FeCl3 catalyzed sp3 C-H amination: Synthesis of aminals with arylamines and amides

Article abstract of DOI:10.1016/j.tetlet.2013.12.043

A simple and efficient amination of sp³ C-H bonds adjacent to a nitrogen atom in amides was introduced. The reaction was catalyzed by cheap and low toxic iron salt and used arylamines as nitrogen source. It provides a straightforward construction of acyclic aminals under mild conditions.

Full text of DOI:10.1016/j.tetlet.2013.12.043

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
FeCl3 catalyzed sp3 C–H amination: synthesis of aminals
with arylamines and amides
⇑
Manman Sun, Tianshui Zhang, Weiliang Bao
Department of Chemistry, Zhejiang University (Xixi Campus), Hangzhou 310028, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
A simple and efficient amination of sp3 C–H bonds adjacent to a nitrogen atom in amides was introduced.
The reaction was catalyzed by cheap and low toxic iron salt and used arylamines as nitrogen source. It
provides a straightforward construction of acyclic aminals under mild conditions.
Ó 2013 Published by Elsevier Ltd.
Article history:
Received 10 October 2013
Revised 3 December 2013
Accepted 10 December 2013
Available online xxxx
Keywords:
Amide
Aminal
Arylamine
C–H amination
Iron catalyst
C–N bond formation methodologies are intensively investi-
gated, for since nitrogen is a key atom in natural product chemis-
try, pharmacy, and materials science. Compared with classical
transformations that ranged from nucleophilic substitution of a
leaving group to reductive amination of carbonyl groups, recently
developed direct C–H amination reactions offer a potentially highly
atom- and step-economical approach.1 In the past decades,
mainly three methodologies have been developed. One important
methodology is direct C–H amination via metal-mediated nitrene
intermediates (Scheme 1, route A).2 In this route, highly active
but sufficiently stable species should be required, such as
azides,2a–c hypervalent iodines,2d–g and N-tosyloxycarbamates.2h,i
The second flexible amination method is combined by two steps:
direct C–H insertion or C–H activation by transition metals and
thereafter coupling with N-atom (Scheme 1, route B).3 In this route,
the C–H bond should sit in a right position to be inserted by a
transition metal, mostly under the help of chelating groups3a–h or
allyl.3i–m Recently, a number of excellent oxidative functionaliza-
tion of sp3 C–H bonds adjacent to heteroatoms, double bonds, or
phenyls has been developed.4 Amination by this oxidative
route is also greatly developed (Scheme 1, route C).5 These reac-
tions go through single-electron-transfer processes, and are pro-
moted mostly by cheap and low toxic metals (Cu, Fe) or even no
metal. Therefore, the route is more economical, simple, and
efficient.
Alkylation of amines via oxidative sp3 C–H bond activations has
been reported by many groups. However, most of the amines were
limited to amides, sulfonamides, azoles, or anilines with strong
electron withdrawing-groups.6 Alkylation of anilines remains an
ongoing challenge. In 2012, Warren group7 and our group8 re-
ported the benzylic and allylic C–H amination reactions with ani-
lines. To the best of our knowledge, alkylation of anilines with
sp3 C–H bonds adjacent to a nitrogen atom via oxidative C–H bond
activation is rarely realized, although it has been achieved in tan-
dem cyclization reactions.9 Maybe the acyclic aminals are more
unstable than the cyclic ones. Aminal is found in a number of nat-
ural products,10 and is recognized as a surrogate of imine and
widely used as electrophile in the metal-catalyzed nucleophilic
addition reactions.11 Classical methods for preparing aminals are
condensation reactions of amines with aldehydes. Herein we re-
port a novel and efficient method for synthesizing acyclic aminals
by the iron-catalyzed sp3 C–H amination of lactams with aryl-
amines under mild conditions.
