Imidomethylation of C-nucleophiles using O-phthalimidomethyl trichloroacetimidate and catalytic amounts of TMSOTf

Article abstract of DOI:10.1016/j.tet.2004.04.011

The O-phthalimidomethyl trichloroacetimidate (1), as a latent aminomethylating agent, exhibits high electrophilicity towards a variety of C-nucleophiles in the presence of catalytic amounts of TMSOTf and mild reaction conditions. The nucleophiles include aromatics, alkenes and active methylene compounds 2-11 whereby a phthalimidomethyl group could be introduced to give compounds 12-22. Removal of the phthaloyl group gave the respective amines, β-amino ketones, and β-amino acids. The O-(trichloroacetamido)methyl trichloroacetimidate (35) was also found to be a good amidomethylating agent.

Full text of DOI:10.1016/j.tet.2004.04.011

Tetrahedron 60 (2004) 4773–4780
Imidomethylation of C-nucleophiles using O-phthalimidomethyl
trichloroacetimidate and catalytic amounts of TMSOTf
Ibrahim A. I. Ali,a El Sayed H. El Ashryb and Richard R. Schmidta
,
*
aDepartment of Chemistry, University of Konstanz, Fach M 725, D-78457 Konstanz, Germany
bDepartment of Chemistry, Faculty of Science, University of Alexandria, Alexandria, Egypt
Received 16 January 2004; revised 12 March 2004; accepted 2 April 2004
Abstract—The O-phthalimidomethyl trichloroacetimidate (1), as a latent aminomethylating agent, exhibits high electrophilicity towards a
variety of C-nucleophiles in the presence of catalytic amounts of TMSOTf and mild reaction conditions. The nucleophiles include aromatics,
alkenes and active methylene compounds 2–11 whereby a phthalimidomethyl group could be introduced to give compounds 12–22.
Removal of the phthaloyl group gave the respective amines, b-amino ketones, and b-amino acids. The O-(trichloroacetamido)methyl
trichloroacetimidate (35) was also found to be a good amidomethylating agent.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
for long periods of time which could reach 24 h.4 Owing to
the importance of amino and amidomethylation in organic
synthesis and compounds possessing such a group, it
became of interest to develop a method which requires
mild reaction conditions and only catalytic amounts of the
promoters. Towards this end, we have investigated the
reaction of the recently developed reagent, O-phthalimido-
methyl (Pim) trichloroacetimidate (1)22 with different types
of C-nucleophiles; this reagent has been also successfully
employed for O-protection via imidomethylation of
O-nucleophiles. Now, a methodology has been developed
for introducing the phthalimidomethyl group on carbon
nucleophiles to form a C–C bond using O-phthalimido-
methyl trichloroacetimidate (1),11 as imidomethylating
agent with the phthalimido group acting as an amino
protecting group (Scheme 1). The reaction proceeded
smoothly in the presence of catalytic amounts of TMSOTf
under mild conditions and at room temperature. Moreover, a
practical approach for the synthesis of b-amino ketones and
b-amino esters will be reported.
The development of methodologies for C–C bond for-
mation,1 particularly those involving introduction of one
carbon atom bearing a functional group into the skeleton of
organic molecules, is of high interest. When such a
functional group is an alkyl- or an acyl-amino group linked
via the nitrogen to a methylene group carrying a leaving
group such as halogen, OR or NR2, the process is called
amino or amidomethylation.1–5 Commonly, these reagents
are electrophiles and for linkage to the other reactant a
nucleophilic center is required. Much work has been
devoted to the aminomethylation of activated carbon
atoms by reaction with formaldehyde and amines.1
Organometallic derivatives derived from alkenes and
aromatic compounds can be aminomethylated.1–9 Such
aminomethylation processes are usually providing products
with amino alkyl groups. On the other hand, amidomethyl-
ations provide amides that could be hydrolyzed to the
corresponding amines. The use of formaldehyde and amides
for the amidomethylation of activated carbons was not
successful.1 However, such reactions were successful when
using N-hydroxy-methyl amides,10 a method which was then
further developed.11–15 The hydroxy group in the latter
reagent has been replaced by a leaving group such as esters,15
halogens13 and substituted amines.12,16,17 The respective
cyclic imides of dicarboxylic or sulfocarboxylic acids were
also used in corresponding imidomethylations.12,18 – 21
The reaction required the use of strong acid and heating
2. Results and discussion
Reaction of the trichloroacetimidate 1 with the silylated
C-nucleophile allyl trimethylsilane (2) in the presence of
catalytic amounts of TMSOTf at room temperature gave 12
in 93% yield (Scheme 1, Table 1); compound 12 was
previously prepared by the nucleophilic displacement of the
tosyloxy group in 1-tosyloxy-3-butene with potassium
phthalimide.23 Similarly, trichloroacetimidate 1 was reacted
with 1,3-dimethoxy-benzene (3) and 1,2,3-trimethoxy-
benzene (4) to give 13 and 14 in 78 and 87% yield,
Keywords: O-Phthalimidomethyl trichloroacetimidate; Imidomethylation;
Amidomethylation; Amino ketones; Amino acids.
