Sn(OTf)2 catalysed regioselective styrene oxide ring opening with aromatic amines

Article abstract of DOI:10.1016/j.tet.2008.09.099

Sn(OTf)₂ is an efficient and versatile catalyst for the highly regioselective opening of styrene oxide with aromatic amines, which allowed for the preparation of fourteen 2-arylamino-2-phenylethanols, some of them described here for the first time (6g, 6i, 6j, 6k and 6m). Sn(OTf)₂ also catalyses the opening of styrene oxide with aliphatic amines in moderate to high yields but with a lower degree of regioselectivity. 2-Akylamino-1-phenylethanols are the predominant products when moderate to high regioselectivity is observed (compounds 4b, 4c and 4d). This is the first report of the use of Sn(OTf)₂ to catalyse the opening of an epoxide by aliphatic amines.

Full text of DOI:10.1016/j.tet.2008.09.099

Tetrahedron 64 (2008) 11732–11737
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Sn(OTf)2 catalysed regioselective styrene oxide ring opening
with aromatic amines
*
´
´
´
´
Gabriela Mancilla, Marienca Femenıa-Rıos, Antonio J. Macıas-Sanchez, Isidro G. Collado
´
´
´
Departamento de Qu´ımica Organica, Facultad de Ciencias, Universidad de Cadiz, s/n, Apdo. 40, 11510 Puerto Real, Cadiz, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Sn(OTf)2 is an efficient and versatile catalyst for the highly regioselective opening of styrene oxide with
aromatic amines, which allowed for the preparation of fourteen 2-arylamino-2-phenylethanols, some of
them described here for the first time (6g, 6i, 6j, 6k and 6m). Sn(OTf)2 also catalyses the opening of
styrene oxide with aliphatic amines in moderate to high yields but with a lower degree of re-
gioselectivity. 2-Akylamino-1-phenylethanols are the predominant products when moderate to high
regioselectivity is observed (compounds 4b, 4c and 4d). This is the first report of the use of Sn(OTf)2 to
catalyse the opening of an epoxide by aliphatic amines.
Received 19 August 2008
Received in revised form
25 September 2008
Accepted 29 September 2008
Available online 8 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
caryophyllene oxide with aromatic amines in acetonitrile, under
reflux, catalysed by Sn(OTf)2 yielded amidinoclovanols as the main
Vicinal amino alcohol is a common structural component, which
can be found in naturally occurring molecules,1 synthetic phar-
macologically active compounds,2 ligands for catalysis3 and more
recently as organocatalysts.4 The classical route for the preparation
of such compounds is the direct aminolysis of 1,2-epoxides.5
However, these reactions, which are typically carried out in the
presence of a large excess of amines at elevated temperatures, often
fail when poorly nucleophilic amines or hindered epoxides or
amines are used and observed regioselectivities can be low. Several
modifications of the classical procedures have been reported such
as the use of metal amides,6,7 Lewis acids6–9 or lithium salts,10 some
of which include poorly nucleophilic counter-anions.6,7,11 Many of
these methods are catalytic, work for both aliphatic and aromatic
amines and show improved regioselectivities, but there are reports
of some catalyst systems, which fail to react with anilines bearing
electron-withdrawing groups9b,c,h or foster the attack of aromatic
amines on oxiranes, failing to promote the reaction with aliphatic
amines.8l,m,9a,b,d,h,12,13,16 There are also methods, which are only
described employing aliphatic11c,14,15 or aromatic8a,b,d,h,i,k,m,9g,i,j
amines.
products and the above mentioned aminoclovanols as secondary
products. Aliphatic amines failed to react under the previously
described conditions, which is consistent with previous observa-
tions on the preparation of vicinal amino alcohols from meso-
epoxides catalysed by Sn(OTf)2.16
When evaluated against the phytopathogenic fungus B. cinerea
while the above mentioned amidinoclovanols were inactive, the
related aminoclovanols showed activities, which were related to
the nature of the amino moiety. Further exploration of the in-
fluence of this amino moiety was hampered by the low yield of
active compounds obtained. Therefore, a different epoxide should
be chosen as the substrate in order to explore structure–activity
relationships of amino alcohols with different substitution patterns
in the amino moiety.
A suitable candidate for this exploration is styrene oxide, which
is expected to react under similar conditions to those employed in
the preparation of aminoclovanols and is also simple enough so as
not to suffer rearrangement reactions. As a non-symmetrically
substituted epoxide, styrene oxide displays a general tendency for
regioselective attack on the benzylic position when aromatic
amines are employed.7,8,9e,10,11a,g–k,20 Aliphatic amines use to show
a preferential attack on the non-benzylic unsubstituted position of
As part of a program to develop environmentally friendly and
selective inhibitors for the fungus Botrytis cinerea,17 we previously
prepared amino alcohols with a clovane skeleton,18 which show
fungistatic activity against the fungus B. cinerea.19 Treatment of
the oxirane ring of styrene oxide, with
a lower degree of
regioselectivity.8c,10e,11a,c,g–i
Here we report on a highly regioselective preparation of amino
alcohols through the opening of styrene oxide with aromatic
amines catalysed by Sn(OTf)2. The reactivity of aliphatic amines on
styrene oxide mediated by this catalyst is also described.
* Corresponding author. Tel.: þ34 956 01 6368; fax: þ34 956 01 6193.
E-mail address: isidro.gonzalez@uca.es (I.G. Collado).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.099

G. Mancilla et al. / Tetrahedron 64 (2008) 11732–11737
11733
1
1
Me
2. Results and discussion
CO2Me
O2C
2
4
HN
HN
1''
Styrene oxide was treated with several representative aliphatic
amines (PhCH2NH2, n-BuNH2, diisopropylamine and pyrrolidine)
under three different sets of reaction conditions (see Table 1).
Sn(OTf)2 catalysed the reaction of styrene oxide with the selected
aliphatic amines under all of the reaction conditions evaluated. All
compounds obtained were characterised by their MS and NMR
spectra. The best yields were found in the case of those reactions
carried out either in CH3CN or in the absence of solvents.