Initially, FeCl3/TBHP was applied to the reaction of aniline 1a
and 1-methylpyrrolidin-2-one 2a. To our delight, the desired cou-
pling product 3a was isolated in 76% yield after 8 h at 75 °C
(Table 1, entry 1). Elevated or lowered temperature did not give
higher yield (Table 1, entries 2 and 3). When the chlorobenzene
was added as solvent, the yield was decreased to 38% (Table 1,
entry 4). When the reaction was conducted under air, the yield
⇑
Corresponding author. Tel./fax: +86 571 8827 3814.
E-mail address: wlbao@css.zju.edu.cn (W. Bao).
0040-4039/$ - see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2013.12.043
Please cite this article in press as: Sun, M.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2013.12.043

2
M. Sun et al. / Tetrahedron Letters xxx (2014) xxx–xxx
H
MLn
X: N2, IPh, OTs, ...
NHR
NHR
NHR
RN=MLn
H
RN=X
A
B
C
MLn
RN
H
MLn
Y
Y
ROOR'
Cu or Fe
RN
Y: C, N, O, ...
H
Scheme 1. Routes of C–H amination.
Table 1
(Table 1, entries 15–17). Taking economic factor into account,
FeCl3 was selected as the best catalyst. Then a lot of oxidants
were studied to enhance the yield of 3a (Table 1, entries 18–
20). No better than TBHP oxidant was found. Eventually, the sat-
isfactory reaction conditions were: using the FeCl3/TBHP as the
oxidative system and carrying out the reaction at 75 °C under
nitrogen atmosphere.
Optimization of the reaction conditionsa
O
H
N
NH2
Catalyst Oxidant
Temp. 8 h
N
+
N
O
1a
Entry
2a
3a
With the optimized reaction conditions in hand, we selected
some substituted arylamines 1 to react with 1-methylpyrroli-
din-2-one 2a to explore the scope of the method (Table 2). Ani-
lines with electron-donating groups did not work well (Table 2,
entries 2–4). 4-Methoxyaniline 1d only gave the corresponding
product 3d in 29% yield after the reaction temperature was re-
duced to 40 °C. Maybe the anilines or the corresponding prod-
ucts with electron-donating groups were not stable in this
oxidizing reaction system. Anilines with electron-withdrawing
groups worked comparatively well, and moderate yields were
obtained (Table 2, entries 5–12). When N-methylaniline 1m re-
acted with 2a, the desired products 3m was obtained in 20%
yield, although N-de-alkylated product 3a was isolated in 39%
yield (Table 2, entry 13). Subsequently, the scope of the present
transformation was further examined using different amides to
react with aniline 1a. 1-Ethylpyrrolidin-2-one 2b and pyrroli-
din-2-one 2c gave the desired products in moderate yields (Ta-
ble 2, entries 14 and 15). When the aniline 1a and acyclic
amide 2d were treated with 1.0 equiv of NEt3 in 90 °C, the de-
sired product was also obtained in 50% yield after 3 h (Table 2,
entry 16).
In this reaction, there should be two products, methylene C–H
amination and methyl C–H amination products. However, the
methylene C–H amination product is the major one. Maybe
the secondary carbon radical intermediate was more stable than
the primary carbon radical intermediate. When 1j and 1k reacted
with 2a, some methyl amination products 3j0 and 3k0 were gen-
erated (Table 2, entries 10 and 11). From 1H NMR spectra the ra-
tio of 3j and 3j0 could be determined as 17:3, and the 3k and 3k0
as 2:1.
Catalyst
Oxidant (1.5 equiv)
Temp (°C)
Yieldb (%)
1
2
3
FeCl3 (10%)
FeCl3 (10%)
FeCl3 (10%)
FeCl3 (10%)
FeCl3 (10%)
—
t-BuOOHc
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
(t-BuO)2
30% H2O2
O2
75
60
100
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
76
62
29
38
32
6
41
47
51
41
43
73
69
63
33
41
22
9
4d
5e
6
7
8
9
FeBr3 (10%)
FeCl3ꢀ6H2O (10%)
FeCl2 (10%)
10
11
12
13
14
15
16
17
18
19
20
FeCl2ꢀ4H2O (10%)
FeSO4ꢀ7H2O (10%)
FeCl2 (3%)
FeCl2 (1%)
FeCl3 (3%)
CuBr (10%)
Cu(OTf)2 (10%)
ZrCl4 (10%)
FeCl3 (10%)
FeCl3 (10%)
6
FeCl3 (10%)
Trace
a
Reaction conditions: Catalyst (0.05 mmol), oxidant (0.75 mmol), and substrate
1a (0.5 mmol) in 2a (2.0 mL, used as solvent also) for 8 h under nitrogen
atmosphere.
b
Isolated yield.
