A one-pot oxidative decarboxylation-Friedel-Crafts reaction of acyclic α-amino acid derivatives activated by the combination of iodobenzene diacetate/iodine and iron dust

Article abstract of DOI:10.1039/b815227f

An efficient one-pot oxidative decarboxylation-Friedel-Crafts reaction of acyclic α-amino acid derivatives with electron-rich aromatic compounds is reported. The reaction is activated by the combination of iodobenzene diacetate, iodine and iron dust, resulting in a mild and simple reaction system. The use of iron avoids the oxidation of aromatic compounds, and in situ generation of Fe(III) salts to promote the Friedel-Crafts reaction avoids the use of the highly hygroscopic FeCl₃.

Full text of DOI:10.1039/b815227f

View Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
A one-pot oxidative decarboxylation–Friedel-Crafts reaction of acyclic
a-amino acid derivatives activated by the combination of iodobenzene
diacetate/iodine and iron dust†
Renhua Fan,* Weixun Li and Bing Wang*
Received 1st September 2008, Accepted 23rd September 2008
First published as an Advance Article on the web 29th October 2008
DOI: 10.1039/b815227f
An efficient one-pot oxidative decarboxylation–Friedel-Crafts reaction of acyclic a-amino acid
derivatives with electron-rich aromatic compounds is reported. The reaction is activated by the
combination of iodobenzene diacetate, iodine and iron dust, resulting in a mild and simple reaction
system. The use of iron avoids the oxidation of aromatic compounds, and in situ generation of Fe(III)
salts to promote the Friedel-Crafts reaction avoids the use of the highly hygroscopic FeCl3.
implementation of this strategy is the realization of a process to
Introduction
oxidize the a-amino acid that would not affect sensitive aromatic
The radical decarboxylation of organic carboxylic acids accom-
compounds. A one-pot stepwise procedure might be suitable for
panied by simultaneous replacement by a nucleophile is an
our proposed oxidative decarboxylation–Friedel-Crafts reaction.
extremely useful and selective procedure in organic synthesis.1
To undergo the subsequent Friedel-Crafts reaction, genera-
a-Amino acids are known to undergo oxidative decarboxyla-
tion with lead tetraacetate,2 silver(I) acetate/peroxydisulfate,3
trichloroisocyanuric acid,4 N-bromosuccinimide,5 potassium per-
manganate in concentrated sulfuric acid,6 copper(II) bromide–
lithium tert-butoxide,7 N-chloro-p-toluenesulfonamide sodium,8
dimethyl dioxirane,9 and iodosobenzene diacetate/iodine.10 Al-
though considerable progress has been made, decarboxylative
functionalization of a-amino acids, which would open an addi-
tional route to amines, remains to be investigated (Scheme 1).
tion of a stable and reactive intermediate from the oxidative
decarboxylation of a-amino acid is required. Sua´rez et al. found
that the reaction of cyclic a-amino acids with PhI(OAc)2 and I2
gave g- or w-amino aldehydes and hemiaminals as the products,
which are stable, but ought to be reactive enough to undergo the
subsequent alkylation reactions.10a In our initial test, treatment
of acyclic 2-phenylglycine derivative 1a with PhI(OAc)2 and I2
in ClCH2CH2Cl resulted in high yields of benzaldehyde and
succinimide, which failed to undergo Friedel-Crafts reaction with
1,3,5-trimethoxybenzene in the presence of BF3·Et2O (Scheme 2).
Scheme 1 Oxidative decarboxylative functionalization of a-amino acid
derivatives.
Sua´rez et al. reported the oxidative decarboxylation of a-
amino acids for the generation of N-acyliminium ions and their
nucleophilic trapping with heteroatomic or carbon nucleophiles.10b
Only cyclic a-amino acid derivatives were used as the substrates
for the decarboxylation–oxidation–alkylation reactions. As a part
of our development of the synthetic application of amines in
the presence of hypervalent iodine,11 we report herein the results
regarding the one-pot oxidative decarboxylation–Friedel-Crafts
reaction of acyclic a-amino acid derivatives activated by the
combination of iodobenzene diacetate/iodine and iron dust.