Regioisomeric mixtures of compounds were observed for all
evaluated combinations of reagents and reaction conditions with
selectivities ranging from almost nil for benzyl amine to the highly
selective formation of the least substituted regioisomer 4b for n-
butyl amine under solvent-free conditions at 25 ꢀC (Table 1, entry
6). The least substituted regioisomers 4c and 4d were also the
main products when pyrrolidine and diisopropylamine were
employed but their selectivities were lower than those exhibited
by preparations of compound 4b under solvent-free conditions.
No amidine formation was observed when acetonitrile was used
as a solvent.18
1''
2'
1'
1' 2'
OH
OH
6j
6i
1
3
MeO2C
CO2Me
CO2Me
4
5
2
NH
HN
1
1''
1''
CO2Me
1'
1'
2'
2'
OH
OH
6k
6m
N
N
OH
OH
OH
H
6p
6n
HN
N
In contrast, the reaction of aniline with styrene oxide catalysed
by Sn(OTf)2 regioselectively yielded the amino alcohol derived from
the attack on the benzylic position of the epoxide. Although this
reaction spread to a number of aromatic amines, either primary
(5a–m) or secondary (5n, 5p), none of the corresponding least
substituted regioisomers could be detected (Table 2); this is an
advantage of this method for the preparation of 2-arylamino-2-
phenylethanols when compared with others described in the lit-
erature.7,8a,c,9a,10b,e,11a, Furthermore, anilines bearing electron-
withdrawing groups do not fail to react in the evaluated reaction
conditions. All compounds obtained were characterised by their MS
and NMR spectra. For instance, the product obtained when methyl
4-aminobenzoate (5i) was used as starting material (compound 6i)
OH
OH
3a
4a
OH
HN
NH
4b
3b
OH
N
N
(80%) showed signals in its 1H NMR at
d
H¼3.80 (s, 3H), 3.91 (dd,
OH
J¼6.3, 11.2 Hz, 1H), 3.99 (dd, J¼4.0, 11.2 Hz, 1H), 4.56 (dd, J¼4.0,
6.3 Hz, 1H), assigned to CO2CH3, H-20a, H-20b and H-10, respectively.
2D COSYand HMBC studies and the observation of a fragment in the
EIMS at m/z 240 corresponding to the loss of a CH2OH unit from the
molecular ion m/z 271, led to an assignment of the substitution on
the phenylethyl moiety. These data led to the assignment of the
structure of compound 6i as methyl 4-(20-hydroxyethyl-10-phenyl-
amino) benzoate.
3c
4c
OH
N
N
OH
3d
4d
Regarding the opening of styrene oxide by aromatic amines,
reaction times were generally much shorter when no solvent was
used. Unfortunately, however, the yields of isolated products were
lower than those observed for reactions carried out in acetonitrile.
Reaction mixtures were harder to purify due to the prevalence of
inseparable mixtures. Reactions were much cleaner and the yields
of isolated products were higher when the reactions were carried
out in acetonitrile. This allowed for the preparation of some pre-
viously described amino alcohols (6a–f, 6h) and of compounds 6g,
6i, 6j, 6k and 6m, which are described here for the first time.
Secondary alkyl aryl amines appear to behave as their primary
aromatic counterparts yielding only products derived from the
attack on the benzylic position even in the case of benzyl phenyl
amine (5p). As observed with aliphatic amines, no amidine for-
mation was detected when the reactions were carried out in
acetonitrile.18
R2
R3
R1
1'
HN
1''
2
1
OH
6a R1 = R2 = R3 = H
6b R1 = OCH3; R2 = R3 = H
6c R1 = NO2; R2 = R3 = H
6d R1 =H; R2 = NO2; R3 = H
6e R1 = R2 = H; R3 = NO2
6f R1 = Br; R2 = R3 = H
6g R1 =H; R2 = Br; R3 = H
6h R1 = R2 = H; R3 = Br
Some of the above described amino alcohols showed activities,
which are comparable to or better than those showed by the

11734
G. Mancilla et al. / Tetrahedron 64 (2008) 11732–11737
Table 1
a
Treatment of styrene oxide (1) with aliphatic amines catalysed by Sn(OTf)2
NR1R2
OH
OH
O
NR1R2
Sn(OTf)2 (10 mol%)
Amine
+
+
(R1R2NH) Solvent, temp., time
1
2
3
4
Entry
Amine (2)
Solvent
Temp (ꢀC)
Time (h)
Yieldb (%)
Productsb (ratio)
Referencec
10b,11h
1
2
3
4
5
6
7
8
Benzyl amine (2a)
2a
2a
n-Butyl amine (2b)
2b
2b
Diisopropylamine (2c)
2c
2c
Pyrrolidine (2d)
2d
2d
CH3CN
CH2Cl2
None
CH3CN
CH2Cl2
None
CH3CN
CH2Cl2
None
CH3CN
CH2Cl2
None
80
40
25
80
40
25
80
40
25
80
40
25
24
24
24
45
45
20
120
105
40
24
24
6
33
33
83
91
3aþ4a (50:50)
3aþ4a (50:50)
3aþ4a (47:53)
3bþ4b (57:43)
3bþ4b (47:53)
3bþ4b (2:98)
3cþ4c (21:79)
3cþ4c (39:61)
3cþ4c (20:80)
3dþ4d (25:75)
3dþ4d (40:60)
3dþ4d (31:69)
10b
10b
21
11
60
59
51
58
>99
83
94
9
10
11
12
a
Reaction conditions: styrene oxide (1) (1.5 mmol), aliphatic amine (2) (3 mmol), Sn(OTf)2 (10 mol %), solvent (5 mL).
Yields and product ratios obtained after chromatographic purification.
