Organocatalytic, oxidative, intramolecular C-H bond amination and metal-free cross-amination of unactivated arenes at ambient temperature

Article abstract of DOI:10.1002/anie.201102984

The twinkling of an I: In a new atom-economical and environmentally friendly organocatalytic method for intramolecular C-H amination, the C-N bond forms at ambient temperature by abstraction of two atoms of hydrogen; only acetic acid and water are formed

Full text of DOI:10.1002/anie.201102984

DOI: 10.1002/anie.201102984
À
C H Functionalization
À
Organocatalytic, Oxidative, Intramolecular C H Bond Amination and
Metal-free Cross-Amination of Unactivated Arenes at Ambient
Temperature**
Andrey P. Antonchick,* Rajarshi Samanta, Katharina Kulikov, and Jonas Lategahn
Table 1: Optimization of the reaction conditions.[a]
The importance and value of nitrogen-containing compounds
stem from their wide occurrence in nature and broad
application in chemistry, biology, and material sciences.[1]
The development of effective methods for the formation of
À
C N bonds is an intensively investigated area of great
significance.[2] In recent work, researchers have focused on
milder versions of the Ullmann reaction and the application
of substoichiometric amounts of metals.[3] A breakthrough in
this area was the development of the Pd-catalyzed Buchwald–
Entry
PG
Solvent
c [m]
t [h]
Yield [%][b]
1
2
3
4
5
6
7
8
Ac
Ac
Ac
Ac
Ac
Ac
H
Bz
Bn
Tos
Tos
Ac
Ac
CH2Cl2
MeOH
MeCN
MeNO2
CF3CH2OH
HFIP
HFIP
HFIP
HFIP
HFIP
0.10
0.10
0.10
0.10
0.10
0.10
0.15
0.15
0.15
0.15
0.05
0.05
0.05
72
72
72
72
4.5
1.25
12
3
12
4
12
12
16
9
n.d.
9
Hartwig amination of aryl halides.[4] In recent reports C N
À
12
41
66
n.d.
47
n.d.
62
68
81
19
À
bonds are formed through direct C H activation using
transition-metal catalysis.[5] However, these reports are lim-
ited to intramolecular processes. Very recently, a new metal-
free approach has been developed for intramolecular, oxida-
À
tive C N bond formation using stoichiometric amounts of a
9
10
11
12
13[c]
hypervalent iodine(III) compound as the oxidant; in the
absence of metal this method had lower efficiency.[6] We
herein report our preliminary results on an atom-economical,
environmentally friendly organocatalytic method for the
HFIP
HFIP
HFIP
[a] Conditions: (diacetoxy)iodobenzene (1.1 equiv) in solvent.
À
preparation of carbazoles through C N bond formation and
PG=protecting group, HFIP=1,1,1,3,3,3-hexafluoro-2-propanol.
[b] Yield of isolated product after column chromatography; n.d.=not
detected. [c] Phenyliodine bis(trifluoroacetate) (1.1 equiv) was used as
the oxidant.
the unprecedented first cross-amination of non-prefunction-
alized arenes which was performed under metal-free con-
ditions.[7]
We began our studies by testing the conversion of 2-
acetaminobiphenyl to N-acetylcarbazole using (diacetoxy)io-
dobenzene as an oxidation reagent at room temperature
(Table 1).[8,9] Preliminary attempts led to the formation of the
desired acyl carbazole in low yield (Table 1, entry 1). In
subsequent solvent screening we found that the yield of direct
amination was higher in polar nonnucleophilic solvents, and
the best results were obtained in hexafluoro-2-propanol
(Table 1, entries 2–6).
We then optimized the protecting groups on 2-amino-
biphenyl, along with the concentration of the substrate and
the oxidant (Table 1, entries 7–13). Application of unpro-
tected or alkyl-protected 2-aminobiphenyl in the amination
under the described reaction conditions was not successful.
Besides 2-acetaminobiphenyl, 2-toluenesulfonamide biphenyl
also reacts to give the corresponding product in good yield.
The yield of the product could be improved to 81% by
dilution of the reaction mixture (Table 1, entry 12). Interest-
ingly, replacement of (diacetoxy)iodobenzene by phenyl-
iodine bis(trifluoroacetate) led to a dramatic drop in yield to
19%. Application of a variety of oxidants based on hyper-
valent iodine (e.g. Koserꢀs reagent, 2-iodoxybenzoic acid,
Dess–Martin periodinane) did not lead to product formation.
