Selective C-N bond oxidation: demethylation of N-methyl group in N-arylmethyl-N-methyl-α-amino esters utilizing N-iodosuccinimide (NIS)

Article abstract of DOI:10.1016/j.tetlet.2007.11.162

Demethylation of N-methyl group in N-methyl-N-arylmethyl-α-amino esters was accomplished by the oxidation of the amino group using the N-iodosuccinimide (NIS)/acetonitrile system followed by treatment with O-methylhydroxylamine hydrochloride. This combina

Full text of DOI:10.1016/j.tetlet.2007.11.162

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 598–600
Selective C–N bond oxidation: demethylation of N-methyl
group in N-arylmethyl-N-methyl-a-amino esters
utilizing N-iodosuccinimide (NIS)
Takahiro Katoh, Tsunefumi Watanabe, Mitsuyoshi Nishitani, Minoru Ozeki,
Tetsuya Kajimoto, Manabu Node *
Department of Pharmaceutical Manufacturing Chemistry, 21st century COE Program, Kyoto Pharmaceutical University, Misasagi,
Yamashina-ku, Kyoto 607-8414, Japan
Received 3 November 2007; accepted 27 November 2007
Available online 3 December 2007
Abstract
Demethylation of N-methyl group in N-methyl-N-arylmethyl-a-amino esters was accomplished by the oxidation of the amino group
using the N-iodosuccinimide (NIS)/acetonitrile system followed by treatment with O-methylhydroxylamine hydrochloride. This combi-
nation of reagents could provide a complementary method to catalytic hydrogenolysis, which certainly cleaves N-arylmethyl groups, in
organic synthesis.
Ó 2007 Elsevier Ltd. All rights reserved.
Recently, a number of asymmetric Michael additions,
where chiral amines having a benzyl group attack a,b-
unsaturated esters as a nucleophile, have been reported,
mainly to establish general procedures for the synthesis
of b-amino acids,1 since structure moieties are crucial to
express biological and pharmaceutical activities in many
naturally occurring compounds and medicines. Therefore,
the development of a method to remove the benzyl group
or chiral auxiliaries from Michael adducts is an important
issue in organic synthesis. In general, the benzyl group is
easily removed by hydrogenolysis performed on palladium
carbon2a–d or palladium hydroxide (Pearlman’s catalyst)2e
or by hydrolysis of imines generated by the oxidation of
the benzylic C–N bond with various reagents.1a,3–15 On
the other hand, the N-methyl group is not easily cleaved
compared with the N-benzyl group. In spite of much effort
by several research groups to develop unique reagents for
demethylation of the N-methyl group, for example, several
chloroformates,16 iodine/calcium oxide (I2/CaO),17 ruthe-
nium chloride hydrate/hydrogen peroxide (RuCl3ÁnH2O/
H2O2),18 N,N-dimethyl-2,7-diazapyrenium (DAP2+)/visi-
ble light,19 and benzeneselenol,20 practical methods to
cleave the C–N bond of alkyl groups in the presence of
the N-benzyl group have not been reported to date. Thus,
we embarked on a study to develop a novel method to
cleave the N-methyl bond selectively, even in the presence
of N-benzyl or N-arylmethyl groups.
At the beginning of the study, we focused on the fact
that N-iodosuccinimide (NIS), which is employed as an
iodonium source in organic synthesis, that is, the activation
of thioglycosides in glycosylation,21 iodination of hydroxyl
groups22 and direct iodination of aromatic rings,23 has
been utilized for the oxidation of tertiary amines to afford
aldehyde and secondary amine. Actually, Abbott’s group
availed the reaction for the demethylation of N,N-dimethyl-
amino group on the glycosyl moiety of a macrolide anti-
biotic.24 Later, Davis and his co-workers reported a
debenzylation of N,N-dibenzyl- and N-benzyl-amino alco-
hols by the oxidation of the C–N bond with iodonium
ion from NIS;25 however, the method utilized excess
amounts of NIS, requiring a tedious work-up procedure.
*
Corresponding author. Tel.: +81 75 595 4639; fax: +81 75 595 4775.
E-mail address: node@mb.kyoto-phu.ac.jp (M. Node).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.162

T. Katoh et al. / Tetrahedron Letters 49 (2008) 598–600
599
Table 2
Recently, we have further found that oxidation with
NIS could cleave N-alkyl groups quickly even in the pres-
ence of the benzylic C–N bond during a study on the devel-
opment of a novel asymmetric Michael addition of a chiral
alkyl amine.26 Thus, making a small modification, we
applied the method to the selective N-demethylation of
N-arylmethyl-N-methylated amino acid derivatives to test
its general applicability.
