Azobisisobutyronitrile initiated aerobic oxidative transformation of amines: Coupling of primary amines and cyanation of tertiary amines

Article abstract of DOI:10.1021/ol302708r

In the presence of a catalytic amount of radical initiator AIBN, primary amines are oxidatively coupled to imines and tertiary amines are cyanated to α-aminonitriles. These "metal-free" aerobic oxidative coupling reactions may find applications in a wide

Full text of DOI:10.1021/ol302708r

ORGANIC
LETTERS
2
012
Vol. 14, No. 22
692–5695
Azobisisobutyronitrile Initiated Aerobic
Oxidative Transformation of Amines:
Coupling of Primary Amines and
Cyanation of Tertiary Amines
5
Lianghui Liu, Zikuan Wang, Xuefeng Fu,* and Chun-Hua Yan
Beijing National Laboratory for Molecular Sciences, State Key Lab of Rare Earth
Materials Chemistry and Applications, College of Chemistry and Molecular
Engineering, Peking University, Beijing, 100871, P. R. China
fuxf@pku.edu.cn
Received October 1, 2012
ABSTRACT
In the presence of a catalytic amount of radical initiator AIBN, primary amines are oxidatively coupled to imines and tertiary amines are cyanated to
R-aminonitriles. These “metal-free” aerobic oxidative coupling reactions may find applications in a wide range of “green” oxidation chemistry.
1
Imines and R-aminonitriles are versatile synthetic inter-
mediates in a variety of organic transformations where
imines are widely used in addition, reduction, aziridination,
β-lactamization, and cyclization reactions, and R-aminoni-
triles are useful precursors to synthesize R-amino acids,
2
R-amino aldehydes, R-amino alcohols, and 1,2-diamines.
Oxidative coupling of primary amines provides an alter-
3
À11
(
1) For reviews on the formation of imines and typical reactions: (a)
native strategy to the synthesis of imines,
and oxidative
Murahashi, S. -I. Angew. Chem., Int. Ed. Engl. 1995, 34, 2443. (b)
Adams, J. P. J. Chem. Soc., Perkin Trans. 1 2000, 125. (c) Samec,
cyanation of tertiary amines represents one of the most
convenient and straightforward methods to prepare
ꢀ
J. S. M.; Ell, A. H.; B €a ckvall, J. -E. Chem.;Eur. J. 2005, 11, 2327.
1
2À19
(2) (a) Dyker, G. Angew. Chem., Int. Ed. Engl. 1997, 36, 1700. (b)
R-aminonitriles.
These two closely related oxidative
Enders, D.; Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359. (c) North, M.
Angew. Chem., Int. Ed. 2004, 43, 4126. (d) Murahashi, S. -I.; Zhang, D.
Chem. Soc. Rev. 2008, 37, 1490.
transformations were proposed to occur through a nu-
cleophilic addition reaction to the key intermediate im-
ines and iminium ions containing CdN units. Compared
(3) For recent examples catalyzed by Cu: (a) Patil, R. D.; Adimurthy,
S. Adv. Synth. Catal. 2011, 353, 1695. (b) Hu, Z.; Kerton, F. M. Org.
Biomol. Chem. 2012, 10, 1618. (c) Largeron, M.; Fleury, M. ÀB. Angew.
Chem., Int. Ed. 2012, 51, 5409.
(
4) Catalyzed by Ru: (a) Prades, A.; Peris, E.; Albrecht, M. Orga-
(7) Catalyzed by V: (a) Nakayama, K.; Hamamoto, M.; Nishiyama,
Y.; Ishii, Y. Chem. Lett. 1993, 1699. (b) Kodama, S.; Yoshida, J.;
Nomoto, A.; Ueta, Y.; Yano, S.; Ueshima, M.; Ogawa, A. Tetrahedron
Lett. 2010, 51, 2450. (c) Chu, G.; Li, C. Org. Biomol. Chem. 2010, 8, 4716.
(8) CatalyzedbysolidÀacid: Landge, S. M.; Atanassova, V.; Thimmaiah,
M.; T o€ r o€ k, B. Tetrahedron Lett. 2007, 48, 5161.
nometallics 2011, 30, 1162. (b) He, L.; Chem, T.; Gong, D.; Lai, Z.;
Huang, K. Organometallics 2012, 31, 5208.