References including spectroscopic data.
b
c
equivalent aminoclovanols. For example, compound 6c exhibited
an EC50 against B. cinerea after 6 days at 35 ppm while the com-
displayed an EC50 against B. cinerea, after 6 days, at 70 ppm.19b The
analysis of the structure–activity relationships will be discussed
elsewhere.
parable clovane derivative, 2
b
-(p-nitrophenylamino)clovan-2a-ol,
Table 2
a
Treatment of styrene oxide (1) with aromatic amines catalysed by Sn(OTf)2
R1
R2
N
O
NHR2
Sn(OTf)2 (10 mol%)
Solvent, temp., time
R1
+
OH
1
5
6
Entry
Amine (5)
Solvent
Temp (ꢀC)
Time (h)
24
0.5
24
0.1
24
0.1
24
0.1
24
0.1
24
0.1
24
0.3
24
0.1
24
0.1
24
0.1
24
0.1
24
0.1
Yieldb (%)
Product (6)
Referenced
11h
1
2
3
4
5
6
7
8
Aniline (5a)
5a
4-Methoxyaniline (5b)
5b
4-Nitroaniline (5c)
5c
3-Nitroaniline (5d)
5d
2-Nitroaniline (5e)
5e
4-Bromoaniline (5f)
5f
3-Bromoaniline (5g)
5g
2-Bromoaniline (5h)
5h
Methyl 4-aminobenzoate (5i)
5i
Methyl 2-aminobenzoate (5j)
5j
Methyl 5-aminoisophthalate (5k)
5k
Methyl 4-aminoterephthalate (5m)
5m
Methyl phenyl amine (5n)
5n
Benzyl phenyl amine (5p)
5p
CH3CN
None
CH3CN
None
CH3CN
None
CH3CN
None
CH3CN
None
CH3CN
None
CH3CN
None
CH3CN
None
CH3CN
None
CH3CN
None
CH3CN
None
CH3CN
None
CH3CN
None
CH3CN
None
25
25
25
40
25
25
25
25
25
25
80
25
25
25
80
25
80
25
25
25
25
25
25
25
25
25
25
25
92
71
90
65
70
41
72
74
56
39
53
55
82
75
70
23
80
33
83
44
64
12
78
48
82
56
62
35
6a
6b
6c
10b
10b
d
6d
6e
6f
9
d
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
22
6g
6hc
6i
d
23
d
6j
d
6k
6m
6n
6pc
d
d
24
1
24
10b,11h
24
0.3
a
Reaction conditions: styrene oxide (1) (1.5 mmol), aromatic amine (2) (3 mmol), Sn(OTf)2 (10 mol %), solvent (5 mL).
Yield obtained after chromatographic purification.
Prepared for first time by oxirane ring opening.
b
c
d
References including spectroscopic data.

G. Mancilla et al. / Tetrahedron 64 (2008) 11732–11737
11735
ꢂ
3. Conclusions
H-3, H-5; MS (EI) m/z (relative intensity): 271 [M]þ (4), 240
[MꢁCH2OH]þ (100), 208 (17), 162 (27), 135 (19), 120 (28), 103 (26),
91 [C7H7]þ (27), 77 [C6H5]þ (18); HRMS m/z: observed 271.1200
[M]þ; C16H17NO3 requires 271.1208.
Sn(OTf)2 is an efficient and versatile catalyst for the highly
regioselective opening of styrene oxide with aromatic amines,
permitting the preparation of novel 2-arylamino-2-phenylethanol
derivatives (6g, 6i, 6j, 6k and 6m), together with nine others
previously described. None of the regioisomeric amino alcohols
was detected and anilines bearing electron-withdrawing groups do
not fail to react in the evaluated reaction conditions. Reaction times
were generally much shorter when no solvent was used, the
regioselectivities were maintained, but yields were lower. Sn(OTf)2
also catalyses the opening of styrene oxide with aliphatic amines
(PhCH2NH2, n-BuNH2, diisopropylamine and pyrrolidine) with
moderate to high yields. 2-Akylamino-1-phenylethanols are the
predominant regioisomers when moderate or high regioselectivity
is observed (compounds 4b, 4c and 4d).
4.3. Selected physical and spectroscopic data
4.3.1. 2-Diisopropylamino-2-phenylethanol (3c)
Yellow oil; IR (KBr) nmax (cmꢁ1): 3406 (
n
O–H), 2963 (
C]C aromatic ring), 1395, 1363
ds CH3 isopropyl); 1H NMR (400 MHz, C6D6):
(ppm) 0.88 (d,
n C–H),
2870 (n C–H, N–CH2), 1602, 1493 (n
(
d
J¼6.8 Hz, 6H, 2Me), 1.15 (d, J¼6.8 Hz, 6H, 2Me), 3.37 (septuplet,
J¼6.8 Hz, 2H, H-100, H-1%), 3.48 (dd, J¼5.7, 10.3 Hz, 1H, H-1a), 3.78
(dd, J¼10.2, 10.3 Hz, H-1b), 4.02 (dd, J¼5.7, 10.2 Hz, 1H, H-2), 7.25–
7.37 (m, 5H, H-20, H-30, H-40, H-50, H-60); 13C NMR (100 MHz, C6D6):
d
(ppm) 21.7 (2c, 2Me), 24.5 (2c, 2Me), 45.2 (2d, C-100, C-1%), 59.6 (d,
C-2), 61.3 (t, C-1), 127.3 (d, C-40), 128.2 (2d, C-30, C-50), 129.2 (2d, C-
20, C-60), 140.8 (s, C-10); HMBC (selected correlations): C-10/H-2;
C-100, C-1%/H-2; MS (EI) m/z (relative intensity): 221 [M]þꢂ (4), 190
[MꢁCH2OH]þ (99), 148 (98), 131 (40), 104 (99), 91 [C7H7]þ (64), 83
(100), 79 (54), 77 [C6H5]þ (50), 47 (36); HRMS m/z: observed
221.1770 [M]þ; C14H23NO requires 221.1780.
4. Experimental
4.1. General
Melting points were measured with a Reichert-Jung Kofler block
and are uncorrected. IR spectra were recorded on a Perkin–Elmer
Spectrum BX FT-IR spectrophotometer. 1H and 13C NMR measure-
ments were obtained on Varian Gemini 300 and INOVA 400 NMR
spectrometers with SiMe4 as the internal reference. NMR assign-
ments were made by a combination of 1D and 2D techniques.