Selective demethylation of N-arylmethyl-N-methyl-L-phenylalanine
methyl ester
Ar
Ar
NIS (2 eq.) then
Me
H
H
Me
N
H2NOMe•HCl (2 eq.)
N
N
+
Ph
Ph
Ph
CH3CN / r.t.
CO2Me
CO2Me
CO2Me
1a-i
2a-i
3
Entry
Ar
Time (h)
Yield (%)
In the present Letter, we would like to report an
excellent result obtained in reactions where N-arylmethyl-
N-methyl-a-amino esters were treated with just two
equimolars of NIS.
2
3
1
2
3
4
5
6
7
8
9a
a
1a Ph
2.5
2
3
2.5
2.5
2.5
2.5
2
2a
2b
2c
2d
2e
2f
83
77
75
79
80
87
83
86
73
14
4
16
6
12
10
9
1b 1-Naphtyl
1c 2-Naphtyl
1d 4-MeO–Ph
1e 3-MeO–Ph
1f 4-Cl–Ph
1g 3-Cl–Ph
1h 2-Cl–Ph
1i 4-NO2–Ph
First, we tried the dealkylation of N-benzyl-N-methyl-
L-phenylalanine methyl ester (1a) by oxidation with NIS
or N-bromosuccinimide (NBS) followed by treatment
with O-methylhydroxylamine hydrochloride, an effective
reagent for the transoximation of iminium intermediates,1a
in various solvents (Table 1). As expected from informa-
tion in the literature,24 the reaction performed with
N,N-dimethylformamide (DMF) predominantly gave the
debenzylated product 3 with either NIS or NBS [59%
(NIS), 27% (NBS)] (Table 1, entry 1). Surprisingly, the
reaction with NIS attained in acetonitrile, a solvent as
polar as DMF, afforded the demethylated product 2a
(83%) accompanied with a small amount of debenzylated
product 3 (14%) (Table 1, entry 2). On the other hand,
the reaction with NBS in acetonitrile gave the debenzylated
product 3 (52%) accompanied with a small amount of
demethylated product 2a (21%) (Table 1, entry 2). The
reaction attained with NIS in dichloromethane, a less-polar
solvent than DMF or acetonitrile, yielded both demethyl-
ated product 2a (59%) and debenzylated product 3 (26%),
while 3 (32%) was given as a sole product when NBS was
employed instead of NIS (Table 1, entry 3).
2g
2h
2i
6
14
3.5
3.0 equiv of NIS were used.
as the major product (Table 2, entries 1–9). The reaction
of 1d,e having an electron-donating group such as the
methoxybenzyl group (Table 2, entries 4 and 5) as well as
those of 1f–i having an electron-withdrawing group such
as the chlorobenzyl or 4-nitrobenzyl group (Table 2, entries
6–9), gave the desired products 2d,e, and 2f–i in good
yields, respectively. On the basis of the results obtained
so far, it seems that the functional groups on the aromatic
ring would not affect the reactivity.
Moreover, we applied the NIS/acetonitrile system to
various types of derivatives, that is, tert-butyl ester 4a, ben-
zyl ester 4b, allyl ester 4c, leucine methyl ester 4d, aspartic
acid dimethyl ester 4e, and serine derivatives 4f to ascertain
the generality. The reaction of L-phenylalanine derivatives
with various ester groups 4a–c proceeded in good yields
without cleavage of the ester groups to give the demethylat-
ed products 5a–c (Table 3, entries 1–3). In addition, methyl
esters of the other N-benzyl-N-methyl-a-amino acids 4d–f
was also N-demethylated with high selectivity to give
5d–f (Table 3, entries 4–7).
In spite of the difficulty in explaining why the solvents
changed the selectivities between demethylation and deben-
zylation, we could further generalize the selectivity in the
demethylation of various tertiary amines 1a–i by using
the NIS/acetonitrile system to afford secondary amines
2a–i (Table 2).27 All reactions proceeded through selective
C–N bond oxidation (1–2 h) followed by transoximation
(1–2 h) and gave N-arylmethylated secondary amines 2a–i
Table 3
Selective demethylation of N-arylmethyl-N-methyl-a-amino esters
Table 1
H
Me
NIS (2 eq.) then
H2NOMe•HCl (2 eq.)
H
Bn
Optimization of solvent
Me
Bn
N
N
N
R1
R1
+
NBS or NIS (each 2 eq.)
then H2NOMe•HCl (2 eq.)
R1
CO2R2
CO2R2
CO2R2
Me
Bn
H
Bn
H
Me
CH3CN / r.t.
N
N
N
6a-h
+
Ph
5a-h
4a-h
Ph
Ph
solvent / r.t.