5-6 M in water.
2a was 1.0 mmol and chlorobenzene is solvent.
Under air atmosphere.
c
d
e
´
According to all the above results, a plausible mechanism was
proposed as shown in Scheme 2. Under the help of Fe2+ catalyst,
TBHP was decomposed into tert-butoxyl radical and hydroxyl
was sharply reduced (Table 1, entry 5). As a radical scavenger, O2
may block this reaction. If no FeCl3 was added, only 6% yield was
obtained (Table 1, entry 6). Subsequently, other iron catalysts,
such as FeBr3, FeCl3ꢀ6H2O, FeCl2, FeCl2ꢀ4H2O, and FeSO4ꢀ7H2O,
were examined. No better than FeCl3 catalyst was found (Table 1,
entries 7–11). In view of Fe2+/TBHP system well known as radical
initiator combination in radical alkylation, we reduced the dosage
of FeCl2 from 10% to 3%. To our delight, the yield was increased
from 51% to 73% (Table 1, entry 12). When the dosage of FeCl2
was further reduced to 1%, the yield was lowered also (Table 1,
entry 13). Reducing the amount of FeCl3 to 3%, the yield was low-
er than FeCl2’s (Table 1, entry 14). Other metal catalysts, such as
CuBr, Cu(OTf)2, and ZrCl4, did not give a higher yield than FeCl3
anion.12 The tert-butoxyl radical abstracted an
a-hydrogen atom
and A was generated. The Fe3+ further oxidized A to give the imin-
ium ion B. Nucleophilic addition of 2a to B produced the desired
coupling product 3a.
In summary, we have introduced a simple and efficient method-
ology for the amination of sp3 C–H bonds adjacent to a nitrogen
atom in amides using arylamines. This reaction was catalyzed by
cheap and low toxic FeCl3 and used arylamines as nitrogen source.
It provides a straightforward construction of acyclic aminals under
mild conditions.
Please cite this article in press as: Sun, M.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2013.12.043

M. Sun et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
Table 2
Synthesis of aminals 3 with arylamines 1 and amides 2a
R2
N
R2
N
O
FeCl3 (10mol%)
H
R1
R1
+ R3
N
N
TBHP (1.5 eq)
N2 75 oC 8 h
O
R3
1
2
3
Entry
1
1
2
3
Yieldb (%)
76
NH2
O
H
N
N
1a
N
O
2a
3a
NH2
H
N
1b
2
3
4c
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
37
42
29
63
67
81
55
N
3b
O
NH2
1c
H
N
N
3c
O
NH2
1d
H
N
MeO
F
N
MeO
F
3d
O
NH2
1e
H
N
N
3e
O
NH2
1f
H
N
Cl
N
Cl
3f
O
NH2
1g
H
N
Br
N
Br
3g
O
NH2
H
N
1h
F3CO
N
F3CO
3h
O
NH2
F
F
H
N
9
2a
2a
50
F
1i
N
F
3i
O
NH2
H
N
H
N
N
+
O
10
60 (3j:3j0 = 17:3)
N
1j
CF3
O
CF3
CF3
+
3j
3j'
NH2
1k
H
H
N
N
N
56 (3k:3k0 = 2:1)
O2N
N
11
12
2a
2a
O
N
O2N
N
O2N
O
3k
3k'
NH2
1l
H
N
62
N
3l
O
(continued on next page)
Please cite this article in press as: Sun, M.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2013.12.043

4
M. Sun et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Table 2 (continued)
Entry
1
2
3
Yieldb (%)
H
N
NH
1m
N
+
3m:20
3a:39
13
2a
N
N
O
O
3m
3a
NH2
H
O
O
N
N
1a
14
15
52
N
3n
3o
2b
O
O
NH2
H
N
HN
1a
53
50
HN
2c
NH2
1a
O
H
N
N
16d
N
3p
O
2d
a
Reaction conditions: FeCl3 (0.05 mmol), TBHP (0.75 mmol, 5–6 M in water), and substrate 1 (0.5 mmol) in 2a (2.0 mL, used as solvent also) in 75 °C for 8 h under nitrogen
atmosphere.
