An unusual peroxide-mediated amination of cycloalkanes with nitroarenes

Article abstract of DOI:10.1002/adsc.200800689

A direct amination of simple cycloalkanes with nitroarenes mediated by peroxides has been discovered. Various secondary arylamines were obtained efficiently from cycloalkanes. The reaction tolerates a wide range of functionalities as well as aqueous condi

Full text of DOI:10.1002/adsc.200800689

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DOI: 10.1002/adsc.200800689
An Unusual Peroxide-Mediated Amination of Cycloalkanes with
Nitroarenes
Guojun Deng,a Wenwen Chen,a and Chao-Jun Lia,*
a
Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec, Canada H3A 2K6
Fax : (+1)-514-398-3797; e-mail: cj.li@mcgill.ca
Received: November 8, 2008; Revised: January 16, 2009; Published online: February 4, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800689.
Abstract: A direct amination of simple cycloalkanes
with nitroarenes mediated by peroxides has been
discovered. Various secondary arylamines were ob-
tained efficiently from cycloalkanes. The reaction
tolerates a wide range of functionalities as well as
aqueous conditions. No metal was required for this
novel amination reaction.
and pre-functionalization of alkanes and reduction of
nitro compounds are necessary (Scheme 1).[5] Direct
amination of simple alkanes is still rare.[6] In 1960,
Jackson and Waters observed that the nitro group in
nitrobenzene could be reduced to a hydroxylamine in
the presence of tert-butyl peroxide.[7] This interesting
reduction of nitrobenzene by peroxide did not attract
much attention due to the substrate limitation and ex-
tremely low yield (6.4%). Recently, we developed a
series of methods to couple cycloalkanes with other
Keywords: amination; cycloalkanes; nitroarenes;
peroxides
À
À
C H bonds to generate new C C bonds mediated by
peroxides.[8] We also found that cyclooctyl radicals
could add to imines, similar to a Grignard reagent.[9]
On the other hand, a Grignard reagent has been
Functionalization of inert alkanes to more valuable shown to add to the nitro group.[10] We thus postulat-
products (e.g., carboxylic acids, alcohols, ketones) has ed that it might be possible to form secondary amines
attracted much attention.[1] Although the selective in one step by reacting the nitro group with cycloal-
and practical functionalization of alkanes is still chal- kanes in the presence of peroxide (Scheme 1).
lenging, great progress has been achieved in the selec- Herein, we report an efficient and unprecedented se-
À
tive cleavage and functionalization of C H bonds of lective arylamination of simple cycloalkanes with ni-
alkanes.[2,3] Secondary amines (especially aromatic troarenes mediated by peroxide in the absence of a
secondary amines) are important motifs of dyes, phar- metal catalyst to give synthetically useful secondary
maceuticals and agrochemicals.[4] The reductive ami- aromatic amines.
nation of aldehydes and ketones is one of the most
To begin our study, the commercially available and
useful methods for synthesizing secondary amines, inexpensive nitrobenzene (1a) was used as a model
Scheme 1. Preparation of N-cyclooctylbenzenamine.
Adv. Synth. Catal. 2009, 351, 353 – 356
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Guojun Deng et al.
Table 2. Reactions of nitroarenes with cyclooctane.[a]
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Table 1. Optimization of the reaction conditions.[a]
[a]
Compound 1a (24.6 mg, 0.2 mmol), cyclooctane (0.5 mL,
3.7 mmol), 16 h in air unless otherwise noted.
Yields determined by using NMR methods in which 1,2-
[b]
dichloroethane was the internal standard.
Under nitrogen.
Under oxygen.
Cyclooctane was reduced to 5 equiv. (1.0 mmol).
[c]
[d]
[e]
[f]
Water (100 mL, 5.5 mmol) was added.
[a]
Conditions: 1 (0.2 mmol), 2a (3.7 mmol, 0.5 mL), 3e
(0.4 mmol), 135–1398C, 16 h, under air.
Isolated yield.
Scheme 2. 1H NMR study of the reaction.
[b]
[c]
Yield in parentheses was carried out at a 2 mmol scale.
substrate. When nitrobenzene was reacted with cyclo-
octane (2a) in the absence of peroxide, no desired
product was formed as determined by GC-MS and (entry 10). A moderate yield was obtained by reduc-
1H NMR methods (Table 1, entry 1). Subsequently, ing the amount of cyclooctane to 5 equiv. (entry 11).
various peroxides were investigated for this reaction Furthermore, an excellent yield was also achieved in
under an atmosphere of air (entries 2–6). When tert- the presence of water (entry 12).
butyl hydroperoxide (3a) was used, the desired prod-
With the optimized conditions in hand, the scope of
uct N-phenylcyclooctanamine (4a) was formed in the reaction with respect to nitrobenzene derivatives
12% yield. Other peroxides showed higher efficiency and alkanes was investigated (Table 2 and Table 3). In
in mediating this reaction. The best yield was ob- general, the dicumyl peroxide-mediated reduction
tained by using dicumyl peroxide (3e) as a mediator and amination occurs smoothly to provide the desired
(entry 6). No alkylation was observed at the position product in good to excellent yields. The substituent at
ortho to the nitro group. Decreasing the reaction tem- different positions of the nitroarenes affects the reac-
perature or the amount of the peroxide decreased the tion yield significantly. The reaction showed good
product yield (entries 7 and 8). A lower yield was ob- functional group tolerance: nitroarenes bearing an
tained when the reaction was carried out in oxygen ester group or acetyl group at the para-position react-
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Adv. Synth. Catal. 2009, 351, 353 – 356