After we had optimized the reaction conditions, we
focused on the development of organocatalytic condi-
tions.[9,10] Since stoichiometric use of (diacetoxy)iodobenzene
results in co-production of an equimolar amount of PhI, a
catalytic procedure would be achieved by in situ oxidation of
iodo(I)arenes to iodine(III) species. Indeed, use of substoi-
chiometric amounts of PhI in the presence of an oxidant such
as meta-chloroperbenzoic acid (mCPBA) provided the target
product in 51% yield (Table 2, entry 1). A similar result was
obtained using peracetic acid as an atom-economical and
environmentally friendly oxidant (Table 2, entry 2). Many
iodine-containing substances were screened in order to
improve the yield of the carbazole and to reduce the loading
of the catalyst (Table 2, entries 3–11). Besides 4-iodoanisole,
substituted iodobenzenes provided access to carbazole 2a in
41–55% yield at a catalyst loading of 25 mol%. Application
of iodoalkane or ionic species was not successful. To our
[*] Dr. A. P. Antonchick, Dr. R. Samanta, K. Kulikov, J. Lategahn
Max-Planck-Institut fꢀr Molekulare Physiologie
Abteilung Chemische Biologie
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
E-mail: andrey.antonchick@mpi-dortmund.mpg.de
[**] We thank Prof. Dr. H. Waldmann for his generous support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102984.
Angew. Chem. Int. Ed. 2011, 50, 8605 –8608
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8605

Communications
Table 2: Optimization of the organocatalytic reaction conditions.[a]
Entry
RI
RI [mol%]
t [h]
Yield [%][b]
1[c]
2
3
4
5
6
7
8
9
10
11
12[d]
13[d,e]
14[d,e]
15[d,e]
PhI
PhI
4-MeC6H4I
3,5-Me2C6H3I
4-MeOC6H4I
4-FC6H4I
4-IC6H4I
nBuI
nBu4NI
NIS
3
3
3
25
25
25
25
25
25
25
25
25
25
10
10
10
5
15
16
16
16
16
16
16
24
45
45
8
51
52
55
55
<10
48
41
traces
<20
traces
63
8
8
16
30
76
77
71
56
3
3
2
[a] Conditions: RI (2–25 mol%), AcOOH (2.2 equiv), HFIP (0.05m).
NIS=N-iodosuccinimide. [b] Yield of isolated product after column
chromatography. [c] mCPBA (2.2 equiv) was used. [d] Solvent: CH2Cl2/
HFIP (1:1). [e] AcOOH (2.0 equiv) was used.
delight, we found that 2,2’-diiodo-4,4’,6,6’-tetramethylbi-
phenyl (3), which was obtained in one step by oxidative
dimerization[10e,11] of 1-iodo-3,5-dimethylbenzene, catalyzes
the intramolecular amination at an even lower catalyst
loadings, resulting in a shorter reaction time and a better
yield of 2a (Table 2, entry 11). Furthermore, we could
increase the yield of 2a to 77% by optimization of the
solvent and the amount of the oxidation reagent (Table 2,
entry 13). A further decrease in the catalyst loading resulted
in lower product yields. However, it is impressive that
2 mol% of simple, cheap, and easily accessible organic
À
Scheme 1. Scope of organocatalytic C H bond amination. Conditions:
acetaminobiphenyl (1a–1r), 3 (10 mol%), AcOOH (2.0 equiv), in
CH2Cl2/HFIP (1:1; 0.05m). Yields are given for isolated products after
À
column chromatography. Newly formed C N bonds are shown in bold.
À
substance is sufficient to catalyze intramolecular C H
[a] Using 3 (20 mol%); additional AcOOH (2.0 equiv) was added after
36 h and the reaction was complete after 40 h. [b] Isomer ratio is 7:1
by 1H NMR analysis; structure and yield given for the isolated major
regioisomer.
amination at room temperature (Table 2, entry 15). The by-
products of the developed methodology are just acetic acid
and water. The desired carbazole was not formed in the
absence of catalyst.[12]
With the optimized reaction conditions in hand, we then
explored the scope and generality of the method. We first
examined the effect of substituents in the aniline part of 2-
acetaminobiphenyl (Scheme 1, products 2a–2i). In general,
we found that the presence of substituents with different
electronic and steric properties in various positions did not
have an effect on the formation of the carbazole. However,
the reaction of 2-acetamino-3-benzoylbiphenyl required
higher catalyst loading and additional peracetic acid
(Scheme 1, product 2i). Afterwards, we examined the sub-
stituents in the phenyl part of 2-acetaminobiphenyl
(Scheme 1, products 2j–2r). To our delight, various groups
with different electronic properties are tolerated and the
developed methodology could be used to construct unsym-
metrically, polysubstituted carbazoles. In the case where two
regioisomers could be formed (Scheme 1, product 2l), one
product was obtained with good selectivity.