*
Corresponding author. Tel.: þ49-7531-88-2538; fax: þ49-7531-88-3135;
e-mail address: richard.schmidt@uni-konstanz.de
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.04.011

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I. A. I. Ali et al. / Tetrahedron 60 (2004) 4773–4780
Scheme 1.
respectively. 1 reacted also with benzene (5) to give 15 in
86% yield which is available by Mitsunobu reaction of
benzyl alcohol with phthalimide24–27 and by reaction of
benzylamine29 or benzylazide28,29 with phthalic anhydride.
Compounds 13–15 were readily identified by 1H NMR
spectra which showed a singlet at d 4.82–4.84 characteristic
for the introduced methylene group, in addition to the
signals of the aromatic protons which confirm the position
of the imidomethyl group on the ring.
mido-2-propene (16) in 85% yield upon reaction with
phenylethylene (styrene) (6); the ratio of Z/E in 16 is 1:1 as
determined from its 1H NMR spectrum. Compound 16 was
already prepared from (3-chloro-allyl)-benzene and the
potassium salt of phthalimide.30
The trichloroacetimidate 1 has been also found to be an
excellent reagent for the imidomethylation of the a-position
of ketones and acids as shown in Table 2. Thus, compound
1731 was readily prepared by reaction of trichloro-
acetimidate 1 with 1-trimethylsiloxy-cyclohexene (7) as
C-nucleophile. The reaction of trichloroacetimidate 1 with
The trichloroacetimidate 1 was found to be also a suitable
precursor for the synthesis of (Z/E)-1-phenyl-3-phthali-
Table 1. Phthalimidomethylation of C-nucleophiles 2–6 by 1
Entry
C-Nucleophile
Product
Time
(min)
Yield
(%)
1
60
60
93
78
2
3
4
5
45
180
60
87
86
85

I. A. I. Ali et al. / Tetrahedron 60 (2004) 4773–4780
Table 2. Phthalimidomethylation of C-nucleophiles 7–11 by 1
Entry C-Nucleophile
4775
Product
Time (min)
Yield (%)
6
30
89
83
7
20
8
10
87
9
45
60
75
82
10
1-phenyl-1-trimethylsiloxy-ethylene (8) in the presence of
TMSOTf gave 18 in 83% yield. The synthesis of 18 was
already reported32 by using Michael-type addition of
phthalimide to phenyl vinyl ketone. The reaction of 1 on
the 6-position of glucose derived enol ether 933 gave 3-O-
benzyl-6,7-dideoxy-1:2-O-isopropylidene-7-(phthalimido)-
a-D-xylo-heptofuranos-5-ulose (19) in 87% yield. The
generated C–C linkage in the product was confirmed by
the presence of two signals at d 3.04 and 3.96 for the CH2–
CH2 group which was confirmed by the 13C NMR spectrum
displaying signals at d 32.4 and 39.0.
refluxing methanol has been selected to remove the
phthalimido group, which worked successfully to give the
respective amines 22,36 23 and 2437 from 14, 15 and 16,
respectively (Table 3). In case of the b-aminoketones 18 and
19, a concomitant reaction of the carbonyl groups with
hydrazine, in addition to the deprotection, had taken place to
give the hydrazones 25 and 26, respectively.
Attempted deprotection of the phthalimido group by heating
with hydroxylamine even for long time and with more
reagent did not cause its hydroxylaminolysis and the
product from the reaction was found to be the corresponding
oxime whose acetylation gave 27. The failure of the
cleavage is due to the lower nucleophilicity of the
hydroxylamine compared to hydrazine (Scheme 2).
b-Amino acids and their derivatives are an important class
of compounds. They are present in many biologically active
compounds and in the free form they show interesting
pharmacological effects.34 They are also precursors of the
b-lactam moiety which is present in some antibiotics.
Again, the trichloroacetimidate 1 was reacted with silylated
reagents such as 3-trimethylsiloxy-2-butenic acid methyl
ester (10) and 1-methoxy-2-methyl-1-trimethylsiloxy-pro-
pene (11) in the presence of TMSOTf to give 20 and 21 in
75 and 82% yield, respectively.37 Compound 20 was
identified by 1H NMR spectroscopy which showed the
newly introduced imidomethylene group at d 4.13 and
signals of the benzene ring at d 7.61–7.88.
