α-methylene-β-trichloroacetylamino alkanoates from trichloroacetimidates of the Baylis-Hillman adducts

Article abstract of DOI:10.1055/s-2004-831235

The Baylis-Hillman adducts 1 were treated with a large amount of CCl ₃CN in the presence of DBU without solvent to give in good yield the corresponding trichloroacetimidates 5 which by thermal [3.3]sigmatropic rearrangement were converted into

Full text of DOI:10.1055/s-2004-831235

2560
PAPER
a-Methylene-b-trichloroacetylamino Alkanoates from Trichloroacetimidates
of the Baylis–Hillman Adducts
a
-Methylene-
b
-tr
o
ichloroacety
b
laminoAlka
e
Dipartimento di Scienze dei Materiali e della Terra, Università Politecnica delle Marche, Via Brecce Bianche, 60131 Ancona, Italy
Fax +39(071)2204714; E-mail: m.orena@univpm.it
Received 11 June 2004
Owing to the presence of the rigid a-methylene group, the
Abstract: The Baylis–Hillman adducts 1 were treated with a large
corresponding non-proteinogenic amino acids can be use-
amount of CCl3CN in the presence of DBU without solvent to give
in good yield the corresponding trichloroacetimidates 5 which by
thermal [3.3]sigmatropic rearrangement were converted into the
ful for inducing conformational restrictions in a peptide
structure.6 Within this area, we envisaged that the trichlo-
corresponding (E)-2-trichloroacetylaminomethyl-2-propenoates 6, roacetimidates of the Baylis–Hillman adducts 5 could be
exclusively. On the contrary, when compounds 5 were treated with
useful for the preparation of 2-methylene-3-trichloro-
a catalytic amount of DABCO in dichloromethane, 2-methylene-3-
acetylamino alkanoates, the lability of the trichloroacetyl
trichloroacetylamino esters 7 were obtained in good yield. Both 5a
group making these compounds attractive for the intro-
and 7a underwent iodocyclization, to give a cyclic intermediate pre-
duction in oligopeptides. Thus, we targeted preparation of
cursor of a polyfunctionalized sequence, and the differences in ste-
reoselectivity were in agreement with computational results.
the trichloroacetimidates 5, as we thought it could be eas-
ily achieved simply following literature methods
(Scheme 2).
Key words: amino acids, amides, rearrangement, cyclization, ste-
reoselectivity
The Baylis–Hillman reaction is an important carbon–car-
bon bond forming reaction leading to 2-methylene-3-hy-
droxy alkanoates 1 starting from acrylates and aldehydes,
via a base-catalyzed tandem Michael reaction-enolate ad-
dition, followed by elimination.1–3
Scheme 2
Recently, we have shown that p-toluenesulfonyl and acyl
carbamates of the Baylis–Hillman adducts 2 can be easily
converted into the corresponding acylamino derivatives 3
or 4 simply by treating with DBU or DABCO in dichlo-
romethane, respectively (Scheme 1).4,5
However, when we treated the Baylis–Hillman adducts 1
with a catalytic amount of NaH in anhydrous THF, fol-
lowed by addition of an equimolar amount of CCl3CN,7
the trichloroacetimidates 5 were isolated only in poor
yield, the rest being starting material. Similar results were
obtained by adding DBU to a solution of the adduct 1 and
CCl3CN in dichloromethane at temperatures ranging from
–15 to 0 °C.8 Changing MeCN for dichloromethane led to
minor improvement, and maximum yield raised to 40%
after silica gel chromatography. In this case a large excess
of DBU or CCl3CN and even prolonged reaction time did
not affect the yield.9 In addition, we observed that a reac-
tion occurs between DBU and CCl3CN in dichlo-
romethane at 0 °C, leading to a strongly polar adduct A
that remained unaffected by subsequent addition of 1. The
structure of A was tentatively assigned as internal salt,
owing to the presence in the 13C NMR spectrum of a peak
at d = 166.1, diagnostic for an iminic carbon (Figure 1).10
Scheme 1
Figure 1 Structure of the adduct A
SYNTHESIS 2004, No. 15, pp 2560–2566
x
x.
x
x
.
2
0
0
4
Advanced online publication: 22.09.2004
DOI: 10.1055/s-2004-831235; Art ID: P05804SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
a-Methylene-b-trichloroacetylamino Alkanoates
2561
Table 1 Preparation of Trichloroacetimidates 5 from the Baylis–Hillman Adducts
Run
1
5
a
a
b
c
c
d
e
e
e
f
R1
R2
DBU(%)
Temp (°C)
Yield (%)a
94
t-C4H9
t-C4H9
C2H5
CH3
C6H5
5
5
r.t.
2
C6H5
0
96
3
C6H5
5
0
95
4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
2-naphthyl
2-naphthyl
(CH3)2CH
(CH3)2CH
CH3
5
r.t.
98
5
CH3
5
0
98
6
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
CH3
5
0
97
7
50
5
r.t.
97
8
0
96
9
5
–15
97
10
11
12
13
14
15
16
17
18
19
20
21
5
0
95
f
5
–15
96
g
g
h
h
i
30
30
100
50
5
0
87
CH3
–15
93
t-C4H9
t-C4H9
t-C4H9
t-C4H9
CH3
–15
83
CH3
–40 to –15
85
H
r.t.
0
94
i
H
5
96
j
(CH3)2CHCH2
(CH3)2CHCH2
(CH3)2CHCH2
(CH3)2CHCH2
50
30
30
30
r.t.
0
79
j
CH3
91
j
CH3
–15
–15
97
k
C2H5
96
a Yields refer to pure isolated products.