After the development of intramolecular organocatalytic
C H bond amination, we focused on the intermolecular
version of this reaction. Interestingly, intermolecular amina-
tion had not been reported previously; the corresponding
transition-metal-catalyzed reactions of aniline derivatives
À
À
with unactivated arenes led to the formation of C C bonds
À
through C H activation.
In preliminary experiments we tested metal-free condi-
tions using stoichiometric amounts of hypervalent iodine(III).
We were pleased to find that in the test reaction 2H-1,4-
benzoxazin-3(4H)-one reacts smoothly with mesitylene to
give the cross-amination product at room temperature
(Scheme 2, product 6a). However, our subsequent attempts
to develop organocatalytic transformations using various aryl
iodides and oxidation reagents were unsuccessful. Applica-
tion of 10 mol% of 3 in the presence of AcOOH led to the
8606 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 8605 –8608

Scheme 3. Proposed catalytic cycle.
Information). Application of 2,6-di-tert-butyl-4-methylphenol
as a radical scavenger was unsuccessful because in a control
experiment the radical trap reacted with (diacetoxy)iodoben-
zene. However, we found that N-tert-butyl-a-phenylnitrone
can be used as a radical scavenger in the presence of
iodine(III), and it does not affect the formation of the desired
intra- and intermolecular products. This finding indicates that
À
radical species do not play a role in the C H amination. Based
on these results, we believe that the reaction proceeds as
follows (Scheme 4). Initially (diacetoxy)iodobenzene reacts
with the amide to give intermediate 8, which is then trans-
formed into nitrenium ion 9 through an oxidative process. The
nucleophilic arene attacks the electron-deficient nitrenium
ion 9 to give the desired product.
Scheme 2. Scope of metal-free cross-amination. Conditions: acetani-
line 4 (1 equiv), arene 5 (2 equiv), (diacetoxy)iodobenzene (1.5 equiv),
0.10m HFIP. Yields are given for isolated products after column
À
chromatography. Newly formed C N bonds are shown in bold. [a] 2-
Oxindole (10 mmol), ortho-xylene (5 equiv) (diacetoxy)iodobenzene
(1.5 equiv), HFIP (0.5m), 1 h.
formation of trace amounts of the product (6a) and after 20 h
the starting material was recovered in 95% yield. Further-
more, with stoichiometric amounts of aryl iodide 3, 6a was
obtained in 32% yield and the starting material was isolated
in 64% yield. Therefore, we focused on investigating the
generality of the discovered metal-free cross-amination using
stoichiometric amounts of (diacetoxy)iodobenzene. Once
again, numerous aniline derivatives having different elec-
tronic and steric properties were tolerated (Scheme 2). Addi-
tionally, diverse mono- and polysubstituted unactivated
arenes underwent the desired transformation without the
use of a large excess. Unfortunately, arenes bearing electron-
withdrawing groups were not reactive. Interestingly, product
6 f, from the cross-amination with meta-xylene, was formed as
single regioisomer.
Finally, we performed experiments on a larger scale to
demonstrate the practicability of the developed methodology.
Applying 5 mmol of 1a and lowering the organocatalyst
loading to 5 mol%, we obtained the desired carbazole (2a) in
75% yield. Additionally, 92% of the catalyst (3) was
recovered from the reaction. Moreover, we performed the
cross-amination of 2-oxindole with ortho-xylene at high
concentrations. The desired product, N-aryl-2-oxindole (6h),
was isolated as a single regioisomer (Scheme 2, product 6h).
Mechanistically, we assume that aryl iodide 3 is oxidized
by peracetic acid to generate the active form of the catalyst, 7,
which facilitates the amination of 1 to give the desired product
2 (Scheme 3). The structure of the m-oxo-bridged reactive
hypervalent iodine(III) species 7 was confirmed in a control
experiment (see the Supporting Information). Furthermore
product 2a was obtained from 1a in 90% yield when a
stoichiometric amount of 7 was used (see the Supporting
À
Scheme 4. Proposed mechanism of C H bond amination. PIDA=(dia-
cetoxy)iodobenzene.
