Conformational change in a urea catalyst induced by sodium cation and its effect on enantioselectivity of a Friedel-Crafts reaction

Article abstract of DOI:10.1016/j.tet.2014.03.068

While developing bis-camphorsulfonyl urea as a hydrogen-bonding catalysts, we discovered that the native conformation of the catalyst is unsuitable for inducing enantioselectivity. By complexing the catalyst with weakly Lewis acidic sodium cations, we wer

Full text of DOI:10.1016/j.tet.2014.03.068

Tetrahedron 70 (2014) 3459e3465
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Conformational change in a urea catalyst induced by sodium cation
and its effect on enantioselectivity of a FriedeleCrafts reaction
Arjun K. Chittoory a, Gayatri Kumari c, Sudip Mohapatra c, Partha P. Kundu c,
,
c
,
b,
*
Tapas K. Maji c , Chandrabhas Narayana , Sridhar Rajaram
*
*
a New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur-P.O., Bangalore 560064, India
b International Centre for Materials Science, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur-P.O., Bangalore 560064, India
c Chemistry and Physics of Materials Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur-P.O., Bangalore 560064, India
a r t i c l e i n f o
a b s t r a c t
Article history:
While developing bis-camphorsulfonyl urea as a hydrogen-bonding catalysts, we discovered that the
native conformation of the catalyst is unsuitable for inducing enantioselectivity. By complexing the
catalyst with weakly Lewis acidic sodium cations, we were able to change the conformation of the
catalyst and attain a significant improvement in the selectivity. We provide structural information from
X-ray crystallography to show that the uncomplexed catalyst is indeed in an unfavorable conformation.
Infrared and Raman spectroscopic studies show that sodium binds the catalyst through the carbonyl and
sulfonyl groups. Simulated IR and Raman spectra match well with the experimentally recorded spectra,
thereby corroborating the proposed conformational change. This result shows that weak Lewis acids can
be used to tune the conformation of hydrogen-bonding catalysts and enhance the selectivity of reaction
catalyzed by these systems.
Received 24 January 2014
Received in revised form 13 March 2014
Accepted 19 March 2014
Available online 28 March 2014
Keywords:
Sulfonyl urea
Hydrogen-bonding catalysts
Conformational control
IR and Raman spectroscopy
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
Sigman group23,24 and the Luo and Cheng groups25 have shown
that the acidity of the hydrogen bond donor can be directly corre-
The conformation of a hydrogen-bonding catalyst is an impor-
tant determinant of the selectivity in the reactions catalyzed by
them.1e6 Modulating the conformational equilibrium will have
a significant impact on the outcome of reactions catalyzed by these
systems. This is usually accomplished by structural modifications to
the catalyst that will engender the required conformational
biasing.7e11 An alternative to this approach is the use of an additive
that will enforce conformational rigidity. During the development
of a bis-sulfonyl urea catalyst, we discovered that the weakly Lewis
acidic sodium cation can bind to Lewis basic sites on the urea. This
results in a change in the conformation of the catalyst and an en-
hancement in the selectivity of the reactions catalyzed by this
system. Conformational change upon sodium binding is supported
by structural studies and theoretical calculations. In nature, a sim-
ilar approach is seen in zinc finger proteins, wherein a zinc cation is
used to stabilize protein conformation.12 Metal coordination that
provides rigid scaffolding to ligands is also seen in the case of fer-
rocenyl phosphine ligands.13e15
lated to reactivity as well as selectivity. More recently, work from
the Schreiner group has shown that the acidity of the donor can be
correlated to the turnover frequency.26 Similarly, the Ellman group
has developed acidic sulfinamide based catalysts for hydrogen-
bond-promoted reactions.27e31 Inspired by these examples, we
decided to explore the use of a C2 symmetric sulfonyl urea (3,
Scheme 1) as a potential catalyst for hydrogen-bond-promoted
reactions. The pKas of N-acyl sulfonamides have been reported to
be around two.32e34 Therefore, we expected the sulfonyl urea 3 to
be a selective hydrogen-bonding catalyst. In order to realize the
potential of 3, we had to first overcome the inherent conforma-
tional bias that prevented good selectivity. We achieved this by
using a weakly Lewis acidic sodium cation. Structural studies based
on IR and Raman spectroscopy reveal that the sodium cation binds
to the oxygen atoms of the carbonyl group and sulfonyl group. The
IR and Raman spectra were simulated from the proposed structure
and this correlated with the experimentally obtained spectra. Lewis
acid coordination to achiral ureas has been explored previously by
the Smith and Mattson groups. This lead to enhanced acidity and
turnover frequency.35e41 To the best of our knowledge, our work is
the first example where a Lewis acid has been used to enhance the
enantioselectivity of a chiral urea catalyzed reaction. Controlling
the conformation of catalysts in this manner should be a broadly
applicable strategy.
Hydrogen-bond-promoted catalysis has been developed over
the last 15 years by several research groups.16e22 Studies from the
* Corresponding authors. Tel.: þ91 080 2208 2826 (T.K.M.); tel.: þ91 080 2208
2810 (C.N.); tel.: þ91 080 2208 2560 (S.R.); e-mail addresses: tmaji@jncasr.ac.in (T.
K. Maji), cbhas@jncasr.ac.in (C. Narayana), rajaram@jncasr.ac.in (S. Rajaram).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.068

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A.K. Chittoory et al. / Tetrahedron 70 (2014) 3459e3465
nitrostyrene binds the urea 3, the bias-inducing camphor groups
will be away from the incipient chiral center, thereby supporting
our hypothesis.
Conformational locking due to dipoleedipole repulsion has
been invoked as the driving force for face selection in the Evans
aldol reaction.44 Alternatively, the dipoles can be brought into
a syn-periplanar orientation by coordination to the Lewis acidic
center that holds the enolate and the aldehyde as seen in the
Crimmins aldol reaction.45e47 As a result, there is a reversal of face
selection. Inspired by this precedent, we hypothesized that a weak
Lewis acid like Naþ would be able to coordinate the oxygen atoms
on the carbonyl and sulfonyl via a six-membered chelate (Scheme
3). The formation of a chelate should in turn push the camphor
groups toward the hydrogen bond donors. Binding of nitrostyrene
in this conformation would ensure that the bias-inducing camphor
groups are closer to the incipient chiral center.
Scheme 1. Synthesis of bis-camphorsulfonyl urea.
2. Results and discussion
Our studies began with the synthesis of bis-camphorsulfonyl
urea (3) in a single step from camphor sulfonamide and tri-
phosgene (Scheme 1). The urea 3 was isolated after a simple ex-
tractive work up followed by recrystallization and the reactions
could be performed on a 1 g scale. To evaluate our catalyst, we
decided to pursue the previously described enantioselective Frie-
deleCrafts reaction of nitrostyrene with pyrrole.42,43 Under the
conditions described in Scheme 2 (panel A), we obtained the
product with low selectivity. A control reaction in the absence of
catalyst showed very little background reaction. We hypothesized
that the lack of selectivity may be due to an unfavorable confor-
mation in which the chiral elements in the catalyst are away from
the incipient chiral center (Scheme 2, panel B). The oxygens on the
carbonyl and sulfonyl groups bear partial negative charges and the
dipoleedipole repulsion between these groups is expected to push
them away from each other. This would put the chiral camphor
groups away from the hydrogen bond donors. When nitrostyrene
binds the urea 3 in this conformation, the camphor groups will be
away from the incipient chiral center. Therefore, the camphor
groups are not able to induce bias in the approach of pyrrole toward
either face of the nitrostyrene, thereby resulting in poor selectivity.
