Mechanistic investigations on the reaction between amines or amides and an alkylperoxy-λ3-iodane

Article abstract of DOI:10.1021/jo0268005

A mechanism involving the intermediate formation of an amine radical cation by single-electron transfer is proposed for the oxidation of secondary amines with alkylperoxy-λ³-iodane. On the other hand, the oxidation of acetamides probably proceeds by a radical process, which involves the direct hydrogen abstraction of the methylene group α to the nitrogen atom.

Full text of DOI:10.1021/jo0268005

Mech a n istic In vestiga tion s on th e Rea ction
betw een Am in es or Am id es a n d a n
Alk ylp er oxy-λ3-iod a n e
Takuya Sueda,* Daisuke Kajishima, and Satoru Goto
Faculty of Pharmaceutical Sciences, University of
Tokushima, 1-78 Shomachi, Tokushima 770-8505, J apan
tsueda@ph2.tokushima-u.ac.jp
Received December 4, 2002
F IGUR E 1. Homolytic cleavage of the hypervalent iodine-
(III)-peroxy oxygen bond.
Abstr a ct: A mechanism involving the intermediate forma-
tion of an amine radical cation by single-electron transfer
is proposed for the oxidation of secondary amines with
alkylperoxy-λ3-iodane. On the other hand, the oxidation of
acetamides probably proceeds by a radical process, which
involves the direct hydrogen abstraction of the methylene
group R to the nitrogen atom.
SCHEME 1. Com p etitive Rea ction s of Oxid a tion
for N-Ben zyla n ilin e Der iva tives 4 w ith 1
Compound 11 is a stable solid alkylperoxy-λ3-iodane
that can be safely stored at room temperature for an
indefinite period of time. In contrast, it gradually de-
composes in solution at room temperature to generate
tert-butylperoxy radical 2 and o-iodobenzoyloxy radical
3 via homolytic bond cleavage of the hypervalent iodine-
(III)-peroxy bond (Figure 1). This property implies that
alkylperoxy-λ3-iodane 1 would be a very important re-
agent capable of performing the radical oxidation of a
variety of organic compounds under mild conditions.2 For
example, we reported that the oxidation of secondary and
tertiary amines with 1 proceeded at room temperature
to yield imines and tert-butylperoxyamino acetals, re-
spectively.3 Alkylperoxy-λ3-iodane 1 also oxidized the
methylene groups R to the nitrogen atom of amides (or
carbamates) yielding imides or tert-butylperoxyamido
acetals.4 We proposed that these reactions probably
proceeded by a radical process. We report here mecha-
nistic investigations on the reactions of amines or amides
with alkylperoxy-λ3-iodane 1 by measuring the relative
rates of oxidation and the kinetic deuterium isotope
effects.
TABLE 1. Rela tive Rea ctivity of N-Ben zyla n ilin es 4a -d
w ith 1 a t 30 °C
a
substrate
krel
4b (R1 ) OMe)
4c (R1 ) Me)
4a (R1 ) H)
1.07
0.88
1.00
1.13
4d (R1 ) Cl)
a
Relative rates were determined by 1H NMR.
significant substituent effect was observed for the p-
substituent R1 on the phenyl ring in the benzylic group
of N-benzylaniline. Furthermore, the Hammett correla-
tion plot for the oxidation of these N-benzylanilines 4a -d
presented in Table 1 did not show a good correlation. This
result indicates that the rate-determing step of the
reactions does not involve C-H bond cleavage of the
benzylic methylene group, which surprised us greatly,
since we reported that the rate-determing step of the
oxidation of benzyl ethers with 12d probably involves a
high degree of benzylic C-H bond breaking.
