First Ritter-type reaction of alkylbenzenes using N-hydroxyphthalimide as a key catalyst

Article abstract of DOI:10.1039/b110638d

The first Ritter-type reaction of alkylbenzenes with nitriles has been successfully achieved by the use of N-hydroxyphthalimide (NHPI) as a key catalyst. Thus, treatment of ethylbenzene with ammonium hexanitratocerate(IV) (CAN) in the presence of a catalytic amount of NHPI in EtCN under argon produced the corresponding amide in good selectivity.

Full text of DOI:10.1039/b110638d

First Ritter-type reaction of alkylbenzenes using N-hydroxyphthalimide
as a key catalyst
Satoshi Sakaguchi, Tomotaka Hirabayashi and Yasutaka Ishii*
Department of Applied Chemistry, Faculty of Engineering, Kansai University, Suita, Osaka 564-8680,
Japan. E-mail: ishii@ipcku.kansai-u.ac.jp
Received (in Corvallis, OR, USA) 20th November 2001, Accepted 16th January 2002
First published as an Advance Article on the web 11th February 2002
The first Ritter-type reaction of alkylbenzenes with nitriles
has been succesfully achieved by the use of N-hydroxy-
phthalimide (NHPI) as a key catalyst. Thus, treatment of
ethylbenzene with ammonium hexanitratocerate(IV) (CAN)
in the presence of a catalytic amount of NHPI in EtCN
under argon produced the corresponding amide in good
selectivity.
To the best of our knowledge, no reports have appeared on the
Ritter-type reaction of alkylbenzenes. Needless to say, no
reaction took place in the absence of either NHPI or CAN (runs
2 and 3). When the reaction was carried out under O2
atmosphere, the yield of 2 decreased (19%) and large amounts
of oxygenated products such as acetophenone (35%) and
benzaldehyde (17%) were formed at 87% conversion (run 4).
This is believed to be due to the fact that the benzyl radical,
generated by the hydrogen abstraction from 1 by the PINO,
would be rapidly trapped by O2. The optimum reaction
temperature was found to be 80 °C (runs 5 and 6).
Functionalization of saturated hydrocarbons via C–H activation
is of considerable interest and remains a challenge to chemists.1
Ritter-type reaction of alkanes such as adamantane is known as
a synthetic tool for the preparation of amide derivatives and
accomplished by the use of Br2–H2SO4,2 NO2BF4,3 AlCl3–
CH2Cl2,4 electrolysis,5 Pb(OAc)46 and HNO3–CCl4.7 However,
these methods are limited to the reaction of adamantane or its
derivatives. Recently, Hill et al. demonstrated that lower
alkanes such as isobutane react with acetonitrile in the presence
of a polyoxometalate under photo-assistance to form the
corresponding acetamide in high selectivity.8 The reaction is
postulated to proceed through the formation of an alkyl radical
followed by one-electron oxidation by a W ion to a carboca-
tion.
Table 2 summarizes the Ritter-type reaction of various
alkylbenzenes and adamantanes using the NHPI–CAN system.
In a similar manner to 1, the reaction of 1-phenyl-2-methylpro-
pane (5) in EtCN using the NHPI–CAN system afforded the
corresponding amide 6 (93%), in which the amide group was
introduced at the benzylic position in preference to the methine
one, at 63% conversion (run 2). The amidation of p-ethyltoluene
(7) with EtCN took place selectively at the ethyl moiety to
afford N-(1-p-tolylethyl)propionamide (8) (run 3). Indane (9)
was also amidated with EtCN even at rt to give 10 in high