To verify this, we grew single crystals of the catalyst and de-
termined the solid state structure using X-ray diffraction (Scheme
2, panel C).
Scheme 3. Proposed change in conformation due to sodium binding.
To test this hypothesis we added 2 equiv of sodium tetraphe-
nylborate with respect to urea 3 to the FriedeleCrafts reaction. A
reversal in face selection was observed along with a slight im-
provement in the enantioselectivity (Table 1, entry 1). Encouraged
by this initial result, we screened tetraphenylborate salts of other
alkali metals along with magnesium bromide etherate (Table 1).
However, the reactions with other alkali metal ions were very slow
and the selectivity did not improve. In the case of magnesium
bromide the reactions were completed immediately with little
selectivity. Control reactions showed that magnesium bromide
etherate can catalyze the rapid reaction of nitrostyrene and pyrrole.
On the other hand, there was very little background reaction in the
presence of NaBPh4. This implied that only weak Lewis acids should
be used for the successful implementation of our idea, as strong
Lewis acids may catalyze rapid background reaction. Addition of
1 equiv of NaBPh4 (with respect to urea 3), did not lead to sub-
stantial improvements in the selectivity.48 This shows that 2 equiv
of sodium cation are required.
A
B
Table 1
Screen of metal salts
C
Entry
Additive
Time (h)
% Yield
% ee
1
2
3
4
5
6
NaBPh4
LiBPh4
KBPh4
RbBPh4
CsBPh4
MgBr2$Et2O
36
72
90
102
102
0.5
69
60
77
76
66
62
16 (S)
3 (S)
15 (R)
15 (R)
15 (R)
2 (R)
Scheme 2. (A) Initial result for FriedeleCrafts reaction catalyzed by 3. (B) Proposed
conformational equilibrium. (C) Crystal structure of urea 3.
The crystal structure revealed that one of the sulfonyl oxygens
(O2 and O4) in each of the sulfonyl groups is in an anti-periplanar
orientation (177.5ꢀ and 174.3ꢀ) with respect to the urea carbonyl
group. The other oxygen (O1 and O3) is in a gauche-like orientation
in each case (49.2ꢀ and 47.2ꢀ, respectively). Notably, each of the
camphor groups is also in a gauche-like conformation with respect
to the urea carbonyl (56.3ꢀ and 59.3ꢀ). This suggests that when
Based on these results, we decided to further optimize the re-
action that used 2 equiv of NaBPh4 (with respect to urea 3) as
the additive. NaBPh4 is poorly soluble in chlorobenzene. We

A.K. Chittoory et al. / Tetrahedron 70 (2014) 3459e3465
3461
Table 3
hypothesized that this might lead to incomplete complexation and
Scope of FriedeleCrafts reaction
optimized the conditions for dissolution and complexation of
NaBPh4. Under our optimized conditions, we were able to obtain
the product 6 in 64% ee (S-isomer). In the absence of NaBPh4 under
otherwise identical conditions, we obtained 15% ee (R-isomer) from
our reaction. This clearly showed that the addition of NaBPh4 had
a beneficial effect on the selectivity of the reaction. To show that
this is indeed generally the case for this catalyst system, we eval-
uated the reaction of other nitrostyrenes with pyrrole and
indole49e54 as the nucleophiles (Table 2) and obtained products
7e10. In each of the cases, there was a clear enhancement of se-
lectivity in the presence of NaBPh4 along with a reversal of face
selection.
Table 2
Comparison of reactions with and without NaBPh4
Product
Timea
h
% Yielda,b
% ee without
NaBPh4
% ee with
NaBPh4
frequency is detectable and is a significant indicator for structural
changes. Binding of sodium cations with the Lewis basic sites on the
catalyst is expected to change the stretching frequency of the bonds
associated with the Lewis basic atoms. The infrared and Raman
spectrum of urea 3 is shown in Fig. 1 (panel A and panel B). A de-
tailed assignment of the IR and Raman spectra is included in the
Supplementary data. Here, we will focus our discussion on the
carbonyl and sulfonyl group frequencies for elucidation of the
conformation. Based on our density functional theory (DFT) cal-
culations57 and the previously reported spectrum of a similar
compound,58 we assigned the mode at 1747 cmꢁ1 to the keto car-
bonyl of camphor and the shoulder at 1706 cmꢁ1 to the urea car-
bonyl. The calculated values of these modes appear at 1760 and
1712 cmꢁ1, respectively. We then recorded the IR spectrum of the
ureaeNaBPh4 complex (3a). In this spectrum the shoulder at
1706 cmꢁ1 disappeared. Instead, a peak around 1620 cmꢁ1 was
observed along with two shoulders. Curve fitting analysis with
c
b,c
6
7
8
9
36 (60)
78 (96)
65 (138)
25 (55)
58 (114)
89 (87)
86 (78)
89 (78)
93 (97)
60 (93)
15 (R)
10 (R)
11 (R)
7 (S)
64 (S)
72 (S)
56 (S)
66 (R)
66 (R)
10
4 (S)
Conditions for reactions with and without NaBPh4: pyrrole or indole (3 equiv),
Na2SO4 (2.5 equiv), nitroalkene (0.56 M). Enantiomeric excess (ee) was measured by
HPLC using a chiral stationary phase. See Supplementary data for details.
a
Values in the parentheses corresponds to results without NaBPh4.
Average of three runs.
Configuration of major isomer was assigned by comparing values from
b
c
literature.55,56
We evaluated the substrate scope of this reaction with various
nitroalkenes (Table 3). Aryl groups with electron donating and
electron withdrawing moieties worked well in this reaction.
However, nitroalkenes with alkyl substituents performed poorly in
the reaction (Table 3, 16 and 17). Next, we sought to clarify the role
of NaBPh4 in enhancing the selectivity of the test reaction. The
sodium complex turned out to be poorly soluble and attempts at
obtaining single crystals suitable for X-ray diffraction studies failed.
The poor solubility also hindered our efforts to obtain NMR spectra
of the complex. Therefore, we sought to study the structure of the
sodium complex using IR and Raman spectroscopy. Vibrational
spectroscopy is a highly sensitive tool for studying complexation.
Subtle changes in the structure, coordination, bond lengths, and
bond angles can cause small to large changes in vibrational spectra
(IR and Raman spectra). These techniques are used commonly for
assessing such changes. A shift of few wavenumbers in the
Lorentzian functions reveals the appearance of a peak at 1602 cmꢁ1
,
which we assigned to the urea carbonyl complexed with sodium.
This overlaps with the OeH bending region of water. To confirm our
assignment, we used DFT to calculate the IR spectrum of our pu-
tative complex.57 Here the sodium bound carbonyl mode appears at
1610 cmꢁ1, thereby confirming our assignment of the experimental
spectrum. Thus the shift of around 100 cmꢁ1, observed in IR spec-
trum, is well reproduced in the theoretical calculations, which
predicted a shift of 102 cmꢁ1 (Fig. 1, panel C).57 In the Raman
spectra of urea 3 (Fig. 1, panel B), the stretching frequencies of the
urea carbonyl and the keto carbonyl are seen at 1708 cmꢁ1 and
1755 cmꢁ1, respectively. In the complex 3a, the 1708 cmꢁ1 mode
disappears. The expected mode around 1600 cmꢁ1 is masked by the

3462
A.K. Chittoory et al. / Tetrahedron 70 (2014) 3459e3465
Fig. 1. (A) Infrared spectra of 3 and 3a. (B) Raman spectra of 3 and 3a. (C) Calculated infrared spectra for 3 and 3a in the C]O stretching region. Inset shows a part of the optimized
structure of 3a. Color representation: whitedhydrogen, graydcarbon, bluednitrogen, reddoxygen, yellowdsulfur, and violetdsodium.
phenyl ring modes of NaBPh4. This clearly showed that the urea
carbonyl is bound to the sodium cation. The sulfonyl stretching
modes in the IR spectrum of urea 3 are seen at 1344 cmꢁ1 (anti-
symmetric) and 1139 cmꢁ1 (symmetric).59,60 Upon complexation,
we observed a sulfonyl mode at 1340 cmꢁ1, which we assigned to
the sodium bound sulfonyl oxygen. Since the symmetric stretching
mode of sulfonyl group in the complex overlaps with tetraphe-
nylborate modes, we were unable to make a clear assignment. In
our DFT calculation, the sulfonyl modes in urea 3 appear at
1303 cmꢁ1 and 1079 cmꢁ1, which shifts upon complexation to 1294
and 1069 cmꢁ1, respectively. Correlation between experimental
and theoretical spectra supports the coordination of sodium to the
sulfonyl oxygen. In the Raman spectrum, the sulfonyl antisym-
metric stretch of urea 3 is seen at 1303 cmꢁ1, which shifts to
1290 cmꢁ1 upon complexation, whereas calculations show a shift
of 5 cmꢁ1. Disagreement between the theory and experimental
value could most probably be due to the fact that in the calculation
we considered a single molecule in gas phase. This ignores the
intermolecular interactions present in real system. The calculations
could be possibly improved by the inclusion of the counter anions
(tetraphenylborate), whose relative position with the catalyst is not
known experimentally. As a control, we have simulated the infrared
spectra for other possible conformations using a lower level theory
(B3LYP/6-31G(d), see Supplementary data, Table S3). The simulated
and experimental spectra did not match well for these conforma-
tions. We have also simulated the structure of a single sodium
complexed to urea (B3LYP/6-31G(d,p), Supplementary data, Table
S4). Again a poor correlation was observed with experimentally
recorded spectrum. Overall the best match was seen between the
experimental and simulated spectra for the conformation shown in
Fig. 1 (panel C) wherein two sodium cations are bound to the urea
carbonyl.61e64 This substantiates our hypothesis that the sodium
cation forms a complex through coordination of the oxygens on the
urea carbonyl and sulfonyl groups. As a result, the camphor groups
should be closer to the hydrogen bond donors as shown in Scheme
3. When nitroalkenes bind the catalyst in this conformation, the
incipient stereocenter is closer to the bias-inducing cam-
phorsulfonyl groups, thereby resulting in greater enantioselection.
results in lower enantioselectivity. Reducing the conformational
mobility is therefore a key principle in the design of novel hydro-
gen-bonding catalysts. This is often accomplished by increasing the
structural complexity of the catalyst. As shown here, conforma-
tional freedom can also be restricted by using weak Lewis acids to
bind Lewis basic sites on the catalyst. Based on our initial study of
a FriedeleCrafts reaction, we conjectured that the urea was locked
in an unfavorable conformation. By complexing with NaBPh4, we
were able to enhance the enantioselectivity of the reaction. Infrared
and Raman studies showed that the urea binds the sodium cation
through the carbonyl and sulfonyl oxygens. Calculation of the ex-
pected IR and Raman spectra from our optimized structure yielded
spectra that closely match with the experimentally obtained one.
This further supports the idea that complexation with sodium locks
the catalyst in a more favorable conformation for enantioselection.
The generality of this approach is currently under evaluation.
4. Experimental section
4.1. General
All glassware was dried overnight in an oven prior to use. Re-
actions were carried out under argon atmosphere using standard
Schlenk techniques. Reactions were monitored by thin layer chro-
matography (TLC) using TLC silica gel plates. Flash chromatography
was performed using silica gel 230e400 mesh. Unless otherwise
noted all reagents were used as received from commercial suppliers
without further purification. Anhydrous dichloroethane and chlo-
robenzene were purchased and used directly for reactions. DMAP
was recrystallized from toluene. Triethylamine and benzene were
distilled from CaH2 prior to use. Analytical grade Na2SO4 was
crushed and dried at 600 ꢀC for 6e7 h under inert atmosphere and
used in the reactions. Analytical grade cyclohexane, dichloro-
methane, and toluene were used for recrystallization. Grease free
solvents were obtained by distillation and used for chromatogra-
phy. Infrared spectra were recorded using an FTIR spectrometer.
Sample pellets for IR spectroscopic studies were prepared by
mixing a few milligrams of compound with dry KBr. 1H and 13C
NMRs were recorded on a 400 MHz Fourier transform NMR spec-
trometer. Chemical shifts are reported in parts per million (ppm)
with respect to the residual undeuterated solvent in CDCl3
3. Conclusions
In conclusion, we have synthesized a novel bis-sulfonyl urea as
a catalyst for enantioselective reactions. The simplicity of the syn-
thesis should allow the wide application of this urea for a variety of
hydrogen-bond-promoted reactions. Currently, we are examining
the use of this catalyst for other reactions. The conformational
flexibility of hydrogen-bonding catalysts leads to smaller free en-
ergy differences between diastereomeric transition states, which
(
d
¼7.27 ppm) at room temperature. 13C NMRs were recorded at
100 MHz using proton decoupling. Chemical shifts are reported
with respect to the deuterated solvent in CDCl3
(CD3)2CO (
using Q-TOF spectrometer. Melting points were recorded using an
electrothermal capillary melting point apparatus and are un-
corrected. Camphor sulfonamide65 and nitro olefins66 were
(
d
¼77.16 ppm) or
d
¼29.84 ppm) at room temperature. HRMS was recorded

A.K. Chittoory et al. / Tetrahedron 70 (2014) 3459e3465
3463
synthesized using previously reported procedures. Compounds
6e8,67 9e10,56 11,67 12e14,68 15e16,67 and 1768 have been reported
previously in the literature. Crystallographic data for the structure
of 3 have been deposited with the Cambridge Crystallographic Data
Centre (CCDC 943949).
