Iron(II)-catalyzed oxidation of sp3 C-H bonds adjacent to a nitrogen atom of unprotected arylureas with tert-butyl hydroperoxide in water

Article abstract of DOI:10.1021/ol200169g

With a FeSO₄/TBHP system in water, direct oxidation of sp ³ C-H bonds adjacent to nitrogen of arylureas to give both unprecedented tert-butoxylated and hydroxylated products 2 was revealed. Under elevated temperatures, either 2-oxo-N-arylpyrrolidine-1-carboxamides 3 or 1,3-diarylureas 4 were attained, depending on the aliphatic ring size of the arylurea substrates.

Full text of DOI:10.1021/ol200169g

ORGANIC
LETTERS
Iron(II)-Catalyzed Oxidation of sp3 C-H
Bonds Adjacent to a Nitrogen Atom of
Unprotected Arylureas with tert-Butyl
Hydroperoxide in Water
2011
Vol. 13, No. 7
1674–1677
Ying Wei, Hongqian Ding, Shaoxia Lin, and Fushun Liang**
Department of Chemistry, Northeast Normal University, Changchun 130024, China
liangfs112@nenu.edu.cn
Received January 19, 2011
ABSTRACT
With a FeSO4/TBHP system in water, direct oxidation of sp3 C-H bonds adjacent to nitrogen of arylureas to give both unprecedented tert-
butoxylated and hydroxylated products 2 was revealed. Under elevated temperatures, either 2-oxo-N-arylpyrrolidine-1-carboxamides 3 or 1,3-
diarylureas 4 were attained, depending on the aliphatic ring size of the arylurea substrates.
Direct formation of a C-X (X = C, N, O, etc.) bond
from unactivated C-H bonds is one of the most challen-
ging projects in organic synthesis.1 In this context, C-X
bond formation via C-H bond functionalization adjacent
to a nitrogen atom has received considerable attention.2 In
our ongoing research, we aimed to explore the sp2 and/or
sp3 C-H bond functionalizations adjacent to nitrogen
atoms toward various C-X bond formations with newly
developed arylureas3 in our laboratory.4 Herein, we wish
to present the reaction of unprotected arylureas with
nontoxic, and cheap tert-butyl hydroperoxide (TBHP) as
the oxidant and iron salts as the catalyst.5 The result
demonstrated that the reactions performed at 50 °C gave
unprecedented oxidative products, 2-tert-butoxy-5-hydro-
xy-N-arylpyrrolidine(piperidine)-1-carboxamides 2, by di-
rect oxidation of sp3 C-H bonds adjacent to the nitrogen
of arylureas.6 Under elevated temperatures of 80 °C, urea
derivatives, either 2-oxo-N-arylpyrrolidine-1-carboxamides
3 or 1,3-diarylureas 4, were attained respectively, depend-
ing on the aliphatic ring size of the arylurea substrates.
(1) For recent reviews on C-H activation and functionalization, see:
(a) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698. (b) Kakiuchi, F.;
Murai, S. Acc. Chem. Res. 2002, 35, 826. (c) Ritleng, V.; Sirlin, C.;
Pfeffer, M. Chem. Rev. 2002, 102, 1731. (d) Jun, C.-H.; Moon, C. W.;
Lee, D.-Y. Chem.;Eur. J. 2002, 8, 2423. (e) Dick, A. R.; Sanford, M. S.
Tetrahedron 2006, 62, 2439. (f) Jia, C. G.; Kitamura, T.; Fujiwara, Y.
Acc. Chem. Res. 2001, 34, 633. (g) Alberico, D.; Scott, M. E.; Lautens,
M. Chem. Rev. 2007, 107, 174. (h) Stuart, D. R.; Fagnou, K. Science
2007, 316, 1172. (i) Ackermann, L.; Althammer, A. Angew. Chem., Int.
Ed. 2007, 46, 1627. (j) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem.
Rev. 2010, 110, 6245.
(4) Wei, Y.; Lin, S.; Liu, J.; Ding, H.; Liang, F.; Zhao, B. Org. Lett.
2010, 12, 4220.
(5) Iron catalysis: (a) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem.
(2) For direct sp3 C-H bond activation adjacent to nitrogen in
heterocycles, see: (a) Campos, K. R. Chem. Soc. Rev. 2007, 36, 1069.
(b) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (c) Doye, S. Angew. Chem.,
Int. Ed. 2001, 40, 3351. (d) Murahashi, S.-I. Angew. Chem., Int. Ed. 1995,
34, 2443.
Rev. 2004, 104, 6217. (b) Sherry, B. D.; Furstner, A. Acc. Chem. Res.
€
~
2008, 41, 1500. (c) Correa, A.; Mancheno, O. G.; Bolm, C. Chem. Soc.
Rev. 2008, 37, 1108. (d) Enthaler, S.; Junge, K.; Beller, M. Angew. Chem.,
Int. Ed. 2008, 47, 3317. (e) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev.
DOI: 10.1021/cr100198w. Published Online: Nov 4, 2010.
(3) Substituted ureas have a wide range of applications in agriculture,
petrochemicals, medicine, and biology and as important intermediates
and bifunctional organocatalysts in organic synthesis. For reviews on
substituted ureas, see: (a) Gallou, I. Org. Prep. Proced. Int. 2007, 4, 355.
(b) Bigi, F.; Maggi, R.; Sartori, G. Green Chem. 2000, 2, 140. (c)
Vishnyakova, T. P.; Golubeva, I. A.; Glebova, E. V. Russ. Chem. Rev.
(Engl. Ed.) 1985, 54, 249.
(6) Selected papers on selective C-H bond oxidation: (a) Wang, Z.;
Zhang, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2008, 10, 1863. (b)
Chen, M. S.; White, M. C. Science 2007, 318, 783. (c) Nakanishi, M.;
Bolm, C. Adv. Synth. Catal. 2007, 349, 861. (d) Guo, X.; Yu, R.; Li, H.;
Li, Z. J. Am. Chem. Soc. 2009, 131, 17387. (e) Shu, X.-Z.; Xia, X.-F.;
Yang, Y.-F.; Ji, K.-G.; Liu, X.-Y.; Liang, Y.-M. J. Org. Chem. 2009, 74,
7464.
r
10.1021/ol200169g
Published on Web 03/04/2011
2011 American Chemical Society

Table 1. Optimization of the Reaction Conditionsa
Table 2. Iron-Catalyzed Oxidation of Unprotected Arylureas
with TBHP in Watera
catalyst
(mol %)
TBHP
T
time
(h)
yield
(%)b
entry
(equiv)
solvent (°C)
entry
1
Ar
n
R
Y
2
time (h) yield (%)b
1
2
3
4
5
6
7
8
1.1
1.1
1.1
1.1
2.2
2.2
2.2
2.2
MeCN
MeCN
DCE
DCE
DCE
DCE
H2O
80
80
80
80
80
50
50
50
8
nr
32
48
55
62
70
75
51
1
2
3
4
5
6
7
8
9
1a C6H5
1
1
1
1
1
1
1
1
2
2
H
H
H
H
H
H
H
H
H
H
H
2a
2b
2c
2d
2e
2f
4
4
75
72
65
70
78
76
50
32
54c
n.r.
FeCl3 (10)
FeCl3 (10)
FeSO4 (10)
FeSO4 (10)
FeSO4 (20)
FeSO4 (20)
CuBr (20)
7
1b 4-OMeC6H4
1c 4-MeC6H4
1d 2,4-Me2C6H3
1e 4-ClC6H4
1f 5-Cl-2-OMeC6H3
1g 2-Py
7
H
4
7
H
5
7
H
3
5
H
5
4.5
4.5
H
2g
2h
2i
4
H2O
1h C6H5
Me
H
11
6
a Conditions: 1a (0.5 mmol) and TBHP (5-6 M in decane or 70% in
1i C6H5
water) under open air. b Isolated yields. DCE = dichloroethane.
10 1j C6H5
H
Me 2j
10
a Conditions: 1 (0.5 mmol) and TBHP (0.15 mL, 70% in water) under
open air. b Isolated yields. c Along with the formation of diphenylurea 4a
(18% yield).
Moreover, all the reactions could proceed efficiently in
water, which represents a facile and convenient oxidation
of unprotected arylureas in a “green” fashion.7 Although
much effort has been devoted to the metal-catalyzed C-H
bond functionalization at the R-position of amines, exam-
ples of C-H bond activation of amides and ureas are
scarce.8 To the best of our knowledge, no report has been
found in the literature on the aliphatic C-H bond activation
of ureas.
as an easily available, cheap, safe, and environmentally
benign solvent, was also tested. To our delight, the reaction
gave the best results and the desired product 2a was obtained
in 75% yield at 50 °C within 4.5 h (entry 7). Comparatively,
copper catalyst CuBr was less efficient for the explored
reaction (entry 8).
Under the optimized conditions (Table 1, entry 7), a
range of reactions were performed with various substrates
1 (Table 2). It was observed that various N-arylpyrrolidine-
1-carboxamides 1a-f afforded the corresponding 2-tert-
butoxy-5-hydroxy-N-arylpyrrolidine-1-carboxamides 2a-f
in good yields (entries 1-6). N-Heteroaryl counterparts
such as N-(2-pyridyl)urea 1g also gave both the desired
hydroxylated and tert-butoxylated product 2g in 50% yield
(entry 7). Comparatively, when N-methyl-protected arylur-
ea 1h was used, the reaction gave the oxidative product 2h
with a yield of merely 32% (entry 8).9 For N-phenylpiper-
idine-1-carboxamide 1i, 2-tert-butoxy-6-hydroxy-N-phe-
nylpiperidine-1-carboxamide 2i was obtained in 54% yield
(entry 9). The reaction with 2-methyl-N-phenylpiperidine-1-
carboxamide 1j did not occur, presumably due to the steric
effect of the methyl group on the piperidine ring (entry 10).
The results shown above demonstrated the efficiency and
synthetic interest of the C-O bond formation reaction via
C-H bond functionalization with respect to arylureas 1
bearing various substituents. Indeed, there are no generally
effective methods for simultanious dioxygenation of both
R-positions to the nitrogen atom.
Initially, optimization of the reaction conditions was
conducted (Table 1). The model reaction of N-phenylpyr-
rolidine-1-carboxamide 1a and TBHP (1.1 equiv) in
CH3CN at 80 °C could not occur in the absence of metal
catalyst (entry 1). When 10 mol % of FeCl3 was introduced
tothe reaction system, 2-tert-butoxy-5-hydroxy-N-phenyl-
pyrrolidine-1-carboxamide (2a) was obtained in 32% yield
(entry 2). Dichloroethane proved to be a more suitable
solvent than CH3CN (entry 3). It was found that when a
low oxidation state iron salt, such as FeSO4, was used as
the catalyst, the reaction of 1a with TBHP in DCE
exhibited higher efficiency with a yield of 55% (entry 4).
When the feed ratio of FeSO4/TBHP was increased, i.e., 20
mol % of FeSO4 and 2.2 equiv of TBHP, the reaction
temperature was lowered and the yields were enhanced
along withshortenedreactiontime (entries 5 and 6). Water,
(7) (a) Li, C.-J.; Chen, L. Chem. Soc. Rev. 2006, 5, 68. (b) Herrerı
´
as,
C. I.; Yao, X.; Li, Z.; Li, C.-J. Chem. Rev. 2007, 107, 2546.
(8) For selected papers on C-H activation based on amides, see: (a)
Kobayashi, S.; Kiyohara, H.; Yamaguchi, M. J. Am. Chem. Soc. 2011,
133, 708. (b) Li, B.; Tian, S.-L.; Fang, Z.; Shi, Z. Angew. Chem., Int. Ed.
2008, 47, 1115. (c) Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int. Ed.
2005, 44, 4046. (d) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 14560. (e) DeBoef, B.; Pastine, S. J.; Sames, D.
J. Am. Chem. Soc. 2004, 126, 6556. For aryl C-H bond activation of
ureas, see:(f) Nishikata, T.; Abela, A. R.; Lipshutz, B. H. Angew. Chem.,
Int. Ed. 2010, 49, 781. (g) Nishikata, T.; Abela, A. R.; Huang, S.;
Lipshutz, B. H. J. Am. Chem. Soc. 2010, 132, 4978. (h) Houlden,
In the following work, the reactions described above
were carried out at elevated temperatures. As a result,
2-oxo-N-arylpyrrolidine-1-carboxamides 3 were cleanly
ꢀ
C. E.; Hutchby, M.; Bailey, C. D.; Ford, J. G.; Tyler, S. N. G.; Gagne,
(9) It appears that the efficiency of N-protected arylurea is lower than
that of unprotected arylurea, which is consistent with the possible
mechanism proposed later.
M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Angew. Chem., Int.
Ed. 2009, 48, 1830.
Org. Lett., Vol. 13, No. 7, 2011
1675

Table 3. Iron-Catalyzed Reaction of N-Arylpyrrolidine-1-car-
boxamides with TBHP in Watera
Scheme 1. Reaction of Acyclic Arylurea with FeSO4/TBHP in
Water
entry
1
Ar
3
time (h)
yield (%)b
1
2
3
4
5
6
1a
1b
1c
1d
1e
1g
C6H5
3a
3b
3c
3d
3e
3g
5
4
83
85
80
82
87
86
Scheme 2. Control Experiments
4-OMeC6H4
4-MeC6H4
2,4-Me2C6H3
4-ClC6H4
2-Py
5
6
5
12
a Conditions: 1 (0.5 mmol) and TBHP (0.15 mL, 70% in water) under
open air. b Isolated yields.
Table 4. Iron-Catalyzed Reaction of N-Arylpiperidine-1-car-
boxamides with TBHP in Watera
under identical conditions proceeded more efficiently,
giving4ain87%yield(entry4).SimilarlytothatinTable2,
entry 10, the reaction of 2-methyl-N-phenylpiperidine-1-
carboxamide 1j did not occur even at 80 °C (entry 5).
Furthermore, when the reaction of 1k with FeSO4/TBHP
was carried out in methanol instead of water, methyl
4-methoxyphenylcarbamate (4e) was obtained in 62%
yield (entry 6).
Acyclicarylureasuchas1,1-diethyl-3-phenylurea under-
went an oxidative N-dealkylation reaction in the presence
of FeSO4/TBHP in water at 50 °C, giving 1-ethyl-3-phe-
nylurea 5 in 35% yield (Scheme 1).10b The low yield was
most probably attributed tothe existence of an equilibrium
between 1n, 5, and acetaldehyde.
To elucidate a possible mechanism, we performed the
following control experiments (Scheme 2). In the reaction
of substrate 1d in the presence of 20 mol % of FeSO4 and
1.1 equiv of TBHP in DCE at 40 °C, N-(tert-butylperoxy)-
N-(2,4-dimethylphenyl)pyrrolidine-1-carboxamide 6, al-
though unstable, was separated and identified by 1H
NMR spectroscopy and HRMS (eq 1).11 Additionally,
entry
1
Ar
C6H5
X
Y
4
yield (%)b
1
1i
CH2
CH2
CH2
O
H
4a
4b
4c
4a
4d
4e
82
2
1k
1l
4-OMeC6H4
4-ClC6H4
C6H5
H
91
3
H
50c
87
4
1m
1j
H
5
6d
C6H5
CH2
CH2
Me
H
n.r.
62e
1k
4-OMeC6H4
a Conditions: 1 (0.5 mmol) and TBHP (0.15 mL, 70% in water) under
open air. b Isolated yields. c With 25 mol % of CuBr as the catalyst.
d Methyl 4-methoxyphenylcarbamate was obtained. e With methanol as
the solvent.
obtained from the five-membered pyrrolidine substrates
(Table 3).10 In particular, treating the substrates 1a-e and
1g with 2.2 equiv of TBHP in the presence of 20 mol % of
FeSO4 in water (0.5 mL) at 80 °C gave products 3a-e and
3g in high yields of 80-87% (entries 1-6). Surprisingly,
when the corresponding six-membered piperidine sub-
strates were subjected to identical conditions, no oxidative
products 3 were observed. Instead, diarylureas 4 such as
1,3-diphenylurea 4a, 1,3-bis(4-chlorophenyl)urea 4b, and
1,3-bis(4-methoxyphenyl)urea 4c were achieved in high
efficiency from N-arylpiperidine-1-carboxamides 1i and
1k,l (Table 4, entries 1-3). It was found that the reaction
of N-phenylmorpholine-4-carboxamide substrate 1m
€
(11) For N-tert-butylperoxylated intermediates, see: (a) Forster, S.;
Rieker, A. J. Org. Chem. 1996, 61, 3320. For C-tert-butylperoxylated
intermediates, see:(b) Xie, J.; Huang, Z.-Z. Angew Chem., Int. Ed. 2010,
49, 10181. (c) An, G.; Zhou, W.; Zhang, G.; Sun, H.; Han, J.; Pan, Y.
Org. Lett. 2010, 12, 4482. (d) Terent’ev, A. O.; Borisov, D. A.; Yar-
emenko, I. A.; Chernyshev, V. V.; Nikishin, G. I. J. Org. Chem. 2010, 75,
5065. (e) Russoa, A.; Lattanzia, A. Adv. Synth. Catal. 2008, 350, 1991. (f)
Yu, J.-Q.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 3232.
(10) For the preparation of N-acylureas, see: (a) Liptrot, D.; Alcaraz,
L.; Roberts, B. Adv. Synth. Catal. 2010, 352, 2183. (b) Constantino, L.;
Iley, J. Org. Biomol. Chem. 2004, 2, 1894.
1676
Org. Lett., Vol. 13, No. 7, 2011

Scheme 3. Possible Mechanism for the Formation of 2
Scheme 4. Possible Mechanism for the Formation of 3 and 4
Followed by hydride transfer and removal of the proton,
2-oxo-N-arylpyrrolidine-1-carboxamides 3 is produced.
As for six-membered counterparts 2, isocyanate VI may
be produced in water via amine elimination.15,16 The
hydrolysis and subsequent decarboxylation of intermedi-
ate VI leads to the formation of amine VII, which under-
goes nucleophilic addition to the isocyanate to give the
final products 4. Obviously, ring size of the cyclic arylurea
determines the formation of different products (3 or 4).17
In conclusion, we have reported an unprecedented iron-
(II)-catalyzed oxidation of sp3 C-H bonds adjacent to a
nitrogen atom of unprotected arylureas with TBHP in
water. At 50 °C, the hydroxylated and tert-butoxylated
products were obtained efficiently. At 80 °C, the oxidative
products undergo either alcohol elimination or amine
elimination to give 2-oxo-N-arylpyrrolidine-1-carboxa-
mides and 1,3-diarylureas, respectively, depending on the
aliphatic ring size of the arylurea substrates. Moreover, we
anticipate that the intact N-H on the unprotected arylurea
may be applicable to a wide variety of valuble transforma-
tions.18 Further work to explore the sp2 and/or sp3 C-H
bond functionalization adjacent to nitrogen atoms of ary-
lureas is ongoing in our laboratory.
nearly quantitative formation of N-(2,4-dimethylphenyl)-
2-oxopyrrolidine-1-carboxamide (3d) and 1,3-diphenylur-
ea (4a) from dioxygenated 2d and 2i, respectively, were
observed in the control reactions performed in water at
80 °C in the absence of the combination of FeSO4 and
TBHP (eqs 2 and 3).