The successful imidomethylation via the trichloroaceti-
midate 1 as shown above, and on the other hand the failure
of reacting formaldehyde and amides with activated
carbons, attracted our attention to explore the reactivity of
the N-methylol amides as amidomethylating agents via their
trichloroacetimidates. Thus N-methyl-olben-zamide (28)38
and N-methylmethylol benzamide (29)39 were reacted with
trichloroacetonitrile in dichloromethane as solvent in the
presence of DBU or NaH for activating the hydroxyl group
towards the reaction with the nitrile group (Scheme 3).40–42
The reaction was carried out at different temperatures
(–50 8C, 0 8C, room temperature). However, in no case the
expected trichloroacetimidates 30 and 31, respectively,
After performing successfully the imidomethylation on the
selected C-nucleophiles, it became interesting to achieve a
deprotection of the amino group. Hydrazine hydrate in

4776
Table 3. Hydrazinolysis of phthalimido derivatives 14–19
Entry Phthaloyl derivatives
I. A. I. Ali et al. / Tetrahedron 60 (2004) 4773–4780
Product
Yield (%)
1
84
2
3
4
92
76
78
5
66
32 which appeared as a doublet of doublet at d 4.98, whereas
that of 33 appeared as a doublet at d 5.00.
When the phenyl group in the above amides was changed to
the electron withdrawing trichloromethyl group as in
N-hydroxymethyl trichloroacetamide (34),43 and reacting
the latter with trichloroacetonitrile in the presence of NaH as
base at room temperature, as expected the trichloro-
acetimidate 35 was formed without rearrangement and in
good yield (Scheme 4). The structure of 35 was confirmed
Scheme 2.
could be obtained; the isolated products were found to have,
in accordance with the Chapman rearrangement, the
structure of the trichloroacetamides 32 and 33. Similar
rearrangements can be also observed upon activation of
O-glycosyl trichloroacetimidates in the presence of poor
glycosyl acceptors.40–42 The structures of 32 and 33 were
established through their 1H NMR spectra which reveal the
presence of a methylene moiety between two NH groups for
1
from its H NMR spectrum which showed a doublet at d
4.93 for the CH2 group in addition to a signal at d 3.95 for
the NH group, whereas the other NH group appeared at d
7.81.
The trichloroacetimidate 35 reacted readily with styrene (6)
Scheme 3.

I. A. I. Ali et al. / Tetrahedron 60 (2004) 4773–4780
4777
Scheme 4.
to give amidomethylation product 3644 which can be
hydrolyzed to the amine 24 with 1 N KOH. Amido-
methylating agents, having different substituents, were
reported to react with styrene, however in lower yields
and accompanied by cyclic products.45 35 reacted also with
the O-silylated nucleophiles 3-trimethylsiloxy-2-butenoic
acid methyl ester (10) and 1-methoxy-2-methyl-1-tri-
methylsiloxy-propene (11) under the same conditions to
afford 37 and 38, respectively, in good yield.
determined at 20 8C with a Perkin–Elmer 241 MC
polarimeter (1 dm cell). NMR spectra were recorded with
Bruker AC 250 and 600 DRX instruments, using tetra-
methylsilane as an internal standard. The assignment of 13C
NMR spectra were based on carbon-proton shift-correlation
heteronuclear multiple quantum coherence (HMQC). Mass
spectra were recorded with MALDI-Kompakt (Kratos) and
FAB with Finningen Mat 312/AMD. Microanalyses were
performed in the Microanalysis Unit at the Department of
Chemistry, University of Konstanz.
In conclusion, a general method has been developed for
introducing the N-phthalimidomethyl group (Pim) on a
variety of carbon nucleophiles. The Pim trichloroaceti-
midate 1 can be considered as a reagent of choice for
forming C–C bonds with nucleophiles under mild con-
ditions in the presence of only catalytic amounts of
TMSOTf. Trichloroacetimidate 1 is characterized by a
high electrophilic reactivity. The high reactivity is due to the
electron withdrawing nature of the carbonyl groups which
increased its electrophilicity.46 Reagent 1 can be stored
without decomposition and the respective derivatives can be
easily isolated and identified. On the other hand, deprotec-
tion of the phthalimido group to give the aminomethylated
analogues can be readily achieved. Thus, novel approaches
for b-amino ketones and b-amino acids are available.
Preliminary results with O-(trichloroacetamidomethyl)tri-
chloroacetimidate 35 proved also its successful application
as amidoalkylating agent.
3.2. General procedure for the reaction of O-phthali-
midomethyl trichloroacetimidate (1) with C-nucleo-
philes
A stirred solution of 1 (0.45 g, 1.4 mmol) and C-nucleo-
philes as acceptor (1.4 mmol) in dry dichloromethane
(40 mL) under nitrogen was treated with TMSOTf (13 mL,
0.06 mmol) at room temperature. After completion of the
reaction (TLC), the mixture was neutralized with solid
sodium bicarbonate, filtered and concentrated in vacuo. The
residue was purified by flash chromatography.