Multiplicities are described using the following abbreviations:
s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet,
br¼broad. In 13C NMR the multiplicities refer to the resonances in
the off-resonance spectra and were elucidated using distortionless
enhancement by polarization transfer (DEPT) spectral editing
technique with secondary pulses at 90ꢀ and 135ꢀ. Electron Impact
mass spectra were recorded on a Finnigan Voyager mass spec-
trometer at 70 eV and high resolution mass spectrometry was
carried out in a Finnigan MAT95S spectrometer. HPLC was per-
formed using a Hitachi/Merck L-6270 apparatus equipped with
a UV–vis detector (L 4250) and a differential refractometer detector
(RI-71). TLC was performed on a Merck Kieselgel 60 F254, 0.2 mm
thick. Silica gel (Merck) was used for column chromatography.
Purification by HPLC was conducted using a Si gel column (Hibar
60, 7 m, 1 cm wide, 25 cm long).
4.3.2. 2-(30-Nitrophenylamino)-2-phenylethanol (6d)
Red solid; mp 89–91 ꢀC; IR (KBr) nmax (cmꢁ1): 3400 (
n
O–H),
C]C aromatic ring, N]O); 1H
(ppm) 1.60 (br s, 1H, OH), 3.82 (dd, J¼6.8,
2932 (
n C–H, N–CH2), 1619, 1527 (n
NMR (400 MHz, CDCl3):
d
11.2 Hz, 1H, H-1b), 4.00 (dd, J¼4.0, 11.2 Hz, 1H, H-1a), 4.54 (dd,
J¼4.0, 6.8 Hz, 1H, H-2), 5.07 (br s, 1H, NH), 6.81 (ddd, J¼0.7, 2.3,
8.1 Hz, 1H, H-60), 7.19 (dd, J¼8.2, 8.2 Hz, 1H, H-50), 7.30 (m, 1H, H-
400), 7.36 (m, 5H, H-20, H-200, H-300, H-500, H-600), 7.48 (ddd, J¼0.6, 2.2,
8.0 Hz, 1H, H-40); 13C NMR (100 MHz, CDCl3):
d (ppm) 59.6 (d, C-2),
66.9 (t, C-1), 107.6 (d, C-20), 112.1 (d, C-40), 119.3 (d, C-60), 126.6 (d,
2C, C-200, C-600), 127.9 (d, C-400), 128.9 (d, 2C, C-300, C-500), 129.6 (d, C-
50), 138.8 (s, C-100), 148.0 (s, C-10), 149.0 (s, C-30); HMBC (selected
correlations): C-100/H-2, 2H-1; C-200, C-600/H-2; MS (EI) m/z
ꢂ
(relative intensity): 258 [M]þ (4), 227 [MꢁCH2OH]þ (100), 207 (18),
181 (40), 180 (26), 103 (16), 91 [C7H7]þ (24), 77 [C6H5]þ (14); HRMS
m/z: observed 258.1009 [M]þ; C14H14N2O3 requires 258.1004.
4.3.3. 2-(20-Nitrophenylamino)-2-phenylethanol (6e)
Red oil; IR (KBr) nmax (cmꢁ1): 3372 (
n
O–H), 2936 (
n C–H, N–CH2),
1618, 1508, 1572 (
CDCl3):
n
C]C aromatic ring, N]O); 1H NMR (400 MHz,
4.2. Standard procedure for the reaction of styrene oxide (1)
with amines
d
(ppm) 2.56 (br s, 1H, OH), 3.92 (dd, J¼6.7, 11.5 Hz, 1H, H-
1b), 4.03 (dd, J¼4.5, 11.5 Hz, 1H, H-1a), 4.71 (ddd, J¼4.5, 6.0, 6.7 Hz,
1H, H-2), 6.62 (m, 2H, H-40, H-60), 7.20 (m, 1H, H-50), 7.28 (m, 1H, H-
400), 7.38 (m, 4H, H-200, H-300, H-500, H-600), 8.18 (dd, J¼1.6, 8.4 Hz, 1H,
H-30), 8.73 (d, J¼6.0 Hz, 1H, NH); 13C NMR (100 MHz, CDCl3):
Tin(II) triflate (73 mg, 0.166 mmol) was added to a magnetically
stirred mixture of styrene oxide (1) (204 mg, 1.66 mmol) and
methyl p-aminobenzoate (5i) (310 mg, 3.32 mmol) in anhydrous
acetonitrile (5 mL), and the reaction was heated to 80 ꢀC. After 24 h,
once compound 1 was consumed (TLC), the solvent was evaporated
under reduced pressure and the crude reaction mixture was puri-
fied by column chromatography on silica gel to yield methyl 4-(20-
hydroxyethyl-10-phenyl-amino) benzoate 6i (368 mg, 1.358 mmol,
80% yield). Orange solid; mp 94–97 ꢀC; IR (KBr) nmax (cmꢁ1): 3399
d
(ppm) 59.2 (d, C-2), 66.8 (t, C-1), 115.1 (d, C-60 ), 115.8 (d, C-40),
*
126.5 (d, 2C, C-200, C-600), 126.6 (d, C-30), 127.9 (d, C-400), 128.9 (d, 2C,
C-300, C-500), 132.3 (s, C-20), 136.0 (d, C-50), 138.7 (s, C-100), 144.6 (s, C-10)
*
interchangeable signals; HMBC (selected correlations): C-10/H-2;
C-100/H-2, 2H-1; C-200, C-600/H-2; C-20/H-40, H-60; MS (EI) m/z
ꢂ
(relative intensity): 258 [M]þ (2), 227 [MꢁCH2OH]þ (100), 194 (46),
180 (32), 104 (23), 91 [C7H7]þ (24), 77 [C6H5]þ (30); HRMS m/z:
(
n
O–H, N–H), 2878 (
n
C–H, N–CH2), 1691 (
n
C]O ester), 1605, 1525
(ppm) 3.80 (s,
observed 258.1015 [M]þ; C14H14N2O3 requires 258.1004.