of chlorobenzene was added. The contents were stirred at room
temperature for 45 min (NOTE: a slow stir rate was used to avoid
deposition of solids above the solvent level). The tube was cooled to
ꢁ20 ꢀC, stirred for 45 min, and a solution of pyrrole in chloroben-
zene (4.03 M, 500
mL, 2 mmol) was added. After completion of
reaction (by TLC), the product was purified by column chroma-
tography on silica gel to yield 127 mg of 6 as a pale yellow solid
(Yield: 88%, Average yield: 89% over three runs). Rf: 0.50 in 20%
4.2. Synthesis of urea catalyst (3)
Camphor sulfonamide (2.35 g, 10.2 mmol) and DMAP (1.24 g,
10.2 mmol) were weighed into a 100 mL 2-neck flask and the flask
was flushed with argon. To this, benzene (25 mL) and triethylamine
(1.42 mL, 10.2 mmol) were added. In a separate flask, triphosgene
(502 mg, 1.7 mmol, equivalent to 5.1 mmol of phosgene) was dis-
solved in benzene (25 mL) under argon and cannulated dropwise in
to the flask containing camphor sulfonamide at 0 ꢀC. After com-
pletion of addition, the reaction mixture was slowly warmed to
40 ꢀC and stirred for 2 h (reaction mixture was a milky white
suspension). The temperature was then raised to 80 ꢀC and the
contents were stirred for 48 h (precipitation of a white solid was
observed as the reaction progressed). It was then cooled to 0 ꢀC and
quenched by dropwise addition of 4 M HCl in dioxane (7 mL) fol-
lowed by stirring for 12 h. The contents were then diluted with
ethyl acetate (w75 mL) and washed with 1 M HCl (3ꢂ75 mL). The
organic layer was extracted with saturated NaHCO3 until all of the
catalyst was extracted in to the aqueous layer (checked by TLC). The
aqueous layer was separated and washed with ethyl acetate. After
acidification with 1 M HCl, it was extracted with dichloromethane
(3ꢂ100 mL). The organic layers were combined, dried over Na2SO4,
and concentrated. The residue (1.58 g) was dissolved in a mixture of
toluene (17.8 mL) and dichloromethane (5.4 mL). After transferring
to a Schlenk tube, the solution was layered with cyclohexane
(30 mL) and crystals of 3 (1.08 g) were collected by filtration after 10
EtOAc/hexanes. Enantiomeric excess (ee)¼65% (Average ee¼64%
ꢁ36.8 (c 0.1, CH2Cl2). 1H NMR (400 MHz,
25
over three runs). [
a
]
D
CDCl3) d 7.84 (br s, 1H, NH), 7.39e7.30 (m, 3H, Harom), 7.26e7.24 (m,
2H, Harom), 6.70 (ddd, J¼2.7, 2.7, 1.5 Hz, 1H, Hpyrrole), 6.19e6.17 (m,
1H, Hpyrrole), 6.11e6.09 (m, 1H, Hpyrrole), 5.00 (dd, J¼12.0, 7.3 Hz, 1H,
O2NCHaHbCH), 4.91 (dd, J¼7.4, 7.4 Hz, 1H, CHCHaHbNO2), 4.82 (dd,
J¼12.0, 7.6 Hz, 1H, O2NCHaHbCH); 13C NMR {1H} (100 MHz, CDCl3)
d
138.1, 129.4, 129.1, 128.3, 128.1, 118.3, 108.8, 106.0, 79.4, 43.1; nmax
(liquid film) 3426,1550,1430,1378, 704 cmꢁ1; HRMS (ESI-TOF) m/z:
[MþH]þ calcd for C12H13N2O2 217.0972; Found 217.0973.
4.3.2. 2-(1-(4-Bromophenyl)-2-nitroethyl)-1H-pyrrole
(7).67 Prepared according to sample procedure using (E)-1-bromo-
4-(2-nitrovinyl)benzene (153 mg, 0.67 mmol) and a solution of
pyrrole in chlorobenzene (4.03 M, 500 mL, 2 mmol) to yield 174 mg
of 7 as a white solid (Yield: 88%, Average yield: 86% over three runs).
Rf: 0.40 in 20% EtOAc/hexanes. Enantiomeric excess¼76% (Average
25
ee¼72% over three runs). [
a
]
ꢁ44.7 (c 0.1, CH2Cl2). 1H NMR
D
(400 MHz, CDCl3)
d
7.84 (br s, 1H, NH), 7.49 (dt, J¼8.9, 2.2 Hz, 2H,
H
arom), 7.12 (dt, J¼8.8, 2.1 Hz, 2H, Harom), 6.72 (ddd, J¼2.6, 2.6,
1.5 Hz, 1H, Hpyrrole), 6.19e6.17 (m, 1H, Hpyrrole), 6.09e6.07 (m, 1H,
pyrrole), 4.98 (dd, J¼12.2, 7.0 Hz, 1H, O2NCHaHbCH), 4.88 (dd, J¼7.5,
7.5 Hz, 1H, CHCHaHbNO2), 4.79 (dd, J¼12.2, 8.0 Hz, 1H,
O2NCHaHbCH); 13C NMR {1H} (100 MHz, CDCl3)
137.2, 132.4, 129.7,
H
d
days (Yield: 44%, Average yield: 40% over three runs). Mp
128.4, 122.3, 118.6, 108.9, 106.1, 79.0, 42.5; nmax (liquid film) 3433,
24
149e152 ꢀC (dec); Rf: 0.5 in 10% MeOH/CH2Cl2. [
a
]
þ42.0 (c 1,
1550, 1488, 1378, 727 cmꢁ1; HRMS (ESI-TOF) m/z: [MþH]þ calcd for
D
CH2Cl2). Crystallographic data for the structure of 3 have been de-
C12H12BrN2O2 295.0077; Found 295.0073.
posited with the Cambridge Crystallographic Data Centre (CCDC
943949). 1H NMR (400 MHz, CDCl3)
d
9.13 (br s, 2H, NH), 3.97 (d,
4.3.3. 2-(1-(4-Methoxyphenyl)-2-nitroethyl)-1H-pyrrole
(8).67 Prepared according to sample procedure using (E)-1-
methoxy-4-(2-nitrovinyl)benzene (120 mg, 0.67 mmol) and a so-
lution of pyrrole in chlorobenzene (4.03 M, 500 mL, 2 mmol) to yield
151 mg of 8 as a yellow oil (Yield: 92%, Average yield: 89% over three
J¼15.1 Hz, 2H, CHaHbSO2), 3.39 (d, J¼15.1 Hz, 2H, CHaHbSO2), 2.43
(ddd, J¼18.7, 4.4, 3.3 Hz, 2H, CH2exoCO), 2.29 (ddd, J¼14.7, 11.7,
3.7 Hz, 2H, CH2CH2exoCH), 2.15 (dd, J¼4.4, 4.4 Hz, 2H, CH),
2.11e2.02 (m, 2H, CH2exoCquaternary), 1.97 (d, J¼18.7 Hz, 2H,
CH2endoCO), 1.89 (ddd, J¼14.0, 9.3, 4.6 Hz, 2H, CH2CH2endoCH), 1.49
(ddd, J¼12.8, 9.3, 3.8 Hz, 2H, CH2endoCquaternary), 1.07 (s, 6H, Me2C),
runs). Rf: 0.36 in 20% EtOAc/hexanes. Enantiomeric excess¼61%
25
(Average ee¼56% over three runs). [
a
]
D
ꢁ54.0 (c 0.1, CH2Cl2). 1H
0.94 (s, 6H, Me2C); 13C NMR {1H} (100 MHz, CDCl3)
d
216.3, 148.1,
NMR (400 MHz, CDCl3)
d
7.84 (br s, 1H, NH), 7.16 (dt, J¼8.7, 2.6 Hz,
59.2, 52.3, 49.0, 43.1, 42.9, 27.1, 26.3, 20.0, 19.6; nmax (KBr) 1747,
1734,1706, 1482, 1470,1344,1162, 1139,1131 cmꢁ1; HRMS (ESI-TOF)
m/z: [MþH]þ calcd for C21H33N2O7S2 489.1724; Found 489.1726.
2H, Harom), 6.89 (dt, J¼8.8, 2.6 Hz, 2H, Harom), 6.70 (ddd, J¼2.7, 2.7,
1.6 Hz, 1H, Hpyrrole), 6.19e6.16 (m, 1H, Hpyrrole), 6.08e6.06 (m, 1H,
H
pyrrole), 4.98 (dd, J¼11.9, 7.0 Hz, 1H, O2NCHaHbCH), 4.86 (dd, J¼7.5,
7.5 Hz, 1H, CHCHaHbNO2), 4.78 (dd, J¼12.0, 8.1 Hz, 1H,
4.3. Sample procedure for the catalytic enantioselective
O2NCHaHbCH), 3.80 (s, 3H, OMe); 13C NMR {1H} (100 MHz, CDCl3)
FriedeleCrafts reaction
d 159.5, 130.0, 129.4, 129.2, 118.2, 114.7, 108.8, 105.7, 79.6, 55.5, 42.4;
nmax (liquid film) 3418, 2919, 1550, 1511, 1249, 1030, 722 cmꢁ1
;
4.3.1. 2-(2-Nitro-1-phenylethyl)-1H-pyrrole (6).67 Sodium tetra-
phenylborate (253 mg) was weighed in to a 10 mL flask and dried at
80 ꢀC for 1 h under high vacuum. To this, catalyst 3 (180 mg) was
added under argon atmosphere followed by 1,2-dichloroethane
(8.8 mL). The flask was fitted with a condenser and the contents
were refluxed for 1 h at 85 ꢀC with vigorous stirring. It was then
cooled to 45 ꢀC and the solvent was removed by sparging with
argon. The residue was dried under high vacuum for an hour (the
solvent can also be removed using a rotary evaporator. In this case
the vacuum is released using argon). The obtained complex 3a was
used immediately to setup three reactions with different nitro
olefins.
HRMS (ESI-TOF) m/z: [MþH]þ calcd for C13H15N2O3 247.1077;
Found 247.1068.
4. 3. 4. 3-[1-(2-Chlorophenyl)-2-nitroethyl]-1H-indole
(9).56 Prepared according to sample procedure using (E)-1-chloro-
2-(2-nitrovinyl)benzene (123 mg, 0.67 mmol) and indole (235 mg,
2 mmol) to yield 186 mg of 9 as a white viscous oil (Yield: 92%,
Average yield: 93% over three runs). Rf: 0.27 in 20% EtOAc/hexanes.
25
Enantiomeric excess¼67% (Average ee¼66% over three runs). [
a]
D
ꢁ22.9 (c 0.1, CH2Cl2). 1H NMR (400 MHz, CDCl3)
d 8.13 (br s, 1H, NH),
7.46e7.44 (m, 2H, Harom), 7.39e7.37 (m, 1H, Harom), 7.25e7.16 (m,
4H, Harom), 7.15e7.14 (m, 1H, Harom), 7.09 (ddd, J¼8.0, 7.1, 1.0 Hz, 1H,
A dried Schlenk tube was charged with 118 mg of complex 3a
(0.1 mmol), 100 mg of (E)-1-(2-nitrovinyl)benzene (0.67 mmol),
and 245 mg of Na2SO4. The tube was flushed with argon and 820
H
arom), 5.76 (dd, J¼7.8, 7.8 Hz, 1H, CHCHaHbNO2), 5.03 (dd, J¼12.9,
8.6 Hz, 1H, O2NCHaHbCH), 4.98 (dd, J¼12.8, 7.1 Hz, 1H,
mL
O2NCHaHbCH); 13C NMR {1H} (100 MHz, CDCl3)
d
136.6, 136.5,133.9,

3464
A.K. Chittoory et al. / Tetrahedron 70 (2014) 3459e3465
130.2, 129.1, 128.9, 127.4, 126.3, 122.8, 122.1, 120.1, 119.0, 113.2, 111.5,
0.7 Hz, 1H, Harom), 6.86 (dt, J¼9.4, 2.6 Hz, 2H, Harom), 5.15 (dd, J¼8.0,
8.0 Hz, 1H, CHCHaHbNO2), 5.06 (dd, J¼12.3, 7.5 Hz, 1H,
O2NCHaHbCH), 4.91 (dd, J¼12.3, 8.4 Hz, 1H, O2NCHaHbCH), 3.79 (s,
77.8, 38.0; nmax (liquid film) 3420, 3060, 1551, 1378, 744 cmꢁ1
;
HRMS (ESI-TOF) m/z: [MþH]þ calcd for C16H14ClN2O2 301.0738;
Found 301.0731.
3H, OMe); 13C NMR {1H} (100 MHz, CDCl3)
d 159.0, 136.6, 131.3,
128.9, 126.2, 122.8, 121.6, 120.0, 119.1, 114.9, 114.4, 111.5, 79.9, 55.4,
41.0; nmax (liquid film) 3414,1550,1512,1249, 746 cmꢁ1; HRMS (ESI-
TOF) m/z: [MþH]þ calcd for C17H17N2O3 297.1234; Found 297.1230.
4.3.5. 3-[1-Naphth-2-yl-2-nitroethyl]-1H-indole
(10).56 Prepared
according to sample procedure using (E)-2-(2-nitrovinyl)naphtha-
lene (134 mg, 0.67 mmol) and indole (235 mg, 2 mmol) to yield
132 mg of 10 as a gray solid (Yield: 62%, Average yield: 60% over
4.3.9. 3-(2-Nitro-1-phenylethyl)-1H-indole
(14).68 Prepared
three runs). Rf: 0.23 in 20% EtOAc/hexanes. Enantiomeric
according to sample procedure using (E)-1-(2-nitrovinyl)benzene
(100 mg, 0.67 mmol) and indole (235 mg, 2 mmol) to yield 172 mg
of 14 as a light yellow oil (Yield: 96%, Average yield: 95% over three
25
excess¼68% (Average ee¼66% over three runs). [
a
]
D
ꢁ3.3 (c 0.1,
CH2Cl2). 1H NMR (400 MHz, CDCl3)
d
8.12 (br s, 1H, NH), 7.82e7.80
(m, 4H, Harom), 7.51e7.43 (m, 4H, Harom), 7.39e7.37 (m, 1H, Harom),
7.21 (ddd, J¼8.1, 7.1,1.0 Hz,1H, Harom), 7.09e7.05 (m, 2H, Harom), 5.38
(dd, J¼8.0, 8.0 Hz, 1H, CHCHaHbNO2), 5.17 (dd, J¼12.6, 7.5 Hz, 1H,
O2NCHaHbCH), 5.07 (dd, J¼12.6, 8.5 Hz, 1H, O2NCHaHbCH); 13C NMR
runs). Rf: 0.27 in 20% EtOAc/hexanes. Enantiomeric excess¼60%
24
(Average ee¼58% over three runs). [
a]
ꢁ18.9 (c 0.1, CH2Cl2). 1H
D
NMR (400 MHz, CDCl3)
d
8.09 (br s, 1H, NH), 7.46 (dd, J¼8.0, 0.8 Hz,
1H, Harom), 7.39e7.31 (m, 5H, Harom), 7.30e7.25 (m, 1H), 7.21 (ddd,
J¼8.2, 7.2, 1.1 Hz, 1H, Harom), 7.08 (ddd, J¼8.0, 7.1, 1.0 Hz, 1H, Harom),
7.06 (dd, J¼2.5, 0.6 Hz, 1H, Harom), 5.21 (dd, J¼8.0, 8.0 Hz, 1H,
CHCHaHbNO2), 5.09 (dd, J¼12.5, 7.6 Hz, 1H, O2NCHaHbCH), 4.96 (dd,
J¼12.5, 8.4 Hz, 1H, O2NCHaHbCH); 13C NMR {1H} (100 MHz, CDCl3)
{1H} (100 MHz, CDCl3)
d 136.8,136.7,133.6,132.9,128.9,128.0,127.8,
126.54, 126.48, 126.3, 126.2, 125.9, 122.9, 121.9, 120.2, 119.1, 114.5,
111.5, 79.5, 41.8; nmax (liquid film) 3426, 3055,1550,1378, 744 cmꢁ1
;
HRMS (ESI-TOF) m/z: [MþH]þ calcd for C20H17N2O2 317.1285;
Found 317.1286.
d 139.3, 136.6, 129.0, 127.9, 127.7, 126.2, 122.8, 121.7, 120.1, 119.1,
114.6, 111.5, 79.7, 41.7; nmax (liquid film) 3423, 1550, 1456, 1379, 744,
703 cmꢁ1; HRMS (ESI-TOF) m/z: [MþH]þ calcd for C16H15N2O2
267.1128; Found 267.1129.
4.3.6. 2-(1-(Naphthalen-2-yl)-2-nitroethyl)-1H-pyrrole
(11).67 Prepared according to sample procedure using (E)-2-(2-
nitrovinyl)naphthalene (134 mg, 0.67 mmol) and a solution of
pyrrole in chlorobenzene (4.03 M, 500
of 11 as a gray solid (Yield: 87%, Average yield: 88% over three runs).
m
L, 2 mmol) to yield 155 mg
4.3.10. 2-(1-(2-Chlorophenyl)-2-nitroethyl)-1H-pyrrole
(15).67 Prepared according to sample procedure using (E)-1-
chloro-2-(2-nitrovinyl)benzene (123 mg, 0.67 mmol) and a solu-
tion of pyrrole in chlorobenzene (4.03 M, 500 mL, 2 mmol) to yield
152 mg of 15 as a white solid (Yield: 91%, Average yield: 88% over
Rf: 0.40 in 20% EtOAc/hexanes. Enantiomeric excess 83% (Average
25
ee¼82% over three runs). [
a]
ꢁ85.3 (c 0.1, CH2Cl2). 1H NMR
D
(400 MHz, CDCl3)
d
7.86e7.81 (m, 4H, Harom), 7.72 (br s, 1H, NH),
7.55e7.49 (m, 2H, Harom), 7.33 (dd, J¼8.5, 1.8 Hz, 1H, Harom),
three runs). Rf: 0.30 in 10% EtOAc/hexanes. Enantiomeric
24
6.71e6.69 (m, 1H, Hpyrrole), 6.22e6.19 (m, 1H, Hpyrrole), 6.15 (m, 1H,
excess¼52% (Average ee¼50% over three runs). [
a
]
ꢁ51.4 (c 0.1,
D
H
pyrrole), 5.12e5.06 (m, 2H, O2NCHaHbCH, CHCHaHbNO2), 4.94 (dd,
CH2Cl2). 1H NMR (400 MHz, CDCl3)
d 8.00 (br s, 1H, NH), 7.46e7.41
J¼15.2, 10.8 Hz, 1H, O2NCHaHbCH); 13C NMR {1H} (100 MHz, CDCl3)
(m, 1H, Harom), 7.26e7.23 (m, 2H, Harom), 7.17e7.12 (m, 1H, Harom),
6.73 (ddd, J¼2.7, 2.7, 1.5 Hz, 1H, Hpyrrole), 6.20e6.18 (m, 1H, Hpyrrole),
d
135.4, 133.5, 133.1, 129.4, 129.0, 128.0, 127.9, 127.1, 126.8, 126.6,
125.5, 118.5, 108.9, 106.0, 79.2, 43.2; nmax (liquid film) 3430, 1550,
1377, 749, 726 cmꢁ1; HRMS (ESI-TOF) m/z: [MþH]þ calcd for
6.15e6.13 (m, 1H,
H
pyrrole), 5.47 (dd, J¼8.8, 6.7 Hz, 1H,
CHCHaHbNO2), 4.95 (dd, J¼13.3, 8.9 Hz, 1H, O2NCHaHbCH), 4.88 (dd,
C
16H15N2O2 267.1128; Found 267.1124.
J¼13.3, 6.6 Hz, 1H, O2NCHaHbCH); 13C NMR {1H} (100 MHz,
(CD3)2CO) d 137.7, 134.2, 130.7, 130.1, 129.8, 128.7, 128.4, 119.1, 108.7,
4. 3. 7. 3-[1-(4-Bromophenyl)-2-nitroethyl]-1H-indole
(12).68 Prepared according to sample procedure using (E)-1-
bromo-4-(2-nitrovinyl)benzene (153 mg, 0.67 mmol) and indole
(235 mg, 2 mmol) to yield 132 mg of 12 as a white solid (Yield: 75%,
107.2, 78.0, 40.2; nmax (liquid film) 3433, 1552, 1377, 1036, 758,
731 cmꢁ1; HRMS (ESI-TOF) m/z: [MþH]þ calcd for C12H12ClN2O2
251.0582; Found 251.0582.
Average yield: 73% over three runs). Rf: 0.27 in 20% EtOAc/hexanes.
4.3.11. 2-(3-Methyl-1-nitrobutan-2-yl)-1H-pyrrole (16).67 Prepared
according to sample procedure using (E)-3-methyl-1-nitrobut-1-
ene (77 mg, 0.67 mmol) and a solution of pyrrole in chloroben-
zene (4.03 M, 500 mL, 2 mmol) to yield 51 mg of 16 as a colorless oil
(Yield: 42%, Average yield: 34% over two runs). Rf: 0.50 in 20%
25
Enantiomeric excess¼76% (Average ee¼72% over three runs). [
a]
D
ꢁ1.3 (c 0.1, CH2Cl2). 1H NMR (400 MHz, CDCl3)
d 8.13 (br s, 1H, NH),
7.46 (dt, J¼8.9, 2.2 Hz, 2H, Harom), 7.42e7.37 (m, 2H, Harom),
7.24e7.20 (m, 3H, Harom), 7.10 (ddd, J¼8.0, 7.1,1.0 Hz,1H, Harom), 7.04
(dd, J¼2.5, 0.6 Hz, 1H,
H
arom), 5.17 (dd, J¼7.9, 7.9 Hz, 1H,
EtOAc/hexanes. Enantiomeric excess¼44% (Average ee¼36% over
CHCHaHbNO2), 5.07 (dd, J¼12.5, 7.3 Hz, 1H, O2NCHaHbCH), 4.92 (dd,
two runs). [
d
a
]
D
þ10.6 (c 0.1, CH2Cl2). 1H NMR (400 MHz, CDCl3)
25
J¼12.5, 8.6 Hz, 1H, O2NCHaHbCH); 13C NMR {1H} (100 MHz, CDCl3)
8.06 (br s, 1H, NH), 6.69 (ddd, J¼2.7, 2.7, 1.5 Hz, 1H, Hpyrrole),
d
138.4, 136.7, 132.2, 129.6, 128.5, 126.0, 123.0, 121.7, 120.3, 118.9,
6.18e6.15 (m, 1H, Hpyrrole), 6.00e5.98 (m, 1H, Hpyrrole), 4.68 (dd,
J¼12.6, 6.1 Hz, 1H, O2NCHaHbCH), 4.59 (dd, J¼12.6, 9.0 Hz, 1H,
O2NCHaHbCH), 3.36 (ddd, J¼9.0, 6.3, 6.3 Hz, 1H, CHCHaHbNO2),
2.03e1.91 (m, 1H, CHMe2), 0.98 (d, J¼6.8 Hz, 3H, Me2CH), 0.91 (d,
114.1,111.6, 79.3, 41.2; nmax (liquid film) 3423,1550,1488, 1378,1011,
744 cmꢁ1; HRMS (ESI-TOF) m/z: [MþH]þ calcd for C16H14BrN2O2
345.0233; Found 345.0231.