Scheme 2 Oxidative decarboxylation of acyclic 2-phenylglycine derivative
1a.
It was, however, surprising to find that the expected product
2a was obtained in 4% yield from the one-pot stepwise oxida-
tive decarboxylation–Friedel-Crafts reaction [Scheme 3, Eq. (1)].
Further investigation indicated that compound 3a, with an O-
acetyl-N,O-acetal structure, was generated besides benzaldehyde
and succinimide in the decarboxylation reaction [Scheme 3, Eq.
(2)], and that this underwent Friedel-Crafts reaction to afford 2a
in good yield [Scheme 3, Eq. (3)]. Similar N,O-acetals have been
prepared by the electrochemical oxidative decarboxylation of a-
amino acids.13
Results and discussion
Since electron-rich aromatic compounds as well as a-amino acids
are reactive toward hypervalent iodine species,12 central to the
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai,
200433, China. E-mail: rhfan@fudan.edu.cn; Fax: +86 21 6510 2412;
Tel: +86 21 6564 3462
† Electronic supplementary information (ESI) available: General experi-
mental information, characterization data. See DOI: 10.1039/b815227f
A proposed reaction pathway for the one-pot oxidative
decarboxylation–Friedel-Crafts reaction is outlined in Scheme 4.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 4615–4621 | 4615
©

View Online
Scheme 4 Proposed reaction pathway for the one-pot oxidative decar-
boxylation–Friedel-Crafts reaction.
Further optimization of decarboxylation conditions was shown
in Table 1. The best ratio of substrate, PhI(OAc)2 and iodine was
1:2:3, with which the reaction time could be shortened to 2 h and
the yield of 3a increased to 35% (Table 1, entry 5). To inhibit the
˚
deleterious hydrolysis of iminium ion C, 4 A molecular sieves were
Scheme 3 Oxidative decarboxylation and Friedel-Crafts reaction of
acyclic 2-phenylglycine derivative 1a.
added to the oxidative decarboxylation reaction, increasing the
yield of 3a to 46% (Table 1, entry 7). To promote the trapping of
intermediate C with acetate, acetic acid was introduced into the
oxidative decarboxylation reaction. As a result a higher yield of
3a (86%) was obtained when 8 equivalents of acetic acid was used
(Table 1, entry 9). The reaction proceeded with variable efficiency
in CH2Cl2 and EtOAc, but no 3a was formed when DMF, THF,
and toluene were used as the solvent (Table 1, entries 11–15).
Various Lewis and protic acids were examined to promote the
aza-Friedel-Crafts reaction of 3a, and FeCl3 was found to be better
than BF3·Et2O.16 However, the use of FeCl3 led to variable yields of
2a, which might be caused by the high hygroscopicity of FeCl3.17
As a comparison, a control experiment with FeCl2 failed in the
Friedel-Crafts reaction. Further investigation indicated that the
In the presence of PhI(OAc)2 and iodine, which work as the
radical precursor,12c,d 2-phenylglycine derivative 1a is converted
into a carboxyl radical intermediate A. The carboxyl radical
decomposes to carbon dioxide and an alkyl radical B, which is a
very easily oxidizable species. After further oxidation, an iminium
ion intermediate C is formed. The trapping of intermediate C with
acetate gives rise to O-acetyl-N,O-acetal 3a, while the hydrolysis
of intermediate C affords benzaldehyde and succinimide. In the
presence of BF3·Et2O, O-acetyl-N,O-acetal 3a is activated to
regenerate the iminium ion C, which undergoes the aza-Friedel-
Crafts reaction14,15 to give rise to the corresponding oxidative
decarboxylation–Friedel-Crafts reaction product 2a.