3.2.1. N-But-3-enyl-phthalimide (12). White powder
(0.26 g, 93%); Rf 0.64 (petroleum ether/ethyl acetate, 5:1).
Mp 48 8C, lit.24 49–50 8C. The analytical data are identical
with the published values.
3.2.2. N-(2,4-Dimethoxybenzyl)phthalimide (13). White
powder (0.32 g, 78%); Rf 0.43 (petroleum ether/ethyl
1
acetate, 5:1). Mp 91 8C. H NMR (250 MHz, CDCl3): d
3. Experimental
3.1. General methods
3.76 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 4.82 (s, 2H, CH2),
6.38–7.13 (m, 3H, Ar-H), 7.67–7.87 (m, 4H, Ar-H); 13C
NMR (62.8 MHz, CDCl3): d 36.5 (CH2), 55.2, 55.4
(2OCH3), 98.5, 103.8, 116.6, 122.8, 123.1, 129.7, 132.1,
133.5, 133.8 (C-Ar), 160.5, 168.1 (2CO); MS: m/z 297.0.
Anal. calcd for C17H15NO4 (297.3): C, 68.68; H, 5.08; N,
4.71. Found: C, 68.58; H, 5.16; N, 4.78.
Melting points are uncorrected. Thin-layer chromatography
(TLC) was performed on plastic plates Silica Gel 60 F254.
The detection was achieved by treatment with a solution of
20 g ammonium molybdate and 0.4 g cerium (IV) sulfate in
400 mL of 10% H2SO4 or with 15% H2SO4 in methanol and
heating at 150 8C. Flash chromatography was carried out on
silica gel (Baker, 30–60 mm). Optical rotations were
3.2.3. N-(2,3,4-Trimethoxybenzyl)phthalimide (14).
White powder (0.40 g, 87%); Rf 0.48 (petroleum ether/

4778
I. A. I. Ali et al. / Tetrahedron 60 (2004) 4773–4780
ethyl acetate, 5:1). Mp 106 8C. 1H NMR (250 MHz,
CDCl3): d 3.81, 3.84, 3.95 (3s, 9H, 3OCH3), 4.84 (s, 2H,
NCH2), 6.58 (d, J¼8.6 Hz, 1H, Ar-H), 6.97 (d, J¼8.6 Hz,
1H, Ar-H), 7.69–7.88 (m, 4H, Ar-H); MS: m/z 327.0. Anal.
calcd for C18H17NO5·0.25H2O (331.8): C, 65.15; H, 5.23;
N, 4.22. Found: C, 65.27; H, 5.13; N, 4.27.
vacuo and the residue dissolved in dichloromethane
(50 mL). The solution was extracted with 1 N NaOH
(5£50 mL) and the organic layer was dried with magnesium
sulfate and concentrated in vacuo. The residue was purified
by flash chromatography (dichloromethane/methanol).
3.3.1. 2,3,4-Trimethoxybenzylamine (22). Yellow oil
(0.08 g, 84%). The analytical data are identical with the
published values.36
3.2.4. N-Benzylphthalimide (15). White powder (0.29 g,
86%); Rf 0.45 (petroleum ether/ethyl acetate, 5:1). Mp
118 8C, lit.28 118 8C. The analytical data are identical with
the published values.
3.3.2. Benzylamine (23). Yellow oil (0.05 g, 92%). The
analytical data are identical with an authentic sample.
3.2.5. N-(Z/E)-Cinnamylphthalimide (16). White powder
(0.31 g, 85%); Rf 0.67 (petroleum ether/ethyl acetate, 5:1).
Mp 153 8C, lit.30 156–158 8C. The analytical data are
identical with the published values.
3.3.3. 3-Phenyl-allylamine (24). Yellow oil (0.05 g, 76%).
The analytical data are identical with the published values.37
3.3.4. 3-Amino-1-phenyl propan-1-one hydrazone (25).
Yellow oil (0.05 g, 78%); Rf 0.34 (chloroform/methanol
2:1). H NMR (250 MHz, CDCl3): d 2.81 (m, 2H, CH2),
2.97 (m, 2H, CH2), 3.51–4.20 (brs, 4H, 2NH2), 7.18–7.68
3.2.6. N-(2-Oxo-cyclohexylmethyl)phthalimide (17).
White powder (0.32 g, 89%); Rf 0.57 (petroleum ether/
ethyl acetate, 5:1). Mp 133 8C, lit.31 134 8C.
1
(m, 5H, Ar-H); MS: m/z¼163.0.