(
Angew. Chem., Int. Ed. 2011, 50, 3934. (b) Lang, X.; Ma, W.; Zhao, Y.;
Chen, C.; Ji, H.; Zhao, J. Chem.;Eur. J. 2012, 18, 2624.
5) Catalyzed by Ti: (a) Lang, X.; Ji, H.; Chen, C.; Ma, W.; Zhao, J.
(
6) Catalyzed by Au: (a) Zhu, B.; Angelici, R. J. Chem. Commun.
(9) Catalyzed by Carbon nitride or graphite oxide: (a) Su, F.;
Mathew, S. C.; M o€ hlmann, L.; Antonietti, M.; Wang, X.; Blechert, S.
Angew. Chem., Int. Ed. 2011, 50, 657. (b) Huang, H.; Huang, J.; Liu, Y.;
He, H.; Cao, Y.; Fan, K. Green Chem. 2012, 14, 930.
(10) Electrochemical methods: (a) Largeron, M.; Neudorffer, A.;
Fleury, M.-B. Angew. Chem., Int. Ed. 2003, 42, 1026. (b) Mure, M. Acc.
Chem. Res. 2004, 37, 131. (c) Xu, D.; Chiaroni, A.; Fleury, M.-B.;
Largeron, M. J. Org. Chem. 2006, 71, 6374. (d) Largeron, M.; Chiaroni,
A.; Fleury, M.-B. Chem.;Eur. J. 2008, 14, 996.
2
007, 2157. (b) Zhu, B.; Lazar, M.; Trewyn, B. G.; Angelici, R. J. J.
Catal. 2008, 260, 1. (c) Aschwanden, L.; Panella, B.; Rossbach, P.;
Keller, B.; Baiker, A. ChemCatChem 2009, 1, 111. (d) Aschwanden, L.;
Mallat, T.; Krumeich, F.; Baiker, A. J. Mol. Catal. A: Chem. 2009, 309,
7. (e) Grirrane, A.; Corma, A.; Garcia, H. J. Catal. 2009, 264, 138. (f)
So, M.-H.; Liu, Y.; Ho, C.-M.; Che, C.-M. Chem.;Asian. J. 2009, 4,
551. (g) So, M.-H.; Liu, Y.; Ho, C.-M.; Lam, K.-Y.; Che, C.-M.
ChemCatChem 2011, 3, 386.
5
1
1
0.1021/ol302708r r 2012 American Chemical Society
Published on Web 10/29/2012

to toxic and/or precious metal systems, metal-free sys-
tems using dioxygen as the sole oxidant for oxidative
The results of control experiments for the oxidative
coupling of benzylamine are illustrated inTable 1. Without
AIBN, only a trace amount of benzylidene-benzylamine
(2% yield) is formed (Table 1, entry 1). In the presence of
10 mol % of AIBN under a nitrogen atmosphere, the imine
product is observed with a 3% yield (Table 1, entry 2).
However, the yield increases to 11% when the reaction is
performed in air (Table 1, entry 3). And the conversion
reaches as high as 95% with good yield (74%) under 1 atm
of dioxygen (Table 1, entry 4). Using 2 equiv of hydrogen
peroxide or tert-butyl peroxide (TBHP) as the oxidant, the
yield is 21% and 15% (Table 1, entries 5À6). The thermal
decomposition of AIBN follows first-order kinetics, and
the half-time in benzene is about 1.4 h at 80°C, 5 h at 70 °C,
2
0
coupling reactions remain scarce.
Azobisisobutyronitrile (AIBN) is extensively used in
initiating radical polymerization under anaerobic reaction
conditions because carbon centered radicals are prone to
capture dioxygen to form peroxy radicals which interrupt
2
1
the polymer chain propagation. Recently, AIBN was
reported to initiate aerobic oxidation reactions by taking
2
2
advantage of peroxy radicals. In this paper we report on
the AIBN initiated metal-free aerobic oxidative coupling
of primary amines to imines and oxidative cyanation of
tertiary amines to R-aminonitriles through highly reactive
imines/iminium ion intermediates.