Our initial studies focused on the substituent effect on
the phenyl ring in the benzylic group or the aniline
moiety of N-benzylaniline (Scheme 1). The relative rates
of oxidation for the p-substituent R1 in the benzylic group
of N-benzylaniline were measured at 30 °C in benzene
by competitive reactions, in which a mixture of 25-fold
excesses of two competing substrates was used. No
We also examined whether the p-substituent R2 on the
phenyl ring in the aniline moiety of N-benzylaniline
(4a ,e-g) influences the reaction rate under similar
reaction conditions described above. The results are
shown in Table 2, and it is observed that the reactivity
of N-benzylaniline 4 depends strongly on the nature of
substituent R2. Electron-releasing groups such as MeO
(4e) and Me (4f) increase the rate of oxidation, and an
electron-withdrawing group such as Cl (4g) decreases the
rate of oxidation, suggesting that the electronic state in
the aniline moiety is very important for the oxidation of
N-benzylaniline with 1.
(1) Synthesis and characterization of alkylperoxy-λ3-iodane 1, see:
Ochiai, M.; Ito, T.; Masaki, Y.; Shiro, M. J . Am. Chem. Soc. 1992, 114,
6269. Alkylperoxy-λ3-iodane 1 can now be purchased from Tokyo Kasei
Kogyo Co., Ltd.
(2) For our studies of oxidation reactions with alkylperoxy-λ3-iodane
1, see the following. (a) Oxidative ring cleavage of cyclic acetals: Sueda,
T.; Fukuda, S.; Ochiai, M. Org. Lett. 2001, 3, 2387. (b) Oxidation of
para-substituted phenols: Ochiai, M.; Nakanishi, A.; Yamada, A.
Tetrahedron Lett. 1997, 38, 3927. (c) Oxidation of sulfides: Ochiai, M.;
Nakanishi, A.; Ito, T. J . Org. Chem. 1997, 62, 4253. (d) Oxidation and
deprotection of benzyl and allyl ethers: Ochiai, M.; Ito, T.; Takahashi,
H.; Nakanishi, A.; Toyonari, M.; Sueda, T.; Goto, S.; Shiro, M. J . Am.
Chem. Soc. 1996, 118, 7716.
(3) Ochiai, M.; Kajishima, D.; Sueda, T. Heterocycles 1997, 46, 71.
(4) Ochiai, M.; Kajishima, D.; Sueda, T. Tetrahedron Lett. 1999, 40,
5541.
The plot of the relative reactivity of 4a or 4e-g vs the
σ+ value gave a linear correlation with a value of F+
)
10.1021/jo0268005 CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/15/2003
J . Org. Chem. 2003, 68, 3307-3310
3307

TABLE 2. Rela tive Rea ctivity of N-Ben zyla n ilin es 4a
a n d 4e-g w ith 1 a t 30 °C
hols were oxidized to the corresponding aldehydes and
ketones in good yield when a catalytic amount of TEMPO
was used in combination with (diacetoxy)iodobenzene as
stoichiometric oxidants. In these reactions, 2,2,6,6-tetra-
methylpiperidinium salt9 generated in situ oxidizes al-
cohols to aldehydes or ketones.8b Furthermore, it is
known that N-oxoammonium salts can oxidize tertiary
amines to give the corresponding immonium salts.10
Therefore, under our conditions, an N-oxoammonium salt
is possibly generated from the reaction of TEMPO with
1 and oxidizes N-benzylaniline 4a to N-benzylidene-
aniline 5a .11 Attempts to further study the effects of a
radical scavenger by addition of a galvinoxyl free-radical
also were unsuccessful.12
a
substrate
krel
σ+b
IPc (eV)
4e
4f
4a
4g
12.80
4.43
1.00
1.02
-0.78
-0.31
0
8.27
8.40
8.52
8.51
0.11
a
b
Relative rates were determined by 1H NMR. See ref 5. c IP
) ionization potential. See ref 6.