CO2Me
CO2Me
CO2Me
Entry
R1
R2
Time (h)
Yield (%)
1a
2a
3
5
6
Entry
Solvent
NBS
Yield (%)
NIS
Yield (%)
1
2
3a
4a
5
4a
4b
4c
4d
4e
4f
Ph
Ph
Ph
iPr
tBu
Bn
Allyl
Me
2.5
2
2
2.5
3
2
5a 88 6a
5b 80 6b 13
5c 55 6c 10
5d 85 6d
5e 88 6e
—
Time (h)
Time (h)
2a
3
2a
3
1
2
3
a
DMF
CH3CN
CH2Cl2
2
3
2.5
15
21
9
27
52
32
2.5
2.5
3.5a
5
83
59
59
14
26
—
—
—
CO2Me Me
OTBS Me
6
5f
64 6f
a
2.5 equiv of NIS were used.
NIS (3.0 equiv) was employed.

600
T. Katoh et al. / Tetrahedron Letters 49 (2008) 598–600
G. E. J. Org. Chem. 1979, 44, 3442–3444; (e) Bernotas, R. C.; Cube,
R. V. Synth. Commun. 1990, 20, 1209–1212.
3. Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. J. Am. Chem.
Soc. 2004, 126, 5192–5201.
Me
Bn
H
R
N
N
NIS (2 eq.) then
H2NOMe•HCl (2 eq.)
CH CN / r.t.,
1 h
3
4. (a) Goti, A.; Romani, M. Tetrahedron Lett. 1994, 35, 6567–6570; (b)
Yamaguchi, K.; Mizuno, N. Angew. Chem., Int. Ed. 2003, 42, 1480–
1483.
5. Yamaguchi, J.; Takeda, T. Chem. Lett. 1992, 1933–1936.
6. (a) Maruyama, K.; Kusukawa, T.; Higuchi, Y.; Nishinaga, A. Chem.
Lett. 1991, 1093–1096; (b) Nishinaga, A.; Yamazaki, S.; Matsuura, T.
Tetrahedron Lett. 1988, 29, 4115–4118.
7
8: 44% (R = Bn)
9: 15% (R = Me)
NIS (2 eq.) then
H2NOMe•HCl (2 eq.)
Me
N
Bn
no reaction
CH CN / r.t.,
24 h
3
10
7. Larsen, J.; Jørgensen, K. A. J. Chem. Soc., Perkin Trans. 2 1992,
1213–1217.
Scheme 1. Demethylation of N-methyl group of the other substrate.
8. Pratt, E. F.; McGovern, T. P. J. Org. Chem. 1964, 29, 1540–1543.
9. Marino, J. P.; Larsen, R. D., Jr. J. Am. Chem. Soc. 1981, 103, 4642–
4643.
10. Keirs, D.; Overton, K. J. Chem. Soc., Chem. Commun. 1987, 1660–
1661.
11. Cornejo, J. J.; Larson, K. D.; Mendenhall, G. D. J. Org. Chem. 1985,
50, 5382–5383.
12. Ochiai, M.; Kajishima, D.; Sueda, T. Heterocycles 1997, 46, 71–76.
13. Mukaiyama, T.; Kawana, A.; Fukuda, Y.; Matsuo, J. Chem. Lett.
2001, 390–391.
Finally, we adopted our method to the N-demethylation
of different types of compounds from 1, in terms of having
no ester groups such as N-benzyl-N-methyl-1-amino-
1,2,3,4-tetrahydronaphthalene (7) and N-benzyl-N-
methyl-2-aminoindane (10) (Scheme 1). The reaction of 7
showed the same selectivity [(828: 44%, 929: 14%)] as in
the case of a-amino ester derivatives, while the substrate
10 was not reacted but almost recovered (75%) under the
same condition. It seems that the iminium cation interme-
diate is stabilized by the participation of the neighboring
group, such as carbonyl and ether groups.24
In conclusion, we established the first practical method
to attain the N-demethylation reaction of N-arylmethyl-
N-methyl-a-amino esters 1 and 4, affording N-arylmethyl-
ated secondary amines 2 and 5 in good yield. Since the
N-methyl group tends to be cleaved more easily than
N-benzyl groups under this condition, our method would
be of use in organic synthesis and provides an attractive
strategy in the synthesis of alkaloids. Further studies on
the elucidation of the reaction mechanism and application
to other substrates are in progress.
14. Hungerhoff, B.; Samanta, S. S.; Roels, J.; Metz, P. Synlett 2000, 77–
79.
15. Choi, H.; Doyle, M. P. Chem. Commun. 2007, 745–747.
16. (a) Bhat, R. G.; Ghosh, Y.; Chandrasekaran, S. Tetrahedron Lett.
