Microwave accelerated aza-claisen rearrangement

Article abstract of DOI:10.3390/molecules131102837

A study of microwave-induced and standard thermal Overman rearrangement of selected allylic trichloroacetimidates 1a-1f, 6-8 to the corresponding acetamides 2a-2f, 9-11 is reported. The microwave-assisted rearrangement of trifluoroacetimidate 13 is also described. Using this methodology, an efficient access to versatile allylic trihaloacetamides building synthons was established.

Full text of DOI:10.3390/molecules131102837

Molecules 2008, 13, 2837-2847; DOI: 10.3390/molecules131102837
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Microwave Accelerated Aza-Claisen Rearrangement
Eva Gajdošíková, Miroslava Martinková, Jozef Gonda* and Patrik Čonka
Institute of Chemical Sciences, Department of Organic Chemistry, P. J. Šafárik University, Moyzesova
11, SK-040 01 Košice, Slovak Republic; E-mails: eva.gajdosikova@gmail.com (E. G.),
miroslava.martinkova@upjs.sk (M. M.), patrik.conka@gmail.com (P. C.)
* Author to whom correspondence should be addressed; E-mail: jozef.gonda@upjs.sk; Tel.: +421-55
6228332; Fax: +421-55 6222421.
Received: 7 October 2008; in revised form: 28 October 2008 / Accepted: 4 November 2008 /
Published: 14 November 2008
Abstract: A study of microwave-induced and standard thermal Overman rearrangement of
selected allylic trichloroacetimidates 1a-1f, 6-8 to the corresponding acetamides 2a-2f, 9-
11 is reported. The microwave-assisted rearrangement of trifluoroacetimidate 13 is also
described. Using this methodology, an efficient access to versatile allylic trihaloacetamides
building synthons was established.
Keywords: Overman rearrangement; Imidate; Microwave irradiation.
Introduction
The [3,3]-sigmatropic rearrangement of allylic trihaloacetimidates into allylic trihaloacetamides is a
useful methodology for the synthesis of nitrogen containing compounds such as amino acids [1-3],
modified nucleosides [4,5] or other complex biologically interesting products [6-9]. This
transformation is very often involved as the key step in the synthetic approaches and can be
accomplished either at elevated temperatures or catalyzed by metal salts such as Hg(OCOCF3)2
[10,11], PdCl2 complexes [12,13] and new Pt(II), Pt(IV), Au(I) and Au(III) catalysts [14] under very
mild reaction conditions.

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A significant acceleration of aza-Claisen rearrangements was observed using microwave irradiation
[15]. This fact eliminated problems with previously required high temperatures and extended reaction
times, and also reduced decomposition of the starting materials and products.
Results and Discussion
In this communication, we wish to report on microwave-assisted thermal Overman rearrangement
of some selected allylic trihaloacetimidates 1a-f, 6-8, 13 that are derived either from simple allylic
alcohols, amino acids or the modified sugars, respectively, and thus illustrate the potential of
microwave irradiation to accelerate this reaction.
Scheme 1. Microwave accelerated Overman rearrangement of simple aliphatic imidates.
Table 1. Microwave accelerated Overman rearrangement of simple aliphatic imidates.
Yielda (%)
Entry
R
Conditions
Time
2a-f
Δ, 140 oC, o-xylene [10,15]
MW, 140 oC, o-xylene, K2CO3
MW, 210 oC, o-xylene, K2CO3
12 h
10 h
50
65
70
1
R1= H, R2= H, R3= H (a)
b
5 min
Δ, 110oC, toluene [18]
Δ, 140 oC, o-xylene, K2CO3
MW, 140 oC, o-xylene, K2CO3 [16]
MW, 180 oC, o-xylene, K2CO3 [16]
Δ, 140 oC, o-xylene [10]
Δ, 140 oC, o-xylene, K2CO3
MW, 140 oC, o-xylene, K2CO3 [16]
MW, 180 oC, o-xylene, K2CO3 [16]
2 h
2 h
53
60
93
89
74
75
97
94
2
R1= H, R2= H, R3= Me (b)
15 min
8 min
2.5 h
2.5 h
5 min
1 min
b
3
4
5
6
R1= H, R2= H, R3= Bu (c)
R1= H, R2= H, R3= Pent (d)
R1= Me, R2= Me, R3= H (e)
R1= Me, R2= H, R3= Me (f)
b
Δ, 140 oC, o-xylene, K2CO3
MW, 140 oC, o-xylene, K2CO3
1.5 h
97
92
5 min
Δ, 140 oC, o-xylene [11]
Δ, 140 oC, o-xylene, K2CO3
MW, 140 oC, o-xylene, K2CO3 [16]
3.5 h
3.5 h
48
80
85
84
20 min
14 min
MW, 180 oC, o-xylene, K2CO3 [16]
b
Δ, 140 oC, o-xylene, K2CO3
MW, 140 oC, o-xylene, K2CO3
45 min
45 min
70
75
aIsolated yield. bMW experiments were performed in the presence of a heating bar, Weflon, Milestone.

