 5fÀ5i). Arenes that are
challenging and sensitive to nucleophiles, such as N-phenyl
succinimides, were functionalized under organocatalytic
(12) For selected organocatalytic application of iodoarenes, see: (a)
Dohi, T.; Maruyama, A.; Yoshimura, M.; Morimoto, K.; Tohma, H.;
Kita, Y. Angew. Chem., Int. Ed. 2005, 44, 6193. (b) Ochiai, M.; Takeuchi,
Y.; Katayama, T.; Sueda, T.; Miyamoto, K. J. Am. Chem. Soc. 2005,
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Ed. 2010, 49, 2175. (d) Ngatimin, M.; Frey, R.; Andrews, C.; Lupton,
D. W.; Hutt, O. E. Chem. Commun. 2011, 47, 11778. (e) Zhong, W.; Liu,
S.; Yang, J.; Meng, X.; Li, Z. Org. Lett. 2012, 14, 3336.
(13) (a) Dohi, T.; Takenaga, N.; Fukushima, K.; Uchiyama, T.;
Kato, D.; Shiro, M.; Fujioka, H.; Kita, Y. Chem. Commun. 2010, 46,
7697. (b) Dohi, T.; Kita, Y. Chem. Commun. 2009, 2073. (c) Dohi, T.;
Nakae, T.; Ishikado, Y.; Kato, D.; Kita, Y. Org. Biomol. Chem. 2011, 9,
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Y. Angew. Chem., Int. Ed. 2011, 50, 3784.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Scope of Hydrazination of Arenes
Scheme 3. Proposed Catalytic Cycle
There was no detection of meta-substituted products
besides ortho- and para-isomers. Reaction rate is excep-
tionallyfasterforelectronricharenescomparedtoelectron
deficient arenes. A primary kinetic isotope effect is equal
1.0 and indicates that CÀH bond cleavage does not occur
as the rate-determining step of the reaction (see the Sup-
porting Information for details). On the basis of these
findings, mechanistically we assume that initially aryl iodide
3 is oxidized by peracetic acid to the active hypervalent
μ-oxo-bridged 6. The ligand substitution at iodine(III) by 1
or 4 generates species 7, which undergoes oxidative frag-
mentation to form nitrenium ion 8 and active hypervalent
species 9, which further converted to 6 under the reaction
conditions. Then the arene attacks the electron-deficient
nitrenium ion 8 to provide the desired products 2 or 5.
In conclusion, we developed a new highly efficient, mild,
atom-economical, oxidative intermolecular process for the
introduction of amine or hydrazine groups into nonpre-
functionalized arenes. Intermolecular formations of CÀN
bonds occur in the presence of substoichiometric amounts
of small organic molecules. The desired products of mono-
amination and hydrazination were selectively formed by the
functionalization of arenes at ambient temperature. The
developed method was utilized for arenes and for the late
stage functionalization of biologically active molecules.
Reaction conditions: 4 (1 equiv), arene (20 equiv), 3 (10 mol %),
AcOOH (2.2 equiv), CF3CO2H (5 equiv), in DCE (0.2 M). Yields are
given for isolated products after chromatography. The minor regioiso-
meric position is labeled with the respective carbon atom number.
aArenes used (2 equiv). bRatio of regioisomeric products was measured
c
by weight of individual isolated products. Ratio of inseparable regio-
1
isomeric products measured by H NMR of isolated products. dArene
used (5 equiv). eReaction conditions: arene (1 equiv), 4 (3 equiv), 3
(10 mol %), AcOOH (2.2 equiv), CF3CO2H (5 equiv), in DCE (0.2 M).
conditions in good yields and exclusive regioselectivity
(Scheme 2, products 5k, 5l). Polysubstituted arenes effi-
ciently hydrazinated under the developed reaction condi-
tions with high selectivity and good to excellent yields
(Scheme 2, products 5mÀ5r). To our delight, a variety of
functional groups such as carboxylic acids, iodides, amides
and ethers were tolerated. As an illustration of the syn-
thetic versatility of the organocatalytic method, we next
demonstrated hydrazination of functionalized biologically
active probes. Using excess of reagent 4, a hydrazinated
analogue of vitamin P was obtained as single regioisomer
with 92% yield (Scheme 2, product 5s). A competitive
hydrazination was observed in the case of ibuprofen
analogue with satisfactory yield (Scheme 2, product 5t).
Future transformations of hydrazination products 5 are
possible to various derivatives of anilines and arylhydra-
zines under mild reaction conditions (see the Supporting
Information for details).
Acknowledgment. We gratefully acknowledge Prof.
€
Dr. H. Waldmann (MPI fur Molekulare Physiologie
and TU Dortmund) for his generous support, and J.O.B.
thanks the Fonds der Chemischen Industrie for a fellowship.
Supporting Information Available. Experimental pro-
cedures, full characterization of new compounds, CIF file
for compound 5s, and copies of 1H and 13C NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX