Thiourea catalyzed aminolysis of epoxides under solvent free conditions. Electronic control of regioselective ring opening

Article abstract of DOI:10.1016/j.tet.2010.02.053

A reactant economizing process for the regioselective aminolysis of epoxides using equimolar quantities of reactants catalyzed by the double hydrogen bond donor N,N′-bis[3,5-bis(trifluoromethyl)phenyl]thiourea is reported. Regioselectivity of the reaction

Full text of DOI:10.1016/j.tet.2010.02.053

Tetrahedron 66 (2010) 3042–3049
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Thiourea catalyzed aminolysis of epoxides under solvent free conditions.
Electronic control of regioselective ring opening
,
a
b
b
Swapandeep Singh Chimni a , Neeraj Bala , Vaibhav A. Dixit , Prasad V. Bharatam
*
a Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, Punjab, India
b Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, SAS Nagar 160062, Punjab, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A reactant economizing process for the regioselective aminolysis of epoxides using equimolar quantities of
reactants catalyzed by the double hydrogen bond donor N,N0-bis[3,5-bis(trifluoromethyl)phenyl]thiourea
is reported. Regioselectivity of the reaction is controlled by the electronic nature of the substituent on the
styrene oxide, which has been substantiated on the basis of 13C NMR data and DFT calculations.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 24 November 2009
Received in revised form
11 February 2010
Accepted 12 February 2010
Available online 17 February 2010
1. Introduction
catalyzed by N,N0-bis[3,5-bis(trifluoromethyl)phenyl]-thiourea
yielding b-amino alcohols in quantitative yields. To gain further
Metal based catalysis has been the mainstay of the traditional
strategies for the activation of the electrophilic species toward
nucleophilic attack. Recently, general acid catalysis with double
hydrogen bond donors has emerged as a convenient alternative for
electrophile activation in organic synthesis.1 Hydrogen bond donors
use a mode of activation, that is, common in enzyme catalysis; for
example, in the action of epoxide hydrolase, tyrosine residues are
involved in epoxides activation through hydrogen bonding.2 Urea
and thiourea derivatives can activate oxygen containing functional
groups, as has been demonstrated in the seminal work of Curran3,1e
and subsequent studies by Jacobson3c and Schreiner.3d,1e As recently
reported, epoxide ring opening in water suffers from poor regiose-
lectivity4a as well as long reaction time;4a,b at the same time regio-
selective alcoholysis of styrene epoxide has been obtained using
twelve times the stoichiometric excess of the nucleophile.4c A study
by Saidi and Azizi5 concerning the addition of amines to epoxides in
water reveal that aromatic amines react sluggishly to provide
adducts in low yields. Connon and co-workers have demonstrated
the application of N-tosyl urea catalyst in a limited study of the
aminolysis of styrene oxide with aromatic amines.6 In order to
systematically evaluate the catalysis by thiourea derivatives we
planned to study the ring opening of different epoxides with variety
of aromatic amines. Further, due to our interest in developing
environmentally benign processes we planned to use solvent free
conditions and low molar equivalent of the reactants. Herein, we
report, a solvent less process for the regioselective epoxide ring
opening reaction using equimolar amount of amine and the epoxide
insights and account for the observed regioselectivities, DFT based
quantum chemical calculations at B3LPY/6-31þG(d) level have
been performed.
The significance of the present study stems from the importance
of
b-amino alcohols, which are important intermediates in the
synthesis of a large number of biologically active natural and
synthetic products: for example, in the synthesis of b2-adreno-
receptor agonists,7a anti HBV-agents,7b anti-malarial agents,7c taxol
side chains,7d liposidomycin B class of antibiotics,7e glycosidase
inhibitors,7f naturally occurring brassinosteroids,7g unnatural
amino acids,7h,i and chiral auxiliaries.7j
2. Results and discussion
Initially the aminolysis of styrene oxide 1a (1 mmol) with aniline
2a(1 mmol) waschosenasa model reactionand the effectofdifferent
urea and thiourea catalysts under solvent free conditions was
investigated at 60 ꢀC (Table 1). We preferred to screen different
diarylurea and diarylthiourea derivatives to observe their catalytic
abilities under solvent free condition, in the hope of identifying other
urea and thiourea derivatives with comparable catalytic effects under
these conditions as N,N0-bis[3,5-bis(trifluoromethyl)phenyl]thiourea.
The experimental results inTable 1 show that thiourea derivatives are
better catalysts than urea derivatives, giving almost complete
conversion to products. This difference in their catalytic ability stems
from the inherent ability of sulfur to stabilize the negative charge,
which increases the hydrogen bond donor ability of thiourea
derivatives relative to urea derivatives. The difference is also reflected
in their acidities, for example, diphenylthiourea (pKa¼13.5) is more
acidic than diphenylurea (pKa¼19.5).8 In addition, self association of
thioureamoleculesislessfavorableduetothe lowerelectronegativity
* Corresponding author. Tel.: þ91 183 2258809x3204; fax: þ91 183 2258820;
E-mail addresses: sschimni.chem@gndu.ac.in, sschimni@yahoo.com (S.S. Chimni).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.053

S.S. Chimni et al. / Tetrahedron 66 (2010) 3042–3049
3043
Table 1
Table 3
Screening of various urea and thiourea catalysts for aminolysis of styrene epoxide
(1a)
Aminolysis of styrene oxide by alkyl- and aryl amine catalyzed by 12 under solvent
free conditions at 60 ꢀC
"
R
Entry
Catalyst
Time (h)
3:4c
Conversionc (%)
O
OH
NH
H
N
12 (5 mol%)
1a
2a
3a
4a
5a
6b
7b
8a
9b
5
6
7
8
3.00
3.00
20 min
20 min
3.00
5.00
3.50
5 min
2.75
65:30
73:27
81:19
85:15
78:22
79:21
83:17
90:10
85:15
20
68
>99
>99
43
70
90
100
100
"
R
NH2
OH
+
+
R"
SFC, 60oC
2a-2m
1a
3aa-3am
4aa-4am
9
10
11
12
12
Entry
Amine
Time (h)
2.75
3:4a
Yieldb(%)
96
TON/TOF10
19.2/6.98
NH2
1
85:15
a
2a
NH2
2a
Amount of catalyst ꢁ30 mol %.
Amount of catalyst ꢁ5 mol %.
b
c
Determined by 1H NMR spectroscopy.
2c
18.00
1.00
70:30
80:20
85
97
d
of sulfur. The lowconversion in the case of thiourea 10 is probably due
to its inability to homogenize with the reaction mixture. Our results
reveal that as the electron withdrawing nature of aromatic ring sub-
stituents of both urea and thiourea derivatives increases, so does the
rate of the reaction. N,N0-bis[3,5-bis(trifluoromethyl)phenyl]thiourea
emerged as the best catalyst for this transformation (Table 1, entry 8).