conversion (93%) and selectivity (74%) (run 4). Notably, the
NHPI–CAN system was also efficient for the Ritter-type
reaction of adamantanes. The reaction of 1,3-dimethylada-
In our previous papers, we showed that N-hydroxyphthali-
mide (NHPI) acts as an efficient catalyst for the generation of
9
10
alkyl radicals from alkanes under O2 and NO2 to form
oxygenated products, such as alcohols and carboxylic acids, and
nitroalkanes, respectively. To extend the synthetic application
using NHPI as a key catalyst, our effort has been directed
toward the generation of carbocations through the formation of
alkyl radicals assisted by NHPI.11 Our strategy is as follows: (i)
abstraction of a hydrogen atom from alkane by phthalimide N-
oxyl (PINO) generated from NHPI and an appropriate oxidant
leading to an alkyl radical, (ii) one-electron oxidation of the
resulting alkyl radical by the oxidant to a carbocation, (iii)
trapping of the carbocation by a nucleophile like alkyl nitrile.
Now, we have found that NHPI combined with ammonium
hexanitratocerate(IV) (CAN) serves as an efficient system for
the generation of both PINO from NHPI and carbocations from
alkyl radicals. Thus, benzylic compounds first undergo amida-
tion with an alkyl nitrile under mild conditions to form amides
in good yields.
n
mantane (13) in EtCN, PrCN, or PhCN afforded the corre-
sponding amides 14a, 14b or 14c in fair to good yields,
respectively (run 6). A lower alkane such as isobutane (15) was
also amidated to give N-tert-butylpropionamide (16), although
the yield of the product was relatively low (run 7).§
It is reasonable to assume that the present reaction is initiated
by the reaction of NHPI with CAN to form PINO, which is
thought to be a key species for the generation of alkyl radicals
(Scheme 1).9–11 In fact, PINO was generated upon treatment of
NHPI with CAN in MeCN at 70 °C.¶ The resulting PINO
abstracts a hydrogen atom from these hydrocarbons to generate
the corresponding alkyl radicals (A), which undergoes the one-
electron oxidation by Ce(IV) to form carbocations (B). The
carbocations B thus generated are trapped by nitriles, followed
by H2O, which would be contained in the solvent, to afford
amide derivatives. When the reaction was carried out under
dioxygen, the alkyl radicals A formed react with O2 in
Ethylbenzene (1) was chosen as a model substrate and
allowed to react with CAN in the presence of a catalytic amount
of NHPI in EtCN.† Table 1 summarizes the representative
results for the Ritter-type reaction of 1 under selected reaction
conditions.
Table 1 Ritter-type reaction of 1 by the NHPI–CAN systema
Run
Conv. (%)
Selectivity of 2 (%)
The reaction of 1 in the presence of CAN and NHPI in EtCN
under argon at 80 °C for 6 h produced N-(1-phenylethyl)propio-
namide (2)‡ in 84% selectivity at 61% conversion (eqn. (1),
Table 1, run 1).
1
61
84
2b
3c
4d
5f
6g
No reaction
No reaction
87
58
74
19e
47
53
a 1 (1 mmol) was allowed to react with CAN (1.5 mmol) in the presence of
NHPI (0.1 mmol) in EtCN (5 mL) at 80 °C for 6 h under Ar. b In the absence
of NHPI. c In the absence of CAN. d Under O2. e See text. f At 60 °C. g At
100 °C
(1)
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CHEM. COMMUN., 2002, 516–517
This journal is © The Royal Society of Chemistry 2002