SCHEME 2. Rea ction of N-Ben zyla n ilin e 4a w ith 1
in th e P r esen ce of TEMP O
We also compared the electron affinities (EA) of alkyl-
peroxy-λ3-iodane 1, tert-butylperoxy radical 2, and o-
iodobenzoyloxy radical 3b by using a computational
analysis. Brinck estimated the EA of 2 to be -1.20 eV,13
and this is in agreement with experimental data (-1.20
eV).14 We also estimate the EA of 1 and 3b to be +0.686
and -2.54 eV, respectively, by using the Gaussian 98
program.15 Compared to those, o-iodobenzoyloxy radical
3b is the most electron-accepting and single-electron
transfer is not likely to occur from N-benzylaniline 4a to
1. This hypothesis should be discussed when the cleavage
of the hypervalent iodine(III)-peroxy bond of the alkyl-
peroxy-λ3-iodane 1 proceeds smoothly. Therefore, we
estimated homolytic bond dissociation enthalpy (BDE)
for the hypervalent iodine(III)-peroxy bond of the alkyl-
peroxy-λ3-iodane 1 to be 1.84 eV.16 Since the BDE is
SCHEME 3. Mech a n ism for Rea ction of
N-Ben zyla n ilin e 4a w ith Alk ylp er oxy-λ3-iod a n e 1
-1.32 (r ) 0.98). This F+ value appears to be comparable
to F+ ) -1.8 or -1.1 for an electron transfer from the
aniline moiety in N-benzylaniline by a cobalt Shiff base
complex.7 Moreover, good correlation of the relative
reactivity with the ionization potential (IP) of 4a or 4e-g
was also observed. These results suggest that the rate-
determining step for oxidation of N-benzylanilines 4 with
1 most probably involves an electron transfer from 4 to
give anilinium radical cations 6a (Scheme 3).
Since it is not clear whether single-electron transfer
occurs from N-benzylaniline 4a to alkylperoxy-λ3-iodane
1 or to tert-butylperoxy radical 2 or o-iodobenzoyloxy
radical 3 generated from decomposition of 1, next we
examined the effect of free-radical scavengers. If the
electron transfer from amine to radical species 2 or 3 is
a major process, the oxidation may be prevented by the
free-radical scavenger. However, the reaction of N-
benzylaniline 4a with 1 in the presence of 2,2,6,6-
tetramethylpiperidinyloxy free-radical (TEMPO) under
an argon atmosphere gave N-benzylideneaniline 5a in
high yield (Scheme 2).
(9) N-Oxoammonium salts have been demonstrated to be useful
reagents for the transformation of alcohols; see: de Nooy, A. E. J .;
Besemer, A. C.; VanBekkum, H. Synthesis 1996, 1153.
(10) (a) Bobbitt, J . M.; Ma, Z. Heterocycles 1992, 33, 641. (b) Hunter,
D. H.; Barton, D. H. R.; Motherwell, W. J . Tetrahedron Lett. 1984, 25,
603.
(11) We calculated the ionization potentials of TEMPO and N-
benzylaniline 4a at the B3LYP/6-311+G(2d,p)//B3LYP/6-31G(d) level
of theory to give very similar values of 6.99 and 7.00 eV, respectively.
(12) Galvinoxyl reacts with tert-amines via single-electron transfer
to give ammonium radical cations; see: Screttas, C. G.; Heropoulos,
G. A. Magn. Res. Chem. 1990, 28, 878.
(13) Brinck, T.; Lee, H.-N.; J onsson, M. J . Phys. Chem. A 1999, 103,
7094.
(14) Clifford, E. P.; Wenthold, P. G.; Garejev, R.; Lineberger, W. C.;
Depuy, C. H.; Bierbaum, V. M.; Ellison, G. B. J . Chem. Phys. 1998,
109, 10293.
(15) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J . R.; Zakrzewski, V. G.; Montgomery, J . A.,
J r.; Stratmann, R. E.; Burant, J . C.; Dapprich, S.; Millam, J . M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J .;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J .; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J . B.; Cioslowski, J .; Ortiz, J . V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J .; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; J ohnson, B. G.; Chen,
W.; Wong, M. W.; Andres, J . L.; Head-Gordon, M.; Replogle, E. S.;
Pople, J . A. Gaussian 98, revision A.11; Gaussian, Inc.: Pittsburgh,
PA, 1998. Optimized and harmonic frequencies for alkylperoxy-λ3-
iodane 1, the radical anion of (alkylperoxy)iodane, o-iodobenzoyloxy
radical 3b, and o-iodobenzoyloxy anion have been computed at the
UHF/3-21G level of theory. We have also performed single-point energy
calculations for the molecules at the UB3LYP/3-21G* level using UHF/
3-21G geometries. The EA energy expression in UB3LYP/3-21G* has
the following form: EA (1) ) E(radical anion of 1) - E(1); EA (3b) )
E(o-iodobenzoyloxy anion) - E(3b).