An Unusual Peroxide-Mediated Amination of Cycloalkanes with Nitroarenes
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Table 3. Reaction of nitrobenzene (1a) with alkanes (2).[a]
metal catalyst. Although commonly used as radical in-
itiator and oxidants, peroxides act as nitro group re-
ducing reagents in this novel amination reaction. The
study opens a new avenue for functionalization of
simple cycloalkanes. Further investigations including
the scope and mechanism of this reaction are in prog-
ress in our laboratory.
Experimental Section
Typical Experimental Procedure (4a)
In a 10-mL microwave tube, nitrobenzene (1a; 24.7 mg,
0.2 mmol), dicumyl peroxide (3e; 108 mg, 0.4 mmol) and cy-
clooctane (2a; 0.5 mL, 3.7 mmol) were added under atmos-
pheric air. Then the tube was sealed with a Teflon-lined cap
and the resulting solution was heated in a 135–1398C oil
bath with vigorous stirring for 16 h. After cooling to room
temperature, the volatiles were removed under vacuum and
the residue was purified by flash column chromatography
on silica gel (hexane to hexane: ethyl acetate=99: 1) to pro-
vide 4a (CAS: 13310–25–3) as a yellow oil; yield: 25.7 mg
(63%). A more pure product for analysis could be obtained
by column chromatography (dichloromethane/hexane=
10:90). 1H NMR (300 MHz, CDCl3): d=7.22–7.14 (dd, J=
8.7, 7.4 Hz, 2H), 6.72–6.65 (tt, J=7.2, 1.1 Hz, 1H), 6.59–6.55
(dd, J=8.7, 1.0 Hz, 2H), 3.58–3.51 (m, 2H), 1.97–1.89 (m,
2H), 1.80–1.56 (m, 12H); 13C NMR (75 MHz, CDCl3): d=
147.2, 129.2, 116.6, 113.2, 52.2, 32.6, 27.0, 25.9, 24.0; MS
(EI): m/z (%)=203, 160, 132 (100), 119, 106, 93, 77. These
values are consistent with those reported in the literature.[5a]
[a]
Conditions: 1a (0.2 mmol), 2 (3.7 mmol), 3e (0.4 mmol),
135–1398C, 24 h, under air.
[b]
[c]
Isolated yield.
Other isomers also formed; total yield (1H NMR) is
about 50%.
ed with cyclooctane to give the corresponding prod-
ucts in moderate yields (Table 2, entries 7 and 8). The
reaction also tolerates the presence of halogens
(Table 2, entries 4–6 and 11). Other cycloalkanes such
as cycloheptane, norbornane also reacted smoothly
with nitrobenzene to give the desired products in
good yields (Table 3, entries 1 and 4). Cyclohexane re-
acted with nitrobenzene and gave the desired product
in only 30% yield (50% NMR yield) due to its low
boiling point (note: to ensure a higher temperature,
the tube was wrapped with aluminum foil) (entry 2).
Besides cycloalkanes, the amination reaction also pro-
ceeded smoothly with cyclooctene to give the allylic
amination product in good yield and selectivity
(Table 3, entry 3). The reaction of linear heptane and
nitrobenzene gave 4q as the major product (Table 3,
entry 5) together with other regioisomers.[11]
Acknowledgements
We are grateful to the Canada Research Chair (Tier 1) Foun-
dation (to CJL), the (US) NSF-EPA Joint Program for a
Sustainable Environment, NSERC, GCI-Pharmaceutical
Green Chemistry Roundtable for support of our research.
The reaction mechanism is not clear at this
moment. To get more information, nitrobenzene was
reacted with cyclooctane in the presence of 1 equiv. of
References
[1] a) B. A. Arndtsen, R. G. Bergman, T. A. Mobley, T. H.
Peterson, Acc. Chem. Res. 1995, 28, 154; b) J. A. Davis,
P. L. Watson, J. F. Liebman, A. Greenberg, (Eds.), Se-
lective Hydrocarbon Activation, Wiley-VCH, New
York, 1990; c) C. L. Hill, Activation and Functionaliza-
tion of Alkanes, Wiley-Interscience, New York, 1989.
[2] For selected recent reviews on alkane functionalization,
see: a) L. Ackermann, R. Born, J. H. Spatz, A. Al-
thammer, C. J. Gschrei, Pure Appl. Chem. 2006, 78,
209; b) M. M. Dꢁaz-Requejo, P. J. Pꢂrez, Chem. Rev.
2008, 108, 3379; c) R. G. Bergman, Nature 2007, 446,
391; d) J. A. Labinger, J. E. Bercaw, Nature 2002, 417,
507; e) K. Godula, D. Sames, Science 2006, 312, 67;
f) A. R. Dick, M. S. Sanford, Tetrahedron 2006, 62,
2439; g) A. S. Goldman, K. I. Goldberg, in: Activation
1
dicumyl peroxide and monitored by H NMR directly,
which showed that the desired product was formed in
44% yield together with acetophenone, cyclooctonone
and 2-phenylpropan-2-ol in 38%, 46% and 110%
yields, respectively (Scheme 2). The results suggest
mechanistic similarity to the Grignard addition to ni-
trobenzene.[10] It was also found that more than 95%
of nitrobenzene remained unchanged when the reac-
tion was carried out in the absence of cyclooctane,
which demonstrated the critical role of cycloalkane in
this reaction.
In summary, we have developed an unprecedented
direct arylamination of cycloalkanes with nitroarenes
mediated by peroxide. Secondary aromatic amines
were formed selectively in the absence of a transition
À
and Functionalization of C H Bonds, (Eds.: K. I. Gold-
berg, A. S. Goldman), ACS Symposium Series 885,
Adv. Synth. Catal. 2009, 351, 353 – 356
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
355