On the basis of all the results mentioned above, a
possible mechanism for the highly efficient transformation
into 2-tert-butoxy-5-hydroxy-N-arylpyrrolidine(piperidi-
ne)-1-carboxamides2 was proposed, as depicted in Scheme
3. TBHP decomposes into a tert-butoxyl radical in the
presence of the ferrous catalyst, which further gives a tert-
butylperoxy radical. The resulting peroxyl radical can
react with aminyl radical I derived from the oxidation of
the arylurea 1 to form the unstable N-(tert-butylperoxyl)
urea 6.11 The elimination of the tert-butylperoxy radical
generates a new carbon radical II via 1,4-hydrogen radical
transfer,12 which is trapped by tert-butanol to give a R-tert-
butoxylated urea III and regenerates TBHP.13a Finally, a
hydroxyl group is introduced to the other R-position of III
via hydrogen abstraction by TBHP (regenerates tert-buta-
nol) and product 2 is formed.
Acknowledgment. Financial support from NSFC (209-
72027), the Department of Science and Technology of Jilin
Province (20100535), and NENU-STC08013 is gratefully
acknowledged.
A possible mechanism for further formation of products
3 and 4 from 2 is given in Scheme 4. For N-arylpyrrolidine-
1-carboxamides 2, an imimium ion IV is generated via
elimination of a tert-butoxyl anion upon heating.13,14
(12) For examples of 1,5-hydrogen transfer, see: (a) Yoshikai, N.;
Mieczkowski, A.; Matsumoto, A.; Ilies, L.; Nakamura, E. J. Am. Chem.
Soc. 2010, 132, 5568. (b) Sun, P.; Sun, C.; Weinreb, S. M. J. Org. Chem.
2002, 67, 4337. (c) Han, G.; LaPorte, M. G.; McIntosh, M. C.; Weinreb,
S. M. J. Org. Chem. 1996, 61, 9483. For examples of 1,4-hydrogen
Supporting Information Available. Detailed synthetic
procedures and characterization. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
ꢀ
transfer, see:(d) Gulea, M.; Lopez-Romero, J. M.; Fensterbank, L.;
(15) For relative reactivity of five- versus six-membered ring N-
acyliminium ions, see: D’Oca, M. G. M.; Moraes, L. A. B.; Pilli,
R. A.; Eberlin, M. N. J. Org. Chem. 2001, 66, 3854.
Malacria, M. Org. Lett. 2000, 2, 2591.
(13) tert-Butoxylation: (a) Shirakawa, E.; Uchiyama, N.; Hayashi, T.
J. Org. Chem. 2011, 76, 25–34. (b) Sasamoto, N.; Dubs, C.; Hamashima,
Y.; Sodeoka, M. J. Am. Chem. Soc. 2006, 128, 14010.
(14) For recent reviews on the chemistry of N-acyliminium ions, see:
(a) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryan-
off, C. A. Chem. Rev. 2004, 104, 1431. (b) Royer, J.; Bonin, M.; Micouin,
L. Chem. Rev. 2004, 104, 2311. (c) Cox, E. D.; Cook, J. M. Chem. Rev.
1995, 95, 1797. (d) Speckamp, W. N.; Hiemstra, H. Tetrahedron1985, 41,
4367. (e) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817.
(16) Hutchby, M.; Houlden, C. E.; Ford, J. G.; Tyler, S. N. G.;
ꢀ
Gagne, M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Angew. Chem.
2009, 121, 8877.
(17) For the possible mechanism of oxidation/dealkylation of acyclic
arylurea, see the Supporting Information.
(18) For an example, see: Wasa, M.; Engle, K. M.; Yu, J-.Q. J. Am.
Chem. Soc. 2010, 132, 3680.
Org. Lett., Vol. 13, No. 7, 2011
1677