TEMPO has recently been reported to promote reac-
tions involving hypervalent organoiodane reagents.8a For
example, Margarita and Piancatelli reported that alco-
(5) Brown, H. C.; Okamoto, Y. J . Am. Chem. Soc. 1958, 80, 4979.
(6) PM3 calculations were carried out using the MOPAC 97 series
of programs. A variety of conformations, generated by internal rotation
about single bonds, were considered, and subsequent IP calculations
were performed on the lowest energy forms.
(7) (a) Maruyama, K.; Kusukawa, T.; Higuchi, Y.; Nishinaga, A.
Chem. Lett. 1991, 1991. (b) Nishinaga, A.; Yamazaki, S.; Matsuura,
T. Tetrahedron Lett. 1988, 29, 4115.
(16) Optimized and harmonic frequencies for tert-butylperoxy radical
2 have been computed at the UB3LYP/6-31G(d) level of theory, and
we have performed single-point energy calculations for
2 at the
(8) (a) de Mico, A.; Margarita, R.; Mariani, A.; Piancatelli, G.
Tetrahedron Lett. 1996, 37, 1889. (b) de Mico, A.; Margarita, R.;
Parlanti, L.; Vescovi, A.; Piancatelli, G. J . Org. Chem. 1997, 62, 6974.
UB3LYP/3-21G* level using UB3LYP/6-31G(d) geometries. The BDE
energy expression in UB3LYP/3-21G* has the following form: BDE
(1) ) [E(2) + E(3b)] - E(1)
3308 J . Org. Chem., Vol. 68, No. 8, 2003

SCHEME 4. Oxid a tion of
SCHEME 5. Com p etitive Rea ction s of Oxid a tion
N-Acetyl-1,2,3,4-tetr a h yd r oisoqu in olin e 8 w ith 1
for N-Ben zyla ceta m id es 10a -e w ith 1
TABLE 3. Oxid a tion of N-Ben zyla ceta m id es 11 w ith
Alk ylp er oxy-λ3-iod a n e 1a
products (yieldsb, %)
entry
11
time
12
11 (recovered)
extremely high as compared with EA of 1 or tert-
butylperoxy radical 2 or o-iodobenzoyloxy radical 3b, it
is very difficult to determine which species accepts an
electron from secondary amines.
1
2
3
4
5
11a
11b
11c
11d
11e
26 h
48 h
48 h
48 h
48 h
12a (52)
12b (65)
12c (45)
12d (37)
12e (34)
11a (42)
11b (21)
11c (29)
11d (49c)
11e (48)
A reaction mechanism for N-benzylaniline 4a with
alkylperoxy-λ3-iodane 1 is illustrated in Scheme 3.
Electron loss from 4a gives anilinium radical cation
6a , which undergoes deprotonation promoted by tert-
butylperoxy anion or o-iodobenzoyloxy anion to give an
R-amino carbon radical 7a . The hydrogen/deuterium
isotope effect for N-benzylaniline 4a labeled at the
methylene group R to nitrogen was measured, and a
small deuterium kinetic isotope effect kH/kD ) 2.9 was
obtained. This value is slightly bigger than kH/kD ) 1.3
previously observed for an electron transfer from the
aniline moiety by a cobalt Shiff base.7a This difference is
now not clear, but it should be noted that comparison of
isotope effects for the deprotonation of amine cation
radicals is very complicated and the isotope effects need
not to be small.17 The R-amino carbon radical 7a , a very
easily oxidizable species,18 is oxidized to a carbocation,
which is then converted into an imine 5a by deprotona-
tion from nitrogen.