It catalyzes the reaction in 5 minwhen used in 30 mol %, we therefore
planned further studies with this catalyst.
MeO
NH2
3
4
19.4/19.4
2b
NH2
1.75
80:20
96
19.2/10.9
OMe
2c
Cl
NH2
5
6
3.00
7.00
87:13
83:17
87
93
17.4/5.8
2d
NH2
18.6/2.65
Cl
F
2e
NH2
7
8
4.00
7.00
85:15
84:16
90
78
18.0/4.5
2f
Optimizing the amount of catalyst shows that on decreasing the
amount of catalyst from 30 to 5 mol %, there is slight change in
regioselectivity, but at 1 mol % regioselectivity decreases (3:4;
71:29) significantly. The decrease in regioselectivity is probably due
to the contribution from the un-catalyzed reaction. Thus for all
subsequent reactions 5 mol % catalyst was used.
NH2
CH3
15.6/2.23
2g
NH2
CH3
CH3
Optimizing the reaction temperature (Table 2) shows that as
the temperature increases the rate of our model reaction also
increases without affecting the regioselectivity; at 60 ꢀC the
reaction completes in 2.75 h. But we were troubled by the
general belief that hydrogen bonding interactions are weak at
higher temperatures. So, in order to know the role of catalyst 12
we performed the reaction using equimolar amounts of styrene
oxide and aniline in the absence of catalyst at 60 ꢀC. We found
that in the absence of catalyst it takes 18 h for the reaction to
complete to 98%. This does suggest that the catalyst 12 activates
the epoxide under solvent free conditions at a higher tempera-
ture. In addition to the differences in reaction time, the catalyzed
and un-catalyzed reactions also show differences in regiose-
lectivities (Table 3, entry 1 and 2, Table 4, entry 1 and 2, entry 6
and 7). The catalyzed reaction shows higher regioselectivity in
9
7.00
5.00
84:16
82:18
75
95
15.0/2.14
19.0/3.8
2h
NH2
10
11
2i
NH
1.00
1.00
30:70
30:70
92
94
18.4/18.4
18.8/18.8
2j
NH
12
13
2k
Table 2
NH2
Effect of temperature on the aminolysis of styrene oxide catalyzed by 12
1.75
2.00
17:83
19:81
94
95
18.8/10.7
19.0/9.5
Temperature (ꢀC)
Time (h)
3:4a
Conversiona (%)
2l
Entry
1
2
3
4
5
70
60
50
40
27
2.50
2.75
3.50
12.00
18.00
75:25
85:15
85:15
85:15
85:15
100
100
100
84
NH2
14
2m
Determined by 1H NMR spectroscopy.
Isolated yield after chromatography.
a
100
b
c
a
Determined by 1H NMR spectroscopy.
Reaction performed in the absence of catalyst.

3044
S.S. Chimni et al. / Tetrahedron 66 (2010) 3042–3049
Table 4
Further optimization of the reaction conditions by increasing
the amount of amine had negligible effect on the rate of the re-
action. At the same time it resulted in decreased regioselectivity.
This clearly indicates that the catalyst controls the rate as well as
the regioselectivity of the reaction. Thus, stirring a mixture of ep-
oxide, amine, and catalytic amount of 12 at 60 ꢀC provides optimal
conditions for this transformation.
Ring opening of epoxides by aniline catalyzed by 12 under solvent free conditions at
60 ꢀC
NH2
OH
O
12 (5 mol%)
H
N
+
NH
+
R'
SFC, 60oC
R'
4ba-4na
OH
R'
3ba-3na
2a
1b-1n
Under the optimized conditions, the aminolysis of styrene oxide
with various amines shows that the aromatic amines preferably
attack at the benzylic position (Ca) of epoxide, whereas the ali-
phatic amines attack at the less hindered methylene carbon (Cb) of
the epoxide (Table 3). Anilines with electron donating as well as
electron withdrawing groups, such as Me, OMe, Cl, F, were well
Entry R0
Time (h) 3:4a
Yieldb (%) TON/TOF10
1
p-OMeC6H4– (1b)
p-OMeC6H4– (1b)
p-MeC6H4– (1c)
0.2 >99:<1 95
19/95
d
2c
3
1.5
0.5
4.0
4.0
6.5
24.0
6.5
3.5
3.5
3.5
3.5
3.5
6.0
45.0
97:3
93
94
94
93
83
84
84
80
81
80
80
80
72
90
87:13
86:14
86:14
30:70
18:82
30:70
0:100
0:100
0:100
0:100
0:100
0:100
0:100
18.8/37.6
18.8/4.7
18.6/4.65
16.6/2.5
d
4
p-FC6H4– (1d)
5
p-ClC6H4– (1e)
6
p-NO2C6H4– (1f)
p-NO2C6H4– (1f)
m-NO2C6H4– (1g)
C6H5OCH2– (1h)
tolerated and gave the corresponding
quantitative yields. Even sterically hindered amines, such as
o-methyl-aniline, o-methoxyaniline, 2,4-dimethylaniline, and
b-amino alcohols in
7c
8
16.8/2.58
16/4.57
16/4.62
16/4.57
16/4.57
16/4.57
14.4/2.4
18.6/0.41
a
-
9
napthylamine also react smoothly. However, the rate of the reaction
depends strongly on the nucleophilicity of the amine so that as the
nucleophilicity of the amine decreases, the rate also decreases.
This protocol was extended to the aminolysis of other styrene
oxide derivatives and alkyl-1,2-epoxides (Table 4). The aminolysis
of styrene oxide derivatives shows that substituents exert a signif-
icant effect on the direction as well as the rate of ring opening. The
electron donating substituents on the styrene oxide ring increase
the rate of reaction (Table 4, entry 1 and 3), while the electron
withdrawing substituents decrease the rate (Table 4, entry 4–6 and
8). 4-Methoxy-, 4-methyl-, 4-fluoro-, and 4-chloro-styrene oxides
gave products with regioselectivity in line with styrene oxide (Table
4, entries 1, 3–5). Surprisingly, 3-nitro- and 4-nitro-styrene oxide
gave products with reversal of regioselectivity11 (Table 4, entries 6
and 8). This reversal of regioselectivity can be attributed to elec-
tronic factors. In case of alkyl-1,2-epoxides, excellent yields of de-
10
11
12
13
14
15
o-MeC6H4OCH2– (1i)
m-Me C6H4OCH2– (1j)
p-MeC6H4OCH2– (1k)
p-Cl C6H4OCH2- (1l)
CH2]CHCH2OCH2– (1m)
CH3(CH2)8CH2– (1n)
a
Determined by 1H NMR spectroscopy.
Isolated yield after chromatography.
b
c
Reaction performed in the absence of catalyst.
favor of 3, which is formed as a result of the attack of amine
nitrogen on Ca of epoxide.9 This indicates the role of thiourea in
enhancing the regioselectivity of the reaction. To obtain further
evidence, we envisaged the use of additives, which form strong
hydrogen bonds with hydrogen bonding donor motifs, and thus
can inhibit the reaction. The model reaction was therefore
performed in the presence of 5 mol % DMSO, which was equi-
molar to the amount of catalyst 12. In 2.75 h only 69% of reaction
occurred, while after 6 h the completion was 90%. In another
similar experiment, the addition of 100 mol % of DMSO resulted
in the formation of trace amounts of adduct after 2.75 h, while
after 24 h the conversion was only 30%. These experiments
clearly show that the catalyst 12 activates the epoxide ring and
facilitates the adduct formation with aniline at 60 ꢀC.
sired
aliphatic epoxides both steric and electronic factors facilitate the
attack of amine at the less hindered -carbon of the epoxide ring.
b-amino alcohols were obtained (Table 4, entries 9–15). In
b
Further, in the case of glycidyl ethers (4h–4m) the hydrogen
bonding between the ethereal oxygen and amine provides the fa-
vorable positioning of amine for attack at
b-carbon via six-
membered cyclic intermediate.12
The epoxide ring activation by the thiourea catalyst toward the
nucleophilic attack is due to electronic features of the thiourea
catalyst. The electron withdrawing group containing phenyl sub-
stituents on the nitrogen atom of thiourea and the inherent ability
of sulfur to stabilize the negative charge (eq. 1) increases the acidity
of N–H bond.8 Thus the mode of activation of the epoxide ring may
be rationalized on the basis of the highly polarized N–H bond,
which may undergo dissociation to provide a proton at higher
temperatures as shown in Scheme 1.
The substituent dependent reversal of regioselectivity of nu-
cleophilic addition to styrene oxide derivative originates from the
activation of the epoxide ring by a thiourea catalyst. The hydrogen
bond donor activation of the epoxide ring results in the activation
of both Ca–O and Cb–O bonds. The incipient positive charge on a-
carbon is stabilized due to conjugation with the phenyl ring, which
leads to the activation and elongation of Ca–O, with respect to the
Cb–O bond. Thus the nucleophile preferentially attacks at the
a
-carbon.11 However, under the powerful electron-withdrawing
S-
S-
S
S-
S-
H+
+
Ar
Ar
+
H
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
+
(1)
N
H
N
N
H
N
H
N
H
N
H
N
N
H
N
H
N
S-
S-
S
S-
Ar
Ar
Ar
Ar
H
proton
transfer
+
Ar
Ar
Ar
Ar
N
N
S
N
N
H
O
N
N
N
H
N
C
α
attack
Ar
Ar
Ph
H
N
N
H
H
H
H
H
+
O
+
NH
Ph
H
H
O
Ph
O
O
α
β
+NH2
Ph
Ph
Ph
Ph
..
NH2
Ph
Scheme 1.

S.S. Chimni et al. / Tetrahedron 66 (2010) 3042–3049
3045
effect of the nitro group, the conjugative stabilization of the posi-
tive charge on Ca is inhibited, which deactivates the Ca toward
nucleophilic attack, consequently the nucleophile then preferably
reacts at Cb, although at a slow rate.
a
(positive) and
b
(negative) carbons of the epoxide upon com-
plexation with thiourea. The electron density at both the carbons
marginally decreased due to complexation with thiourea, however
the difference between the atomic charges at
a and b carbons are
Further, 13C NMR spectroscopy provides a useful measure of
electron density on the carbon atom. The upfield chemical shift of
carbon resonance corresponds to higher electron density and hence
greater shielding of the carbon nuclei. The comparison of the 13C
NMR resonance of Ca and Cb of the substituted styrene oxides
(Table 5) shows that Ca-carbon resonates downfield than Cb-carbon
except in the case of nitrostyrene oxide. Thus the lower electron
density at Cb in nitrostyrene oxide makes it the preferred site for
nucleophilic attack. The difference in chemical shift of Ca and Cb,
deterministically modulated. The positive charge at both the
carbons marginally increases due to complexation. NBO charge
analysis shows that the charge difference between
a and b carbons
in styrene oxide–thiourea complex is 0.168, which decreases to
0.154 in p-nitrostyrene oxide–thiourea complex but increases
marginally to 0.171 in p-methoxystyrene oxide–thiourea complex
(Table 6). This analysis indicates that the charge balance at
a and
b
carbons in styrene oxide–thiourea complex is differentially
modulated by nitro and methoxy groups at the para-position of
phenyl ring in styrene oxide–thiourea complex. Though these
values are very small, they seem to contribute to the delicate
Dd(C
) can be correlated with regioselectivity of the nucleophilic
–Cb
a
epoxide ring opening reaction. In case of nitro derivatives the Dd is
the reverse of that obtained with substituted styrene oxides that
have positive Dd values (Table 5).
balance between
a and b preference for nucleophilic attack and the
trends are in line with experimental observations.
Table 5
Table 6
13C NMR resonance of Ca and Cb carbons of styrene oxide and its derivatives
NBO Charge analysis of the epoxide, epoxide–thiourea complexes and the transition
states at B3LYP/6-31þG(d)
Epoxide
d(C
d(C
Dd
(C
a)
b
)
aꢁCb)
1a
1b
1c
1d
1e
1f
52.11
51.96
52.28
51.79
51.53
51.39
50.97
50.70
51.02
51.11
50.96
51.63
1.14
1.26
1.26
0.68
0.43
Mol.
a
-C
b
-C
O
S
Epoxide
1a
1b
1f
0.038
0.040
0.030
ꢁ0.130
ꢁ0.133
ꢁ0.124
ꢁ0.554
ꢁ0.557
ꢁ0.546
ꢁ0.24
Epoxide–thiourea complexes
C1a
C1b
C1f
0.044
0.045
0.034
ꢁ0.124
ꢁ0.126
ꢁ0.120
ꢁ0.590
ꢁ0.595
ꢁ0.577
ꢁ0.290
ꢁ0.293
ꢁ0.266
In order to obtain atomic level details of the model reaction
and to estimate the thermodynamic versus kinetic control on the
reaction, quantum chemical calculations have been performed.
The epoxides 1a, 1b, and 1f have been chosen as representative
epoxides; reaction with aniline (2a) in the presence of the
unsubstituted thiourea (13) was studied using B3LYP/6-31þG(d)
method.
Since, under the studied experimental conditions it is evident
that the activation of epoxide by thiourea takes place prior to the
nucleophilic attack by aniline, it is necessary to study the com-
plexation of thiourea with various epoxides to understand the
potential energy surface of the nucleophilic epoxide ring opening.
The stabilization energy due to complexation of thiourea (13) with
1a, 1b, and 1f, respectively, are 6.31, 6.76, and 4.40 kcal/mol. This
can be traced to the electron density (charge) on the bridging
oxygen atom of the epoxides: ꢁ0.554 (1a), ꢁ0.557 (1b), and ꢁ0.546
(1f). The greater the charge on the O-atom of the epoxide, the
greater is the complexation energy. The complexation energy in
p-nitrostyrene oxide is much less than styrene oxide and
p-methoxystyrene oxide, co-relatable to the relatively low rate of
reaction. Also, the complexation energy in p-methoxystyrene oxide
is largest among the three and again co-relatable to the highest rate
of the reaction observed in the experimental conditions.
Compounds 1a, 1b, and 1f correspond to styrene, p-methoxystyrene, and p-nitro-
styrene oxide, respectively; C1a, C1b, C1f epoxide–thiourea complexes.
Further, following trends have been observed during the
analysis of the potential energy surface of the epoxide ring opening
reaction (Fig.1, Table 7).
Complexation with Hþ has been shown to increase the C–O
bond length in epoxides like 2-methyl-1,2-epoxypropane,13
however only a marginal lengthening of C–O bond lengths
(w0.01 Å) has been observed for the epoxide–thiourea complexes.
Notable changes have been observed in the atomic charges at
Figure 1. Comparison of the potential energy surface of the thiourea catalyzed epoxide
ring opening reaction. C: Epoxide–thiourea complex, TSC: TS of catalyzed reaction, IC:
Intermediate in the catalyzed reaction, P: Product (b-amino alcohol).
Table 7
Transition state barriers (kcal/mol) for the catalyzed and un-catalyzed epoxide ring opening reaction with anilne
R¼
Ph
MeOPh
NO2Ph
a
b
a
ꢁb
a
b
a
ꢁb
a
b
aꢁb
Un-catalyzed
Catalyzed
Difference
39.24
26.68
12.56
33.61
23.73
9.88
5.63
2.95
38.51
25.77
12.74
34.04
24.03
10.01
4.47
1.74
39.28
26.41
12.87
32.04
22.01
10.03
7.59
4.40

3046
S.S. Chimni et al. / Tetrahedron 66 (2010) 3042–3049
Thiourea stabilizes the transition state leading to the products
by about w12 kcal/mol. The intermediates are stabilized to a simi-
4. Experimental
4.1. General
lar extent. For the aliphatic class of epoxides the
b-attack is favored
over the -attack (on kinetic scale) by w2.5 kcal/mol in the
a
un-catalyzed reaction. This difference is only marginally affected in
the catalyzed reaction. (See Supplementary data).
NMR spectra were obtained at 300 MHz (JEOL AL-300) using
either CDCl3 as solvents with Me4Si in CDCl3 as internal standard.
The nucleophilic attack can take place on
of the epoxide. In styrene epoxide the barrier for
(39.24 kcal/mol) is only marginally larger than that of
a
as well as
b
carbons
The chemical shifts are reported in d values relative to TMS and
a
-attack
-attack
coupling constants (J) are expressed in hertz. Spectral patterns are
designated as s¼singlet; d¼doublet; dd¼doublet of doublets;
q¼quartet; t¼triplet; br¼broad; m¼multiplet. Carbon NMR spec-
tra were recorded on the same instrument (75.45 MHz) with total
proton decoupling. High-resolution mass spectra (HRMS) were
recorded with a Micromass Q-TOF mass spectrometer. Analytical
thin-layer chromatography (TLC) was performed on either (i)
aluminum sheets pre-coated with silica gel 60F254 (Merck, India)
or (ii) glass plates (7.5ꢂ2.5 cm) coated with silica gel GF-254
(Spectrochem India) containing 13% calcium sulfate as binder
and various combinations of ethyl acetate and hexane were used
as eluents. Visualization of the spots was accomplished by
exposing to UV light or iodine vapors. Column chromatography
was performed on Acme’s silica gel (60–120 mesh) using mixture
b
(33.61 kcal/mol) under un-catalyzed conditions. This indicates that
there is a delicate balance between and nucleophilic attacks,
a
b
supporting the observed experimental trends. This balance gets
further delicate under the catalytic conditions as the difference
between barriers in
a and b paths gets reduced from 5.63 to
2.95 kcal/mol. Electron releasing groups like methoxy show
a decrease in the difference of the reaction barrier (4.47 kcal/mol
for un-catalyzed and 1.74 kcal/mol for catalyzed reaction), while
electron withdrawing substituents like nitro lead to an increase in
this difference (7.59 kcal/mol for un-catalyzed and 4.40 kcal/mol
for catalyzed reaction).
In catalyzed reaction the barrier for the
a greater extent than that of -attack (Table 7), showing that in the
presence of thiourea catalyst the preference for -attack is
a-attack is reduced to
b
of ethyl acetate and hexane as eluent. b
-Amino alcohols 3aa,14a
a
3ab,14b 3ac,14c 3ad,14a 3ag,14a 3ai,4b 3aj,14b 3ak,14d 3al,14b 3am,14e
and 3ha14a were identified by comparing their spectral data with
that reported in the literature.
increased. These results are in accordance with our experimental
observations (Fig. 2).
The nucleophilic attack follows an SN2 mechanism thus as the
nucleophile approaches the epoxide carbons C–O bond elongation
Ab initio DFT calculations have been performed using B3LYP
method and 6-31þG(d) basis set. Complete optimization of all the
systems under consideration has carried out using Gaussian03 suite
of programmes.15 Analytical frequencies have been estimated by
carrying out frequency calculations at the B3LYP/6-31þG(d) level to
characterize the optimized structures as minima or transition state
(one negative frequency) on the potential energy surface. The
estimated zero point vibrational energy (ZPVE) values have been
scaled by 0.980616 and employed in correcting the absolute energy
values. Partial atomic charges have been estimated by performing
Natural Bond Orbital (NBO) analysis.17
takes place. The C–O bond elongation during
larger than that of C–O bond elongation during
angles in the transition state structure are also significantly dif-
ferent during
-attack (w97ꢀ) in comparison to -attack (w87ꢀ).
The transition state is achieved relatively late in the case of -attack
(C/N distance w1.92 Å) in comparison to the -attack (C/N dis-
tance w1.95 Å). All these geometric details indicate that the tran-
sition structures during -attack are relatively more close to that of
intermediates during the -attack in comparison to -attack.
a
-attack is relatively
b
-attack. The O–C–C
a
b
a
b
a
a
b
Also the comparison of the Ca–O bond lengths in p-nitrostyrene
oxide (2.12 Å), styrene oxide (2.16 Å) and p-methoxystyrene oxide
4.2. General procedure for the nucleophilic ring opening
reaction
(2.19 Å) during the
in p-methoxystyrene oxide. This shows that there is higher pref-
erence for -attack in p-methoxystyrene oxide.
Thus from the above discussion it can be summarized that, the
nucleophilic attack can take place at both and carbons in
aromatic epoxides. On purely electrostatic count the attack at
position should be preferred. However, steric factors seem to
counter the preference due to electrostatic factors. The barrier for
the nucleophilic (aniline) attack at position in styrene oxide is
26.68 kcal/mol and for the attack at position is 23.73 kcal/mol,
thus preference for -attack is 2.95 kcal/mol in terms of energy.
a-attack shows the greatest elongation of Ca–O
a
To a 10 ml RBF amine (1 mmol), epoxide (1 mmol) and thiourea
catalyst were consecutively added and the resulting mixture was
stirred at 60 ꢀC for the time indicated. The progress of the reaction
was monitored by TLC. After the completion of the reaction, the
reaction mixture was loaded on the chromatography column and
eluted with mixture of ethyl acetate and hexane to obtain the pure
regioisomers.
a
b
a
a
b
b
4.2.1. 2-(30-Chlorophenylamino)-2-phenylethanol (3ae). The title
compound was isolated by column chromatography (hexane/AcOEt
85:15) as yellow oil; Rf (hexane/AcOEt 85:15) 0.50; IR (CHCl3) nmax
(cmꢁ1): 3404, 3062, 3028, 2926, 2875, 1597, 1485; 1H NMR
However, this preference gets reduced to 1.74 kcal/mol in
p-methoxystyrene oxide but increases to 4.40 kcal/mol in the
p-nitrostyrene oxide. Also the comparison of the bond lengths
shows the marginal elongation of Ca–O in p-methoxystyrene oxide.
(300 MHz, CDCl3):
d
1.60–1.95 (br s, 1H, OH), 3.74 (dd, J¼6.6 and
This clearly indicates that the balance in the
a/b
product ratios gets
11.1 Hz, 1H, CH2), 3.93 (dd, J¼4.2 and 11.1 Hz, 1H, CH2), 4.45 (dd,
J¼4.2 and 6.6 Hz, 1H, CH), 6.39–6.43 (m, 1H, ArH), 6.53 (t, J¼2.1 Hz,
1H, ArH), 6.61–6.64 (m, 1H, ArH), 6.98 (t, J¼8.1 Hz, 1H, ArH), 7.25–
7.36 (m, 6H, ArH, NH); 13C NMR (75.45 MHz, CDCl3): 59.6, 67.2,
111.9, 113.5, 117.6, 126.6, 127.8, 128.7, 128.8, 130.1, 134.8, 139.4, 148.3;
MS (m/z): 247, 249 (Mþ, 3:1).
opposite due to nitro and methoxy substitution.
3. Conclusion
In conclusion, we have developed a reactant economizing
and environmentally benign process for the regioselective
aminolysis of epoxides using equimolar quantities of reactants
under solvent free conditions catalyzed by N,N0-bis[3,5-bis(tri-
fluoromethyl)phenyl]thiourea catalyst. The study reveals the
electronic control of regioselective ring opening of substituted
styrene oxides as substantiated by 13C NMR data and DFT based
quantum chemical calculations at B3LPY/6-31þG(d) level.
4.2.2. 2-(40-Fluorophenylamino)-2-phenylethanol (3af). The title
compound was isolated by column chromatography (hexane/AcOEt
85:15) as yellow oil; Rf (hexane/AcOEt 85:15) 0.45; IR (CHCl3) nmax
(cmꢁ1): 3386, 3061, 3030, 2926, 2876, 1614, 1510; 1H NMR
(300 MHz, CDCl3):
11.4 Hz, 1H, CH2), 3.84 (dd, J¼4.2 and 11.4 Hz, 1H, CH2), 4.32 (dd,
d
2.40–2.90 (br s, 2H), 3.64 (dd, J¼6.9 and

S.S. Chimni et al. / Tetrahedron 66 (2010) 3042–3049
3047
Figure 2. Structures of the transition states along the path of aniline attack on 1a, 1b, and 1f epoxide–thiourea complex. The geometrical parameters are obtained at B3LYP/6-
31þG(d) level, distances are in Å units and angles in degrees.
J¼4.2 and 6.9 Hz,1H, CH), 6.35–6.42 (m, 2H, ArH), 6.65–6.77 (m, 2H,
ArH), 7.16–7.32 (m, 5H, ArH); 13C NMR (75.45 MHz, CDCl3): (52.8),
60.1, 67.1, (72.2), 114.9, 115.0, 115.4, 115.6, 115.9, 125.8, 126.7, 126.9,
127.7, 128.0, 128.5, 128.6, 128.8, 139.7, 143.2, 154.5, 157.6; HRMS:
calculated for C14H14FNO 254.0957 [MþNa]þ; found 254.0943.
AcOEt 85:15) as yellow oil; Rf (hexane/AcOEt 85:15) 0.46; IR (CHCl3)
nmax (cmꢁ1): 3402, 3062, 3026, 3005, 2921, 2858,1619,1513; 1H NMR
(300 MHz, CDCl3):
d
3.74 (dd, J¼7.2 and 11.1 Hz, 1H, CH2), 3.94 (dd,
J¼4.2 and 11.1 Hz, 1H, CH2), 4.70 (dd, J¼4.2 and 7.2 Hz, 1H, CH), 6.22
(d, J¼8.1 Hz, 1H, ArH), 6.57 (d, J¼8.1 Hz, 1H, ArH), 6.68–6.71 (m, 1H,
ArH), 7.20–7.34 (m, 5H, ArH); 13C NMR (75.45 MHz, CDCl3): (17.4),
17.6, 20.4, 52.2, 60.2, 67.4, 72.2, (111.1), 111.9, 122.7, (123.0), 125.8,
126.7, 127.2, 127.3, 127.4, 127.5, 127.9, 128.8, 130.1, 131.2, 140.4, 142.6,
4.2.3. 2-(20,40-Dimethylphenylamino)-2-phenylethanol (3ah). The
title compound was isolated by column chromatography (hexane/

3048
S.S. Chimni et al. / Tetrahedron 66 (2010) 3042–3049
143.1, 127.7, 128.0, 128.5, 128.6, 128.8, 139.7, 143.2, 154.5, 157.6;
(cmꢁ1): 3387, 2922, 2852, 1603, 1528; 1H NMR (300 MHz, CDCl3):
2.58 (br s, 1H), 3.26 (dd, J¼8.7 and 13.5 Hz, 1H, CH2), 3.47 (dd,
HRMS: calculated for C16H19NO 264.1364 [MþNa]þ; found 264.1351.