Table 1 Optimization of oxidative decarboxylation of 1a
Entry
PhI(OAc)2 (equiv)
I2 (equiv)
Solvent
Additive (equiv)
Yield (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1
2
3
2
2
2
2
2
2
2
2
2
2
2
2
1
1
1
2
3
4
3
3
3
3
3
3
3
3
3
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
CH2Cl2
—
—
—
—
—
—
6
18
17
21
35
28
46
66
86
76
64
47
0
˚
4 A MS
˚
4 A MS, AcOH (4)
˚
4 A MS, AcOH (8)
˚
4 A MS, AcOH (12)
˚
4 A MS, AcOH (8)
˚
EtOAc
DMF
toluene
THF
4 A MS, AcOH (8)
˚
4 A MS, AcOH (8)
˚
4 A MS, AcOH (8)
0
0
˚
4 A MS, AcOH (8)
a Isolated yield based on 1a.
4616 | Org. Biomol. Chem., 2008, 6, 4615–4621
This journal is
The Royal Society of Chemistry 2008
©

View Online
yield of product from the one-pot oxidative decarboxylation–
Friedel-Crafts reaction was lower than the total yield of the
two-step reaction (Scheme 5). Some oxidation products of 1,3,5-
trimethoxybenzene were isolated as the by-products because of
the existence of excess oxidants [PhI(OAc)2 and I2].
the reaction (Table 2, entry 8). Mesitylene was also effective,
but the reaction only gave the product in a moderate yield
(Table 2, entry 9). When o- and p-xylene were employed, the one-
pot reactions proceeded sluggishly and resulted in low yields of
the products. The corresponding products could be obtained in
moderate yields when the reactions were carried out in two steps
(Table 2, entries 9–11). The reaction with N,N-dimethylaniline
was very complex, and no isolable amount of product was formed
(Table 2, entry 12). Reactions with heteroaromatic compounds
were also examined (Table 2, entries 13–16). The reaction with
furan proceeded smoothly, and afforded the product in good yield.
In the case of thiophene, a low yield was obtained. Pyridine and
indole were found to be sensitive to the reaction conditions, and
complex product mixtures were observed.
The influence of the nitrogen protecting group was studied
(Scheme 7). Under the same condition, the reaction of phthalimide
derivative proceeded smoothly, and gave rise to the corresponding
product 4a in 91% yield. However, when tert-butyl carbamate,
sulfonamide, acetamide, and benzamide derivatives were em-
ployed, only the reaction of benzamide derivative afforded the
corresponding product.
Scheme 5 FeCl3 catalyzed Friedel-Crafts reaction of 3a.
These results prompted us to investigate the possibility of
using iron dust for the one-pot oxidative decarboxylation–Friedel-
Crafts reaction; iron could consume the excess oxidants to avoid
oxidation of the aromatic compounds. Moreover, the in situ-
generated Fe(III) salts could promote the Friedel-Crafts reaction
to avoid the use of the highly hygroscopic FeCl3.
As shown in Scheme 6, the solution of 1a was treated with
PhI(OAc)2 and I2 at room temperature. After decarboxylation
reaction, iron dust and 1,3,5-trimethoxybenzene were added to
the reaction mixture, and the reaction was then allowed to stir
at 40 ◦C. When 1 or 2 equivalents of iron dust were used, only
low yields of product 2a were obtained. When the amount of
iron dust was increased to 3 equivalents, the expected product
was isolated in 87% yield. Further increase of the amount of
iron dust did not improve the yield. No double Friedel-Crafts
reaction product, which is generally formed in the aza-Friedel-
Crafts reaction of aromatic imines,18 was isolated from the one-pot
oxidative decarboxylation–Friedel-Crafts reaction of 1a.
Scheme 7 The influence of the nitrogen protecting group of 2-phenyl-
glycine derivative.
The reaction of leucine derivatives was then investigated
(Scheme 8). The oxidative decarboxylation of the corresponding
succinimide and phthalimide derivatives proceeded smoothly, but
the resulted N,O-acetals did not undergo the subsequent Friedel-
Crafts reaction under the same conditions. The one-pot oxidative
decarboxylation–Friedel-Crafts reaction of benzamido leucine
gave rise to the expected product 5e in 57% yield.