b
c
Isolated yield.
The temperature is 40 °C.
The reaction was conducted in 90 °C for 3 h with the additive of NEt3 (0.5 mmol).
d
t-BuOOH
Fe2+
Fe3+
OH
+
NH2
2a
H2O
O
H
N
O
O
t-BuO
t-BuOH
Fe3+
N
N
N
N
O
A
Fe2+
B
3a
1a
Scheme 2. A plausible mechanism.
Chem. Soc. 2008, 130, 16184; (g) Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130,
14058; (h) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 1932; (i)
Fraunhoffer, K. J.; White, M. C. J. Am. Chem. Soc. 2007, 129, 7274; (j) Srivastava,
R. S.; Nicholas, K. M. J. Org. Chem. 1994, 59, 5365; (k) Srivastava, R. S.; Tarver, N.
R.; Nicholas, K. M. J. Am. Chem. Soc. 2007, 129, 15250; (l) Reed, S. A.; White, M.
C. J. Am. Chem. Soc. 2008, 130, 3316; (m) Liu, G.; Yin, G.; Wu, L. Angew. Chem.,
Int. Ed. 2008, 47, 4733.
Acknowledgment
This work is financially supported by the Natural Science Foun-
dation of China (No. 21072168).
4. For selected examples, see: (a) Li, C. Acc. Chem. Res. 2009, 42, 335; (b) Sun, C.; Li,
B.; Shi, Z. Chem. Rev. 2011, 111, 1293; (c) Yang, F.; Li, J.; Xie, J.; Huang, Z. Org.
Lett. 2010, 12, 5214; (d) Cheng, D.; Bao, W. Adv. Synth. Catal. 2008, 350, 1263;
(e) Cheng, D.; Bao, W. J. Org. Chem. 2008, 73, 6881; (f) Mo, H.; Bao, W. Adv.
Synth. Catal. 2009, 351, 2845; (g) Yang, J.; Wang, Z.; Pan, F.; Li, Y.; Bao, W. Org.
Biomol. Chem. 2010, 8, 2975.
5. (a) Powell, D. A.; Fan, H. J. Org. Chem. 2010, 75, 2726; (b) Pelletier, G.; Powell, D.
A. Org. Lett. 2006, 8, 6031; (c) Wang, Z.; Zhang, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Org.
Lett. 2008, 10, 1863; (d) Liu, X.; Zhang, Y.; Wang, L.; Fu, H.; Jiang, Y.; Zhao, Y. J.
Org. Chem. 2008, 73, 6207; (e) Xia, R.; Niu, H.; Qu, G.; Guo, H. Org. Lett. 2012, 14,
5546.
6. For selected examples, see: (a) Zhang, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett.
2007, 9, 3813; (b) Harvey, M. E.; Musaev, D. G.; Du Bois, J. J. Am. Chem. Soc.
2011, 133, 17207; (c) Xia, Q.; Chen, W.; Qiu, H. J. Org. Chem. 2011, 76, 7577; (d)
Zhang, J.; Wai, P.; Chan, H.; Che, C. Tetrahedron Lett. 2005, 46, 5403; (e) Xia, Q.;
Chen, W.; Qiu, H. J. Org. Chem. 2012, 77, 9366.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.12.
043.
References and notes
1. (a) Collet, F.; Dodd, R. H.; Dauban, P. Chem. Commun. 2009, 5061; (b) Lu, H.;
Zhang, X. P. Chem. Soc. Rev. 2011, 40, 1899; (c) Collet, F.; Lescot, C.; Dauban, P.