In conclusion, we have developed a highly efficient, atom-
economical, environmentally friendly organocatalytic method
for the preparation of carbazoles through intramolecular C
À
H amination. Our method can be used to synthesize various
carbazoles without any additives such as bases, acids, tran-
sition metals, and alkali metals. Since the desired products
form smoothly at ambient temperature, the reaction mixture
must not be cooled or heated, which would require additional
energy. Moreover, the developed methodology has been
extended to the unprecedented metal-free cross-amination of
nonactivated arenes with various aniline derivatives. Further
work is in progress.
Received: April 30, 2011
Revised: May 25, 2011
Published online: July 26, 2011
À
Keywords: amination · C H functionalization ·
hypervalent compounds · iodine · organocatalysis
.
[1] a) T. Henkel, R. M. Brunne, H. Muller, F. Reichel, Angew.
Chem. 1999, 111, 688 – 691; Angew. Chem. Int. Ed. 1999, 38, 643 –
647; b) F. Fache, E. Schulz, M. L. Tommasino, M. Lemaire,
Chem. Rev. 2000, 100, 2159 – 2231; c) M. Feher, J. M. Schmidt, J.
Angew. Chem. Int. Ed. 2011, 50, 8605 –8608
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 8607

Communications
Chem. Inf. Comput. Sci. 2003, 43, 218 – 227; d) N. K. Boaen,
Zhdankin, ARKIVOC 2009, 1 – 62; c) M. Uyanik, K. Ishihara,
Chem. Commun. 2009, 2086 – 2099; d) E. A. Merritt, B. Olofs-
son, Angew. Chem. 2009, 121, 9214 – 9234; Angew. Chem. Int.
Ed. 2009, 48, 9052 – 9070; e) V. V. Zhdankin, P. J. Stang, Chem.
Rev. 2008, 108, 5299 – 5358; f) U. Ladziata, V. V. Zhdankin,
ARKIVOC 2006, 26 – 58; g) T. Wirth, Angew. Chem. 2005, 117,
3722 – 3731; Angew. Chem. Int. Ed. 2005, 44, 3656 – 3665;
h) R. M. Moriarty, J. Org. Chem. 2005, 70, 2893 – 2903.
M. A. Hillmyer, Chem. Soc. Rev. 2005, 34, 267 – 275; e) M. A.
Koch, A. Schuffenhauer, M. Scheck, S. Wetzel, M. Casaulta, A.
Odermatt, P. Ertl, H. Waldmann, Proc. Natl. Acad. Sci. USA
2005, 102, 17272 – 17277; f) R. Hili, A. K. Yudin, Nat. Chem.
Biol. 2006, 2, 284 – 287.
[2] a) D. N. Zalatan, J. Du Bois, Top. Curr. Chem. 2010, 292, 347 –
378; b) D. S. Surry, S. L. Buchwald, Angew. Chem. 2008, 120,
6438 – 6461; Angew. Chem. Int. Ed. 2008, 47, 6338 – 6361; c) J. F.
Hartwig, Acc. Chem. Res. 2008, 41, 1534 – 1544; d) M. Carril, R.
SanMartin, E. Dominguez, Chem. Soc. Rev. 2008, 37, 639 – 647;
e) S. L. Buchwald, C. Mauger, G. Mignani, U. Scholz, Adv. Synth.
Catal. 2006, 348, 23 – 39; f) S. V. Ley, A. W. Thomas, Angew.
Chem. 2003, 115, 5558 – 5607; Angew. Chem. Int. Ed. 2003, 42,
5400 – 5449.
[3] a) J. P. Finet, A. Y. Fedorov, S. Combes, G. Boyer, Curr. Org.
Chem. 2002, 6, 597 – 626; b) I. P. Beletskaya, A. V. Cheprakov,
Coord. Chem. Rev. 2004, 248, 2337 – 2364; c) F. Monnier, M.
Taillefer, Angew. Chem. 2009, 121, 7088 – 7105; Angew. Chem.
Int. Ed. 2009, 48, 6954 – 6971.
[9] T. Dohi, Y. Kita, Chem. Commun. 2009, 2073 – 2085.
[10] a) T. Dohi, A. Maruyama, M. Yoshimura, K. Morimoto, H.
Tohma, Y. Kita, Angew. Chem. 2005, 117, 6349 – 6352; Angew.
Chem. Int. Ed. 2005, 44, 6193 – 6196; b) M. Ochiai, Y. Takeuchi,
T. Katayama, T. Sueda, K. Miyamoto, J. Am. Chem. Soc. 2005,
127, 12244 – 12245; c) T. Dohi, A. Maruyama, Y. Minamitsuji, N.
Takenaga, Y. Kita, Chem. Commun. 2007, 1224 – 1226; d) M.