(n
C]C aromatic ring); 1H NMR (400 MHz, C6D6):
d
3H, CO2CH3), 3.91 (dd, J¼6.3, 11.2 Hz, 1H, H-20b), 3.99 (dd, J¼4.0,
11.2 Hz, 1H, H-20a), 4.56 (dd, J¼4.0, 6.3 Hz, 1H, H-10), 5.05 (br s, 1H,
OH), 6.51 (dd, J¼2.6, 8.8 Hz, 2H, H-2, H-6), 7.22–7.35 (5H, H-200,
H-300, H-400, H-500, H-600), 7.77 (dd, J¼2.6, 8.8 Hz, 2H, H-3, H-5); 13C
4.3.4. 2-(30-Bromo-phenyl-amino)-2-phenylethanol (6g)
Brown solid; mp 81–84 ꢀC; IR (KBr) nmax (cmꢁ1): 3404 (
n
O–H),
2877 (
(400 MHz, C6D6):
1H, H-1b), 3.95 (dd, J¼4.0, 11.1 Hz, 1H, H-1a), 4.47 (dd, J¼4.2, 6.6 Hz,
1H, H-2), 4.73 (sa, 1H, NH), 6.47 (ddd, J¼0.8, 2.2, 8.2 Hz, 1H, H-600),
6.73 (dd, J¼1.9, 2.2 Hz, 1H, H-200), 6.79 (ddd, J¼0.8, 1.9, 7.9 Hz, 1H, H-
400), 6.93 (dd, J¼7.9, 8.2 Hz, 1H, H-500), 7.26–7.37 (m, 5H, H-20, H-30,
n C–H, N–CH2), 1595, 1480 (n
C]C aromatic ring); 1H NMR
d
(ppm) 1.61 (sa, 1H, OH), 3.79 (dd, J¼6.6, 11.1 Hz,
NMR (100 MHz, C6D6):
d
(ppm) 51.5 (q, CO2CH3), 59.2 (d, C-10), 67.1
(t, C-20), 112.5 (2C, d, C-2, C-6), 118.6 (s, C-1), 126.6 (2d, C-200, C-600),
127.8 (d, C-400), 128.9 (2C, d, C-300, C-500), 131.3 (2C, d, C-3, C-5), 139.3
(s, C-100), 151.1 (s, C-4), 167.4 (s, CO2Me); HMBC (selected correla-
tions): C-1/H-2, H-6, CO2CH3; C-100/H-10, H-20a, H-20b; C-4/H-10,
H-40, H-50, H-60); 13C NMR (100 MHz, C6D6):
d (ppm) 59.5 (d, C-2),

11736
G. Mancilla et al. / Tetrahedron 64 (2008) 11732–11737
67.1 (t, C-1), 112.2 (d, C-600), 116.4 (d, C-200), 120.5 (d, C-400), 123.0 (s,
C-300), 126.6 (2d, C-20, C-60), 127.7 (d, C-40), 128.8 (2d, C-30, C-50),
130.4 (d, C-500), 139.4 (s, C-10), 148.5 (s, C-100); HMBC (selected cor-
relations): C-100/H-2; C-20, C-60/H-2; MS (EI) m/z (relative in-
2/H-10; C-1/CH3-2%; C-4/CH3-2IV; C-200, C-600/H-10; C-1%/
ꢂ
H-6; C-1IV/H-3, H-5; MS (EI) m/z (relative intensity): 329 [M]þ
(2), 311 (9), 298 [MꢁCH2OH]þ (72), 266 (100), 238 (14), 207
[NHC6H4(CO2Me)2]þ (21), 177 (34), 150 (16), 119 [PhCHCH2OH]þ
(18), 104 (22), 91 [C7H7]þ (38), 77 [C6H5]þ (18); HRMS m/z: ob-
served 329.1280 [M]þ; C18H19NO5 requires 329.1263.
ꢂ
tensity): 291/293 [M]þ (5/4), 273/275 (8/6), 260/262 [MꢁCH2OH]þ
(100/80), 182 (24), 180 (23), 155/157 [C6H4Br]þ (24/20), 103 (20), 91
[C7H7]þ (38), 77 [C6H5]þ (32); HRMS m/z: observed 291.0255 [M]þ;
C14H14NOBr requires 291.0259.
Acknowledgements
4.3.5. Methyl 2-(20-hydroxyethyl-10-phenyl-amino)benzoate (6j)
This research was supported by grants from MEC, AGL2006-
Yellow solid; mp 78–80 ꢀC; IR (KBr) nmax (cmꢁ1): 3357 (
n
O–H),
´
13401-C02-01/AGR, and the Junta de Andalucıa, P07-FQM-02689
2877 (
matic ring); 1255 (
d
n C–H, N–CH2), 1684 (n C]O ester), 1581, 1516 (n C]C aro-
´
(Spain). G.M. thanks CONACYT (Mexico) and the Fundacion Caro-
n
C–O–C ester); 1H NMR (400 MHz, C6D6):
lina (Spain) for a studentship.
(ppm) 2.63 (br s, 1H, OH), 3.86 (dd, J¼6.6, 11.1 Hz, 1H, H-20b), 3.90
(s, 3H, CO2CH3), 3.94 (dd, J¼4.5, 11.1 Hz, 1H, H-20a), 4.65 (dd, J¼4.5,
6.6 Hz, 1H, H-10), 6.49 (dd, J¼1.1, 8.6 Hz, 1H, H-3), 6.57 (ddd, J¼1.1,
7.1, 8.1 Hz, 1H, H-5), 7.18 (ddd, J¼1.6, 7.1, 8.6 Hz, 1H, H-4), 7.26 (m,
1H, H-400), 7.31–7.38 (4H, H-200, H-300, H-500, H-600), 7.91 (dd, J¼1.6,
8.1 Hz, 1H, H-6), 8.49 (br s, 1H, NH); 13C NMR (100 MHz, C6D6):
References and notes
1. For selected examples, see: (a) Bestatin (immunomodulant): Bergmeier, S. C.;
Stanchina, D. M. J. Org. Chem. 1999, 64, 2852–2859; (b) Sphingosine (cell sig-
nalling): Abraham, E.; Davies, S. G.; Millican, N. L.; Nicholson, R. L.; Roberts, P.
M.; Smith, A. D. Org. Biomol. Chem. 2008, 6, 1655–1664; (c) Penaresidin A (ac-
tomyosin ATPase activator): Liu, D. G.; Lin, G. Q. Tetrahedron Lett. 1999, 40, 337–
340; (d) K01-0509 B (antibacterial): Tsuchiya, S.; Sunazuka, T.; Hirose, T.; Mori,
R.; Tanaka, T.; Iwatsuki, M.; Omura, S. Org. Lett. 2006, 8, 5577–5580; (e) Usti-
loxin D (antimitotic): Sawayama, A. M.; Tanaka, H.; Wandless, T. J. J. Org. Chem.
2004, 69, 8810–8820; (f) Febrifugine (antimalarial): Katoh, M.; Matsune, R.;
Nagase, H.; Honda, T. Tetrahedron Lett. 2004, 45, 6221–6223; (g) Halaminols A–C
(antifungal): Clark, R. J.; Garson, M. J.; Hooper, J. N. A. J. Nat. Prod. 2001, 64,
1568–1571; (h) Balanol (protein kinase C inhibitor): Miyabe, H.; Torieda, M.;
Inoue, K.; Tajiri, K.; Kiguchi, T.; Naito, T. J. Org. Chem. 1998, 63, 4397–4407.
2. Peptidomimetics: (a) Gante, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1699–1720;
(b) Axel, T. N. Angew. Chem., Int. Ed. 2004, 43, 2937–2940; Aminoglycoside
antibiotics surrogates: (c) Tok, J. B. H.; Rando, R. R. J. Am. Chem. Soc. 1998, 120,
8279–8280; (d) Hanessian, S.; Szychowski, J.; Campos-Reales Pineda, N. B.;
Furtos, A.; Keillor, J. W. Bioorg. Med. Chem. Lett. 2007, 17, 3221–3225 Human
NOS inhibitor: (e) Hallinan, E. A.; Tsymbalov, S.; Finnegan, P. M.; Moore, W. M.;
Jerome, G. M.; Currie, M. G.; Pitzele, B. S. J. Med. Chem. 1998, 41, 775–777.
3. (a) McManus, H. A.; Guiry, P. J. Chem. Rev. 2004, 104, 4151–4202; (b) Kacprzak,
K.; Ski, J. Synthesis 2001, 961–998; (c) Fache, F.; Schulz, E.; Tommasino, M. L.;
Lemaire, M. Chem. Rev. 2000, 100, 2159–2232; (d) Ager, D. J.; Prakash, I.; Schaad,
D. R. Chem. Rev. 1996, 96, 835–876.
4. Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638–4660; (b) Mielgo,
A.; Palomo, C. Chem. Asian J. 2008, 3, 922–948; (c) Pellissier, H. Tetrahedron
2007, 63, 9267–9331.
5. (a) Boa, A. N.; Clark, S.; Hirst, P. H. Tetrahedron Lett. 2003, 44, 9299; (b) Hanson,
R. M. Chem. Rev. 1991, 91, 437–476; (c) Mitsunobu, O. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 6, pp 88–
93; (d) Deyrup, J. A.; Moyer, C. L. J. Org. Chem. 1969, 34, 175–179; (e) Freifelder,
M.; Stone, G. R. J. Org. Chem. 1961, 26, 1477–1480.
6. Cossy, J.; Bellosta, V.; Hamoir, C.; Desmurs, J. R. Tetrahedron Lett. 2002, 43, 7083–
7086 and references cited therein.
7. Chakraborti, A. K.; Kondaskar, A.; Rudrawar, S. Tetrahedron 2004, 60, 9085–9091
and references cited therein.
8. (a) Zr(DS)4: Bonollo, S.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. Synlett 2007, 2683–
2686; (b) RuCl3: De, S. K.; Gibbs, R. A. Synth. Commun. 2005, 35, 2675–2680; (c)
Silica gel: Chakraborti, A. K.; Rudrawar, S.; Kondaskar, A. Org. Biomol. Chem.
2004, 2, 1277–1280; (d) [Bmim]BF4: Yadav, J. S.; Reddy, B. V. S.; Basak, A. K.;
Venkat Narsaiah, A. Tetrahedron Lett. 2003, 44, 1047–1050; (e) Monodispersed
silica nanoparticles: Sreedhar, B.; Radhika, P.; Neelima, B.; Hebalkar, N. J. Mol.
Catal. A: Chem. 2007, 272, 159–163 Heteropoly acids: (f) Kumar, S. R.; Leelavathi,
P. J. Mol. Catal. A: Chem. 2007, 266, 65–68; (g) Azizi, N.; Saidi, M. R. Tetrahedron
2007, 63, 888–891; (h) NbCl5: Narsaiah, A. V.; Sreenu, D.; Nagaiah, K. Synth.
Commun. 2006, 36, 3183–3189; (i) SnCl2$H2O: Alam, M. M.; Varala, R.; Enugala,
R.; Adapa, S. R. Lett. Org. Chem. 2006, 3, 187–190; (j) Sulfamic acid: Kamal, A.;
Prasad, B. R.; Reddy, A. M.; Khan, M. N. Catal. Commun. 2007, 8, 1876–1880; (k)
(NH4)8[CeW10O36]$20H2O: Mirkhani, V.; Tangestaninejad, S.; Yadollahi, B.;
Alipanah, L. Catal. Lett. 2005, 101, 93–97; (l) H3PW12O40: Babu, K. S.; Raju, B. C.;
Kumar, S. P.; Mallur, S. G.; Reddy, S. V.; Rao, J. M. Synth. Commun. 2005, 35, 879–
885; (m) ZnBBATOH: Eshghi, H.; Rahimizadeh, M.; Shoryabi, A. Synth. Commun.
d
(ppm) 51.5 (q, CO2CH3), 59.1 (d, C-10), 67.2 (t, C-20), 110.5 (s, C-1),
112.6 (d, C-3), 115.1 (d, C-5), 126.6 (2C, d, C-200, C-600), 127.4 (d, C-400),
128.6 (2C, d, C-300, C-500), 131.4 (d, C-6), 134.4 (d, C-4), 139.9 (s, C-100),
150.2 (s, C-2), 169.1 (s, CO2CH3); HMBC (selection of correlations):
C-2/H-10; C-100/H-10, H-20a, H-20b; C-200, C-600/H-10; MS (EI) m/z
ꢂ
(relative intensity): 271 [M]þ (3), 253 [MꢁOH]þ (15), 240
[MꢁCH2OH]þ (52), 224 (24), 208 (100), 180 (23), 151
[NHC6H5CO2Me]þ (22), 119 (30), 104 (24), 92 (24), 91 [C7H7]þ (40),
ꢂ
77 [C6H5]þ (36); HRMS m/z: observed 271.1215 [M]þ ; C16H17NO3
requires 271.1208.
4.3.6. Dimethyl 5-(20-hydroxyethyl-10-phenyl-amino)-
isophthalate (6k)
Yellow solid; mp 136–141 ꢀC; IR (KBr) nmax (cmꢁ1): 3386 (
n
O–
H), 2871 (
aromatic ring), 1246, 1024 (
n C–H, N–CH2), 1718 (n C]O ester), 1605, 1438 (n
C]C
n
C–O–C ester); 1H NMR (400 MHz,
C6D6):
d
(ppm) 2.21 (sa, 1H, OH), 3.81 (dd, J¼6.7, 11.2 Hz, 1H, H-20b),
3.86 (s, 6H, CH3-2%, CH3-2IV), 3.97 (dd, J¼4.1, 11.2 Hz, 1H, H-20a),
4.60 (dd, J¼4.1, 6.7 Hz, 1H, H-10), 4.84 (sa, 1H, NH), 7.27 (m, 1H, H-
400), 7.35 (m, 4H, H-200, H-300, H-500, H-600), 7.41 (d, J¼1.6 Hz, 2H, H-4,
H-6), 7.96 (t, J¼1.6 Hz, 1H, H-2); 13C NMR (100 MHz, C6D6):
d (ppm)
52.2 (2c, CH3-2%, CH3-2IV), 59.5 (d, C-10), 67.0 (t, C-20), 118.5 (2d, C-
4, C-6), 119.7 (d, C-2), 126.7 (2d, C-200, C-600), 127.8 (d, C-400), 128.9
(2d, C-300, C-500), 131.1 (2s, C-1, C-3), 139.2 (s, C-100), 147.5 (s, C-5),
166.7 (2s, C-1%, C-1IV); HMBC (selected correlations): C-100/H-10,
2H-20; C-200, C-600/H-10; C-1%/H-2, H-6; C-1IV/H-2, H-4; MS
ꢂ
(EI) m/z (relative intensity): 329 [M]þ (3), 311 (10), 298
[MꢁCH2OH]þ (100), 281 (20), 220 (18), 209 (19), 207
[NHC6H4(CO2Me)2]þ (48), 193 [C6H4(CO2Me)2]þ (17), 178 (20), 150
(10), 133 (12), 103 (16), 91 [C7H7]þ (33), 77 [C6H5]þ (14); HRMS m/z:
observed 329.1291 [M]þ; C18H19NO5 requires 329.1263.
4.3.7. Dimethyl 2-(20-hydroxyethyl-10-phenyl-amino)-
terephthalate (6m)
Yellow solid; mp 147–149 ꢀC; IR (KBr) nmax (cmꢁ1): 3358 (
n
O–
H), 2877 (
aromatic ring), 1245 (
n C–H, N–CH2), 1691 (n C]O ester), 1578, 1450 (n
C]C
n
C–O–C ester); 1H NMR (400 MHz, C6D6):
(ppm) 3.81 (s, 3H, CH3-2%), 3.89 (dd, J¼6.8, 11.2 Hz, 1H, H-20b),
2005, 35, 791–798; (n) K5CoW12O40$3H2O: Rafiee, E.; Tangestaninejad, S.;
Habibi, M. H.; Mirkhani, V. Synth. Commun. 2004, 34, 3673–3681.
d
3.92 (s, 3H, CH3-2IV), 3.98 (dd, J¼6.4, 6.8 Hz, 1H, H20a), 4.74 (dd,
J¼6.4, 11.2 Hz, 1H, H-10), 7.17 (dd, J¼1.4, 8.4 Hz, 1H, H-5), 7.22 (d,
J¼1.4 Hz, 1H, H-3), 7.26 (m, 1H, H-400), 7.36 (4H, H-200, H-300, H-500, H-
600), 7.95 (d, J¼8.4 Hz, 1H, H-6), 8.55 (br s, 1H, NH); 13C NMR
9. CoCl2: (a) Sundararajan, G.; Vijayakrishna, K.; Varghese, B. Tetrahedron Lett.
2004, 45, 8253–8256; (b) Iqbal, J.; Pandey, A. Tetrahedron Lett. 1990, 31, 575–
576; (c) SmI2: Carree, F.; Gil, R.; Collin, J. Tetrahedron Lett. 2004, 45, 7749–7751;
(d) InBr3: Rodriguez, J. R.; Navarro, A. Tetrahedron Lett. 2004, 45, 7495–7498; (e)
Al(DS)3$H2O: Firouzabadi, H.; Iranpoor, N.; Khoshnood, A. J. Mol. Catal. A: Chem.
2007, 274, 109–115; (f) Transition metal-based Lewis acids: Zhao, P. Q.; Xu, L.