3.2.7. N-(3-Oxo-3-phenylpropyl)phthalimide (18). White
powder (0.32 g, 83%); Rf 0.52 (petroleum ether/ethyl
acetate, 5:1). Mp 128 8C, lit.32 130 8C. The analytical data
are identical with the published values.
3.3.5. 7-Amino-3-O-benzyl-6,7-dideoxy-1:2-O-isopropyl-
idene-a-D-xylo-heptofuranos-5-ulose hydrazone (26).
Colorless oil (0.44 g, 66%); Rf¼0.41 (chloroform/methanol
1
2:1); [a]D¼24.6 (c¼0.5, CH2Cl2). H NMR (250 MHz,
3.2.8. 3-O-Benzyl-6,7-dideoxy-1:2-O-isopropylidene-7-
(phthalimido)-a-D-xylo-heptofuranos-5-ulose (19). Col-
orless oil (0.55 g, 87%); Rf 0.72 (petroleum ether/ethyl
acetate, 5:1); [a]D¼218.5 (c¼0.5, CH2Cl2). 1H NMR
(600 MHz, CDCl3): d 1.29, 1.44 (2s, 6H, 2CH3), 3.04 (m,
2H, CH2), 3.96 (m, 2H, CH2), 4.24 (d, J¼3.5 Hz, 1H, 4-H),
4.46 (d, Jgem¼11.9 Hz, 1H, CHPh), 4.53 (d, Jgem¼11.9 Hz,
1H, CHPh), 4.55 (d, J¼3.4 Hz, 1H, 2-H), 4.64 (d, J¼3.5 Hz,
1H, 3-H), 6.01 (d, J¼3.4 Hz, 1H, 1-H), 7.20–7.33 (m, 5H,
Ar-H), 7.67–7.80 (m, 4H, Ar-H); 13C NMR (150.8 MHz,
CDCl3): d 26.3, 26.9 (2CH3), 32.4, 39.0, 72.4 (3CH2), 81.7
(2-C), 83.5 (4-C), 85.2 (3-C), 105.9 (1-C), 112.4, 123.1,
123.8, 127.6, 128.0, 128.5, 132.1, 133.8, 134.5, 136.7
(C-Ar), 167.9 (CO), 206.3 (NCO); MALDI, positive mode,
Matrix: DHB): m/z¼473.9 (MþNa)þ, 490.0 (MþK)þ.
Anal. calcd for C25H25NO7·H2O (469.5): C, 63.90; H,
5.75; N, 2.98. Found: C, 63.84; H, 5.66; N, 3.03.
CDCl3): d 1.27, 1.44 (2s, 6H, 2CH3), 2.45 (m, 2H, CH2),
2.85 (m, 2H, CH2), 4.01 (d, J¼3.5 Hz, 1H, 4-H), 4.42 (d,
Jgem¼11.8 Hz, 1H, CHPh), 4.45 (d, Jgem¼11.8 Hz, 1H,
CHPh), 4.55 (d, J¼3.5 Hz, 1H, 2-H), 4.70 (d, J¼3.5 Hz, 1H,
3-H), 5.11 (brs, 2H, NH2), 5.95 (d, J¼3.5 Hz, 1H, 1-H),
7.13–7.31 (m, 5H, Ar-H). Anal. calcd for
C17H25N3O4·0.25H2O (340.4): C, 60.07; H, 7.41; N,
12.36. Found: C, 60.14; H, 7.49; N, 11.74.
3.3.6. 1-Phenyl-3-(phthalimido)-propan-1-one O-acetyl-
oxime (27). Compound 17 (0.2, 0.7 mmol) was dissolved in
dry methanol (20 mL) and hydroxylamine hydrochloride
(0.15 g) was added. A solution of 10% NaOMe in methanol
was added dropwise until pH¼10 and then stirred for 1 h.
The mixture was filtered and evaporated in vacuo. The
residue was dissolved in pyridine (5 mL), treated with acetic
anhydride (2.5 mL) and the mixture was stirred at room
temperature for 12 h. The solvent was evaporated in vacuo
and then co-evaporated with toluene and the residue was
purified by flash chromatography (dichloromethane/metha-
nol 10:1) to afford 27 (0.19 g, 79%) as colorless oil; Rf 0.71
(chloroform/methanol 5:1). 1H NMR (250 MHz, CDCl3): d
2.17 (s, 3H, CH3CO), 3.24 (t, J¼7.2 Hz, 2H, CH2), 3.96 (t,
J¼7.2 Hz, NCH2), 7.24–7.38 (m, 5H, Ar-H), 7.67–7.82 (m,
4H, Ar-H); MALDI, positive mode, Matrix: DHB):
m/z¼358.4 (MþNa)þ, 375.1 (MþK)þ. Anal. calcd for
C19H16N2O4·0.5H2O (345.34): C, 66.08; H, 4.95; N, 8.11.