2
3
and 21 h at 60 °C. The reaction conditions are examined,
and the optimum conditions are 70 °C in toluene where the
yield is up to 83% (Table 1, entries 7À9; Table 1S).
(
11) (a) Hirao, T.; Fukuhara, S. J. Org. Chem. 1998, 63, 7534. (b) Chi,
K.; Hwang, H. Y.; Park, J. Y.; Lee, C. W. Synth. Met. 2009, 159, 26. (c)
Wan, X.; Xing, D.; Fang, Z.; Li, B.; Zhao, F.; Zhang, K.; Yang, L.; Shi,
Z. J. Am. Chem. Soc. 2006, 128, 12046. (d) Dhakshinamoorthy, A.;
Alvaro, M.; Garcia, H. ChemCatChem 2010, 2, 1438. (e) Liu, L.; Zhang,
S.; Fu, X.; Yan, C.-H. Chem. Commun. 2011, 47, 10148. (f) Furukawa,
S.; Ohno, Y.; Shishido, T.; Teramura, K.; Tanaka, T. ACS Catal. 2011,
a
Table 1. AIBN Initiated Oxidation of Benzylamine
1, 1150. (g) Zhou, X.; Ren, Q.; Ji, H. Tetrahedron Lett. 2012, 53, 3369. (h)
Wendlandt, A. E.; Stahl, S. S. Org. Lett. 2012, 14, 2850. (i) Yuan, H.;
Yoo, W.; Miyamura, H.; Kobayashi, S. J. Am. Chem. Soc. 2012, 134,
1
3970.
12) For recent examples catalyzed by Ru, see: (a) Murahashi, S.-I.;
Komiya, N.; Terai, H.; Nakae, T. J. Am. Chem. Soc. 2003, 125, 15312.
b) Murahashi, S.-I.; Komiya, N.; Terai, H. Angew. Chem., Int. Ed. 2005,
4, 6931. (c) Murahashi, S.-I.; Nakae, T.; Terai, H.; Komiya, N. J. Am.
(
b
b
initiator
(mol)
additive
(equiv)
temp conv
yield
(%)
entry
gas
(°C)
(%)
(
4
1
2
3
4
5
6
7
8
À
O
2
À
80
80
80
80
80
80
60
70
70
2
3
2
3
Chem. Soc. 2008, 130, 11005. (d) Verma, S.; Jain, S. L.; Sain, B. Catal.
Lett. 2011, 141, 882. (e) Verma, S.; Jain, S. L.; Sain, B. ChemCatChem
AIBN (10%)
N
2
À
À
À
H
2011, 3, 1329.
AIBN (10%) Air
11
95
36
15
44
95
94
11
74
21
15
41
77
83
(
13) Catalyzed by Fe: (a) Han, W.; Ofial, A. R. Chem. Commun.
AIBN (10%)
AIBN (10%)
AIBN (10%)
AIBN (10%)
AIBN (10%)
AIBN (10%)
O
2
2009, 5024. (b) Singhal, S.; Jain, S. L.; Sain, B. Adv. Synth. Catal. 2010,
N
N
2
2
2 2
O (2)
352, 1338. (c) Liu, P.; Liu, Y.; Wong, E. L.; Xiang, S.; Che, C.-M. Chem.
TBHP (2)
Sci. 2011, 2, 2187.
14) Catalyzed by V: Singhal, S.; Jain, S. L.; Sain, B. Chem. Commun.
009, 2371.
15) Catalyzed by Au: Zhang, Y.; Peng, H.; Zhang, M.; Cheng, Y.;
Zhu, C. Chem. Commun. 2011, 47, 2354.
16) Catalyzed by Mo: Alagiri, K.; Prabhu, K. R. Org. Biomol.
Chem. 2012, 10, 835.
17) Catalyzed by Cu: (a) Li, Z.; Li, C.-J. Eur. J. Org. Chem. 2005,
O
O
O
2
2
2
À
À
À
(
2
c
(
9
(
a
Reaction conditions: benzylamine (0.60 mmol), benzene (1 mL), in
a 45 mL Schlenk tube, the gaseous pressure Pinitial = 1 bar, 12 h. GC
b
(
c
results. In toluene, 8 h.
3173. (b) Boess, E.; Schmitz, C.; Klussmann, M. J. Am. Chem. Soc. 2012,
134, 5317.
(
18) For recent photolytic systems: (a) Hari, D. P.; K o€ nig, B. Org.
The oxidation of various primary amines under optimum
conditions is listed in Table 2. Benzylamine is oxidized to
benzylidene-benzylamine in a yield of 89% using 7 mol % of
AIBN (Table 2, entry 1). A variety of substituted benzyl
amine derivatives are also observed to form imines in good
to excellent yields (Table 2, entries 2À7). Electronic effects
associated with electron-donating and -withdrawing sub-
stituents on the phenyl ring have little effect on the efficiency
of the oxidation reaction (Table 2, entries 2À6). A note-
worthy feature of this method is the formation of imine P7
Lett. 2011, 13, 3852. (b) Pan, Y.; Wang, S.; Kee, C. W.; Dubuisson, E.;
Yang, Y.; Loh, K. P.; Tan, C.-H. Green Chem. 2011, 13, 3341. (c)
Rueping, M.; Zhu, S.; Koenigs, R. M. Chem. Commun. 2011, 47, 12709.
d) Rueping, M.; Zoller, J.; Fabry, D. C.; Poscharny, K.; Koenigs,
R. M.; Weirich, T. E.; Mayer, J. Chem.;Eur. J. 2012, 18, 3478.
19) Using a stoichiometric oxidant: (a) Shu, X.; Xia, X.; Yang, Y.;
(
(
Ji, K.; Liu, X.; Liang, Y. J. Org. Chem. 2009, 74, 7464. (b) Allen, J. M.;
Lambert, T. H. J. Am. Chem. Soc. 2011, 133, 1260.
(
20) Typical examples: (a) Schmidt, V. A.; Alexanian, E. J. Angew.
ꢀ
Chem., Int. Ed. 2010, 49, 4491. (b) Pint ꢀe r, A.; Sud, A.; Sureshkumar, D.;
Klussmann, M. Angew. Chem., Int. Ed. 2010, 49, 5004. (c) Giglio, B. C.;
Schmidt, V. A.; Alexanian, E. J. J. Am. Chem. Soc. 2011, 133, 13320. (d)
Schmidt, V. A.; Alexanian, E. J. Chem. Sci. 2012, 3, 1672.
(
21) Kishore, K.; Paramasivam, S.; Sandhya, T. E. Macromolecules
996, 29, 6973.
22) (a) Bentrude, W. G.; Sopchik, A. E.; Gajda, T. J. Am. Chem. Soc.
989, 111, 3981. (b) Fukuda, O.; Sakaguchi, S.; Ishii, Y. Tetrahedron
Lett. 2001, 42, 3479. (c) Aoki, Y.; Sakaguchi, S.; Ishii, Y. Adv. Synth.
Catal. 2004, 346, 199. (d) Aoki, Y.; Sakaguchi, S.; Ishii, Y. Tetrahedron
(Table 2, entry 7), which is a significant improvement for the
preparation of sterically hindered imines.
1
1
1e,24
(
Hetero-
1
cyclic methylamines containing sulfur, oxygen, and nitro-
gen atoms which usually coordinate and deactive the
metal catalysts could also be converted to imines in
moderate to high yields indicating a good tolerance of
heteratoms (Table 2, entries 8À10). Oxidative coupling of
furfurylamine to imine P9 requires 15 mol % of AIBN to
2
005, 61, 5219. (e) Aoki, Y.; Hirai, N.; Sakaguchi, S.; Ishii, Y. Tetra-
hedron 2005, 61, 10995. (f) Nakamura, R.; Obora, Y.; Ishii, Y. Chem.
Commun. 2008, 3417. (g) Kamae, K.; Obora, Y.; Ishii, Y. Bull. Chem.
Soc. Jpn. 2009, 82, 891. (h) Look, J. L.; Wick, D. D.; Mayer, J. M.;
Goldberg, K. I. Inorg. Chem. 2009, 48, 1356. (i) Boisvert, L.; Denney,
M. C.; Hanson, S. K.; Goldberg, K. I. J. Am. Chem. Soc. 2009, 131,
15802. (j) Lloyd, R.; Jenkins, R. L.; Piccinini, M.; He, Q.; Kiely, C. J.;
Carley, A. F.; Golunski, S. E.; Bethell, D.; Bartley, J. K.; Hutchings,
G. J. J. Catal. 2011, 283, 161.
(23) Hook, J. P. V.; Tobolsky, A. V. J. Am. Chem. Soc. 1958, 80, 779.
(24) Love, B. E.; Ren, J. J. Org. Chem. 1993, 58, 5556.
Org. Lett., Vol. 14, No. 22, 2012
5693

give a 46% yield (Table 2, entry 9) which is higher than
5
Zhao’s reported results (33%À38% yield). Surprisingly,
Table 3. AIBN Initiated Oxidative Cyanation of N,N-Di-
methylaniline
2
-picolylamine is efficiently oxidized to imine P10 in the
a
presence of only 3 mol % of AIBN with good yield and
high selectivity (Table 2, entry 10). The oxidation of alipha-
tic amines under the same reaction conditions produces low
yields of imines (Table 2, entry 11).
The high efficiency of the AIBN initiated aerobic oxida-
tive coupling of primary amines prompted us to try oxida-
tive cyanation of tertiary amines which may occur in a
similar pathway where highly reactive iminium ion inter-
mediates are generated and trapped by the nucleophile
cyanide ion to form R-aminonitriles.
AIBN
HO Ac
(equiv)
t
conv
yield
b
b
entry
(mol %)
(h)
(%)
(%)
1
2
3
4
15
50
50
20
13
À
12
12
12
12
24
45
93
99
93
94
36
63
80
89
89
À
1.0
1.6
1.6
c
5
a
Reaction conditions: amine (0.20 mmol), TMSCN (0.24 mmol),
a
Table 2. Scope of the Primary Amines
methanol (1 mL), in a 45 mL Schlenk tube, oxygen pressure P
1
initial
=
b
c
bar, 70 °C. GC results. TMSCN (0.40 mmol), methanol (2 mL).
However, N,N-dimethyl-m-toluidine and N,N-dimethyl-
p-toluidine are both converted to cyanated products effec-
tively with 82% and 89% yields, respectively (Table 4,
entries 3À4). This system can also be applied to bromo-
and fluoro-substituted compounds (Table 4, entries 5À6)
and cyclic amines (Table 4, entries 7À8). In order to ex-
plore the potential practical application of this meth-
od, the scale-up experiments were performed in a
5
5
00 mL Schlenk flask under 1 bar of oxygen containing
.0 mmol of p-bromo-N,N-dimethylaniline; a 90%
conversion and 78% isolated yield were obtained
(Table 4, entry 5).
The mechanism of alkane autoxidation generally occurs
2
2h,i,25
via pathways described in Scheme 1.
In the initiation
step, the 2-cyano-2-propylperoxyl radical (CPOO ) is pro-
3
posed to be the active species which grabs a hydrogen atom
from alkane to form 2-cyano-2-propyl hydrogen peroxide
(
CPOOH) and radical R initiating chain reactions.
3
It has been reported that, after releasing one molecule of
oxygen, two alkylperoxyl radicals produce two alkyloxyl
radicals. Janzen and cowokers also detected 2-cyano-2-
propyl peroxide (CPOOCP) by ESR-MS after heating the
AIBN solution under air conditions. We observed that
CPOOCP was the main product in the absence of amines
while acetone was the dominant product in the presence of
amines from H and C NMR analysis (Figures 11S, 12S).
Combining this information, we propose that the effective
initiating species is the 2-cyano-2-propyloxyl radical
2
6a
a
Reaction conditions: amine (0.60 mmol), AIBN (0.060 mmol,
0 mol %), toluene (1 mL), in a 45 mL Schlenk tube, oxygen pressure
2
6b
1
b
c
d
e
Pinitial =1bar, 70°C, 8 h. GC results. 12 h. 7mol%ofAIBN. 15 mol %
f
of AIBN. 3 mol % of AIBN.