d
J¼3.6 and 13.5 Hz, 1H, CH2), 5.02 (dd, J¼3.6 and 8.7 Hz, 1H, CH),
6.64–6.75 (m, 3H, ArH), 7.14–7.30 (m, 2H, ArH), 7.54 (t, J¼7.8 Hz, 1H,
ArH), 7.74 (d, J¼7.8 1H, Hz, ArH), 8.14–8.18 (m, 1H, ArH), 8.28 (s, 1H,
ArH); 13C NMR (75.45 MHz, CDCl3): 52.0, 71.4, 113.6, 118.8, 120.9,
122.8, 129.4, 129.5, 131.8, 144.4, 147.4, 148.6; HRMS: calculated for
C14H14N2O3 281.0902 [MþNa]þ; found 281.0896.
4.2.4. 2-(40-Methoxyphenyl)-2-(phenylamino)ethanol
title compound was isolated by column chromatography (hexane/
AcOEt 85:15) as yellow oil; Rf (hexane/AcOEt 85:15) 0.48; IR (CHCl3)
nmax (cmꢁ1): 3395, 3051, 2933, 2836,1603,1510; 1H NMR (300 MHz,
(3ba). The
CDCl3):
d
3.20–3.50 (br s, 2H), 3.62 (dd, 1H, J¼7.5, and 11.0 Hz, CH2),
3.72 (s, 3H, OCH3), 3.80 (dd, J¼4.2 and 11.1 Hz, 1H, CH2), 4.38 (dd,
J¼4.2 and 7.5 Hz, 1H, CH), 6.52–6.55 (m, 2H, ArH), 6.63–6.65 (m, 1H,
ArH), 6.68–6.84 (m, 2H, ArH), 7.04–7.10 (m, 2H, ArH) 7.19–7.24 (m,
2H, ArH); 13C NMR (75.45 MHz, CDCl3): 55.1, 59.2, 67.2, 113.8, 114.1,
117.7, 127.7, 129.0, 132.0, 147.2, 158.8; HRMS: calculated for
C15H17NO2 266.1157 [MþNa]þ; found 266.1161.
4.2.10. 1-(20-Methylphenoxy)-3-(phenylamino)propan-2-ol (3ia). The
title compound was isolated by column chromatography
(hexane/AcOEt 85:15) as yellow oil; Rf (hexane/AcOEt 85:15) 0.50;
IR (CHCl3) nmax (cmꢁ1): 3406, 3053, 2923, 2852, 1602, 1493; 1H
NMR (300 MHz, CDCl3):
d
2.25 (s, 3H, CH3), 3.27 (dd, J¼7.1 and
13.0 Hz, 1H, CH2), 3.45 (dd, J¼4.2 and 13.0 Hz, 1H, CH2), 4.03 (d,
J¼4.9 Hz, 2H, CH2), 4.19–4.32 (m, 1H, CH), 6.64–6.92 (m, 5H, ArH),
7.11–7.22 (m, 4H, ArH); 13C NMR (75.45 MHz, CDCl3): 16.7, 47.3,
69.3, 70.6, 111.6, 113.8, 118.5, 121.5, 127.4, 129.8, 131.3, 148.2, 157.3;
HRMS: calculated for C16H19NO2 280.1313 [MþNa]þ; found
280.1310.
4.2.5. 2-(40-Methylphenyl)-2-(phenylamino)ethanol (3ca). The title
compound was isolated by column chromatography (hexane/AcOEt
85:15) as yellow oil; Rf (hexane/AcOEt 85:15) 0.55; IR (CHCl3) nmax
(cmꢁ1): 3395, 3021, 2923, 2870, 1602, 1504; 1H NMR (300 MHz,
CDCl3):
d
2.28 (s, 3H), 3.24–3.33 (br s, 2H, NH, OH), 3.63 (dd, J¼7.2
and 11.1 Hz, 1H, CH2), 3.82 (dd, J¼4.2 and 11.1 Hz, 1H, CH2), 4.40 (dd,
J¼4.2, and 7.2 Hz, 1H, CH), 6.53 (d, J¼7.8 Hz, 2H, ArH), 6.65 (t,
J¼7.5 Hz, 1H, ArH), 7.04–7.11 (m, 4H, ArH), 7.14–7.25 (m, 2H, ArH);
13C NMR (75.45 MHz, CDCl3): 21.0, 59.6, 67.2, 113.8, 117.7, 126.5,
129.0, 129.2, 129.4, 137.0, 137.1, 147.3; HRMS: calculated for
C15H17NO 250.1208 [MþNa]þ; found 250.1208.
4.2.11. 1-(30-Methylphenoxy)-3-(phenylamino)propan-2-ol (3ja). The
title compound was isolated by column chromatography
(hexane/AcOEt 85:15) as yellow oil; Rf (hexane/AcOEt 85:15) 0.45;
IR (CHCl3) nmax (cmꢁ1): 3383, 3054, 3025, 2923,1602,1497; 1H NMR
(300 MHz, CDCl3):
d
2.23 (s, 3H, CH3), 3.23 (dd, J¼7.0 and 13.0 Hz,
1H, CH2), 3.38 (dd, J¼4.2 and 13.0 Hz, 1H, CH2), (3.00–3.44, br s, 2H,
NH and OH), 3.97–3.98 (m, 2H, CH2), 4.12–4.22 (m, 1H, CH), 6.62–
6.82 (m, 5H, ArH), 7.05–7.21 (m, 4H, ArH); 13C NMR (75.45 MHz,
CDCl3): 16.2, 46.7, 68.7, 69.9, 111.0, 113.2, 117.9, 120.9, 126.5, 126.8,
129.2, 130.7, 148.0, 156.3; C16H19NO2 280.1313 [MþNa]þ; found
280.1310.
4.2.6. 2-(40-Fluorophenyl)-2-(phenylamino)ethanol (3da). The title
compound was isolated by column chromatography (hexane/AcOEt
90:10) as yellow oil; Rf (hexane/AcOEt 85:15) 0.5; IR (CHCl3) nmax
(cmꢁ1): 3391, 2925, 2854, 1602, 1506; 1H NMR (300 MHz, CDCl3):
d
2.83–2.90 (br s, 2H), 3.67 (dd, J¼7.2 and 11.0 Hz,1H, CH2), 3.88 (dd,
J¼4.2 and 11.0 Hz, 1H, CH2), 4.44 (dd, J¼4.2 and 7.2 Hz, 1H, CH),
6.51–6.54 (m, 2H), 6.65–6.71 (m, 1H), 6.97–7.19 (m, 4H), 7.29–7.35
(m, 2H); 13C NMR (75.45 MHz, CDCl3): 59.2, 67.2, 113.5, 113.8, 115.5,
115.7, 118.0, 128.2, 128.3, 129.1, 129.4, 135.7, 135.8, 147.0, 160.5,
163.8; HRMS: calculated for C14H14FNO 254.0957 [MþNa]þ; found
250.0950.
4.2.12. 1-(40-Methylphenoxy)-3-(phenylamino)propan-2-ol (3ka). The
title compound was isolated by column chromatography
(hexane/AcOEt 85:15) as yellow oil; Rf (hexane/AcOEt 85:15) 0.48;
IR (CHCl3) nmax (cmꢁ1): 3399, 3028, 2922, 2855,1604, 1510; 1H NMR
(300 MHz, CDCl3):
d
2.28 (s, 3H, CH3), 3.23 (dd, J¼7.0 and 13.0 Hz,
1H, CH2), 3.38 (dd, J¼4.2 and 13.0 Hz, 1H, CH2), 3.96 (m 2H, CH2),
4.14–4.24 (m, 1H, CH), 6.62–6.82 (m, 5H, ArH), 7.05–7.21 (m, 4H,
ArH); 13C NMR (75.45 MHz, CDCl3): 20.6, 46.7, 68.9, 70.3, 113.4,
114.5, 118.1, 129.4, 130.2, 130.7, 148.2, 156.4; HRMS: calculated for
C16H19NO2 258.1494 [MþNa]þ; found 258.1493.
4.2.7. 2-(40-Chlorolphenyl)-2-(phenylamino)ethanol (3ea). The title
compound was isolated by column chromatography (hexane/AcOEt
85:15) as yellow oil; Rf (hexane/AcOEt 85:15) 0.48; IR (CHCl3) nmax
(cmꢁ1): 3385, 2955, 2924, 2853, 1602, 1503, 1491; 1H NMR
(300 MHz, CDCl3):
d
3.67 (dd, J¼7.2 and 11.0 Hz, 1H, CH2), 3.88 (dd,
J¼4.2 and 11.0 Hz, 1H, CH2), 4.43 (dd, J¼4.2 and 7.2 Hz, 1H, CH),
6.50–6.53 (m, 2H, ArH), 6.66–6.71 (m, 1H, ArH), 7.06–7.12 (m, 2H,
ArH), 7.28 (m, 5H, ArH); 13C NMR (75.45 MHz, CDCl3): 59.3, 67.1,
113.5, 113.8, 118.1, 118.4, 127.2, 128.1, 128.7, 128.9, 129.1, 129.4, 133.2,
133.6, 133.7, 147.5; HRMS: calculated for C14H14ClNO 286.0401
[MþK]þ; found 286.0878.
4.2.13. 1-(40-Chlorophenoxy)-3-(phenylamino)propan-2-ol (3la). The
title compound was isolated by column chromatography
(hexane/AcOEt 85:15) as yellow oil; Rf (hexane/AcOEt 85:15) 0.47;
IR (CHCl3) nmax (cmꢁ1): 3404, 3053, 3022, 2926, 2854, 1602, 1492;
1H NMR (300 MHz, CDCl3):
d
3.05 (br s, 1H), 3.29 (dd, J¼7.2 and
13.5 Hz, 1H, CH2), 3.46 (dd, J¼4.2 and 12.9 Hz, 1H, CH2), 3.97–4.09
(m, 2H CH2), 4.21–4.28 (m, 1H, CH), 6.62–6.86 (m, 5H, ArH), 7.13–
7.25 (m, 4H, ArH); 13C NMR (75.45 MHz, CDCl3): 46.5, 68.6, 70.3,
113.3, 115.8, 118.1, 126.1, 129.3, 129.4, 147.9, 157.0; HRMS: calculated
for C15H16ClNO2 300.0767 [MþNa]þ; found 300.0780.
4.2.8. 1-(40-Nitrophenyl)-2-(phenylamino)ethanol (4fa). The title
compound
was
isolated
by
column
chromatography
(hexane/AcOEt 85:15) as yellow oil; Rf (hexane/AcOEt 85:15)
0.48; IR (CHCl3) nmax (cmꢁ1): 3406, 2923, 2853, 1602, 1517; 1H
NMR (300 MHz, CDCl3):
d
3.06 (br s, 2H, NH and OH), 3.22 (dd,
4.2.14. 1-(Allyloxy)-3-(phenylamino)propan-2-ol (3ma). The title
compound was isolated by column chromatography (hexane/AcOEt
90:10) as yellow oil; Rf (hexane/AcOEt 85:15) 0.47; IR (CHCl3) nmax
(cmꢁ1): 3395, 3053, 3013, 2917, 2856, 1604; 1H NMR (300 MHz,
J¼8.7 and 13.5 Hz, 1H, CH2), 3.43 (dd, J¼3.6 and 13.5 Hz, 1H, CH),
4.99 (dd, J¼3.6 and 8.7 Hz, 1H, CH), 6.64 (m, 3H, ArH), 6.72–6.76
(m, 2H, ArH), 7.55 (d, J¼8.7 Hz, 2H, ArH), 8.14–8.22 (m, 2H, ArH);
13C NMR (75.45 MHz, CDCl3): 51.9, 71.4, 113.6, 118.8, 123.7, 126.6,
129.5, 147.3, 147.5, 149.0; HRMS: calculated for C14H14N2O3
258.10; found 241[MþHꢁH2O]þ.
CDCl3):
d
2.70–3.00 (br s, 1H), 3.14 (dd, J¼7.2 and 12.9 Hz, 1H, CH2),
3.30 (dd, J¼4.2 and 12.9 Hz, 1H, CH2), 3.45–3.57 (m, 2H, CH2), 4.00–
4.04 (m, 3H, CH2, CH), 5.19–5.31 (m, 2H, CH2 olefinic), 5.86–5.95 (m,
1H, CH), 6.61–6.74 (m, 3H, ArH), 7.14–7.24 (m, 2H, ArH); 13C NMR
(75.45 MHz, CDCl3): 46.6, 68.9, 72.2, 72.3, 113.09, 117.4, 117.6, 129.1,
134.2, 148.1; HRMS: calculated for C12H17NO2 230.1157 [MþNa]þ;
found 230.1013.