Scheme 6 One-pot oxidative decarboxylation–Friedel-Crafts reaction
The synthetically relevant deprotection of product 4a to afford
the corresponding diaryl methylamine 6a can be cleanly achieved
under the Ing-Manske condition (Scheme 9).19
using iron dust.
The scope of oxidative decarboxylation–Friedel-Crafts reaction
with respect to the aromatic compounds was then investigated.
Reactions of electron-rich aromatic compounds with alkoxy sub-
stitutions proceeded smoothly, and gave rise to the corresponding
products in moderate to good yields (Table 2, entries 1–7).
Electron-withdrawing substitution on methoxybenzene inhibited
Conclusions
In summary, we report here an efficient one-pot oxidative
decarboxylation–Friedel-Crafts reaction of acyclic a-amino acid
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 4615–4621 | 4617
©

View Online
Table 2 One-pot oxidative decarboxylation–Friedel-Crafts reaction of 1a with aromatic compounds
Entry
1
Product 2
Yield (%)a
Entry
9
Product 2
Yield (%)a
2a 87
2i 50 (75)c,d
2j 12 (57)c,d
2k 13 (61)c,d (80:20)b
2l 0
2
3
4
2b 78
2c 88
2d 70
10
11
12
5
2e 65
13
2m 70
6
7
2f 77
14
15
2n 37
2g 55b (55:45)
2o 0
derivatives activated by the combination of iodobenzene diac-
etate/iodine and iron dust. The use of iron avoids the oxidation
of aromatic compounds, and in situ generation of Fe(III) salts to
promote the Friedel-Crafts reaction avoids the use of the highly
hygroscopic FeCl3, resulting in a mild and simple reaction system.
The scope, mechanism, synthetic application, and asymmetric
reaction (using tartaric derivatives as the protecting groups) are
ongoing and will be reported in due course.
4618 | Org. Biomol. Chem., 2008, 6, 4615–4621
This journal is
The Royal Society of Chemistry 2008
©

View Online
Table 2 One-pot oxidative decarboxylation–Friedel-Crafts reaction of 1a with aromatic compounds
Entry
8
Product 2
Yield (%)a
Entry
16
Product 2
Yield (%)a
2h 0
2p 0
a Isolated yield based on 1a. b Determined by 1H NMR. c Reaction carried out in two steps: after the oxidative decarboxylation, the corresponding
intermediate 3 was isolated, and then treated with 3 equivalents of iron dust and 3 equivalents of ArH in ClCH2CH2Cl at 40 ◦C. d Isolated yield over two
steps based on 1.
◦
(house vacuum) at 25–35 C. Commercial reagents and solvents
were used as received.
Oxidative decarboxylation of 1a
˚
A mixture of 1a (93 mg, 0.4 mmol), 4 A molecular sieves (100 mg)
and PhI(OAc)2 (258 mg, 0.8 mmol) in ClCH2CH2Cl (3 mL) was
stirred at room temperature for 30 min, and then was treated with
I2 (305 mg, 1.2 mmol) and AcOH (192 mg, 3.2 mmol). The reaction
was allowed to stir at room temperature until the disappearance
of 1a. The reaction was quenched with saturated Na2S2O3, and
extracted by ethyl acetate (20 mL ¥ 3). The organic layer was
dried over Na2SO4. After concentration in vacuo, the residue was
purified by column chromatography on silica gel (20% ethyl acetate
in hexanes) to provide the desired product 2,5-dioxopyrrolidin-1-
yl)(phenyl)methyl acetate (3a) in 86% yield. 1H NMR (400 MHz,
CDCl3) d 7.53–7.51 (m, 2H), 7.45 (s, 1H), 7.38–7.34 (m, 3H), 2.71
(s, 4H), 2.20 (s, 3H); 13C NMR d 175.1, 169.3, 134.5, 129.2, 128.5,
126.6, 75.2, 28.1, 20.8; IR (neat cm-1): v = 3011, 2963, 1752, 1708,
1605, 1458, 1387; HRMS calcd for C13H13NNaO4 ([M + Na]+):
270.0742, found: 270.0751.