J¼6.7 Hz, 3H, Me2CH); 13C NMR {1H} (100 MHz, CDCl3)
d 128.7, 117.2,
4.3.8. 3-[1-(4-Methoxyphenyl)-2-nitroethyl]-1H-indole
(13).68 Prepared according to sample procedure using (E)-1-
methoxy-4-(2-nitrovinyl)benzene (120 mg, 0.67 mmol) and in-
dole (235 mg, 2 mmol) to yield 126 mg of 13 as a white solid (Yield:
63%, Average yield: 60% over three runs). Rf: 0.23 in 20% EtOAc/
hexanes. Enantiomeric excess¼73% (Average ee¼70% over three
108.8, 106.2, 78.4, 44.3, 30.9, 20.8, 19.6; nmax (liquid film) 3422,
2964, 1551, 1381, 721 cmꢁ1; HRMS (ESI-TOF) m/z: [MþH]þ calcd for
C9H15N2O2 183.1128; Found 183.1122.
4.3.12. 3-(3-Methyl-1-nitrobutan-2-yl)-1H-indole (17).68 Prepared
according to sample procedure using (E)-3-methyl-1-nitrobut-1-
ene (77 mg, 0.67 mmol) and indole (235 mg, 2 mmol) to yield
20 mg of 17 as a light yellow oil (Yield: 13%, Average yield: 13% over
two runs). Rf: 0.30 in 20% EtOAc/hexanes. Enantiomeric excess¼24%
runs). [
a
]
24 ꢁ24.8 (c 0.1, CH2Cl2). 1H NMR (400 MHz, CDCl3)
d 8.08
D
(br s, 1H, NH), 7.46e7.44 (m, 1H, Harom), 7.37 (dt, J¼8.1, 0.8 Hz, 1H,
H
arom), 7.26 (dt, J¼9.5, 2.5 Hz, 2H, Harom), 7.21 (ddd, J¼8.2, 7.1, 1.1 Hz,
1H, Harom), 7.09 (ddd, J¼8.0, 7.1, 1.0 Hz, 1H, Harom), 7.04 (dd, J¼2.5,
(Average ee¼22% over two runs). [
a
]
D
25 þ11.5 (c 0.1, CH2Cl2). 1H NMR

A.K. Chittoory et al. / Tetrahedron 70 (2014) 3459e3465
3465
26. Jakab, G.; Tancon, C.; Zhang, Z.; Lippert, K. M.; Schreiner, P. R. Org. Lett. 2012, 14,
1724e1727.
27. Kimmel, K. L.; Weaver, J. D.; Lee, M.; Ellman, J. A. J. Am. Chem. Soc. 2012, 134,
9058e9061.
28. Kimmel, K. L.; Robak, M. T.; Thomas, S.; Lee, M.; Ellman, J. A. Tetrahedron 2012,
68, 2704e2712.
29. Robak, M. T.; Herbage, M. A.; Ellman, J. A. Tetrahedron 2011, 67, 4412e4416.
30. Kimmel, K. L.; Robak, M. T.; Ellman, J. A. J. Am. Chem. Soc. 2009, 131, 8754e8755.
31. Robak, M. T.; Trincado, M.; Ellman, J. A. J. Am. Chem. Soc. 2007, 129, 15110e15111.
32. Yates, M. H.; Kallman, N. J.; Ley, C. P.; Wei, J. N. Org. Process Res. Dev. 2009, 13,
255e262.
33. Lobb, K. L.; Hipskind, P. A.; Aikins, J. A.; Alvarez, E.; Cheung, Y.-Y.; Considine, E.
L.; De Dios, A.; Durst, G. L.; Ferrito, R.; Grossman, C. S.; Giera, D. D.; Hollister, B.
A.; Huang, Z.; Iversen, P. W.; Law, K. L.; Li, T.; Lin, H.-S.; Lopez, B.; Lopez, J. E.;
Cabrejas, L. M. M.; McCann, D. J.; Molero, V.; Reilly, J. E.; Richett, M. E.; Shih, C.;
Tiecher, B.; Wikel, J. H.; White, W. T.; Mader, M. M. J. Med. Chem. 2004, 47,
5367e5380.
(400 MHz, CDCl3)
d 8.08 (br s, 1H, NH), 7.63e7.61 (m, 1H, Hindole),
7.39e7.36 (m, 1H, Hindole), 7.21 (ddd, J¼8.1, 7.1, 1.1 Hz, 1H, Hindole),
7.14 (ddd, J¼8.0, 7.2, 1.1 Hz, 1H, Hindole), 7.03 (d, J¼2.4 Hz, 1H, Hin-
dole), 4.81 (dd, J¼12.0, 6.3 Hz, 1H, O2NCHaHbCH), 4.73 (dd, J¼12.0,
9.1 Hz, 1H, O2NCHaHbCH), 3.69 (ddd, J¼9.1, 6.7, 6.7 Hz, 1H,
CHCHaHbNO2), 2.25e2.13 (m, 1H, CHMe2), 1.02 (d, J¼6.8 Hz, 3H,
Me2CH), 0.94 (d, J¼6.7 Hz, 3H, Me2CH); 13C NMR {1H} (100 MHz,
CDCl3) d 136.4,127.0,122.4,122.2,119.8,119.2,113.4,111.5, 78.8, 42.7,
30.8, 20.8, 20.2; nmax (liquid film) 3420, 2962, 1550, 1383, 743 cmꢁ1
;
HRMS (ESI-TOF) m/z: [MþH]þ calcd for C13H17N2O2 233.1285;
Found 233.1284.
Acknowledgements
34. Wright, J. B.; Willitte, R. E. J. Med. Chem. 1962, 5, 815e822.
35. Nickerson, D. M.; Angeles, V. V.; Auvil, T. J.; So, S. S.; Mattson, A. E. Chem.
Commun. 2013, 4289e4291.
The authors thank JNCASR and Department of Science and
Technology, Ministry of Science and Technology for funding. A.K.C.,
S.M., and P.P.K. thank Council of Scientific and Industrial Research
for pre-doctoral research fellowships. We gratefully acknowledge
Prof. K.R. Prasad’s help with HPLC measurements for compounds 15
and 17.