2004, 45, 7983–7985; (b) Olofson, R. A.; Schnur, R. C.; Bunes, L.;
Pepe, J. P. Tetrahedron Lett. 1977, 1567–1570; (c) Montzka, T. A.;
Matiskella, J. D.; Partyka, R. A. Tetrahedron Lett. 1974, 1325–
1327.
17. Acosta, K.; Cessac, J. W.; Rao, P. N.; Kim, H. K. J. Chem. Soc.,
Chem. Commun. 1994, 1985–1986.
18. Murahashi, S.-I.; Naota, T.; Miyaguchi, N.; Nakato, T. Tetrahedron
Lett. 1992, 33, 6991–6994.
19. Santamaria, J.; Ouchabane, R.; Rigaudy, J. Tetrahedron Lett. 1989,
30, 2927–2928.
20. Reich, H. J.; Cohen, M. L. J. Org. Chem. 1979, 44, 3148–3151.
21. (a) Kajimoto, T.; Ishioka, Y.; Katoh, T.; Node, M. J. Carbohydr.
Chem. 2007, 26; (b) Kajimoto, T.; Ishioka, Y.; Katoh, T.; Node, M.
Bioorg. Med. Chem. Lett. 2006, 16, 5736–5739.
Acknowledgments
22. Bose, A. K.; Lal, B. Tetrahedron Lett. 1973, 3937–3940.
23. (a) Olah, G. A.; Wang, Q.; Sandford, G.; Prakash, G. K. S. J. Org.
Chem. 1993, 58, 3194–3195; (b) Bovonsombat, P.; Angara, G. J.;
McNelis, E. Synlett 1992, 131–132.
24. Stenmark, H. G.; Brazzale, A.; Ma, Z. J. Org. Chem. 2000, 65, 3875–
3876.
This research was financially supported in part by the
Frontier Research Program and the 21st Century Center
of Excellence Program ‘Development of Drug Discovery
Frontier Integrated from Tradition to Proteome’ of the
Ministry of Education, Culture, Sports and Technology,
Japan.
25. Grayson, E. J.; Davis, B. G. Org. Lett. 2005, 7, 2361–2364.
26. The manuscript is now in preparation.
27. General procedure of demethylation with NIS/acetonitrile system: To
an acetonitrile (1 ml) solution of 3a (40 mg, 0.14 mmol) was added
NIS (64 mg, 0.28 mmol), and then the mixture was stirred at rt. After
standing for 1 h, O-methylhydroxylamine hydrochloride (24 mg,
0.28 mmol) was added to the reaction mixture, which was stirred at
rt for 1.5 h. The mixture was poured into a saturated aqueous solution
of sodium hydrogen carbonate, which was extracted with chloroform.
The combined organic layer was washed with a 5% aqueous solution
of sodium thiosulfate and brine, dried over with potassium carbonate,
filtered, and concentrated in vacuo. The crude residue was purified by
silica gel column chromatography (eluent; hexane:ethyl acetate = 8:1
to 1:1) to give 2a (32 mg, 83%) and 4 (4 mg, 14%).
28. Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1996, 118, 4916–4917.
References and notes
1. For example of asymmetric Michael addition: (a) Sakai, T.; Doi, H.;
Tomioka, K. Tetrahedron 2006, 62, 8351–8359; (b) Doi, H.; Sakai, T.;
Iguchi, M.; Yamada, K.; Tomioka, K. J. Am. Chem. Soc. 2003, 125,
2886–2887; (c) Sewald, N.; Hiller, K. D.; Helmreich, B. Liebigs Ann.
1995, 925–928; (d) Matsubara, S.; Yoshioka, M.; Utimoto, K. Chem.
Lett. 1994, 827–830; (e) Davies, S. G.; Ichihara, O. Tetrahedron:
Asymmetry 1991, 2, 183–186; (f) Estermann, H.; Seebach, D. Helv.
Chim. Acta 1988, 71, 1824–1839.
2. (a) Adger, B. M.; O’Farrell, C.; Lewis, N. J.; Mitchell, M. B. Synthesis
1987, 53–55; (b) Ram, S.; Spicer, L. D. Synth. Commun. 1987, 17,
415–418; (c) Ram, S.; Spicer, L. D. Tetrahedron Lett. 1987, 28, 515–
516; (d) ElAmin, B.; Anantharamaiah, G. M.; Royer, G. P.; Means,
29. Verdaguer, X.; Lange, U. E. W.; Reding, M. T.; Buchwald, S. L. J.
Am. Chem. Soc. 1996, 118, 6784–6785.