Scheme 8 One-pot oxidative decarboxylation–Friedel-Crafts reaction of
leucine derivatives.
FeCl3-catalyzed Friedel-Crafts reaction of 3a with
1,3,5-trimethoxybenzene
Scheme 9 Deprotection of product 4a.
A solution of 3a (74 mg, 0.3 mmol) in ClCH2CH2Cl (3 mL) was
treated with 1,3,5-trimethoxybenzene (151 mg, 0.9 mmol) and
FeCl3 (97 mg, 0.6 mmol). The reaction was stirred at 40 ◦C until
the disappearance of 3a. The reaction was quenched with 4% HCl
aqueous solution, and extracted by ethyl acetate (20 mL ¥ 3).
The organic layer was dried over Na2SO4, and was concentrated
in vacuo. The residue was purified by column chromatogra-
phy on silica gel (20% ethyl acetate in hexanes) to provide
the desired product 1-(phenyl-(2,4,6-trimethoxyphenyl)methyl)-
pyrrolidine-2,5-dione (2a) in 58% yield. 1H NMR (400 MHz,
CDCl3) d 7.25-7.10 (m, 5H), 6.79 (s, 1H), 6.12 (s, 2H),
3.79 (s, 3H), 3.63 (s, 6H), 2.63 (s, 4H); 13C NMR d 176.7,
161.0, 159.8, 138.6, 127.7, 127.4, 126.6, 106.6, 91.2, 55.9,
55.3, 51.5, 28.2; IR (neat cm-1): v = 2937, 1705, 1606, 1454,
Experimental section
General comments
All reactions were performed in test tubes under nitrogen at-
mosphere. Flash column chromatography was performed using
silica gel (60 A pore size, 32–63 mm, standard grade). Analytical
thin–layer chromatography was performed using glass plates pre-
coated with 0.25 mm 230–400 mesh silica gel impregnated with
a fluorescent indicator (254 nm). Thin layer chromatography
plates were visualized by exposure to ultraviolet light. Organic
solutions were concentrated on rotary evaporators at ~20 Torr
˚
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 4615–4621 | 4619
©

View Online
1391, 1121; HRMS calcd for C20H21NNaO5 ([M + Na]+):
378.1318, found: 378.1326.
Acknowledgements
We thank our colleague, Prof. Jie Wu, for his invaluable advice
during the course of this research. Financial support from
the National Natural Science Foundation of China (20702006),
the Shanghai Rising-Star program (07QA14007), and Fudan
University is gratefully acknowledged.
General procedure for one-pot oxidative
decarboxylation–Friedel-Crafts reaction
˚
A mixture of 1 (0.4 mmol), 4 A molecular sieves (100 mg) and
PhI(OAc)2 (258 mg, 0.8 mmol) in ClCH2CH2Cl (3 mL) was stirred
at room temperature for 30 min, and then was treated with I2
(305 mg, 1.2 mmol) and AcOH (192 mg, 3.2 mmol). The reaction
was allowed to stir at room temperature until the disappearance
of 1 (about 2 h). Iron dust (67 mg, 1.2 mmol) and ArH (1.2 mmol)
were added into the reaction mixture, and the resulting reaction
was allowed to stir at 40 ◦C. Upon completion as shown by TLC
(about 3 h), the reaction was quenched with 4% HCl aqueous
solution, and extracted with ethyl acetate (20 mL ¥ 3). The organic
layer was washed with saturated Na2S2O3, and then dried over
Na2SO4. After concentration in vacuo, the residue was purified
by column chromatography on silica gel (20% ethyl acetate in
hexanes) to provide the desired product. The characterization data
is available in the ESI†.