Found: C, 66.14; H, 4.90; N, 7.91.
3.2.9. Methyl 3-oxo-2-(phthalimidomethyl)butanoate
(20). Colorless oil (0.29 g, 75%); Rf 0.48 (petroleum
1
ether/ethyl acetate, 5:1). H NMR (250 MHz, CDCl3): d
2.20 (s, 3H, CH3), 3.62 (s, 3H, OCH3), 3.95 (m, 1H, CH),
4.13 (m, 2H, CH2), 7.61–7.88 (m, 4H, Ar-H); MS:
m/z¼275.0. Anal. calcd for C14H13NO5 (275.3): C, 61.09;
H, 4.76; N, 5.09. Found: C, 60.81; H, 4.68; N, 5.68.
3.2.10. Methyl 2,2-dimethyl-3-(phthalimido)propionate
(21). White powder (0.30 g, 82%); Rf 0.53 (petroleum ether/
ethyl acetate, 5:1). Mp 92 8C, lit.35 92–94 8C. The analytical
data are identical with the published values.
3.3.7. N-(Trichloroacetamidomethyl)benzamide (32). A
stirred solution of N-hydroxymethylol benzamide (28)
(0.76 g, 5.0 mmol) in dry dichloromethane (20 mL) and
trichloroacetonitrile (5 mL, 50 mmol) was treated with
DBU (71 mL) at room temperature and then left for 12 h.
The solvent was evaporated and the product was purified by
column chromatography (2% triethylamine in toluene) to
give 32 as a white powder (0.80 g, 54%); Rf 0.62 (2%
3.3. General procedure for the removal of the phthaloyl
group
The phthalimide derivative (0.50 mmol) was dissolved in
methanol (30 mL) and hydrazine hydrate (2 mL) and then
heated under reflux for 1 h. The solvent was evaporated in

I. A. I. Ali et al. / Tetrahedron 60 (2004) 4773–4780
4779
1
triethylamine in toluene). Mp 115 8C. NaH can be used
instead of DBU to give (1.3 g, 86.5%). 1H NMR (250 MHz,
CDCl3): d 4.98 (dd, J¼7.0 Hz, 2H, CH2), 7.41–7.81 (m, 6H,
NH, Ar-H), 8.12 (br, 1H, NH). 1H NMR (250 MHz, DMSO-
d6): d 5.00 (s, 2H, CH2), 7.68–8.21 (m, 5H, Ar-H), 9.40 (br,
1H, NH), 9.81 (br, 1H, NH); MS: m/z¼295.5. Anal. calcd
for C10H9Cl3N2O2 (295.5): C, 40.64; H, 3.07; N, 9.48.
Found: C, 40.62; H, 3.10; N, 9.35.
(petroleum ether/ethyl acetate, 5:1). H NMR (250 MHz,
CDCl3): d 1.19 (s, 6H, 2CH3), 3.39 (d, J¼6.1 Hz, 2H, CH2),
3.68 (s, 3H, OCH3), 7.51 (brs, 1H, NH); MS: m/z¼276.5.
Anal. calcd for C8H12Cl3NO3 (276.5): C, 34.74; H, 4.37; N,
5.06. Found: C, 34.67; H, 4.73; N, 4.97.
3.5. Removal of the trichloroacetimido group
The trichloroacetamide derivative 36 (0.5 g, 1.87 mmol)
was dissolved in methanol (10 mL) and 2 N KOH (5 mL)
and the reaction mixture was refluxed for 1 h. The solvent
was evaporated in vacuo and the residue dissolved in
dichloromethane (50 mL). The solution was extracted with
1 N NaOH (5£50 mL) and the organic layer dried with
magnesium sulfate and concentrated in vacuo to give 2437
(see above).
3.3.8. N-(Trichloroacetamidomethyl)-N-methyl-benza-
mide (33). A stirred solution of N-hydroxymethyl N-methyl
benzamide 29 (0.83 g, 5.0 mmol) in dry dichloromethane
(20 mL) and trichloroacetonitrile (5 mL, 50 mmol) was
treated with NaH (0.12 g, 5 mmol) at room temperature and
then left for 8 h. The reaction mixture was processed as
above. The crude residue was purified by column chroma-
tography (2% triethylamine in toluene) to give 33 as a white
powder (0.1 g, 73%); Rf 0.71 (2% triethylamine in toluene).
1
Mp 95 8C. H NMR (250 MHz, CDCl3): d 3.11 (s, 3H,
Acknowledgements
CH3), 4.98 (d, J¼5.8 Hz, 2H, CH2), 7.42 (m, 5H, Ar-H),
8.01 (br, 1H, NH). MALDI, positive mode, Matrix: DHB):
m/z¼332.0 (MþNa)þ. Anal. calcd for C11H11Cl3N2O2
(309.6): C, 42.68; H, 3.58; N, 9.05. Found: C, 42.69; H,
3.59; N, 9.20.