Guojun Deng et al.
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American Chemical Society, Washington, DC, 2004,
pp 1–43; h) C. I. Herrerias, X. Yao, Z. Li, C.-J. Li,
Chem. Rev. 2007, 107, 2546.
2007, 119, 8440; Angew. Chem. Int. Ed. 2007, 46, 8291;
b) K. Fujita, Y. Enoki, R. Yamaguchi, Tetrahedron
2008, 64, 1943; c) H. Sajiki, T. Ikawa, K. Hirota, Org.
Lett. 2004, 6, 4977.
[3] For recent representative examples on alkane function-
alization, see: a) J. Y. K. Tsang, M. S. A. Buschhaus, P.
Legzdins, J. Am. Chem. Soc. 2007, 129, 5372; b) M. V.
Kirillova, A. M. Kirillov, P. M. Reis, J. A. L. Silva, J.
Frafflsto da Silva, A. J. L. Pombeiro, J. Catal. 2007, 248,
130; c) J. F. Hartwig, K. S. Cook, M. Hapke, C. D. Web-
ster, M. B. Hall, J. Am. Chem. Soc. 2005, 127, 2538;
d) B. Sezen, R. Franz, D. Sames, J. Am. Chem. Soc.
2002, 124, 13372; e) Y. Kondo, D. Garcia-Cuadrado,
J. F. Hartwig, M. A. Hillmyer, J. Am. Chem. Soc. 2002,
124, 1164; f) K. M. Waltz, J. F. Hartwig, J. Am. Chem.
Soc. 2000, 122, 11358; g) K. M. Waltz, J. F. Hartwig, Sci-
ence 1997, 277, 211; h) T. Sen. A. Hogan, J. Am. Chem.
Soc. 1997, 119, 2642.
[6] For successful direct amination of alkanes via nitrene,
see: C. G. Liang, F. Collet, F. Robert-Peillard, P.
Müller, R. H. Dodd, P. Dauban, J. Am. Chem. Soc.
2008, 130, 343.
[7] R. A. Jackson, W. A. Waters, J. Chem. Soc. 1960, 1653.
[8] a) Y. Zhang, C.-J. Li, Eur. J. Org. Chem. 2007, 4654;
b) Y. Zhang, J. Feng, C.-J. Li, J. Am. Chem. Soc. 2008,
130, 2900; c) G. Deng, L. Zhao, C.-J. Li, Angew. Chem.
2008, 120, 6374; Angew. Chem. Int. Ed. 2008, 47, 6278;
d) G. Deng, K. Ueda, S, Yanagisawa, K. Itami, C.-J.
Li, Chem. Eur. J. 2009, 15, 333; e) for a review on the
CDC reactions, see: C.-J. Li, Acc. Chem. Res. ASAP,
DOI: 10.1021/ar800164n.
[4] S. A. Lawrence, Amines: Synthesis Properties and Ap-
plications, Cambridge University Press, Cambridge,
2004.
[5] For reductive amination of aldehydes and ketones, see:
M. J. Bhanushali, N. S. Nandurkar, M. D. Bhor, B. M.
Bhanage, Tetrahedron Lett. 2007, 48, 1273, and referen-
ces cited therein. For other representative amination
methods involving the cycloalkyl group, see: a) D. Holl-
mann, S. Bähn, A. Tillack, M. Beller, Angew. Chem.
[9] G. Deng, C.-J. Li, Tetrahedron Lett. 2008, 49, 5601.
[10] H. Gilman, R. McCracken, J. Am. Chem. Soc. 1929, 51,
821.
[11] Nitrosobenzene and aniline also reacted with cyclooc-
tane under similar conditions and gave the same prod-
uct 4a in 51% and 28% yield, respectively. Surprisingly,
old bottles of reagents gave better yields of the desired
product than new ones and purified ones. The reason is
not clear.
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