preference to Ce(IV) to give the oxygenated products as shown
in Table 1, run 4.
nitrogen oxides like NO2 from CAN during the reaction. In fact,
for 13, a small amount (1%) of nitrated product, 1-nitro-
3,5-dimethyladamantane, was obtained.
According to this reaction pathway (Scheme 1), 2 equiv. of
CAN with regard to the substrate is required to complete the
reaction. In the reactions using 1.5 equiv. of CAN, the
conversion would be less than 75%. However, the conversions
of substrates, 7, 9 and 13, in the present reactions were much
higher than 75% (Table 2, runs 3, 4, and 6). This is believed to
be due to the generation of PINO from NHPI by the action of
In addition, the NHPI–CAN system was found to promote the
acetoxylation of 5 in AcOH in the presence of Na2CO3.
Treatment of 5 with 1.5 equiv. of CAN under the influence of
NHPI catalyst (10 mol %) and 1.2 equiv. of Na2CO3 in AcOH
under Ar atmosphere afforded the corresponding acetylated
compound, 1-acetoxy-1-phenyl-2-methylpropane (17) (88%),
at 66% conversion. The reaction with AcONa in place of
Na2CO3 resulted in 67% selectivity of 17 (84% conversion).
In conclusion, the Ritter-type reaction of alkylbenzenes was
first achieved by the use of NHPI combined with CAN. Thus,
various benzylic compounds as well as adamantanes were
successfully converted into the corresponding amides.
This work was partly supported by a Grant-in-Aid for
Scientific Research (S) (No.13853008) from Japan Society for
the Promotion of Science (JSPS).
Table 2 Ritter-type reaction of various alkanes by the NHPI–CAN
systema
Conv.
(%)
Selectivity
(%)
Run
1
Substrate
Product
69
63
93
93
51
69
93
74
74
80
Notes and references
2b
3b
4c
5
† A typical procedure for the Ritter-type reaction of 1: to a solution of 1 (1
mmol) and CAN (1.5 mmol) in EtCN (5 mL) in a three-necked flask was
added NHPI (0.1 mmol). The flask was cooled to 278 °C to freeze the
solvent, and degassed in vacuo and filled with Ar gas. Then the frozen
solvent was melted at rt, and refrozen to reiterate the evacuation–Ar purge
procedure. The series of operations was repeated three times. The reaction
mixture was allowed to react under an atmospheric pressure of Ar at 80 °C
for 6 h. Selectivity (%) of the product was based on the substrate reacted. All
starting materials were commercially available and used without any
purification.
‡ Spectral data for 2: 1H NMR d 7.36–7.21 (m, 5H), 5.81 (s, 1H), 5.18–5.08
(m, 1H), 2.20 (q, J = 7.3 Hz 2H), 1.48 (d, J = 7.3 Hz, 3H), 1.14 (t, J = 7.3
Hz, 3H); 13C NMR d 172.6, 143.2, 128.5, 127.2, 126.0, 48.6, 29.8, 21.8,
9.89; IR (neat) 3289, 2977, 1644, 699 cm21; MS (70 eV) m/e = M+ 177,
120, 106, 77.
§ A procedure for the Ritter-type reaction of 15: the reaction was carried out
in a 50 mL glass autoclave. 15 was treated as a liquid at 215 °C. To a
solution of CAN (1 mmol) and NHPI (0.1 mmol) in EtCN (5 mL) was added
15 (2 mL, ca. 20 mmol). After the atmosphere in the autoclave was replaced
with Ar, the reaction mixture was allowed to react at 100 °C for 15 h.
¶ Electron spin resonance (ESR) measurments were carried out under
selected conditions. To an ESR tube was added NHPI (0.025 mmol) and
CAN (0.025 mmol) in PhCN (0.05 mL), and the mixture was reacted under
argon at 25 °C for 5 min. The ESR spectrum attributed to PINO was clearly
observed as a triplet signal based on hyperfine splitting (hfs) by the nitrogen
atom (g = 2.0074, aN = 0.46 mT). The g-value and hfs constant observed
for PINO were consistent with those reported by Mackor et al.12
6d
57
14a (R = Et)
14b (R = nPr)
14c (R = Ph)
93
91
83
82e
72f
7
—
28g
a Substrate (1 mmol) was allowed to react with CAN (1.5 mmol) in the
presence of NHPI (0.1 mmol) in EtCN (5 mL) at 100 °C for 6 h under Ar.
b At 80 °C. c At 25 °C. d At 50 °C. e nPrCN was used as a solvent. f PhCN
was used as a solvent. g The yield was based on CAN (See footnote§).
1 (a) A. Sen, Acc. Chem. Res., 1998, 31, 550; (b) A. E. Shilov and G. B.
Shul’pin, Chem. Rev., 1997, 97, 2879; (c) Activation and Functionaliza-
tion of Alkanes, ed. C. L. Hill, John Wiley and Sons, New York,
1989.
2 M. Ohsugi, Y. Inamoto, N. Takaishi, Y. Fujikura and K. Aigami,
Synthesis, 1972, 632.
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R. Golam, N. J. Trivedi and G. A. Olah, J. Am. Chem. Soc., 1993, 115,
7246.
4 G. A. Olah and Q. Wang, Synthesis, 1992, 1090.
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6 S. R. Jones and J. M. Mellor, J. Chem. Soc., Perkin Trans. 1, 1976,
2576.
7 J. M. Bakke and C. B. Storm, Acta. Chem. Scand., 1989, 43, 399.
8 C. L. Hill, Synlett, 1995, 2, 127.
9 Y. Ishii, S. Sakaguchi and T. Iwahama, Adv. Synth. Catal., 2001, 343,
393; ; NHPI has been used as a mediator for electrochemical oxidation:
C. Ueda, M. Noyama, H. Ohmori and M. Masui, Chem. Pharm. Bull.,
1987, 35, 1372.
10 S. Sakaguchi, Y. Nishiwaki, T. Kitamura and Y. Ishii, Angew. Chem.,
Int. Ed. Engl., 2001, 40, 222.
11 Previously, we have reported the Ritter-type reaction of adamantane
with nitrile by the NHPI–NO system: S. Sakaguchi, M. Eikawa and Y.
Ishii, Tetrahedron Lett., 1997, 38, 7075.
Scheme 1 A possible reaction path.
12 A. Mackor, A. J. Wajar and J. de Boer, Tetrahedron, 1968, 24, 1623.
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