Molecules 2008, 13
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Thermally driven [3,3]-sigmatropic rearrangements (Scheme 1) were carried out according to the
procedure described by Overman [10]. In the microwave-assisted thermal aza-Claisen rearrangement,
the imidate was dissolved in o-xylene, powdered anhydrous K2CO3 [17] (2 mg/mL) was added, and
the solution was heated under sealed vessel conditions. The scope of this method was investigated and
all synthesized imidates (only imidates 1e and 1f were not characterized and used immediately to
avoid problems connected with their instability) in Table 1 were converted to the corresponding
trichloroacetamides 2a–2f in considerably shorter reaction times, compared to the conventional
thermal rearrangement. We have observed that the use of microwave irradiation lead to a substantial
reduction of the reaction times (from hours to minutes, Table 1, Entry 1-5). On the other hand, the
conversion of 1f to compound 2f was achieved at the same reaction time in the both cases (the
microwave-assisted and standard thermal conditions, Table 1, Entry 6).
Scheme 2. Microwave accelerated Overman rearrangement of the chiral imidates.
Table 2. Microwave accelerated Overman rearrangement of the chiral imidates 6, 7, 8 and 13.
Entry Starting
material
Conditions
Time
Yielda (%)
Δ, 140 oC, o-xylene, de=10% [12]
24 h
2 h
75
80
80
69
71
68
1
2
3
4
6
7
MW, 140 oC, o-xylene, K2CO3 de=14% [16]
MW, 200 oC, o-xylene, K2CO3 de=12% [16]
Δ, 140 oC, o-xylene, de=10% [12]
MW, 140 oC, o-xylene, K2CO3 de=12% [16]
MW, 200 oC, o-xylene, K2CO3 de=13% [16]
5 min
24 h
2 h
5 min
Δ, 140 oC, o-xylene, de=2%
MW, 160 oC, o-xylene, K2CO3 de=2%
42 h
1 h
80
86
8
Δ, 180 °C, o-xylene, K2CO3, de ≈ 20%
MW, 180 °C, o-xylene, K2CO3, de ≈ 19%
MW, 180 °C, o-xylene, de ≈ 18%
aIsolated yields.
12 h
30 min
1 h
31
68
15
13
In earlier studies was found that Pd(II)-catalyzed Overman rearrangement of trichloroacetimidates
6, 7 derived from primary allylic alcohols with an adjacent centre of chirality proceeded with an
excellent diastereoselectivity (de ≥ 98%) [12]. In the next phase of our work we decided to study
whether the described microwave-assisted Overman rearrangement could lead to a certain degree of

Molecules 2008, 13
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diastereoselection. The conversion of known allylic alcohols [12,14] into trichloroacetimidates 6-8 was
achieved using trichloroacetonitrile and DBU as a base in dichloromethane (Scheme 2). The results of
the thermal and microwave induced Overman rearrangements of imidates 6-8 are summarized in Table
2. We have found that microwave irradiation of 6- 8 led to the rearranged products 9, 10 [12] and 11
[14] (as the mixtures of diastereoisomers) with substantial shortening of the reaction times (from 24 h
to 5 min) with good yields (Table 2), however, it has shown that in these cases microwave-induced
rearrangement had practically no influence on the diastereoselectivity of aza-Claisen rearrangement
(Table 2).
Scheme 3. Microwave accelerated Overman rearrangement of the sugar trifluoroacetimidate 13.
Finally, we have investigated Overman rearrangement of the sugar allylic trifluoroacetimidate 13
under microwave irradiation. Trifluoroacetimidate 13 was prepared from the corresponding allylic
alcohol 12 derived from D-glucose [19] by reaction with CF3CN in THF (Scheme 3). Rearrangement
of 13 afforded trifluoroacetamide 14 as the mixture of diastereoizomers (de=19%) (Scheme 3). In
order to determine the best reaction conditions, a series of the thermally and microwave accelerated
rearrangements of imidate 13 was performed. Studies showed that microwave irradiation accelerated
of the rearrangement 13→14a,b (24 times) in comparison with conventional thermal conditions (Table
2, entry 4) without any improvement in the stereoselectivity. Extension of the reaction time led to the
decomposition of product 14.
Conclusions
In summary, a remarkable acceleration of the Overman rearrangemet of allylic trihaloimidates to
the corresponding allylic trihaloamides was observed using microwave irradiation conditions. The
[3,3]-sigmatropic rearrangement carried out under conventional conditions (reflux temperature of the
solvent) required long reaction times and produced moderate yields, usually a result of connected with
the decomposition of starting materials. This paper demonstrates the practical usability of microwave
acceterated thermal Overman rearrangement for the synthesis of various amides.
Experimental
All commercially available reagents were used without further purification and solvents were dried
according to standard procedures. Column chromatography was carried out on Silica Gel 60 (Merck,

Molecules 2008, 13
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0.040-0.063 mm, 230-400 mesh). Analytical thin-layer chromatography (TLC) was performed on
Merck silica gel 60 F254 analytical plates; detection was carried out with either UV (254 nm), or
spraying with a solution of phosphomolybdic acid, and with a basic solution of KMnO4, with
subsequent heating. NMR spectra were recorded at room temperature on a Varian Mercury Plus 400
13
FT NMR spectrometer (1H at 400.13 MHz and C at 100.6 MHz), in CDCl3 as the solvent (unless
1
otherwise noted) with tetramethylsilane as internal reference. For those fully assigned H- and 13C-
NMR spectra standard NMR (COSY, DEPT, HSQC) experiments were conducted. Optical rotations
o
were measured with a P3002 Krüss polarimeter in chloroform at 25 C. All moisture-sensitive
reactions were performed under a nitrogen atmosphere. Microwave experiments were conducted using
a focused microwave system (CEM Discover). Reactions were performed in a glass vessel (10 mL)
sealed with a septum. At the end of the reaction the vessels together with their contents were cooled
rapidly using a stream of compressed air. The melting points were determined on the Kofler block and
are uncorrected.
General procedure for preparation of trichloroacetimidates
To a solution of allyl alcohol in dry dichloromethane were added 1,8-diazabicyclo[5,4,0]undec-7-
ene (DBU, 2 eq) and trichloroacetonitrile (2 eq) at 0 oC. The reaction mixture was stirred at 0 oC for 1
h. The insoluble material was removed by filtration and the filtrate was concentrated under reduced
pressure to give a residue, which was purified by chromatography on silica gel (cyclohexane-ethyl
acetate) to afford corresponding imidates 1a-1d, 6, 7, 8.
O-Allyl-2,2,2-trichloroacetimidate: Allyl alcohol (0.50 g, 8.61 mmol), DBU (2.57 mL, 17.22 mmol),
trichloroacetonitrile (1.73 mL, 17.22 mmol) in CH2Cl2 (20 mL) afforded after flash chromatography
1
(cyclohexane-ethyl acetate, 10:1) compound 1a (1.56 g, 89.5%) as a colorless oil; H-NMR: δ 4.81
(2H, m, CH2), 5.31 (1H, dd, J=10.5 Hz, J=1.3 Hz, CH2=), 5.44 (1H, ddd, J=17.2 Hz, J=3.1 Hz, J=1.5
13
Hz, CH2=), 6.03 (1H, ddd, J=17.2 Hz, J=10.5 Hz, J=5.4 Hz, CH=), 8.32 (1H, bs, NH); C-NMR: δ
69.6, 109.7, 118.5, 131.4, 162.5; Anal. Calcd. for C5H6Cl3NO (202.47): C 29.66, H 2.99, N 6.91;
1
found C 29.53, H 2.87, N 6.74. The procedure and H-NMR spectroscopic data were previously
reported [10]. 13C-NMR data have not been reported before [10].
O-(But-3-en-2-yl)-2,2,2-trichloroacetimidate (1b): But-3-en-2-ol (0.50 g, 6.93 mmol), DBU (1.45 mL,
9.70 mmol, 1.4 eq), trichloroacetonitrile (1.04 mL, 10.4 mmol, 1.5 eq) in CH2Cl2 (25 mL) afforded
(1.30 g, 87%) of compound 1b after flash chromatography (cyclohexane-ethyl acetate, 5:1) as a pale
yellow oil; 1H-NMR: δ 1.44 (3H, d, J=6.5 Hz, CH3), 5.20 (1H, d, J=10.6 Hz, H4), 5.36 (1H, d, J=17.3
Hz, H4), 5.49 (1H, m, H3), 5.94 (1H, m, H2), 8.29 (1H, bs, NH); 13C-NMR: δ 19.4, 75.7, 91.8, 115.9,
136.8, 161.8.; Anal. Calcd. for C6H8Cl3NO (216.49): C 33.29, H 3.72, N 6.47; found C 33.10, H 3.45,
1
13
N 6.28. The procedure and H-NMR spectroscopic data have been reported [18]. C-NMR data have
not previously been reported [18].
2,2,2-Trichloro-O-(hept-1-en-3-yl)acetimidate (1c): Hept-1-en-3-ol (0.50 g, 4.38 mmol), DBU (1.31
mL, 8.76 mmol), trichloroacetonitrile (0.88 mL, 8.76 mmol) in CH2Cl2 (20 mL) afforded after flash

Molecules 2008, 13
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chromatography (cyclohexane-ethyl acetate, 10:1) compound 1c (1.11 g, 98%) as a pale yellow oil;
1H-NMR: δ 0.90 (3H, t, J=6.9 Hz, CH3), 1.38 (4H, m, 2 x CH2), 1.74 (2H, m, CH2), 5.21 (1H, dd,
J2,1=10.6 Hz, J1,1=0.7 Hz, H1), 5.36 (2H, m, H1, H3), 5.80 (1H, m, H2), 8.27 (1H, s, NH); 13C-NMR: δ
14.2, 22.6, 27.3, 34.0, 79.7 92.1, 116.8, 135.8, 162.2; Anal. Calcd for C9H14Cl3NO2 (258.57): C 41.76,
1
H 5.41, N 5.41; found C 41.65, H 5.21, N 5.33. The procedure and H-NMR spectroscopic data were
reported [10]. 13C-NMR data have not previously been reported [10].
2,2,2-Trichloro-O-(oct-1-en-3-yl)acetimidate (1d): Oct-1-en-3-ol (0.50 g, 3.90 mmol), DBU (1.17 mL,
7.8 mmol), trichloroacetonitrile (0.78 mL, 7.80 mmol) in CH2Cl2 (20 mL) afforded after flash
chromatography (cyclohexane-ethyl acetate, 10:1) compound 1d (0.90 g, 85%) as a pale yellow oil;
1H-NMR: δ 0.88 (3H, t, J=7.1 Hz, CH3), 1.29-1.47 (6H, m, 3 x CH2), 1.65-1.82 (2H, m, CH2), 5.21
(1H, m, H1), 5.30 (2H, m, H1, H3), 5.86 (1H, m, H2), 8.26 (1H, bs, NH); 13C-NMR: δ 14.2, 79.7, 22.7,
24.8, 31.7, 34.3, 92.1, 116.7, 136.0, 162.2; Anal. Calcd. for C10H16Cl3NO (272.60): C 44.06, H 5.91, N
5.14; found C 43.95, H 5.77, N 5.01.
tert-Butyl N-[(3S,4E)-6-(trichloroacetimidyloxy)hex-4-en-3-yl]carbamate (6): Compound 3 (0.30 g,
1.393 mmol), DBU (0.42 mL, 2.79 mmol), trichloroacetonitrile (0.28 mL, 2.79 mmol) in CH2Cl2 (15
mL) afforded after flash chromatography (cyclohexane-ethyl acetate, 3:1) compound 6 (0.40 g, 80%)
as a colorless oil; 1H-NMR: δ 0.92 (3H, t, J=7.4 Hz, CH3), 1.44 (9H, s, 3 x CH3), 1.53 (2H, m, CH2),
4.08 (1H, m, H3), 4.45 (1H, bs, NH), 4.77 (2H, m, H6), 5.79 (2H, m, H4, H5), 8.29 (1H, bs, NH); 13C-
NMR: δ 10.1, 28.2, 28.4 (3x), 53.1, 68.9, 79.4, 123.4, 135.8, 155.4, 162.5; Anal. Calcd. for
1
13
C13H21Cl3N2O3 (359.68): C 43.37, H 5.83, N 7.78; found C 43.01, H 5.64, N 7.64. H and C-NMR
spectroscopic data have not previously been reported [12].
tert-Butyl N-[(3S,4E)-6-(trichloroacetimidyloxy)-2-methylhex-4-en-3-yl]carbamate (7): Compound 4
(0.10 g, 0.436 mmol), DBU (0.13 mL, 0.87 mmol), trichloroacetonitrile (0.087 mL, 0.87 mmol) in
CH2Cl2 (10 mL) afforded after flash chromatography (cyclohexane-ethyl acetate, 3:1) compound 7
1
(0.12 g, 74%) as white crystals; m.p. 42 – 43 oC; H-NMR: δ 0.89 (6H, m, 2 x CH3), 1.44 (9H, s, 3 x
CH3), 1.78 (1H, m, CH), 4.04 (1H, m, H3), 4.52 (1H, m, NH), 4.80 (2H, m, H6), 5.79 (2H, m, H4, H5),
13
8.30 (1H, bs, NH); C-NMR: δ 18.1, 18.7, 28.4, (3 x C), 32.4, 56.9, 68.9, 79.4, 91.4, 123.9, 134.5,
155.5, 162.4; Anal. Calcd. for C14H23Cl3N2O3 (373.71): C 44.99, H 6.20, N 7.49; found C 44.78, H
6.05, N 7.21. 1H- and 13C-NMR spectroscopic data have not previously been reported [12].
O-[(4S,2E)-4-(tert-Butyldimethylsilyoxy)pent-2-enyl]-2,2,2-trichloroacetimidate (8): Compound 5
(0.35 g, 1.62 mmol), DBU (0.48 mL, 3.24 mmol), trichloroacetonitrile (0.325 mL, 3.24 mmol) in
1
CH2Cl2 (18 mL) afforded compound 8 (0.50 g, 85.5%) as a colorless oil; H-NMR: δ 0.05 (3H, s,
CH3), 0.06 (3H, s, CH3), 0.89 (9H, s, 3 x CH3), 1.23 (3H, d, J=6.7 Hz, CH3), 4.35 (1H, m, H4), 4.77
(2H, m, H1), 5.86 (2H, m, H2, H3), 8.28 (1H, bs, NH); 13C-NMR: δ -4.8, -4.7, 18.3, 24.1, 25.9 (3 x C),
68.4, 69.1, 121.4, 139.8, 162.5; Anal. Calcd. for C13H24Cl3NO2Si (360.78): C 43.28, H 6.71, N 3.88;
1
found C 43.17, H 6.56, N 3.59. The procedure and H-NMR spectroscopic data were reported before
[14]. 13C-NMR data have not previously been reported [14].

Molecules 2008, 13
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General procedure for Overman rearrangement
Conventional method (Procedure A): To a solution of imidates in dry solvent (see Tables 1, 2) was
added anhydrous K2CO3 (1.1 eq). The reaction mixture was heated (for temperatures see Tables 1, 2).
The solvent was evaporated under reduced pressure and chromatography of the residue on the silica
gel (cyclohexane-ethyl acetate) afforded corresponding amides 2a-2f, 9-11, 14 (Tables 1, 2). (B1)
Microwave-assisted synthesis (Procedure B): To a solution of the corresponding imidate in o-xylene in
a 10 mL glass pressure microwave tube equipped with a magnetic stirrer bar was added anhydrous
K2CO3 (1.1 eq) and the tube was closed with a silicon septum. The reaction mixture was subjected to
microwave irradiation (power: 300W; for temperatures, reaction times and yields see Tables 1, 2). The
solvent was removed under reduced pressure and the residue was purified by flash chromatography on
silica gel (cyclohexane-ethyl acetate) to give amides 2a-2f, 9-11, 14 (Tables 1, 2). (B2)
N-Allyl-2,2,2-trichloroacetamide (2a): Following general procedure A, 1a (0.30 g, 1.48 mmol), K2CO3
(0.23 g, 1.63 mmol) in o-xylene (3 mL) afforded after flash chromatography (cyclohexane-ethyl
acetate, 10:1) compound 2a (0.195 g, 65%). 2a: white crystals; m.p. 28 - 32 oC (Ref. [10] m.p. 28–31
oC); 1H-NMR: δ 3.99-4.02 (2H, m, CH2), 5.24-5.32 (2H, m, CH2=), 5.84-5.93 (1H, m, CH=), 6.78 (1H,
bs, NH); 13C-NMR: δ 43.6, 92.5, 117.8, 132.2, 161.8; Anal. Calcd. for C5H6Cl3NO (202.46): C 29.66,
1
H 2.98, N 7.90; found C 29.59, H 2.83, N 7.75. The procedure and H-NMR spectroscopic data were
reported [10]. 13C-NMR data have not previously been reported [10].
N-[(E)-But-2-enyl]-2,2,2-trichloroacetamide (2b): Following general procedure A, 1b (0.10 g, 0.462
mmol), K2CO3 (70.2 mg, 0.508 mmol) in o-xylene (2 mL) afforded after flash chromatography
(cyclohexane-ethyl acetate, 10:1) compound 2b (0.093 g, 93%). Following general procedure B, 1b
(0.30 g, 1.386 mmol), K2CO3 (0.21 g, 1.525 mmol) in o-xylene (5 mL) afforded after flash
chromatography (cyclohexane-ethyl acetate, 10:1) compound 2b (0.18 g, 60%). 2b: white crystals;
o
o
1
m.p. 27 - 29 C (Ref. [10] m.p. 28 – 29 C); H-NMR: δ 1.72 (3H, d, J=6.5 Hz, CH3), 3.91 (2H, m,
CH2), 5.50 (1H, m, CH=), 5.74 (1H, m, CH=), 6.68 (1H, bs, NH); 13C-NMR: δ 17.7, 43.3, 109.7,
124.8, 130.3, 161.6; Anal. Calcd. for C6H8Cl3NO (216.49): C 33.26, H 3.72, N 6.47; found C 33.14, H
3.55, N 6.38. The procedure, 1H-NMR and 13C-NMR data spectroscopic data have been reported [18].
2,2,2-Trichloro-N-[(E)-hept-2-enyl]acetamide (2c): Following general procedure A, 1c (0.20 g, 0.773
mmol), K2CO3 (0.117 g, 0.85 mmol) in o-xylene (2 mL) afforded after flash chromatography
(cyclohexane-ethyl acetate, 10:1) compound 2c (0.18 g, 90%). Following general procedure B, 1c
(0.40 g, 1.55 mmol), K2CO3 (0.236 g, 1.71 mmol) in o-xylene (4 mL) afforded after flash
chromatography (cyclohexane-ethyl acetate, 10:1) compound 2c (0.30 g, 75%). 2c: a colorless oil; 1H-
NMR: δ 0.90 (3H, t, J=7.1 Hz, CH3), 1.28-1.39 (4H, m, 2 x CH2), 2.02-2.07 (2H, m, CH2), 3.92 (2H,
m, CH2); 5.44-5.51 (1H, m, CH=), 5.68-5.76 (1H, m, CH=), 6.67 (1H; bs, NH); 13C-NMR: δ 14.1,
22.4, 31.3, 32.1, 43.6, 92.8, 123.7, 135.9, 161.8; Anal. Calcd. for C9H14Cl3NO2 (258.57): C 41.77, H
1
5.45, N 5.41; found C 41.63, H 5.24, N 5.35. The procedure and H-NMR spectroscopic data were
reported before [10]. 13C-NMR data have not previously been reported [10].

Molecules 2008, 13
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(E)-2,2,2-Trichloro-N-(oct-2-enyl)acetamide (2d): Following general procedure A, 1d (0.40 g, 1.47
mmol), K2CO3 (0.224 g, 1.62 mmol) in o-xylene (4 mL) afforded after flash chromatography
(cyclohexane-ethyl acetate, 10:1) compound 2d (0.37 g, 92.5%). Following general procedure B, 1d
(0.40 g, 1.47 mmol), K2CO3 (0.224 g, 1.62 mmol) in o-xylene (4 mL) afforded after flash
chromatography (cyclohexane-ethyl acetate, 10:1) compound 2d (0.39 g, 97.5%). 2d: a colorless oil;
1H-NMR: δ 0.87 (3H, t, J=7.0 Hz, CH3), 1.26-1.40 (6H, m, 3 x CH2), 2.04 (2H, q, J=7.0 Hz, CH2),
3.93 (2H, t, J=5.9 Hz, CH2), 5.46 (1H, m, CH=), 5.73 (1H, m, CH=), 6.69 (1H, bs, NH); 13C-NMR: δ
14.6, 22.7, 28.8, 31.6, 32.4, 43.5, 92.8, 123.6, 135.8, 161.7; Anal. Calcd. for C10H16Cl3NO (272.60): C
44.02, H 5.92, N 5.13; found C 43.90, H 5.84, N 5.04.
2,2,2-Trichloro-N-(2-methylbut-3-en-2-yl)acetamide (2e): Following general procedure A, 1e (0.3 g,
1.30 mmol), K2CO3 (0.198 g, 1.43 mmol) in o-xylene (3 mL) afforded after flash chromatography
(cyclohexane-ethyl acetate, 10:1) compound 2e (0.25 g, 83%). Following general procedure B, 1e
(0.5g, 2.17 mmol), K2CO3 (0.33 g, 2.39 mmol) in o-xylene (5 mL) afforded after flash chromatography
(cyclohexane-ethyl acetate, 10:1) compound 2e (0.40 g, 80%). 2e: white crystals; m.p. 48 – 50 oC (Ref.
[11] m.p. 49 – 50 oC); 1H-NMR: δ 1.54 (6H, s, 2 x CH3), 5.17 (2H, m, H4), 6.00 (1H, m, H3), 6.59 (1H,
bs, NH); 13C-NMR: δ 26.5 (2 x C), 56.1, 93.4, 113.3, 142.1, 160.4; Anal. Calcd. for C7H10Cl3NO
1
(230.52): C 36.43, H 4.32, N 6.07, found C 36.30, H 4.11, N 5.98. The H-NMR spectrum was
previously reported [11].
2,2,2-Trichloro-N-[(E)-pent-3-en-2-yl]acetamide (2f): Following general procedure A, 1f (0.10 g,
0.434 mmol), K2CO3 (66 mg, 0.48 mmol) in o-xylene (2 mL) afforded after flash chromatography
(cyclohexane-ethyl acetate, 10:1) compound 2f (75 mg, 75%). Following general procedure B, 1f (66
mg, 0.26 mmol), K2CO3 (43.5 mg, 0.315 mmol) in o-xylene (1 mL) afforded after flash
chromatography (cyclohexane-ethyl acetate, 10:1) compound 2f (46 mg, 70%) 2f: white crystals; m.p.
o
57 – 59 C (Ref. [20] m.p. 60 oC); 1H-NMR (DMSO [20]): δ 1.31 (3H, d, J =6.8 Hz, CH3), 1.71 (3H,
m, CH3), 4.43-4.50 (1H, m, H2), 5.43-5.49 (1H, m, CH=), 5.65-5.75 (1H, m, CH=), 6.52 (1H, bs, NH);
13C-NMR (DMSO [20]): δ 17.9, 20.4, 49.0, 93.0, 127.6, 130.76, 161.03; Anal. Calcd. for C7H10Cl3NO
(230.52): C 36.44, H 4.37, N 6.07, found C 36.35, H 4.21, N 5.97.
Methyl (Z)-2,3,4-tri-O-benzyl-6,7-dideoxy-8-(trifluoroacetimidyloxy)-α-D-gluco-oct-6-enpyranoside
(13): To a suspension of NaH (0.09 g, 2.244 mmol, 60% dispersion in mineral oil, freed of oil with
anhydrous THF) in dry THF (3 mL) was added allylic alcohol 12 (1.0 g, 2.04 mmol) in dry THF (5
mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min and then treated with gaseous
trifluoroacetonitrile (15 g, 0.158 mol, prepared in situ by heating trifluoroacetamide (4.57 g, 0.040
mol) and P2O5 (11.43 g, 0.102 mol) for 2 h at 150 °C). The solid was removed by filtration and solvent
evaporated under reduced pressure. The residue was purified by chromatography on silica gel (hexane-
ethyl acetate, 3:1) to afford 0.95 g (79.5%) of compound 13 as a pale yellow oil; 1H-NMR: δ 3.27 (1H,
dd, J4,3=9.6 Hz, J5,4=9.1 Hz, H4), 3.40 (3H, s, OCH3), 3.52 (1H, dd, J3,2=9.7 Hz, J2,1=3.6 Hz, H2), 3.99
(1H, dd, J3,2=9.7 Hz, J4,3=9.6 Hz, H3), 4.45 (1H, ddd, J5,4=9.1 Hz, J6,5=9.0 Hz, J7,5=1.0, H5), 4.57 (1H,
d, J=10.8 Hz, CH2Ph), 4.57 (1H, d, J2,1=3.6 Hz, H1), 4.67 (1H, d, J=12.1 Hz, CH2Ph), 4.70 (1H, ddd,
J8,8=11.9 Hz, J8,7=5.4 Hz, J8,6=1.4 Hz, H8), 4.79 (1H, d, J=10.6 Hz, CH2Ph), 4.80 (1H, d, J=12.1 Hz,

Molecules 2008, 13
2845
CH2Ph), 4.82 (1H, J=10.6 Hz, CH2Ph), 4.96 (1H, J=10.8 Hz, CH2Ph), 5.01 (1H, ddd, J8,8=11.9 Hz,
J8,7=7.4 Hz, J8,6=1.4 Hz, H8), 5.61 (1H, dddd, J7,6=11.2 Hz, J6,5=9.0 Hz, J8,6=1.4 Hz, J8,6=1.4 Hz, H6)
5.81 (1H, dddd, J7,6=11.2 Hz, J8,7=7.4 Hz, J8,7=5.4 Hz, J7,5=1.0 Hz, H7), 7.22-7.37 (15H, m, Ph), 8.20
(1H, bs, NH); 13C-NMR: δ 55.5, 62.0, 66.8, 73.4, 75.3, 75.8, 79.8, 81.6, 81.9, 98.2, 127.6, 127.7,
127.7, 2x127.8, 127.9, 2x128.0, 2x128.1, 2x128.3, 2x128.4, 2x128.5, 131.2, 138.0, 138.1, 138.6,
157.3, 157.7; Anal. Calcd. for C32H34F3NO6 (585.63): C 65.63, H 5.85, N 2.39; found C 65.59, H 5.80,
N 2.31.
Methyl 2,3,4-tri-O-benzyl-6-[(trifluoroacetyl)amino]-7,8-dideoxy-D-glycero-α-D-galacto-oct-7-
enpyranoside 14a, Methyl 2,3,4-tri-O-benzyl-6-[(trifluoroacetyl)amino]-7,8-dideoxy-L-glycero-
α-D-galacto-oct-7-enpyranoside (14b): Following general procedure A, 13 (0.25 g, 0.43 mmol),
K2CO3 (65.4 mg, 0.47 mmol) in o-xylene (2 mL) afforded after flash chromatography (hexane-ethyl
acetate, 9:1) compounds 14a and 14b (0.08 g, 32%, see Table 4). Following general procedure B, 13
(0.10g, 0.171 mmol), K2CO3 (26 mg, 0.188 mmol) in o-xylene (2 mL) afforded after flash
chromatography (hexane-ethyl acetate, 15:1) compounds 14a and 14b (0.07 g, 70%, see Table 2).