W.; Xia, C. G. Synlett 2004, 846–850; (g) ZrCl4: Swamy, N. R.; Goud, T. V.; Reddy,
S. M.; Krishnaiah, P.; Venkateswarlu, Y. Synth. Commun. 2004, 34, 727–734; (h)
Mesoporous aluminosilicate: Robinson, M. W. C.; Timms, D. A.; Williams, S. M.;
Graham, A. E. Tetrahedron Lett. 2007, 48, 6249–6251 BiCl3: (i) Ollevier, T.; Lavie-
Compin, G. Tetrahedron Lett. 2002, 43, 7891–7893; (j) Swamy, N. R.; Kondaji, G.;
(100 MHz, C6D6):
d
(ppm) 51.9 (q, CH3-2IV), 52.2 (q, CH3-2%), 58.9
(d, C-10), 67.2 (t, C-20), 113.76 (d, C-3), 113.83 (s, C-1), 115.6 (d, C-5),
126.7 (2C, d, C-200, C-600), 127.8 (d, C-400), 128.9 (2C, d, C-300, C-500),
131.7 (d, C-6), 134.9 (s, C-4), 139.4 (s, C-100), 150.0 (s, C-2), 166.6 (s, C-
1IV), 168.7 (s, C-1%); HMBC (selected correlations): C-100/H-10; C-

G. Mancilla et al. / Tetrahedron 64 (2008) 11732–11737
11737
Nagaiah, K. Synth. Commun. 2002, 32, 2307–2312; (k) Zirconium sulfophenyl
phosphonate: Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O. Eur. J. Org.
Chem. 2001, 4149–4152.
H.; Bartolincic, A.; Vinkovic, V. Tetrahedron 2003, 59, 2435–2439; (m) Yb(OTf)3:
Shi, M.; Chen, Y. J. Fluorine Chem. 2003, 122, 219–227.
12. SmCl3, CeCl3: Fu, X.-L.; Wu, S.-H. Synth. Commun. 1997, 27, 1677–1683.
13. TaCl5: Chandrasekhar, S.; Ramachandar, T.; Prakash, S. J. Synthesis 2000, 1817–
1818.
10. LiClO4 and various metal salts: (a) Chini, M.; Crotti, P.; Macchia, F. Tetrahedron
Lett. 1990, 31, 4661–4664; (b) Chini, M.; Crotti, P.; Macchia, F. J. Org. Chem. 1991,
56, 5939–5942; (c) Chini, M.; Crotti, P.; Flippin, L. A.; Macchia, F. J. Org. Chem.
1991, 56, 7043–7048 LiClO4: (d) Azizi, N.; Saidi, M. R. Can. J. Chem. 2005, 83,
505–507; (e) LiBr: Chakraborti, A. K.; Rudrawar, S.; Kondaskar, A. Eur. J. Org.
Chem. 2004, 3597–3600.
11. (a) Er(OTf)3: Procopio, A.; Gaspari, M.; Nardi, M.; Oliverio, M.; Rosati, O. Tetra-
hedron Lett. 2008, 49, 2289–2293; (b) Zn(ClO4)2–Al2O3: Maheswara, M.; Rao,
K. S. V. K.; Do, J. Y. Tetrahedron Lett. 2008, 49, 1795–1800 Bi(OTf)3: (c) Ollevier, T.;
Nadeau, E. Tetrahedron Lett. 2008, 49, 1546–1550; (d) Ollevier, T.; Lavie-Compin,
G. Tetrahedron Lett. 2004, 45, 49–52; (e) Sm(OTf)3: Yadav, J. S.; Reddy, A. R.;
Narsaiah, A. V.; Reddy, B. V. S. J. Mol. Catal. A: Chem. 2007, 261, 207–212; (f)
Al(OTf)3: Williams, D. B.; Lawton, M. Tetrahedron Lett. 2006, 47, 6557–6560; (g)
Zn(ClO4)2$6H2O: Shivani; Pujala, B.; Chakraborti, A. K. J. Org. Chem. 2007, 72,
3713–3722; (h) Sc(OTf)3: Placzek, A. T.; Donelson, J. L.; Trivedi, R.; Gibbs, R. A.;
De, S. K. Tetrahedron Lett. 2005, 46, 9029–9034; (i) Cu(BF4)2: Kamal, A.; Ramu,
R.; Azhar, M.; Khanna, G. B. R. Tetrahedron Lett. 2005, 46, 2675–2677 Bi(OTf)3,
Bi(TFA)3: (j) Khosropour, A. R.; Khodaei, M. M.; Ghozati, K. Russ. J. Org. Chem.
2004, 40, 1332–1336; (k) Khodaei, M. M.; Khosropour, A. R.; Ghozati, K. Tetra-
hedron Lett. 2004, 45, 3525–3529; (l) Ca(OTf)2: Cepanec, I.; Litvic, M.; Mikuldas,
14. Ln(OTf)3: Chini, M.; Crotti, P.; Favero, L.; Macchia, F.; Pineschi, M. Tetrahedron
Lett. 1994, 35, 433–436.
15. LiOTf: Auge´, J.; Leroy, F. Tetrahedron Lett. 1996, 37, 7715–7716.
16. Sn(OTf)2 and Cu(OTf)2: Sekar, G.; Singh, V. K. J. Org. Chem. 1999, 64, 287–289.
17. Collado, I. G.; Macı´as-Sa´nchez, A. J.; Hanson, J. R. Nat. Prod. Rep. 2007, 24, 674–
686 and references cited therein.
18. Macı´as-Sa´nchez, A. J.; Amigo, C. F. D.; Collado, I. G. Synlett 2003, 1989–1992.
19. (a) Collado, I. G.; Hanson, J. R.; Macı´as-Sa´nchez, A. J. Span. Patent 2 154 185,
´
´
2001; Chem. Abstr. 2001, 135, 195688; (b) Collado I. G.; Macıas-Sanchez, A. J.;
Amigo, C. F. D. Span. Patent 2 241 482, 2005; Chem. Abstr. 2005, 144, 192394.
20. VCl3: Sabitha, G.; Kiran Kumar Reddy, G. S.; Bhaskar Reddy, K.; Yadav, J. S.
Synthesis 2003, 2298–2300.
21. de Sousa, S. E.; O’Brien, P.; Poumellec, P. J. Chem. Soc., Perkin Trans. 1 1998, 1483–
1493.
22. Bonollo, S.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. Green Chem. 2006, 8, 960–964.
23. Job, G. E.; Buchwald, S. L. Org. Lett. 2002, 4, 3703–3706.
24. Chidichimo, G.; Cum, G.; Lelj, F.; Sindona, G.; Uccella, N. J. Am. Chem. Soc. 1980,
102, 1372–1377.