36. So, S. S.; Mattson, A. E. J. Am. Chem. Soc. 2012, 134, 8798e8801.
37. Nickerson, D. M.; Mattson, A. E. Chem.dEur. J. 2012, 18, 8310e8314.
38. So, S. S.; Auvil, T. J.; Garza, V. J.; Mattson, A. E. Org. Lett. 2012, 14, 444e447.
39. So, S. S.; Burkett, J. A.; Mattson, A. E. Org. Lett. 2011, 13, 716e719.
40. Hughes, M. P.; Smith, B. D. J. Org. Chem. 1997, 62, 4492e4499.
41. Hughes, M. P.; Shang, M. Y.; Smith, B. D. J. Org. Chem. 1996, 61, 4510e4511.
42. Sheng, Y.-F.; Gu, Q.; Zhang, A.-J.; You, S.-L. J. Org. Chem. 2009, 74, 6899e6901.
43. Liu, H.; Lu, S.-F.; Xu, J.; Du, D.-M. Chem.dAsian J. 2008, 3, 1111e1121.
44. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127e2129.
45. Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem. 2001, 66,
894e902 For other examples of dipoleedipole repulsion in selective reaction
see Refs. 46e47.
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.03.068.
46. Clayden, J.; McCarthy, C.; Westlund, N.; Frampton, C. S. J. Chem. Soc., Perkin
Trans. 1 2000, 1363e1378.
47. Giese, B.; Damm, W.; Wetterich, F.; Zeitz, H.-G. Tetrahedron Lett. 1993, 34,
5885e5888.
48. The obtained selectivity with 1 equiv of NaBPh4 with respect to catalyst is
0% ee.
49. Schafer, A. G.; Wieting, J. M.; Mattson, A. E. Org. Lett. 2011, 13, 5228e5231.
50. Ganesh, M.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 16464e16465.
51. Itoh, J.; Fuchibe, K.; Akiyama, T. Angew. Chem., Int. Ed. 2008, 47, 4016e4018.
52. Fleming, E. M.; McCabe, T.; Connon, S. J. Tetrahedron Lett. 2006, 47, 7037e7042.
53. Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem., Int. Ed. 2005, 44,
6576e6579.
References and notes
1. Lippert, K. M.; Hof, K.; Gerbig, D.; Ley, D.; Hausmann, H.; Guenther, S.;
Schreiner, P. R. Eur. J. Org. Chem. 2012, 5919e5927.
2. Knowles, R. R.; Jacobsen, E. N. Proc. Natl. Acad. Sci. U.S.A. 2010, 107,
20678e20685.
3. Wittkopp, A.; Schreiner, P. R. Chem.dEur. J. 2003, 9, 407e414 For examples of
conformational effects in other organocatalysts see Refs. 4e6.
ꢀ
ꢀ
ꢀ
ꢀ
4. Tarkanyi, G.; Kiraly, P.; Soos, T.; Varga, S. Chem.dEur. J. 2012, 18, 1918e1922.
5. Zimmer, L. E.; Sparr, C.; Gilmour, R. Angew. Chem., Int. Ed. 2011, 50, 11860e11871.
54. Zhuang, W.; Hazell, R. G.; Jørgensen, K. A. Org. Biomol. Chem. 2005, 3,
2566e2571.
€
6. Burgi, T.; Baiker, A. J. Am. Chem. Soc. 1998, 120, 12920e12926.
€
55. Trost, B. M.; Muller, C. J. Am. Chem. Soc. 2008, 130, 2438e2439.
7. Miller, S. J. Acc. Chem. Res. 2004, 37, 601e610.
56. Lu, S.-F.; Du, D.-M.; Xu, J. Org. Lett. 2006, 8, 2115e2118.
8. Greenfield, S. J.; Agarkov, A.; Gilbertson, S. R. Org. Lett. 2003, 5, 3069e3072.
9. Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481e2495.
10. Gilbertson, S. R.; Collibee, S. E.; Agarkov, A. J. Am. Chem. Soc. 2000, 122,
6522e6523.
57. Kundu, P. P. Experimental and Quantum Calculation Studies of Molecular
Systems of Biological and Chemical Importance by Raman, Infrared, and SERS.
Ph.D. Thesis, Jawaharlal Nehru Centre for Advanced Scientific Research, 2014.
58. Meganathan, C.; Sebastian, S.; Sivanesan, I.; Lee, K. W.; Jeong, B. R.; Oturak, H.;
Sudha, S.; Sundaraganesan, N. Spectrochim. Acta, Part A 2012, 95, 331e340.
59. Chandran, A.; Mary, Y. S.; Varghese, H. T.; Panicker, C. Y.; Pazdera, P.; Rajendran,
G.; Babu, N. J. Mol. Struct. 2011, 992, 77e83.
11. Imperiali, B.; Kapoor, T. M. Tetrahedron 1993, 49, 3501e3510.
12. Branden, C.; Tooze, J. Specific Transcription Factors Belong to a Few Families. In-
troduction to Protein Structure, 2nd ed.; Garland Publishing, Taylor & Francis
Group: New York, 1998; pp 175e203.
60. Chohan, Z. H.; Youssoufi, M. H.; Jarrahpour, A.; Hadda, T. B. Eur. J. Med. Chem.
ꢀ
13. Hierso, J.-C.; Beauperin, M.; Meunier, P. Eur. J. Inorg. Chem. 2007, 3767e3780.
2010, 45, 1189e1199.
14. Barbaro, P.; Bianchini, C.; Giambastiani, G.; Parisel, S. L. Coord. Chem. Rev. 2004,
248, 2131e2150.
15. Colacot, T. J. Chem. Rev. 2003, 103, 3101e3118.
61. For an example of a urea carbonyl bound to two sodium cations see: Armen-
tano, D.; De Munno, G.; Rossi, R. New J. Chem. 2006, 30, 13e17 For other ex-
amples see Refs. 62e64.
16. Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713e5743.
17. Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520e1543.
18. Connon, S. J. Chem.dEur. J. 2006, 12, 5418e5427.
19. Pihko, P. M. Angew. Chem., Int. Ed. 2004, 43, 2062e2064.
20. Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289e296 For pioneering earlier work
see Refs. 21e22.
21. Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901e4902.
22. Schreiner, P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217e220.
23. Jensen, K. H.; Sigman, M. S. Angew. Chem., Int. Ed. 2007, 46, 4748e4750.
24. Jensen, K. H.; Sigman, M. S. J. Org. Chem. 2010, 75, 7194e7201.
25. Li, X.; Deng, H.; Zhang, B.; Li, J.; Zhang, L.; Luo, S.; Cheng, J.-P. Chem.dEur. J.
2010, 16, 450e455.
62. Al-Harbi, A.; Sattler, W.; Sattler, A.; Parkin, G. Chem. Commun. 2011, 3123e3125.
€
63. Geier, J.; Harmer, J.; Grutzmacher, H. Angew. Chem., Int. Ed. 2004, 43,
4093e4097.
64. Gilroy, J. B.; Lemaire, M. T.; Patrick, B. O.; Hicks, R. G. CrystEngComm 2009, 11,
2180e2184.
65. Davis, F. A.; Jenkins, R. H.; Awad, S. B.; Stringer, O. D.; Watson, W. H.; Galloy, J. J.
Am. Chem. Soc. 1982, 104, 5412e5418.
66. Kumaran, G.; Kulkarni, G. H. Tetrahedron Lett. 1994, 35, 9099e9100.
67. Guo, F.; Chang, D.; Lai, G.; Zhu, T.; Xiong, S.; Wang, S.; Wang, Z. Chem.dEur. J.
2011, 17, 11127e11130.
68. Lin, S.-Z.; You, T.-P. Tetrahedron 2009, 65, 1010e1016.