Notes and references
1 (a) A. Itoh, T. Kodama, S. Inagaki and Y. Masaki, Org. Lett., 2000, 2,
331; (b) K. D. Moeller, Tetrahedron, 2000, 56, 9527; (c) A. G. Griesbeck,
W. Kramer and M. Oelgemoller, Synlett, 1999, 1169; (d) A. Graven,
K. A. Jorgensen, S. Dahl and A. Stanczak, J. Org. Chem., 1994, 59, 3543;
(e) V. M. Paradkar, T. B. Latham and D. M. Demko, Synlett, 1995,
1059; (f) F. Fontana, F. Minisci, M. C. N. Barbosa and E. Vismara,
J. Org. Chem., 1991, 56, 2866; (g) D. Crich and L. Quintero, Chem. Rev.,
1989, 89, 1413; (h) A. P. Gledhill, C. J. McCall and M. D. Threadgill,
J. Org. Chem., 1986, 51, 3196; (i) D. H. R. Barton, D. Crich and W. B.
Motherwell, Tetrahedron, 1985, 41, 3901; (j) J. I. Concepcio´n, C. G.
Francisco, R. Freire, R. Herna´ndez, J. A. Salazar and E. Sua´rez, J. Org.
Chem., 1986, 51, 402; (k) T. B. Patrick, K. K. Johri and D. H. White,
J. Org. Chem, 1983, 48, 4158; (l) J. S. Cristol and W. C. Firth, J. Org.
Chem., 1961, 26, 280.
2 R. C. Corcoran and J. M. Green, Tetrahedron Lett., 1990, 31, 6827.
3 (a) Y. Zelechonok and R. B. Silverman, J. Org. Chem., 1992, 57, 5787;
(b) F. Fontana, F. Minisci, M. C. N. Barbosa and E. Vismara, J. Org.
Chem., 1991, 56, 2866.
2-(Phenyl(2,4,6-trimethoxyphenyl)methyl)isoindoline-1,3-dione
(4a). 1H NMR (400 MHz, CDCl3) d (ppm) 7.76–7.75 (m, 2H),
7.66–7.64 (m, 2H), 7.26–7.20 (m, 5H), 7.00 (s, 1H), 6.12 (s, 2H),
3.78 (s, 3H), 3.61 (s, 6H); 13C NMR d (ppm) 168.1, 161.1, 159.8,
139.2, 133.7, 132.2, 127.8, 127.4, 126.6, 123.0, 107.0, 91.1, 90.6,
55.9, 55.3, 50.6; IR 2937, 1771, 1716, 1606, 1495, 1389 cm-1;
HRMS calcd for C24H21NNaO5 ([M + Na]+): 426.1318, found:
426.1334.
4 G. A. Hiegel, J. C. Lewis and J. W. Bae, Synth. Commun., 2004, 34,
3449.
5 G. Laval and B. T. Golding, Synlett, 2003, 542.
6 B. R. Sahu, V. R. Chourey, S. Pandey, L. V. Shastry and V. R. Shastry,
J. Indian Chem. Soc., 1999, 76, 131.
7 T. Takeda, S. Yamauchi and T. Fujiwara, Synthesis, 1996, 600.
8 B. T. Gowda, S. D. Quine and P. S. K. Kumar, J. Indian Chem. Soc.,
2000, 77, 413.
9 V. M. Paradkar, T. B. Latham and D. M. Demko, Synlett, 1995, 1059.
10 (a) A. Boto, R. Herna´ndez, Y. de Leo´n and E. Sua´rez, J. Org. Chem.,
2001, 66, 7796; (b) A. Boto, R. Herna´ndez and E. Sua´rez, J. Org.
Chem., 2000, 65, 4930; (c) A. Boto, R. Herna´ndez and E. Sua´rez,
Tetrahedron Lett., 2000, 41, 2495; (d) A. Boto, R. Herna´ndez and E.
Sua´rez, Tetrahedron Lett., 2000, 41, 2899; (e) A. Boto, R. Herna´ndez
and E. Sua´rez, Tetrahedron Lett., 1999, 40, 5495.