Alkylperoxy-λ3-iodane 1 also oxidizes the methylene
group R to the nitrogen atom of amides (or carbamates)
yielding imides or tert-butylperoxyamido acetals.3 This
reaction is sensitive to the reaction conditions. When the
reaction was carried out in argon, the peroxyamido
acetals were produced as a major product, while in
oxygen, the major product was imides. In this case,
oxidation of N-acetyl-1,2,3,4-tetrahydroisoquinoline 8 in
the presence of a catalytic amount of 1 yielded 2-acetyl-
3,4-dihydro-2H-isoquinolin-1-one 10 in high yield (Scheme
4).
a
Reactions were carried out using 2 equiv of 1a and 10 equiv
b
of K2CO3 at room temperature in benzene under O2. Isolated
yields. c NMR yield.
TABLE 4. Rela tive Rea ctivity of N-Ben zyla ceta m id es 11
w ith 1 a t 30 °C
a
substrate
krel
σ
σ+ b
IPc (eV)
11b (p-OMe)
11c (p-Me)
11a (H)
11d (p-Cl)
11e (m-Cl)
1.62
1.38
1
0.843
0.690
-0.268
-0.17
0
0.227
0.37
-0.778
-0.311
0
0.114
0.40
9.19
9.47
9.60
9.43
9.47
a
b
Relative rates were determined by 1H NMR. See ref 5. c IP
) ionization potential. See ref 6.
1 also may involve hydrogen abstraction of the methylene
group R to the nitrogen atom, generating R-amido carbon
radicals. Actually, we have reported that the radical
nature of the oxidation was substantiated by the inhibi-
tion of the reaction with an added radical scavenger, a
galvinoxyl free-radical, in a previous paper.3
To gain further detailed insight into the mechanism
of the oxidation of amides by 1, the relative rates of
oxidation for the substituent R in the benzylic group of
N-benzylacetamides 11 were measured at 30 °C in
benzene by competitive reactions under molecular oxy-
gen, in which a mixture of 25-fold excesses of two
competing substrates was used (Scheme 5). Table 3 shows
that the reactions of N-benzylacetamides 11a -e with 1
are very slow, and even after 48 h, a large amount of the
starting amides was recovered.
The effect of substituents on the rate of oxidation is
also shown in Table 4. Electron-releasing groups such
as p-MeO and p-Me increase the rate of oxidation.
Hammett correlation plots for the oxidation of these
acetamides 11a -e showed a good correlation of relative
rate factors with the σ and σ+ constants of substituents
in the aromatic ring and afforded the reaction constants
F ) -0.56 (r ) 0.99) and F+ ) -0.33 (r ) 0.97). These
negative small F and F+ values appear to be comparable
to F+ ) -0.30 for benzylic hydrogen abstractions from
benzyl butyl ethers by an iodanyl radical or a benzoyloxy
The variations in the product profiles are in good
agreement with the alkylperoxy-λ3-iodane 1 oxidation of
benzyl ethers, involving intermediacy of the R-oxy ben-
zylic radicals generated from benzylic hydrogen abstrac-
tion of benzyl ethers with iodanyl radical 3a or benzoyl-
oxy radical 3b.2d Accordingly, oxidation of amides with
(17) (a) Karki, S. B.; Dinnocenzo, J . P.; J ones, J . P.; Korzekwa, K.
R. J . Am. Chem. Soc. 1995, 117, 3657. (b) Dinnocenzo, J . P.; Karki, S.
B.; J ones, J . P. J . Am. Chem. Soc. 1993, 115, 7111.
(18) (a) Baciocchi, E.; Gerini, M. F.; Lanzalunga, O.; Lapi, A.;
Mancinelli, S.; Mencarelli, P. Chem. Commun. 2000, 393. (b) We
calculated the ionization potential of anilinium radical cation 6a at
the B3LYP/6-311+G(2d,p)//B3LYP/6-31G(d) level of theory as 5.62 eV.