1
13
In the presence of a catalytic amount of AIBN, metal-
free oxidative cyanation of tertiary amines was accom-
plished. A 36% yield is produced with 15 mol % of AIBN
(CPO ) which is in equilbrium with CPOOCP. After
grabbing a hydrogen atom from amines, CPO is con-
3
3
(
Table 3, entry 1), and 50 mol % of AIBN leads to a 63%
verted to the acetone cyanohydrin (CPOH) intermediate
with the formation of an R-aminoalkyl radical A. Subse-
quently, CPOHisrapidlydeprotonated toformacetone by
yield (Table 3, entry 2). However, the yield dramatically
increases to 80% with the addition of 1 equiv of acetic acid
(
Table 3, entry 3) and is up to 89% using only 20 mol % of
À
releasing a CN anion (Scheme 2).
AIBN when 1.6 equiv of acid is added (Table 3, entry 4).
Prolonging the reaction time resulted in an excellent yield
using 13 mol % of AIBN (Table 3, entry 5).
Substituted N,N-dimethylanilines, with electron-donating
or -withdrawing groups, give the corresponding cyanated
products with excellent yields (Table 4) except for N,N-
dimethyl-o-toluidine with a yield of 50% (Table 4, entry 2).
(
25) (a) Boozer, C. E.; Hammond, G. S.; Hamilton, C. E.; Sen, J. N.
J. Am. Chem. Soc. 1955, 77, 3233. (b) Mayo, F. R. Acc. Chem. Res. 1968,
, 193. (c) Betts, J. Rev. Chem. Soc. 1971, 25, 265–288. (d) Porter, N. A.
Acc. Chem. Res. 1986, 19, 262.
26) (a) Bartlett, P. D.; Traylor, T. G. Org. Biol. Chem. 1963, 85, 2407.
b) Janzen, E. G.; Krygsman, P. H.; Lindsay, D. A.; Haire, D. L. J. Am.
Chem. Soc. 1990, 112, 8279.
1
(
(
5
694
Org. Lett., Vol. 14, No. 22, 2012

a
Table 4. Scope of Tertiary Amines
Scheme 1. General Pathways for AIBN Initiated Autoxidation
Scheme 2. Proposed Pathways of the AIBN Transformation in
Our System
Scheme 3. Proposed Mechanism of the Chain-Propagating and
Product-Forming Steps
a
Reaction conditions: amine (0.20 mmol), TMSCN (0.40 mmol),
HOAc (0.32 mmol, AIBN (0.025 mmol), methanol (2 mL), in a 45 mL
b
Schlenk tube, oxygen pressure Pinitial = 1 bar, 70 °C, 24 h. GC results.
Amine (5.0 mmol), TMSCN (10 mmol), HOAc (8.0 mmol), AIBN (0.63
c
d
mmol), methanol (50 mL), in a 500 mL Schlenk flask. 10% of amine
e
was recycled. Isolated yield.
The radical A is readily trapped by oxygen to generate a
peroxide radical B which abstracts a hydrogen atom from
free amines to form one molecule of C (Scheme 3). C
releases a hydrogen peroxide to give an imine intermediate
D or an iminium cation E which rapidly reacts with a
nucleophile (amine or cyanide ion) to form the product
imine or R-aminonitrile. The lower reactivity of aliphatic
amine compared with the aromatic methylamine may ori-
ginate from the lower stability and poorer selectivity of
of tertiary amines to R-aminonitriles. A catalytic amount
of AIBN is consumed, and dioxygen is the sole oxidant in
this metal-free system. This clean and mild synthetic
method may provide an ideal strategy for the rational
3
design of systems for the functionalization of sp CÀH
bonds adjacent to nitrogen.
Acknowledgment. This work was supported by Na-
tional Science Foundation of China (Grants 20801002
and 21171012).
5
a
the radical intermediate formed in these processes.
The enhanced rate of cyanation reactions by acid most
probably results from (1) acid promoting formation of
free cyanide anions from the reaction of the acetic
anion with TMSCN and (2) suppression of the side
reaction by inhibiting the hydrolysis of the iminium
cation to a secondary amine.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
In summary, we developed the AIBN initiated aerobic
oxidative coupling of primary amines to imines and cyanation
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 22, 2012
5695