As a matter of fact, the preparation of trichloroacetimi- (Table 2). The rearrangement proceeded with total stereo-
dates 5 required appropriate reaction conditions under selectivity, and a single product was invariably observed
which DBU can deprotonate the adduct 1 before forming in the reaction mixture, whose configuration was assigned
irreversibly the addition product A. Thus, all reactions as E on the basis of NOE experiments and literature meth-
were carried out without solvent by using a 5:1 ratio of ods.13 The presence of the Z-isomer, which might be
CCl3CN/adduct 1 for 1 hour at temperatures ranging from present in trace amounts in the reaction mixtures, could
–40 °C to room temperature, in order to optimize the prep- never be evidenced.
aration of compounds 5, as summarized in Table 1.11,12
As a further development aimed to extend the usefulness
With the trichloroacetimidates 5 in hand, we carried out of trichloroacetimidates 5, these compounds were treated
the preparation of both unsaturated b-amino acid deriva- with a catalytic amount of DABCO in dichloromethane at
tives 6 and 7, analogs of 3 and 4, respectively, in which room temperature, to give in good yield the corresponding
R3 = CCl3. At first, compounds 5 were heated in toluene trichloroacetylamino derivatives 7 (Table 3).
at reflux and the expected thermal [3.3]sigmatropic rear-
The formation of compounds 7 deserves some comments.
In fact the reaction mechanism probably proceeds via a
tandem SN2¢-SN2¢ sequence involving the initial formation
rangement occurred,7 to give the corresponding 2-trichlo-
roacetylaminomethyl alkenoates
6 in high yields
Synthesis 2004, No. 15, 2560–2566 © Thieme Stuttgart · New York

2562
R. Galeazzi et al.
PAPER
Table 2 Preparation of 2-Trichloroacetylaminomethyl Alkenoates 6
from Trichloroacetimidates 5 by Thermal Rearrangement
Run
1
6
a
b
c
R1
R2
Yield (%)a
t-C4H9
t-C4H9
C2H5
C2H5
CH3
C6H5
93
89
94
92
94
2
CH3
3
4-ClC6H4
2-naphthyl
(CH3)2CH
Scheme 3 Reaction pathways leading to 7.
4
d
e
5
a Yields refer to pure isolated products.
Table 3 Preparation of Trichloroacetamides 7 Starting from
Trichloroacetimidates 5
Scheme 4
Run
1
7
a
b
c
d
e
f
R1
R2
Yield (%)a
t-C4H9
C2H5
C2H5
C2H5
t-C4H9
C2H5
C6H5
86
69
74
82
74
83
On the contrary, when the iodocyclization reaction was
carried out under the same conditions but starting from the
trichloroacetamide 7a, the cis-4,5-dihydro-1,3-oxazole 9
was exclusively obtained in good yield and its configura-
tion was assigned by means of 1H NMR spectral data and
NOE experiments (Scheme 5).
2
(CH3)2CHCH2
4-ClC6H4
2-naphthyl
CH3
3
4
5
6
C6H5
a Yields refer to pure isolated products.
of a quaternary ammonium ion, followed by elimination
of the trichloroacetamide anion. This anion eventually at-
tacks the intermediate cation to give the observed prod-
ucts 7, in analogy with behavior already observed for N-
acyl carbamates 2 (Scheme 3).14
Scheme 5
The presence of a single significant conformer for com-
pound 7a can account for the observed stereoselectivity.
In fact the lower stereoselectivity observed in the cycliza-
tion of 5a could be tentatively ascribed to the presence of
a number of significant conformations within 1.0 Kcal/
mol, as determined by molecular mechanics calcula-
tions.13
Both trichloroacetimidates 5 and trichloroacetamides 7,
arising from the Baylis–Hillman adducts, can be convert-
ed into cyclic intermediates which are useful precursors of
polyfunctional compounds. In fact, when the trichloroace-
timidate 5a was treated with NIS in CHCl3,15 the diaste-
reomeric 4,5-dihydro-1,3-oxazoles 8a and 8b were
obtained in good yield and 80:20 dr, the cis-isomer being
the major component of the reaction mixture. The diaste- In conclusion, the trichloroacetimidates 5, prepared start-
reomers were separated by silica gel chromatography and ing from the Baylis–Hillman adducts 1, were useful inter-
configurations were assigned by means of 1H NMR spec- mediates for accessing both b-amino acid derivatives 6
tral data and subsequently confirmed by NOE experi- and 7. Work is currently underway towards the synthesis
ments (Scheme 4).
of 7 in the enantiomerically pure form, with the aim to in-
Synthesis 2004, No. 15, 2560–2566 © Thieme Stuttgart · New York

PAPER
a-Methylene-b-trichloroacetylamino Alkanoates
EIMS: m/z = 396 (MH+), 366, 278, 235, 160, 122.
2563
duce conformational restrictions in oligopeptides and to
prepare polyfunctionalized sequences present in bioactive
compounds.
Anal. Calcd for C14H13Cl3N2O5: C, 42.50; H, 3.31; N, 7,08. Found:
C, 42.44; H, 3.26; N, 7.04.
Ethyl 3-(4-Chlorophenyl)-2-methylene-3-trichloroacetiminoxy-
propanoate (5e)
1H and 13C NMR spectra were recorded on Varian Gemini 200 in
CDCl3: chemical shifts are quoted in ppm and J values are given in
Hz. IR spectra were recorded on an FT-IR spectrophotometer Nico-
let XS. Mass spectra were recorded on a Hewlett-Packard 5989B
mass spectrometer. Column chromatography was performed using
silica gel 60 (230–400 mesh).
IR (CHCl3): 3341, 1719, 1669 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.26 (t, 3 H, J = 7.3 Hz), 4.11–4.27
(m, 2 H), 5.99 (s, 1 H), 6.44 (s, 1 H), 6.75 (s, 1 H), 7.33 (d, 2 H, ArH,
J = 8.6 Hz), 7.42 (d, 2 H, ArH, J = 8.6 Hz), 8.44 (s, 1 H, NH).
13C NMR (50 MHz, CDCl3): d = 14.6, 61.6, 77.1, 126.4, 129.0,
129.3, 129.6, 132.1, 134.8, 136.4, 139.8, 160.9, 165.2.
Trichloroacetimidates 5; General Procedure
To a solution of the Baylis–Hillman adduct 1 in CCl3CN (5 equiv),
was added DBU (see Table 1 for amounts and temperature) directly
(1 mL/sec) under vigorous stirring. After 1 h the mixture was direct-
ly purified by silica gel chromatography (cyclohexane–EtOAc,
95:5) to give trichloroacetimidates 5 as colorless oils (Table 1).
EIMS: m/z = 386 (MH+), 356, 268, 225, 157, 114.
Anal. Calcd for C14H13Cl4NO3: C, 43.67; H, 3.40; N, 3.64. Found:
C, 43.61; H, 3.43; N, 3.59.
Ethyl 2-Methylene-3-(2-naphthyl)-3-trichloroacetiminoxypro-
panoate (5f)
tert-Butyl 2-Methylene-3-phenyl-3-trichloroacetiminoxypro-
panoate (5a)
IR (CHCl3): 3339, 1719, 1668 cm–1.
IR (CHCl3): 3340, 1695, 1660 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.24 (t, 3 H, J = 7.2 Hz), 4.10–4.29
(m, 2 H), 6.03 (s, 1 H), 6.47 (s, 1 H), 6.97 (s, 1 H), 7.46–7.59 (m, 3
H, ArH), 7.82–7.95 (m, 4 H, ArH), 8.45 (s, 1 H, NH).
1H NMR (200 MHz, CDCl3): d = 1.42 (s, 9 H), 5.83 (s, 1 H), 6.36
(s, 1 H), 6.78 (s, 1 H), 7.29–7.52 (m, 5 H, ArH), 8.42 (s, 1 H, NH).
13C NMR (50 MHz, CDCl3): d = 14.6, 61.7, 78.1, 125.6, 126.7,
126.8, 127.0, 127.7, 128.3, 128.8, 133.6, 133.8, 135.1, 140.1, 161.3,
165.6.
13C NMR (50 MHz, CDCl3): d = 28.4, 78.1, 82.0, 126.2, 128.1,
128.8, 137.9, 141.4, 161.3, 164.7.
EIMS: m/z = 379 (MH+), 321, 278, 261, 219, 160, 117.
EIMS: m/z = 401 (MH+), 371, 284, 240, 113.
Anal. Calcd for C16H18Cl3NO3: C, 50.75; H, 4.79; N, 3.70. Found:
C. 50.69; H, 4.75; N, 3.73.
Anal. Calcd for C18H16Cl3NO3: C, 53.96; H, 4.02; N, 3.50. Found:
C, 53.91; H, 3.98; N, 3.97.
Ethyl 2-Methylene-3-phenyl-3-trichloroacetiminoxypro-
panoate (5b)
Methyl 4-Methyl-2-methylene-3-trichloroacetiminoxypen-
tanoate (5g)
IR (CHCl3): 3342, 1697, 1661 cm–1.
IR (CHCl3): 3344, 1693, 1663 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.26 (t, 3 H, J = 7.1 Hz), 4.12–4.28
(m, 2 H), 5.96 (s, 1 H), 6.93 (s, 1 H), 6.80 (s, 1 H), 7.29–7.55 (m, 5
H, ArH), 8.43 (s, 1 H, NH).
13C NMR (50 MHz, CDCl3): d = 14.6, 61.6, 77.9, 126.6, 128.1,
128.9, 129.0, 137.8, 140.2, 161.2, 165.6.
1H NMR (200 MHz, CDCl3): d = 0.99 (d, 3 H, J = 7.1 Hz), 1.03 (d,
3 H, J = 7.1 Hz), 2.04–2.20 (m, 1 H), 3.80 (s, 3 H), 5.55 (d, 1 H,
J = 4.8 Hz), 5.88 (s, 1 H), 6.35 (s, 1 H), 8.30 (s, 1 H, NH).
13C NMR (50 MHz, CDCl3): d = 16.6, 18.9, 32.2, 51.9, 80.4, 91.6,
125.4, 138.4, 161.2, 165.9.
EIMS: m/z = 351 (MH+), 321, 233, 190, 160.
EIMS: m/z = 303 (MH+), 287, 170, 142.
Anal. Calcd for C14H14Cl3NO3: C, 47.96; H, 4.02; N, 3.99. Found:
C, 47.92; H, 3.98; N, 4.03.
Anal. Calcd for C10H14Cl3NO3: C, 39.69; H, 4.66; N, 4.63. Found:
C, 39.65; H. 4.71; N, 4.58.
Methyl 2-Methylene-3-(4-nitrophenyl)-3-trichloroacetiminoxy-
propanoate (5c)
tert-Butyl 2-Methylene-3-trichloroacetiminoxybutanoate (5h)
IR (CHCl3): 3341, 1694, 1660 cm–1.
IR (CHCl3): 3340, 1698, 1664 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.51 (s, 9 H), 1.51 (d, 3 H, J = 6.4
Hz), 5.81 (q, 1 H, J = 6.4 Hz), 5.89 (s, 1 H), 6.23 (s, 1 H), 8.36 (s, 1
H, NH).
1H NMR (200 MHz, CDCl3): d = 3.76 (s, 3 H), 6.11 (s, 1 H), 6.49
(s, 1 H), 6.84 (s, 1 H), 7.66 (d, 2 H, ArH, J = 8.9 Hz), 8.22 (d, 2 H,
ArH, J = 8.9 Hz), 8.50 (s, 1 H, NH).
13C NMR (50 MHz, CDCl3): d = 20.0, 28.5, 73.5, 81.8, 124.2, 142.5,
161.7, 165.0.
13C NMR (50 MHz, CDCl3): d = 52.2, 76.1, 90.8, 123.6, 126.9,
128.3, 138.3, 144.5, 147.8, 160.4, 165.0.
EIMS: m/z = 317 (MH+), 259, 215, 199, 156.
EIMS: m/z = 382 (MH+), 366, 264, 221, 122.
Anal. Calcd for C11H16Cl3NO3: C, 41.73; H, 5.09; N, 4.42. Found:
C, 41.68; H, 5.11; N, 4.38.