11 (a) R. Fan and Y. Ye, Adv. Synth. Catal., 2008, 350, 1526; (b) R. Fan,
W. Li, Y. Ye and L. Wang, Adv. Synth. Catal., 2008, 350, 1531; (c) R.
Fan, D. Pu, F. Wen, Y. Ye and X. Wang, J. Org. Chem., 2008, 73, 3623;
(d) R. Fan, D. Pu, J. Gan and B. Wang, Tetrahedron Lett., 2008, 49,
4925; (e) R. Fan, D. Pu and F. Wen, J. Org. Chem., 2007, 72, 8994; (f) R.
Fan, F. Wen, L. Qin, D. Pu and B Wang, Tetrahedron Lett., 2007, 48,
7444.
12 For reviews of hypervalent iodine: (a) R. M. Moriarty, J. Org. Chem.,
2005, 70, 2893; (b) P. J. Stang, J. Org. Chem., 2003, 68, 2997; (c) V. V.
Zhdankin and P. J. Stang, Chem. Rev., 2002, 102, 2523; (d) P. J. Stang,
Chem. Rev., 1996, 96, 1123; (e) R. M. Moriarty and R. K. Vaid,
Synthesis, 1990, 431.
N-(Phenyl(2,4,6-trimethoxyphenyl)methyl)benzamide (4e). 1H
NMR (400 MHz, CDCl3) d 8.06 (d, J = 9.6 Hz, 1H), 7.83-781
(m, 2H), 7.47–7.40 (m, 3H), 7.29–7.13 (m, 6H), 6.19 (s, 2H), 3.80
(s, 9H); 13C NMR d 166.27, 160.8, 158.8, 142.8, 135.1, 131.3,
128.6, 128.1, 127.0, 126.5, 126.4, 110.2, 91.5, 56.1, 55.4, 47.4; IR
(neat cm-1): v = 3445, 2938, 1661, 1510, 1332, 1204 cm-1; HRMS
calcd for C23H23NNaO4 ([M + Na]+): 400.1525, found: 400.1524.
N-(3-Methyl-1-(2,4,6-trimethoxyphenyl)butyl)benzamide (5e).
1H NMR (400 MHz, CDCl3) d 8.01–7.99 (m, 2H), 7.43–7.39 (m,
3H), 6.12 (s, 2H), 5.54 (d, J = 6.9 Hz, 1H), 4.40 (t, J = 7.2 Hz,
1H), 3.79 (s, 3H), 3.72 (s, 6H), 1.87-1.90 (m, 1H), 1.20–1.25 (m,
2H), 1.03 (d, J = 6.8 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H); 13C NMR
d 163.5, 160.8, 159.6, 130.8, 128.2, 128.6, 110.7, 91.2, 89.5, 63.5,
55.9, 55.3, 33.4, 18.1, 17.3; IR (neat cm-1): v = 2958, 2927, 1608,
1465, 1419, 1152, 1025 cm-1; HRMS calcd for C21H27NNaO4 ([M +
Na]+): 380.1838, found: 380.1834.
13 D. Seebach, R. Charczuk, C. Gerber, P. Renaud, H. Berner and H.
Schneider, Helv. Chim. Acta, 1989, 72, 401.
14 For reviews, see: (a) V. Nair, S. Thomas, S. C. Mathew and K. G.
Abhilash, Tetrahedron, 2006, 62, 6731; (b) M. S. Shchepinov and V. A.
Korshun, Chem. Soc. Rev., 2003, 32, 170; (c) D. F. Duxbury, Chem.
Rev., 1993, 93, 381.
15 (a) Q. Kang, Z. A. Zhao and S. L. You, J. Am. Chem. Soc., 2007,
129, 1484; (b) W. W. Ong, A. B. Beeler, S. Kesavan, J. S. Panek and
J. A. Porco, Angew. Chem., Int. Ed., 2007, 46, 7470; (c) M. Terada, S.
Yokoyama, K. Sorimachi and D. Uraguchi, Adv. Synth. Catal., 2007,
349, 1863; (d) Y. Q. Wang, J. Song, R. Hong, H. Li and L. Deng, J. Am.