14a: a colorless oil; [α]D25 = -19.6 (c 0.23); 1H-NMR: δ 3.30 (1H, dd, J5,4=10.0 Hz, J4,3=9.2 Hz, H5),
3.33 (3H, s, OCH3), 3.49 (1H, dd, J3,2=9.3 Hz, J2,1=3.6 Hz, H2), 3.76 (1H, dd, J5,4=10.0 Hz, J6,5=1.4
Hz, H5), 4.01 (1H, dd, J3,2=9.3 Hz, J4,3=9.2 Hz, H3), 4.50 (1H, d, J=10.1 Hz, CH2Ph), 4.56 (1H, d,
J2,1=3.6. Hz, H1), 4.66 (1H, d, J=12.1 Hz, CH2Ph), 4.82 (1H, d, J=12.1 Hz, CH2Ph), 4.84 (1H, d,
J=10.7 Hz, CH2Ph), 4.90 (1H, d, J=10.1 Hz, CH2Ph), 4.97 (1H, ddd, J6,NH=9.4 Hz, J7,6=5.4 Hz,
J6,5=1.4 Hz, H6), 5.01 (1H, d, J=10.7 Hz, CH2Ph), 5.23 (1H, dd, J8cis,7=10.3 Hz, J8cis,8trans=1.6 Hz,
H8cis), 5.23 (1H, dd, J8trans,7=17.1 Hz, J8trans,8cis=1.6 Hz, H8trans), 5.81 (1H, ddd, J8trans,7=17.1 Hz,
J8cis,7=10.3 Hz, J7,6=5.4 Hz, H7), 6.71 (1H, d, J6,NH=9.4 Hz, NH), 7.27-7.39 (15H, m, Ph); 13C-NMR: δ
50.8, 55.4, 71.0, 73.6, 75.6, 75.9, 78.0, 80.0, 81.8, 98.1, 117.2, 127.8, 2x128.0, 4x128.1, 2x128.4,
2x128.5, 4x128.6, 133.8, 137.4, 137.9, 138.2, 156.6, 157.0; Anal. Calcd. for C32H34F3NO6 (585.63): C
65.63, H 5.85, N 2.39; found C 65.56, H 5.79, N 2.32.
14b: a colorless oil; [α]D25 = +30.5 (c 0.19); 1H-NMR: δ 3.35 (3H, s, OCH3), 3.41 (1H, dd, J5,4=10.0
Hz, J4,3=8.9 Hz, H4), 3.48 (1H, dd, J3,2=9.6 Hz, J2,1=3.5 Hz, H2), 3.81 (1H, dd, J5,4=10.0 Hz, J6,5=2.7
Hz, H5), 4.01 (1H, dd, J3,2=9.6 Hz, J4,3=8.9 Hz, H3), 4.57 (1H, J2,1=3.5 Hz, H1), 4.61 (1H, d, J=11.1
Hz, CH2Ph), 4.65 (1H, d, J=12.1 Hz, CH2Ph), 4.78 (1H, d, J=11.1 Hz, CH2Ph), 4.81 (1H, d, J=12.1
Hz, CH2Ph), 4.89 (1H, ddd, J6,NH=9.0 Hz, J7,6=8.2 Hz, J6,5=2.7 Hz, H6), 4.93 (1H, d, J=10.8 Hz,
CH2Ph), 4.99 (1H, d, J=10.8 Hz, CH2Ph), 5.25 (1H, dd, J8trans,7=17.1 Hz, J8trans,8cis=1.0 Hz, H8trans),
5.29 (1H, dd, J8cis,7=10.3 Hz, J8trans,8cis=1.0 Hz, H8cis), 5.71 (1H, ddd, J8trans,7=17.1 Hz, J8cis,7=10.3 Hz,
J7,6=8.2 Hz, H7), 6.70 (1H, d, J6,NH=9.0 Hz, NH), 7.27-7.39 (15H, m, Ph); 13C-NMR: δ 52.4, 55.5,
71.6, 73.8, 74.7, 76.0, 77.8, 80.1, 82.1, 98.5, 121.4, 2x127.8, 128.0, 128.1, 2x128.2, 3x128.3, 2x128.7,
4x128.8, 131.1, 2x138.1, 138.6, 156.3, 156.7; Anal. Calcd. for C32H34F3NO6 (585.63): C 65.63, H
5.85, N 2.39; found C 65.53, H 5.76, N 2.45

Molecules 2008, 13
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Acknowledgements
The present work was supported by Grant Agency (No. 1/0281/08 and No. 1/3557/06) of the
Ministry of Education, the Research and Development Support Agency (APVV No. 20-038405),
Slovak Republic and COST Action D32/011/05 Chemistry in High-Energy Microenvironments.
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Sample Availability: Samples of compounds 2d, 14a,b are available from the authors.
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