This work was supported by the Deutsche Forschungs-
gemeinschaft and the Fonds der Chemischen Industrie.
I.A.I. Ali is grateful for a stipend within the fellowship
programme from the Egyptian government. The continued
support from the Alexander von Humboldt Stiftung for
E.S.H. El Ashry is highly appreciated.
3.3.9. O-(Trichloroacetamidomethyl) trichloroaceti-
midate (35). A stirred solution of N-hydroxymethyl-
trichloroacetamide (34) (0.96 g, 5.0 mmol) in dry dichloro-
methane (20 mL) and trichloroacetonitrile (5 mL, 50 mmol)
was treated with NaH (0.12 g, 5 mmol) at room temperature
and then left for 8 h. The reaction was processed as above.
The crude residue was purified by column chromatography
(2% triethylamine in toluene) to give 35 as an oil (1.2 g,
References and notes
1. Mathieu, J.; Weill-Raynal, J. Formation of C–C bonds; Georg
Thieme: Stuttgart, 1973; Vol. 1. pp 78–119.
1
71.5%); Rf 0.69 (2% triethylamine in toluene). H NMR
2. Blicke, F. F. Org. React. 1942, 1, 303–341.
3. Mironov, G. S.; Farberov, M. I. Russ. Chem. Rev. 1964, 33,
311–319.
(250 MHz, CDCl3): d 3.95 (br, 1H, NH), 4.93 (d, J¼6.4 Hz,
2H, CH2), 7.81 (brs, 1H, NH). (C5H4Cl6N2O2) 337.0;
m/z¼337.0.
4. Zaugg, H. Synthesis 1970, 49–73. Zaugg, H. Synthesis 1984,
181. Zaugg, H. Synthesis 1984, 85–110.
3.4. General procedure for the reaction of trichloro-
acetimidate 35 with C-nucleophiles
5. Knight, D. W. Comprehensive organic synthesis; Trost, B. M.,
Fleming, I., Pattenden, G., Eds.;, 1995; Vol. 3, pp 241–270.
6. Germon, C.; Alexakis, A.; Normant, J. F. Synthesis 1984,
40–43.
A solution of 35 (0.47 g, 1.4 mmol) and acceptor
(1.4 mmol) in dry dichloromethane (40 mL) was stirred
under nitrogen at room temperature and then TMSOTf
(13 mL, 0.06 mmol) was added. After 1–3 h, the reaction
mixture was neutralized with solid sodium bicarbonate,
filtered and concentrated in vacuo. The residue was purified
by flash chromatography (petroleum ether/ethyl acetate).
7. Germon, C.; Alexakis, A.; Normant, J. F. Tetrahedron Lett.
1980, 21, 3763–3766.
8. Campbell, E. F.; Park, A. K.; Kinney, W. A.; Fengl, R. W.;
Liebeskind, L. S. J. Org. Chem. 1995, 60, 1470–1472.
9. Knochel, P.; Chou, T.-S.; Jubert, C.; Rajagopal, D. J. Org.
Chem. 1993, 58, 588–599.
10. Monti, L. Gazz. Chim. Ital. 1930, 60, 39. Chem. Abstr. 1930,
24, 4013.
3.4.1. N-(3-Phenyl-allyl)-trichloroacetamide (36). Yellow
oil (0.21g, 79%). The analytical data are identical with the
published values.44
11. Hellmann, H. Angew. Chem. 1957, 69, 463–471.
12. Hellmann, H.; Aichinger, G.; Wiedemann, H. P. Liebigs Ann.
Chem. 1959, 626, 35–46.
3.4.2. Methyl 3-oxo-2-(trichloroacetamidomethyl)-
butanoate (37). Colorless oil (0.27 g, 68%); Rf 0.46
(petroleum ether/ethyl acetate, 5:1). H NMR (250 MHz,
CDCl3): d 2.35 (s, 3H, CH3), 3.79 (s, 3H, OCH3), 3.92 (m,
3H, CH, NCH2), 7.51 (brs, 1H, NH). Anal. calcd for
C8H10Cl3NO4 (290.5): C, 33.07; H, 3.47; N, 4.82. Found: C,
32.55; H, 3.54; N, 5.01.
13. Schmidt, R. R. Angew. Chem. 1973, 85, 235–247. Schmidt,
R. R. Angew. Chem. Int. Ed. Engl. 1973, 12, 212–224.
14. Feuer, H.; Lynch-Hart, U. E. J. Org. Chem. 1961, 26,
391–394. Feuer, H.; Lynch-Hart, U. E. J. Org. Chem. 1961,
26, 587–589.
1
15. Hellmann, H.; Haas, G. Chem. Ber. 1957, 90, 1357–1363.
¨
16. Hellmann, H.; Loschmann, I.; Lingens, F. Chem. Ber. 1954,
87, 1690–1699.
3.4.3. Methyl-2,2-dimethyl-3-(trichloroacetamido)-pro-
panoate (38). Colorless oil (0.28 g, 74%); Rf 0.53
¨
17. Bohme, H.; Eiden, F. Arch. Pharm. 1959, 292, 642–649.
18. Schetty, G. Helv. Chem. Acta 1948, 1229–1239.

4780
I. A. I. Ali et al. / Tetrahedron 60 (2004) 4773–4780
19. Ziegler, E.; Roßmann, U.; Litvan, F. Montash. 1957, 88,
587–596.
33. Abdel-Rahman, A. A.-H.; Takhi, M.; El-Ashry, E. S. H.;
Schmidt, R. R. J. Carbohydr. Chem. 2002, 21, 113–122.
34. Juaristi, E. Enantioselective synthesis of b-amino acids;
Wiley-VCH: New York, 1997; pp 1–66.
20. Zaugg, H. E.; Schaefer, A. D. J. Org. Chem. 1963, 28,
2925–2927.
21. Sato, Y.; Nakai, H.; Wada, M.; Mizoguchi, T.; Hatanaka, Y.;
Migita, Y.; Kanaoka, Y. Liebigs Ann. Chem. 1985,
1099–1118.
35. Ducry, L.; Reinelt, S.; Seiler, P.; Diederich, F. Helv. Chim.
Acta 1999, 82, 2432–2447.
36. Lin, A. J.; Driscoll, L. S. J. Pharm. 1981, 70, 806–808.
37. Hendrickson, J. B.; Bergeron, R.; Sternbach, D. D.
Tetrahedron 1975, 31, 2517–2521.
22. Ali, I. A. I.; Abdel-Rahman, A. A.-H.; El-Ashry, E. S. H.;
Schmidt, R. R. Synthesis 2003, 7, 1065–1070.
23. Takamizawa, A.; Matsumoto, S. Chem. Pharm. Bull. 1978, 26,
790–797.
38. Einhorn, A.; Bischkopff, E.; Szelinski, B. Ann. Chem. 1905,
343, 223–224.
¨
39. Bohme, H.; Dick, A.; Driesen, G. Chem. Ber. 1961, 94,
1879–1882.
24. Arnold, L. D.; Assil, H. I.; Vederas, J. C. J. Am. Chem. Soc.
1989, 111, 3973–3976.
25. Wada, M.; Sano, T.; Mitsunobu, O. Bull. Chem. Soc. Jpn 1973,
46, 2833–2835.
40. Schmidt, R. R.; Jung, K.-H. Carbohydr. Eur. 1999, 27, 12–21.
41. Schmidt, R. R.; Jung, K.-H. Chemistry of saccharides; Ernst,
B., Hart, G. W., Sinay, P., Eds.; Wiley-VCH: Weinheim,
2000; Vol. 1, pp 5–59.
26. Rastetter, W. H.; Spero, D. M.; Adam, J.; Harpp, D. N.; Ash,
D. K. J. Org. Chem. 1982, 47, 2785–2787.
27. Chmielewski, M.; Jurczak, J.; Zamojski, A. Tetrahedron 1978,
34, 2977–2981.
42. Schmidt, R. R.; Kinzy, W. Adv. Carbohydr. Chem. Biochem.
1994, 50, 21–123.
28. Vidal, T.; Petit, A.; Loupy, A.; Gede, R. N. Tetrahedron 2000,
56, 5473–5478.
43. Rivier, J. E.; Jiang, G.; Porter, J.; Hoeger, C. A.; Craig, A. C.;
Corrigan, A.; Vale, W.; Rivier, C. L. J. Med. Chem. 1995, 38,
2649–2662.
29. Kamal, A.; Laxman, E.; Laxman, N.; Rao, N. V. Tetrahedron
Lett. 1998, 39, 8733–8734.
44. Commercon, A.; Ponsinet, G. Tetrahedron Lett. 1990, 31,
3871–3874.
30. Posnert, T. Chem. Ber. 1893, 26, 1856–1865.
31. Patent, Farben Fabr. Bayer, DE 933339, 1954..
32. Hammen, P. D.; Braisted, A. C.; Northrup, D. L. Synth.
Commun. 1991, 21, 2157–2163.
45. Merten, R.; Mu¨ller, G. Angew. Chem. 1962, 74, 866.
46. Hlaney, H. Comprehensive organic synthesis; Trost, B. M.,
Fleming, I., Heathcock, C., Eds.;, 1995; Vol. 2, p 953.