4.2.9. 1-(30-Nitrophenyl)-2-(phenylamino)ethanol (4ga). The title
compound was isolated by column chromatography (hexane/AcOEt
85:15) as yellow oil; Rf (hexane/AcOEt 85:15) 0.48; IR (CHCl3) nmax

S.S. Chimni et al. / Tetrahedron 66 (2010) 3042–3049
3049
Chem., Int. Ed. 1999, 38, 326–329; (i) Li, G.; Chang, H.-T.; Sharpless, K. B. Angew.
Chem., Int. Ed. 1996, 35, 451–454; (j) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev.
1996, 96, 835–876.
8. Bordwell, F. G.; Algrim, D. J.; Harrelson, J. A. J. Am. Chem. Soc. 1988, 110,
5903–5904.
Acknowledgements
The authors are grateful to CSIR India for financial assistance
(Grant No. 01(2168)/07/EMR-II) and UGC, India for award of re-
search fellowship to NB.
9. Upon activation by acids styrene epoxides are known to react at Ca of styrene
epoxide. Chini, M.; Crotti, P.; Macchia, F. J. Org. Chem. 1991, 56, 5939–5942.
10. TON, turnover number (number of substrate molecules converted to product
per catalyst molecule), i.e, conversion/catalyst mol %. TOF, turnover
frequency¼TON per unit hour.
Supplementary data
11. (a) Kayser, M. M.; Morand, P. Can. J. Chem. 1980, 58, 302–306; (b) Mitsuru, S.;
Tomoyuki, S.; Kozo, S. Tetrahedron Lett. 2004, 45, 9265–9268.
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.02.053.
12. Reines, S. A.; Griffith, J. R.; Orear, J. G. J. Org. Chem. 1970, 36, 2772–2777.
13. (a) Carlier, P. R.; Deora, N.; Crawford, T. D. J. Org. Chem. 2006, 71, 1592–1597; (b)
Zhao, Y.; Truhlar, D. G. J. Org. Chem. 2007, 72, 295–298.
References and notes
14. (a) Shivani; Pujala, B.; Chakraborti, A. K. J. Org. Chem. 2007, 72, 3713–3722; (b)
Maheswara, M.; Rao, K. S. V. K.; Do, J. Y. Tetrahedron Lett. 2008, 49, 1795–1800;
(c) Reddy, L. R.; Reddy, M. A.; Bhanumathi, N.; Rao, K. R. New J. Chem. 2001, 25,
221–222; (d) Placzek, A. T.; Donelson, J. L.; Trivedi, R.; Gibbs, R. A.; De, S. K.
Tetrahedron Lett. 2005, 46, 9029–9034; (e) Ollevier, T. N. E. Tetrahedron Lett.
2008, 49, 1546–1550.
1. (a) Connon, S. J. Synlett 2009, 354–376; (b) Dondoni, A.; Massi, A. Angew. Chem.,
Int. Ed. 2008, 47, 4638–4660; (c) Yu, X.; Wang, W. Chem. Asian. J. 2008, 3, 516–
532; (d) Connon, S. J. Chem.dEur. J. 2006, 12, 5418–5427; (e) Wittkopp, A.;
Schreiner, P. R. Chem.dEur. J. 2003, 9, 407–414.
2. Rink, R.; Kingma, J.; Spelberg, J. H. L.; Janssen, D. B. Biochemistry 2000, 39,
5600–5613.
3. (a) Curran, D. P.; Kuo, L. H. J. Org. Chem. 1994, 59, 3259–3261; (b) Curran, D. P.;
Kuo, L. H. Tetrahedron Lett. 1995, 36, 6647–6650; (c) Sigman, M. S.; Jacobsen, E.
N. J. Am. Chem. Soc. 1998, 120, 4901–4902; (d) Schreiner, P. R.; Wittkopp, A. Org.
Lett. 2002, 4, 217–220.
4. (a) Kleiner, C. M.; Schreiner, P. R. Chem. Commun. 2006, 4315–4317; (b) Bonollo, S.;
Fringuelli, F.; Pizzo, F.; Vaccaro, L. Green Chem. 2006, 8, 960–964; (c) Weil, T.;
Kotke, M.; Kleiner, M.; Schreiner, P. R. Org. Lett. 2008, 10, 1513–1516.
5. Azizi, N.; Saidi, M. R. Org. Lett. 2005, 7, 3649–3651.
6. Fleming, E. M.; Quigley, C.; Rozas, I.; Connon, S. J. J. Org. Chem. 2008, 73, 948–956.
7. (a) Alikhani, V.; Beer, D.; Bentley, D.; Bruce, I.; Cuenoud, B. M.; Fairhurst, R. A.;
Gedeck, P.; Haberthuer, S.; Hayden, C.; Janus, D.; Jordan, L.; Lewis, C.; Smithies, K.;
Wissler, E. Bioorg. Med. Chem. Lett. 2004, 14, 4705–4710; (b) Ruediger, E.; Martel,
A.; Meanwell, N.; Solomon, C.; Turmel, B. Tetrahedron Lett. 2004, 45, 739–742; (c)
Zhu, S.; Meng, L.; Zhang, Q.; Wei, L. Bioorg. Med. Chem. Lett. 2006, 16, 1854–1858;
(d) Yamaguchi, T.; Harada, N.; Ozaki, K.; Hashiyama, T. Tetrahedron Lett. 1998, 39,
5575–5578; (e) Moore, W. J.; Luzzio, F. A. Tetrahedron Lett. 1995, 36, 6599–6602;
(f) Lindsay, K. B.; Pyne, S. G. Tetrahedron 2004, 60, 4173–4176; (g) Mori, K.; Sa-
kakibara, M.; Okada, K. Tetrahedron 1984, 40, 1767–1781; (h) O’Brien, P. Angew.
15. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A.
J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G.
A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.;
Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Fores-
man, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov,
B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; 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.; Gonzalez, C.; Pople, J. A. In Gaussian
03, Revision E.01; Gaussian, Inc.: Wallingford CT, 2004.
16. Scott, A. P.; Radom, L. J. Phys. Chem. 1996, 100, 16502–16513.
17. (a) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. Rev. 2002, 88, 899–926;
(b) Reed, A. E.; Weinstock, R. B.; Weinhold, F. J. Chem. Phys. 1985, 83,
735–746.