Chem. Soc. Rev. 2011, 40, 1926; (d) Ramirez, T. A.; Zhao, B.; Shi, Y. Chem. Soc. Rev.
2012, 41, 931.
2. (a) King, E. R.; Hennessy, E. T.; Betley, T. A. J. Am. Chem. Soc. 2011, 133, 4917; (b)
Lyaskovskyy, V.; Olivos Suarez, A. I.; Lu, H.; Jiang, H.; Peter Zhang, X.; de Bruin,
B. J. Am. Chem. Soc. 2011, 133, 12264; (c) Lu, H.; Tao, J.; Jones, J. E.; Wojtas, L.;
Peter Zhang, X. Org. Lett. 2010, 12, 1248; (d) Díaz-Requejo, M. M.; Belderraín, T.
R.; Nicasio, M. C.; Trofimenko, S.; Pérez, P. J. J. Am. Chem. Soc. 2003, 125, 12078;
(e) Fructos, M. R.; Trofimenko, S.; Mar Díaz-Requejo, M.; Pérez, P. J. J J. Am.
Chem. Soc. 2006, 128, 11784; (f) Kurokawa, T.; Kim, M.; Du Bois, J. Angew. Chem.,
Int. Ed. 2009, 48, 2777; (g) Zalatan, D. N.; Du Bois, J. J. Am. Chem. Soc. 2008, 130,
9220; (h) Lebel, H.; Huard, K.; Lectard, S. J. Am. Chem. Soc. 2005, 127, 14198; (i)
Huard, K.; Lebel, H. Chem. -Eur. J. 2008, 14, 6222.
7. Gephart, R. T., III; Huang, D. L.; Aguila, Mae J. B.; Schmidt, G.; Shahu, A.; Warren,
T. H. Angew. Chem., Int. Ed. 2012, 51, 6488.
8. Wang, Z.; Mo, H.; Cheng, D.; Bao, W. Org. Biomol. Chem. 2012, 10, 4249.
9. (a) Zhang, C.; Kanta De, C.; Mal, R.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 416;
(b) Zeng, L.; Yi, W.; Cai, C. Eur. J. Org. Chem. 2012, 559; (c) Sun, M.; Zhang, T.;
Bao, W. J. Org. Chem. 2013, 78, 8155.
10. (a) Crich, D.; Banerjee, A. Acc. Chem. Res. 2007, 40, 151; (b) Hajicek, J.; Taimr, J.;
Budesinsky, M. Tetrahedron Lett. 1998, 39, 505.
11. (a) Katritzky, A. R.; Shobana, N.; Harris, P. A. Tetrahedron Lett. 1991, 32, 4247;
(b) Katritzky, A. R.; Manju, K.; Singh, S. K.; Meher, N. K. Tetrahedron 2005, 61,
2555; (c) Hatano, B.; Nagahashi, K.; Kijima, T. J. Org. Chem. 2008, 73, 9188; (d)
Zhou, Y.; Xie, Y.; Yang, L.; Xie, P.; Huang, H. Tetrahedron Lett. 2013, 54, 2713.
12. Pan, S.; Liu, J.; Li, H.; Wang, Z.; Guo, X.; Li, Z. Org. Lett. 2010, 12, 1932.
3. (a) Dick, A. R.; Remy, M. S.; Kampf, J. W.; Sanford, M. S. Organometallics 2007,
26, 1365; (b) Thu, H.; Yu, W.; Che, C. J. Am. Chem. Soc. 2006, 128, 9048; (c)
Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560; (d)
Li, B.; Tian, S.; Fang, Z.; Shi, Z. Angew. Chem., Int. Ed. 2008, 47, 1115; (e) Inamoto,
K.; Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya, K. Org. Lett. 2007, 9, 2931; (f)
Jordan-Hore, J. A.; Johansson, C. C. C.; Gulias, M.; Beck, E. M.; Gaunt, M. J. J. Am.
Please cite this article in press as: Sun, M.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2013.12.043