Anal. Calcd for C13H11Cl3N2O5: C, 40.92; H, 2.91; N, 7.34. Found:
C, 40.87; H, 2.94; N, 7.28.
tert-Butyl 2-Methylene-3-trichloroacetiminoxypropanoate (5i)
Ethyl 2-Methylene-3-(4-nitrophenyl)-3-trichloroacetiminoxy-
propanoate (5d)
IR (CHCl3): 3342, 1694, 1661 cm–1.
IR (CHCl3): 3340, 1694, 1660 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.50 (s, 9 H), 5.00 (s, 1 H), 5.89
(s, 1 H), 6.33 (s, 1 H), 8.38 (br s, 1 H, NH).
13C NMR (50 MHz, CDCl3): d = 28.0, 67.1, 81.4, 126.2, 136.2,
162.2, 164.1.
1H NMR (200 MHz, CDCl3): d = 1.26 (t, 3 H, J = 7.1 Hz), 4.12–4.28
(m, 2 H), 6.08 (s, 1 H), 6.49 (s, 1 H), 6.85 (s, 1 H), 7.67 (d, 2 H, ArH,
J = 8.7 Hz), 8.22 (d, 2 H, ArH, J = 8.7 Hz), 8.51 (s, 1 H, NH).
13C NMR (50 MHz, CDCl3): d = 14.6, 61.9, 76.7, 124.1, 127.3,
128.9, 139.0, 145.1, 148.3, 160.9, 165.0.
EIMS: m/z = 303 (MH+), 245, 201, 185, 142.
Synthesis 2004, No. 15, 2560–2566 © Thieme Stuttgart · New York

2564
R. Galeazzi et al.
PAPER
Anal. Calcd for C10H14Cl3NO3: C, 39.69; H, 4.66; N, 4.63. Found:
C, 39.64; H, 4.70; N, 4.59.
1H NMR (200 MHz, CDCl3): d = 1.38 (t, 3 H, J = 7.1 Hz), 4.36 (q,
2 H, J = 7.1 Hz), 4.41 (d, 2 H, J = 6.1 Hz), 7.35–7.51 (m, 4 H, ArH
+ NH), 7.82 (s, 1 H).
Methyl 5-Methyl-2-methylene-3-trichloroacetiminoxyhex-
anoate (5j)
13C NMR (50 MHz, CDCl3): d = 14.1, 38.4, 61.5, 127.0, 129.0,
130.6, 132.2, 135.4, 141.7, 161.3, 167.0.
IR (CHCl3): 3344, 1690, 1663 cm–1.
EIMS: m/z = 386 (MH+), 356, 268, 240, 195, 111, 84.
1H NMR (200 MHz, CDCl3): d = 0.95 (d, 3 H, J = 6.5 Hz), 0.97 (d,
3 H, J = 6.5 Hz), 3.80 (s, 3 H), 5.77 (dd, 1 H, J = 2.8, 9.2 Hz), 5.93
(s, 1 H), 6.30 (s, 1 H), 8.33 (s, 1 H, NH).
Anal. Calcd for C14H13Cl4NO3: C, 43.67; H, 3.40; N, 3.64. Found:
C, 43.67; H, 3.40; N, 3.64. Found: C, 43.61; H, 3.44; N, 3.68.
13C NMR (50 MHz, CDCl3): d = 21.4, 23.3, 24.9, 44.3, 51.9, 75.1,
Ethyl (E)-3-(2-Naphthyl)-2-trichloroacetylaminomethylpro-
penoate (6d)
124.2, 140.2, 161.2, 165.7.
EIMS: m/z = 317 (MH+), 301, 257, 199, 156, 99.
IR (CHCl3): 3345, 1717, 1668 cm–1.
Anal. Calcd for C11H16Cl3NO3: C, 41.73; H, 5.09; N, 4.42. Found:
C, 41.69; H, 5.05; N, 4.46.
1H NMR (200 MHz, CDCl3): d = 1.42 (t, 3 H, J = 7.2 Hz), 4.37 (q,
2 H, J = 7.2 Hz), 4.56 (d, 2 H, J = 5.9 Hz), 7.15–8.06 (m, 8 H, 7 H,
ArH + NH).
Ethyl 5-Methyl-2-methylene-3-trichloroacetiminoxyhexanoate
13C NMR (50 MHz, CDCl3): d = 14.9, 39.3, 62.1, 123.2, 126.8,
127.0, 128.2, 128.8, 129.1, 129.2, 130.0, 131.7, 133.6, 134.0, 144.0,
162.0, 168.1, 192.4.
(5k)
IR (CHCl3): 3342, 1692, 1663 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.96 (d, 3 H, J = 6.5 Hz), 0.98 (d,
3 H, J = 6.5 Hz), 1.33 (t, 3 H, J = 7.2 Hz), 1.52–1.68 (m, 1 H), 1.70–
1.95 (m, 2 H), 4.25 (q, 2 H, J = 7.2 Hz, 50%), 4.26 (q, 2 H, J = 7.2
Hz, 50%), 5.78 (dd, 1 H, J = 3.3, 9.5 Hz), 5.91 (s, 1 H), 6.28 (s, 1
H), 8.33 (s, 1 H, NH).
13C NMR (50 MHz, CDCl3): d = 14.6, 22.0, 23.9, 25.4, 44.8, 61.3,
75.6, 124.4, 141.0, 161.6, 165.7.
EIMS: m/z = 401 (MH+), 371, 283, 255, 212, 127.
Anal. Calcd for C18H16Cl3NO3: C, 53.96; H, 4.02; N, 3.50. Found:
C, 53.90; H, 3,97; N, 3.53.
Methyl (E)-4-Methyl-2-trichloroacetylaminomethylpentenoate
(6e)
IR (CHCl3): 3347, 1721, 1670 cm–1.
EIMS: m/z = 331 (MH+), 301, 213, 170, 113.
1H NMR (200 MHz, CDCl3): d = 1.01 (d, 6 H, J = 6.6 Hz), 2.82–
3.01 (m, 1 H), 3.74 (s, 3 H), 4.16 (d, 2 H, J = 6.2 Hz), 6.72 (d, 1 H,
J = 10.5 Hz), 7.41 (br s, 1 H, NH).
Anal. Calcd for C12H18Cl3NO3: C, 43.59; H, 5.49; N, 4.24. Found:
C, 43.55; H, 5.45; N, 4.28.
13C NMR (50 MHz, CDCl3): d = 22.1, 28.1, 37.4, 51.9, 92.5, 124.4,
Trichloroacetamides 6; General Procedure
154.0, 161.2, 167.7.
A solution containing the trichloroacetimidates 5 (5 mmol) in tolu-
ene (20 mL) was refluxed for 3 h under argon. The solvent was then
removed under reduced pressure and the residue was purified by sil-
ica gel chromatography (cyclohexane–EtOAc, 80:20), to give
trichloroacetamides 6 as colorless oils (Table 2).
EIMS: m/z = 317 (MH+), 301, 198, 170, 132, 97.
Anal. Calcd for C11H16Cl3NO3: C, 41.73; H, 5.09; N, 4.42. Found:
C, 41.67; H, 5.13; N, 4.37.
Trichloroacetamides 7; General Procedure
tert-Butyl (E)-3-Phenyl-2-trichloroacetylaminomethylpro-
penoate (6a)
To a solution containing the trichloroacetimidates 5 (5 mmol) in
CH2Cl2 (20 mL), was added DABCO (0.11 g, 1 mmol) and the mix-
ture was stirred for 6 h at r.t. It was then diluted with EtOAc (150
mL) and the organic layer was washed with 1 M HCl (30 mL) and
brine (100 mL). After drying (Na2SO4), the solvents were removed
under reduced pressure and the residue was purified by silica gel
chromatography (cyclohexane–EtOAc, 80:20), to give pure trichlo-
roacetamides 7 as colorless oils (Table 3).
IR (CHCl3): 3344, 1719, 1668 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.57 (s, 9 H), 4.40 (d, 2 H, J = 5.9
Hz), 7.28–7.54 (m, 5 H, ArH + NH), 7.79 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 28.1, 38.7, 82.2, 128.7, 129.2,
134.0, 142.6, 161.3, 166.5.
EIMS: m/z = 379 (MH+), 321, 261, 233, 188, 111.
tert-Butyl 2-Methylene-3-phenyl-3-trichloroacetylaminopro-
panoate (7a)
Anal. Calcd for C16H18Cl3N3O3: C, 50.75; H, 4.79; N, 3.70. Found:
C, 50.70; H, 4.83; N, 3.74.
IR (CHCl3): 3344, 1719, 1666 cm–1.
tert-Butyl (E)-2-Trichloroacetylaminomethylbut-2-enoate (6b)
1H NMR (200 MHz, CDCl3): d = 1.36 (s, 9 H), 5.89 (s, 1 H), 5.90
(d, 1 H, J = 8.8 Hz), 6.37 (s, 1 H), 7.18–7.43 (m, 5 H, ArH), 8.00 (d,
1 H, NH, J = 8.8 Hz).
13C NMR (50 MHz, CDCl3): d = 28.4, 57.4, 82.9, 93.2, 126.5, 128.4,
128.6, 129.3, 138.9, 139.6, 161.6, 165.2.
IR (CHCl3): 3347, 1721, 1670 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.50 (s, 9 H), 1.98 (d, 3 H, J = 7.3
Hz), 4.17 (d, 2 H, J = 6.1 Hz), 5.97 (q, 1 H, J = 7.3 Hz), 7.36 (br s,
1 H, NH).
13C NMR (50 MHz, CDCl3): d = 14.3, 28.0, 37.1, 81.2, 129.1, 141.3,
EIMS: m/z = 379 (MH+), 321, 261, 233, 190, 113.
161.3, 166.0.
Anal. Calcd for C16H18Cl3NO3: C, 50.75; H, 4.79; N, 3.70. Found:
C, 50.71; H, 4,74; N, 3.75.
EIMS: m/z = 317 (MH+), 259, 199, 171, 57.
Anal. Calcd for C11H16Cl3NO3: C, 41.73; H, 5.09; N, 4.42. Found:
C, 41.67; H, 5.04; N, 4.47.
Ethyl 5-Methyl-2-methylene-3-trichloroacetylaminohexanoate
(7b)
IR (CHCl3): 3347, 1717, 1667 cm–1.
Ethyl (E)-3-(4-Chlorophenyl)-2-trichloroacetylaminomethyl-
propenoate (6c)
1H NMR (200 MHz, CDCl3): d = 0.94 (d, 3 H, J = 6.1 Hz), 0.96 (d,
3 H, J = 6.1 Hz), 1.33 (t, 3 H, J = 7.1 Hz), 1.45–1.82 (m, 3 H), 4.26
IR (CHCl3): 3343, 1717, 1667 cm–1.
Synthesis 2004, No. 15, 2560–2566 © Thieme Stuttgart · New York

PAPER
a-Methylene-b-trichloroacetylamino Alkanoates
2565
(q, 2 H, J = 7.1 Hz), 4.75 (dt, 1 H, J = 6.5, 8.9 Hz), 5.83 (s, 1 H),
6.26 (s, 1 H), 7.71 (d, 1 H, NH, J = 8.9 Hz).
13C NMR (50 MHz, CDCl3): d = 14.5, 22.7, 22.8, 25.4, 43.6, 53.3,
61.5, 93.2, 127.8, 139.0, 161.2, 166.2.
( )-(4S*,5R*)-4-tert-Butoxycarbonyl-4-iodomethyl-5-phenyl-2-
trichloromethyl-4,5-dihydro-1,3-oxazole (8a) and its ( )-
(4R*,5S*)-Isomer (8b)
To a solution containing the trichloroacetimidate 5a (1.89 g, 5
mmol) in CHCl3 (50 mL), was added NIS (1.25 g, 5.5 mmol) and
the mixture was stirred at r.t. for 24 h. Then a sat. aq solution of
Na2S2O4 (50 mL) was added and the mixture was extracted with
CH2Cl2 (2 × 100 mL). After drying (Na2SO4), the solvents were re-
moved under reduced pressure. The residue was purified by silica
gel chromatography (cyclohexane–EtOAc, 95:5) to give 8a and 8b
as colorless oils in 80:20 dr and 88% overall yield.
EIMS: m/z = 331 (MH+), 301, 273, 258, 216, 164, 115.
Anal. Calcd for C12H18Cl3NO3: C, 43.59; H, 5.49; N, 4.24. Found:
C, 43,54; H, 5.53; N, 4.20.
Ethyl 3-(4-Chlorophenyl)-2-methylene-3-trichloroacetylamino-
propanoate (7c)
IR (CHCl3): 3346, 1718, 1668 cm–1.
8a
1H NMR (200 MHz, CDCl3): d = 1.26 (t, 3 H, J = 7.2 Hz), 4.19 (q,
2 H, J = 7.2 Hz), 5.88 (d, 1 H, J = 8.9 Hz), 6.01 (s, 1 H), 6.45 (s, 1
H), 7.23 (d, 2 H, ArH, J = 8.8 Hz), 7.34 (d, 2 H, ArH, J = 8.8 Hz),
8.18 (d, 1 H, NH, J = 8.9 Hz).
IR (CHCl3): 1741, 1668 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.59 (s, 9 H), 3.02 (ABq, 2 H,
J = 10.7 Hz), 6.11 (s, 1 H), 7.31–7.43 (m, 5 H, ArH).
13C NMR (50 MHz, CDCl3): d = 4.7, 27.9, 80.7, 84.1, 88.4, 126.7,
128.7, 129.3, 129.4, 132.9, 168.5.
13C NMR (50 MHz, CDCl3): d = 14.5, 56.9, 62.0, 93.1, 128.1, 129.3,
129.4, 129.7, 132.1, 134.3, 137.3, 138.0, 161.6, 166.0.
EIMS: m/z = 505 (MH+), 447, 403, 387, 377, 363, 260, 183, 141,
105, 77.
EIMS: m/z = 386 (MH+), 356, 268, 240, 163, 148, 98.
Anal. Calcd for C14H13Cl4NO3: C, 43.67; H, 3.40; N, 3.64. Found:
C, 43.62; H, 3.44; N, 3.59.
Anal. Calcd for C16H17Cl3INO3: C, 38.09; H, 3.40; N, 2.78. Found:
C, 38.04; H, 3.44; N, 2.82.
Ethyl 2-Methylene-3-(2-naphthyl)-3-trichloroacetylaminopro-
panoate (7d)
8b
IR (CHCl3): 1739, 1668 cm–1.
IR (CHCl3): 3345, 1717, 1668 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.51 (s, 9 H), 3.82 (ABq, 2 H,
J = 11.3 Hz), 5.81 (s, 1 H), 7.31–7.43 (m, 5 H, ArH).
13C NMR (50 MHz, CDCl3): d = 13.9, 27.6, 81.9, 84.1, 92.0, 127.0,
128.9, 129.0, 129.7, 135.3, 164.6.
1H NMR (200 MHz, CDCl3): d = 1.23 (t, 3 H, J = 7.1 Hz), 4.17 (q,
2 H, J = 7.1 Hz), 6.07 (s, 1 H), 6.09 (d, 1 H, J = 8.7 Hz), 6.50 (s, 1
H), 7.39–7.55 (m, 3 H, ArH), 7.71–7.92 (m, 4 H, ArH), 8.24 (d, 1
H, J = 8.7 Hz, NH).
13C NMR (50 MHz, CDCl3): d = 14.6, 57.6, 62.0, 93.4, 124.8, 125.7,
126.9, 127.3, 128.2, 128.6, 129.2, 129.3, 133.4, 133.7, 136.1, 138.4,
161.7, 166.3.
EIMS: m/z = 505 (MH+), 447, 403, 387, 377, 363, 260, 183, 141,
105, 77.
Anal. Calcd for C16H17Cl3INO3: C, 38.09; H, 3.40; N, 2.78. Found:
C, 38.15; H, 3.36; N, 2.75.
EIMS: m/z = 401 (MH+), 371, 283, 255, 240, 141, 99.
Anal. Calcd for C18H16Cl3NO3: C, 53.96; H, 4.02; N, 3.50. Found:
C, 53.91; H, 3.97; N, 3.54.
( )-(4R*,5S*)-5-tert-Butoxycarbonyl-5-iodomethyl-4-phenyl-2-
trichloromethyl-4,5-dihydro-1,3-oxazole (9)
To a solution containing the trichloroacetamide 7a (1.89 g, 5 mmol)
in CHCl3 (50 mL), was added NIS (1.25 g, 5.5 mmol) and the mix-
ture was stirred at r.t. for 48 h. Then an aq sat. solution of Na2S2O4
(50 mL) was added and the mixture was extracted with CH2Cl2
(2 × 100 mL). After drying (Na2SO4), the solvents were removed
under reduced pressure. The residue was purified by silica gel chro-
matography (cyclohexane–EtOAc, 95:5) to give 9 in 87% yield as a
colorless oil.
t-Butyl 2-Methylene-3-trichloroacetylaminopropanoate (7e)
IR (CHCl3): 3343, 1721, 1667 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.43 (d, 3 H, J = 6.9 Hz), 1.51 (s,
9 H), 4.79 (dq, 1 H, J = 6.9, 8.8 Hz), 5.73 (s, 1 H), 6.14 (s, 1 H), 7.71
(d, 1 H, NH, J = 8.8 Hz).
13C NMR (50 MHz, CDCl3): d = 20.4, 28.0, 50.2, 82.1, 91.2, 125.5,
140.5, 160.7, 165.0.
EIMS: m/z = 303 (MH+), 245, 185, 157, 142, 57.
IR (CHCl3): 1738, 1665 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.61 (s, 9 H), 2.95 (ABq, 2 H,
J = 11.1 Hz), 5.53 (s, 1 H), 7.15–7.26 (m, 2 H, ArH), 7.31–7.43 (m,
3 H, ArH).
Anal. Calcd for C10H14Cl3NO3: C, 39.69; H, 4.66; N, 4.63. Found:
C, 39.65; H, 4.70; N, 4.59.
Ethyl 2-Methylene-3-phenyl-3-trichloroacetylaminopro-
panoate (7f)
13C NMR (50 MHz, CDCl3): d = 3.9, 28.5, 76.1, 85.2, 92.5, 127.9,
129.4, 129.7, 134.0, 162.5, 169.0.
IR (CHCl3): 3345, 1718, 1668 cm–1.
EIMS: m/z = 505 (MH+), 447, 403, 387, 377, 363, 272, 260, 183,
155, 141, 77.
1H NMR (200 MHz, CDCl3): d = 1.24 (t, 3 H, J = 7.1 Hz), 4.18 (q,
2 H, J = 7.1 Hz), 5.92 (d, 1 H, J = 8.8 Hz), 6.00 (s, 1 H, Hz), 6.44
(s, 1 H), 7.24–7.44 (m, 5 H, ArH), 8.15 (d, 1 H, NH, J = 8.8 Hz).
13C NMR (50 MHz, CDCl3): d = 14.5, 57.4, 61.9, 93.4 126.7, 127.2,
128.5, 128.8, 129.0, 129.3, 138.4, 138.6, 161.5, 166.1.
Anal. Calcd for C16H17Cl3INO3: C, 38.09; H, 3.40; N, 2.78. Found:
C, 38.03; H, 3.44; N, 2.83.
EIMS: m/z = 351 (MH+), 321, 252, 233, 205, 190, 112.
Acknowledgment
Anal. Calcd for C14H14Cl3NO3: C, 47.96; H, 4.02; N, 3.99. Found:
C, 47.89; H, 3.98; N, 4.05.
We gratefully acknowledge financial support from M.I.U.R.
(Rome, Italy) within the framework PRIN 2002.
Synthesis 2004, No. 15, 2560–2566 © Thieme Stuttgart · New York

2566
R. Galeazzi et al.
PAPER
calculations the hybrid functional B3LYP, which contains
gradient corrections for both exchange and correlation was
chosen. The molecular electrostatic potential and the frontier
molecular orbital were calculated for all the compounds
showing no remarkable differences. The stability of both the
reactants and the conjugate bases was calculated referring to
the isodesmic reactions and the correlated pKa values and the
geometry of both reactants and products were fully
optimized at B3LYP/6-31G* theory level: 1c, DE 14.08
kcal/mol; 1d, DE 13.51 kcal/mol; 1b, DE 5.09 kcal/mol; 1e,
DE 4.59 kcal/mol; 1a, DE 0.0 kcal/mol; 1g, DE –3.98 kcal/
mol; 1i, DE –5.46 kcal/mol; 1h, DE –5.76 kcal/mol; 1k, DE
–5.51 kcal/mol; 1j, DE –5.71 kcal/mol. For leading
references, see: (b) Weiner, S. J.; Kollman, P. A.; Nguyen,
D. T.; Case, D. A. J. Comput. Chem. 1986, 7, 230.
References
(1) (a) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44,
4653. (b) Basavaiah, D.; Rao, P. D.; Hyma, R. S.
Tetrahedron 1996, 52, 8001. (c) Ciganek, E. Org. React.
1997, 51, 201. (d) Basavaiah, D.; Rao, A. J.; Satyanarayana,
J. Chem. Rev. 2003, 103, 811.
(2) (a) Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn.
1968, 41, 2815. (b) Baylis, A. B.; Hillman, M. E. D. German
Patent 2155113, 1972; Chem. Abstr. 1972, 77, 34174.
(3) (a) Brzezinski, L. J.; Rafel, S.; Lehavy, J. W. J. Am. Chem.
Soc. 1997, 119, 4317. (b) Aggarwal, V. K.; Mereu, A.;
Tarver, G. J.; McCague, R. J. Org. Chem. 1998, 63, 7183.
(c) Kataoka, T.; Iwama, T.; Tsujiyama, S.; Iwamura, T.;
Watanabe, S. Tetrahedron 1998, 54, 11813. (d) Shi, M.;
Jiang, J.-K.; Feng, Y.-S. Org. Lett. 2000, 2, 2397. (e) Yang,
K.-S.; Chen, K. Org. Lett. 2000, 2, 729.
(c) Chang, G.; Guida, W. C.; Still, W. C. J. Am. Chem. Soc.
1989, 111, 4379. (d) Mohamadi, H.; Richards, N. G. J.;
Guida, W. C.; Liskamo, R.; Lipton, M.; Caulfield, C.;
Chang, G.; Hendrickson, T.; Still, W. C. J. Comput. Chem.
1990, 11, 440. (e) Frisch, M. J.; Trucks, G. W.; Schlegel, H.
B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.;
Zakrzewski, V. G.; Montgomery, J. A. Jr.; Stratmann, R. E.;
Burant, J. C.; Dapprich, S.; Millan, J. M.; Daniels, A. D.;
Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone,
V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.;
Adamo, C.; Clifford, S.; Ochterski, J.; Patersson, G. A.;
Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malik, D. K.; Rabuck,
A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.;
Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng,
C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.;
Gonzales, C.; Head-Gordon, M.; Replogle, E. S.; Pople, J.
Gaussian 98 Revision A.9; Gaussian Inc.: Pittsburgh, 1998.
(f) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B: Condens.
Matter Mater. Phys. 1988, 37, 785. (g) Becke, A. D. Phys.
Rev. A: At., Mol., Opt. Phys. 1988, 38, 3098. (h) Mihelich,
B.; Savin, A.; Stoll, H.; Preuss, H. Chem. Phys. Lett. 1989,
157, 200. (i) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
(12) It is worth mentioning that molecular mechanics
calculations carried out for all compounds 5 indicate the
presence of a number of conformers within a short energy
range. Rotameric mixtures are evidenced by the 1H NMR
spectra of the ethyl derivatives 5b,d,f,k, where a multiplet or
a double quartet collapsing at 50 °C into a quartet takes place
for the ethyl quartet.
(4) Ciclosi, M.; Fava, C.; Galeazzi, R.; Orena, M.; Sepulveda-
Arques, J. Tetrahedron Lett. 2002, 58, 2199.
(5) For synthesis of similar compounds, see: (a) Perlmutter, P.;
Teo, C. C. Tetrahedron Lett. 1984, 25, 5951.
(b) Bertenshaw, S.; Kahn, M. Tetrahedron Lett. 1989, 30,
2731. (c) Cyrener, J.; Burger, K. Monatsh. Chem. 1994, 125,
1279. (d) Kündig, E. P.; Xu, L. H.; Schnell, B. Synlett 1994,
413. (e) Campi, E. M.; Holmes, A.; Perlmutter, P.; Teo, C.
C. Aust. J. Chem. 1995, 48, 1535. (f) Richter, H.; Jung, G.
Tetrahedron Lett. 1998, 39, 2729. (g) Bucholz, R.;
Hoffmann, H. M. R. Helv. Chim. Acta 1991, 74, 1213.
(h) Kim, H. S.; Kim, T. Y.; Chung, Y. M.; Lee, H. J.; Kim,
J. N. Tetrahedron Lett. 2000, 41, 2613. (i) Rajesh, S.;
Banerji, B.; Iqbal, J. J. Org. Chem. 2002, 67, 7852.
(6) (a) Galeazzi, R.; Mobbili, G.; Orena, M. Tetrahedron 1996,
52, 1069. (b) Galeazzi, R.; Geremia, S.; Mobbili, G.; Orena,
M. Tetrahedron: Asymmetry 1996, 7, 79. (c) Galeazzi, R.;
Geremia, S.; Mobbili, G.; Orena, M. Tetrahedron:
Asymmetry 1996, 7, 3573. (d) Galeazzi, R.; Mobbili, G.;
Orena, M. Tetrahedron: Asymmetry 1997, 8, 133.
(e) Galeazzi, R.; Mobbili, G.; Orena, M. Tetrahedron 1999,
55, 261. (f) Galeazzi, R.; Mobbili, G.; Orena, M.
Tetrahedron 1999, 55, 4029. (g) Galeazzi, R.; Martelli, G.;
Mobbili, G.; Orena, M.; Rinaldi, S. Tetrahedron: Asymmetry
2003, 14, 3353. (h) Fava, C.; Galeazzi, R.; Mobbili, G.;
Orena, M. Tetrahedron: Asymmetry 2003, 14, 3697.
(7) (a) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597.
(b) Overman, L. E. J. Am. Chem. Soc. 1976, 98, 2901.
(c) Mehmandust, M.; Petit, Y.; Larcheveque, M.
Tetrahedron Lett. 1992, 33, 4313. (d) Martin, C.;
Bortolussi, M.; Bloch, R. Tetrahedron Lett. 1999, 40, 3735.
(8) Nishikawa, T.; Asai, M.; Ohyabu, N.; Isobe, M. J. Org.
Chem. 1998, 63, 188.
(9) (a) Kang, S. H.; Kim, G. T.; Yoo, Y. S. Tetrahedron Lett.
1997, 38, 603. (b) Kang, S. H.; Kim, J. S.; Youn, J.-H.
Tetrahedron Lett. 1998, 39, 9047.
(13) Foucaud, A.; El Guemmout, F. Bull. Soc. Chim. Fr. 1989,
403.
(14) A concerted four-centers mechanism cannot be excluded,
and investigation is currently underway. For a similar
reaction recently reported in the literature, see: Mamaghani,
M.; Badrian, A. Tetrahedron Lett. 2004, 45, 1547.
(10) (a) An adduct of DBU with alkyl bromides has been already
reported: Oediger, H.; Kabbe, H.; Moller, F.; Either, K.
Chem. Ber. 1966, 99, 2012. (b) Spectral data for the adduct
A: 1H NMR (CDCl3, 200 MHz): d = 1.42–1.76 (m, 6 H),
1.78–1.92 (m, 2 H), 2.56–2.71 (m, 2 H), 3.15–3.39 (m, 6 H).
13C NMR (CDCl3, 50 MHz): d = 19.5, 24.0, 26.8, 28.9, 32.0,
37.8, 48.7, 54.4, 77.2, 166.1.
(11) (a) The reactivity of the Baylis–Hillman adducts agrees with
the relative acidity of the hydroxy functionality obtained
from calculations. All the geometries were optimized at DFT
level of theory. Ab initio DFT calculations were carried out
using the GAUSSIAN 98 program package. For DFT
(15) (a) Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321.
(b) Orena, M. Amination Reactions Promoted by
Electrophiles, In Houben-Weyl, Methods of Organic
Chemistry, Stereoselective Synthesis, Vol. E 2le; Helmchen,
G.; Hofmann, R. W.; Mulzer, J.; Schauman, E., Eds.;
Thieme: Stuttgart, 1995, 5291–5355. (c) Jordá-Gregori, J.
M.; González-Rosende, M. E.; Sepùlveda-Arques, J.;
Galeazzi, R.; Orena, M. Tetrahedron: Asymmetry 1999, 10,
1135. (d) Jordà-Gregori, J. M.; Gonzalez-Rosende, M. E.;
Cava-Montesinos, P.; Sepùlveda-Arques, J.; Galeazzi, R.;
Orena, M. Tetrahedron: Asymmetry 2000, 11, 3769.
Synthesis 2004, No. 15, 2560–2566 © Thieme Stuttgart · New York