Chem. Soc., 2006, 128, 8156; (e) S. Shirakawa and S. Kobayashi, Org.
Lett., 2006, 8, 4939; (f) P. D. MacLeod, Z. Li, J. Feng and C. J. Li,
Tetrahedron Lett., 2006, 47, 6791; (g) D. Uraguchi, K. Sorimachi and
M. Terada, J. Am. Chem. Soc., 2004, 126, 11804; (h) K. A. Jorgensen,
Synthesis, 2003, 1117; (i) F. Lei, Y. J. Chen, S. Yong, L. Liu and
Deprotection of product 4a
A mixture of 4a (101 mg, 0.25 mmol) in hydrazine monohy-
drate (2 mL) was stirred at 100 ◦C for 24 h. The hydrazine
monohydrate was removed in vacuo, and the residue was purified
by column chromatography on silica gel (5% MeOH inCH2Cl2)
to provide the desired product phenyl-(2,4,6-trimethoxyphenyl)-
methanamine (6a)20 in 88% yield. 1H NMR (400 MHz, CDCl3) d
7.36–7.14 (m, 5H), 6.12 (s, 2H), 5.71 (s, 1H), 3.79 (s, 3H), 3.73 (s,
6H), 3.23 (br, 2H).
4620 | Org. Biomol. Chem., 2008, 6, 4615–4621
This journal is
The Royal Society of Chemistry 2008
©

View Online
D. Wang, Synlett, 2003, 1160; (j) Y. J. Chen, F. Lei, L. Liu and D.
Wang, Tetrahedron, 2003, 59, 7609.
18 (a) C. R. Liu, M. B. Li, C. F. Yang and S. K. Tian, Chem. Commun.,
2008, 1249; (b) J. Esquivias, R. G. Arrayas and J. C. Carretero, Angew.
Chem., Int. Ed., 2006, 45, 629; (c) Y. X. Jia, J. H. Xie, H. F. Duan, L. X.
Wang and Q. L. Zhou, Org. Lett., 2006, 8, 1621; (d) M. Soueidan, J.
Collin and R. Gil, Tetrahedron Lett., 2006, 47, 5467; (e) B. Y. Wang,
R. S. Jiang, J. Li and M. Shi, Eur. J. Org. Chem., 2005, 18, 4002; (f) B.
Ke, Y. Qin, Q. He, Z. Huang and F. Wang, Tetrahedron Lett., 2005, 46,
1751; (g) X. L. Mi, S. Z. Luo, J. Q. He and J. P. Cheng, Tetrahedron
Lett., 2004, 45, 4567.
16 (a) W. Huang, Q. Shen, J. Wang and X. Zhou, J. Org. Chem., 2008,
73, 1586; (b) Z. Li, Z. Duan, J. Kang, H. Wang, L. Yu and Y. Wu,
Tetrahedron, 2008, 64, 1924; (c) U. Jana, S. Maiti and S. Biswas,
Tetrahedron Lett., 2007, 48, 7160; (d) W. A. Riddell and C. R. Noller,
J. Am. Chem. Soc., 1932, 54, 290; (e) Iovel K. Mertins, J. Kischel,
A. Zapf and Matthias Beller, Angew. Chem., Int. Ed., 2005, 44, 3913;
(f) Z. P. Zhan, Y. Y. Cui and H. J. Liu, Tetrahedron Lett., 2006, 47,
9143.
19 H. R. Ing and R. H. F. Manske, J. Chem. Soc., 1926, 2348.
20 J. Esquivias, R. G. Arrayas and J. C. Carretero, Angew. Chem., Int. Ed.,
2006, 45, 629.
17 G. Cahiez, V. Habiak, C. Duplais and A. Moyeux, Angew. Chem., Int.
Ed., 2007, 46, 4364.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 4615–4621 | 4621
©