Ochiai, Chem. Rec. 2007, 7, 12 – 23; e) T. Dohi, N. Takenaga, K.
Fukushima, T. Uchiyama, D. Kato, M. Shiro, H. Fujioka, Y. Kita,
Chem. Commun. 2010, 46, 7697 – 7699; f) M. Uyanik, T. Yasui,
K. Ishihara, Angew. Chem. 2010, 122, 2221 – 2223; Angew. Chem.
Int. Ed. 2010, 49, 2175 – 2177; g) C. Zhu, C. Sun, Y. Wei, Synthesis
2010, 4235 – 4241; h) Z. Yu, X. H. Ju, J. Y. Wang, W. Yu,
Synthesis 2011, 860 – 866.
[11] a) H. Tohma, M. Iwata, T. Maegawa, Y. Kita, Tetrahedron Lett.
2002, 43, 9241 – 9244; b) T. Dohi, D. Kato, R. Hyodo, D.
Yamashita, M. Shiro, Y. Kita, Angew. Chem. 2011, 123, 3868 –
3871; Angew. Chem. Int. Ed. 2011, 50, 3784 – 3787; c) D. Mirk, A.
Willner, R. Frohlich, S. R. Waldvogel, Adv. Synth. Catal. 2004,
346, 675 – 681.
[12] For recent results on transformations mediated by hypervalent
iodine(III) species, see: a) T. Dohi, M. Ito, N. Yamaoka, K.
Morimoto, H. Fujioka, Y. Kita, Angew. Chem. 2010, 122, 3406 –
3409; Angew. Chem. Int. Ed. 2010, 49, 3334 – 3337; b) T. Dohi, N.
Yamaoka, Y. Kita, Tetrahedron 2010, 66, 5775 – 5785; c) Y. Kita,
H. Tohma, K. Hatanaka, T. Takada, S. Fujita, S. Mitoh, H.
Sakurai, S. Oka, J. Am. Chem. Soc. 1994, 116, 3684 – 3691; d) T.
Dohi, M. Ito, K. Morimoto, M. Wata, Y. Kita, Angew. Chem.
2008, 120, 1321 – 1324; Angew. Chem. Int. Ed. 2008, 47, 1301 –
1304; e) T. Dohi, M. Ito, N. Yamaoka, K. Morimoto, H. Fujioka,
Y. Kita, Tetrahedron 2009, 65, 10797 – 10815; f) Y. Kita, K.
Morimoto, M. Ito, C. Ogawa, A. Goto, T. Dohi, J. Am. Chem.
Soc. 2009, 131, 1668 – 1669.
[4] a) F. Paul, J. Patt, J. F. Hartwig, J. Am. Chem. Soc. 1994, 116,
5969 – 5970; b) A. S. Guram, S. L. Buchwald, J. Am. Chem. Soc.
1994, 116, 7901 – 7902.
[5] a) W. C. P. Tsang, N. Zheng, S. L. Buchwald, J. Am. Chem. Soc.
2005, 127, 14560 – 14561; b) M. Yamamoto, S. Matsubara, Chem.
Lett. 2007, 36, 172 – 173; c) J. A. Jordan-Hore, C. C. C. Johans-
son, M. Gulias, E. M. Beck, M. J. Gaunt, J. Am. Chem. Soc. 2008,
130, 16184 – 16186; d) B. H. Li, S. L. Tian, Z. Fang, Z. H. Shi,
Angew. Chem. 2008, 120, 1131 – 1134; Angew. Chem. Int. Ed.
2008, 47, 1115 – 1118; e) W. C. P. Tsang, R. H. Munday, G.
Brasche, N. Zheng, S. L. Buchwald, J. Org. Chem. 2008, 73,
7603 – 7610; f) J. J. Neumann, S. Rakshit, T. Drçge, F. Glorius,
Angew. Chem. 2009, 121, 7024 – 7027; Angew. Chem. Int. Ed.
2009, 48, 6892 – 6895.
[6] S. H. Cho, J. Yoon, S. Chang, J. Am. Chem. Soc. 2011, 133, 5996 –
6005.
À
[7] For our previous work on C H activation, see: R. Samanta, A. P.
Antonchick, Angew. Chem. 2011, 123, 5323 – 5326; Angew.
Chem. Int. Ed. 2011, 50, 5217 – 5220.
[8] a) A. Duschek, S. F. Kirsch, Angew. Chem. 2011, 123, 1562 –
1590; Angew. Chem. Int. Ed. 2011, 50, 1524 – 1552; b) V. V.
8608 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 8605 –8608