J . Org. Chem, Vol. 68, No. 8, 2003 3309

TABLE 5. Rea ctivity of ter t-Bu tylp er oxya m id o Aceta l 9a
SCHEME 6. Mech a n ism for Oxid a tion of
N-Acetyl-1,2,3,4-tetr a h yd r oisoqu in olin e 8 w ith
Alk ylp er oxy-λ3-iod a n e 1
entry
1
K2CO3
10
9 (recovered)
1
2
3
4
0
0
0
0
99
76
97
83
1.2
1.2
10
10
a
Reactions were carried out at room temperature in PhH under
O2 for 3 h.
the mechanism involves hydrogen atom abstraction.20 In
the presence of oxygen, the following alternative pathway
would be preferred: (a) reactions of R-amido carbon
radicals 13 with oxygen generating peroxy radical 14 and
(b) hydrogen abstraction with the peroxy radical 14
yielding the hydroperoxy amido acetal 15 with concomi-
tant R-amido carbon radicals 13 and decomposition of the
hydroperoxy amido acetal 15 to produce imide 10. Note
that the decomposition of the tert-butylperoxy amido
acetal 9 to produce imide 10 does not occur under the
reaction conditions (Table 5).
An alternative pathway to the formation of the R-amido
carbon radicals 13 involves electron transfer, which
generates amide cation radicals, and subsequent proton
transfer. But this reaction process seems not to proceed
since the oxidation of acetamides 11a -e showed no
correlation of the relative rate factors with the corre-
sponding calculated ionization potential of amides. Fur-
thermore, deuterium kinetic isotope effects are signifi-
cantly larger than those observed for the electron-transfer
mechanism22 and are consistent with a mechanism
involving hydrogen atom abstraction.
radical generated from bond cleavage of the hypervalent
iodine(III)-peroxy bond of alkylperoxy-λ3-iodane 1.2d
As illustrated in Scheme 6, a reaction mechanism for
the oxidation of amides with 1 probably involves the
following key steps: (a) homolytic bond cleavage of the
hypervalent iodine(III)-peroxy bond of 1 generating tert-
butylperoxy radical 2 and iodanyl radicals 3a ,b, (b)
hydrogen abstraction of the methylene group R to the
nitrogen atom by iodanyl radical 3a or benzoyloxy radical
3b,19 or (c) nucleophilic attack of the R-amido carbon
radical 13 to the iodine(III)-peroxy bond of (alkylperoxy)-
iodane 1 yielding the tert-butylperoxyamido acetal 9.
Hydrogen abstraction of the methylene group R most
likely involves a rate-limiting step from the deuterium
kinetic isotope effect kH/kD ) 3.3 measured for the
oxidation of protonated and deuterated N-acetyl-1,2,3,4-
tetrahydroisoquinolines 8-d2 in dichloromethane at 30 °C
under argon. Similarly, Hall and Hanzlik reported that
intramolecular kinetic deuterium isotope effects mea-
sured for the enzymic N-demethylation of aromatic and
aliphatic N-methyl-N-trideuteriomethyl amides, RCON-
(CH3)CD3, varied from 3.6 to 6.9, and this suggests that
Ack n ow led gm en t. This work was supported in part
by a research grant from Faculty of Pharmaceutical
Sciences, The University of Tokushima.
Su p p or tin g In for m a tion Ava ila ble: Text describing ex-
perimental details. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O0268005
(20) Hall, L, R.; Hanzlik, R. P. J . Bio. Chem. 1990, 265, 12349.
(21) (a) Murata, S.; Miura, M.; Nomura, M. J . Chem. Soc., Perkin
Trans. 1 1987, 1259. (b) Shono, T.; Hamaguchi, H.; Matsumura, Y. J .
Am. Chem. Soc. 1975, 97, 4264.
(22) Davis, R. V.; Brian, I. B.; Suschitzky, H.; Gittos, M. W. J . Chem.
Soc., Perkin Trans. 1 1978, 180.
(19) Abstraction of benzylic R-hydrogen by an iodanyl radical or an
o-iodobenzoyloxy radical was discussed in ref 2d and references therein
in detail.
3310 J . Org. Chem., Vol. 68, No. 8, 2003