Synthesis of Bis(oxazoline) Ligands Possessing C-5 gem-Disubstitution and Their Application in Asymmetric Friedel-Crafts Alkylations

Article abstract of DOI:10.1021/acs.joc.5b01767

A series of eight novel bis(oxazoline) ligands incorporating gem-disubstitution on one of the oxazoline rings were prepared from (S)-valine. These ligands are designed as a cost-effective alternative to similar ligands possessing an oxazolinyl C(5)-tert-b

Full text of DOI:10.1021/acs.joc.5b01767

Article
pubs.acs.org/joc
Synthesis of Bis(oxazoline) Ligands Possessing C‑5 gem-
Disubstitution and Their Application in Asymmetric Friedel−Crafts
Alkylations
Steven O’Reilly, Miriam Aylward, Caoimhe Keogh-Hansen, Brian Fitzpatrick, Helen A. McManus,
Helge Muller-Bunz, and Patrick J. Guiry*
̈
Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin
4, Ireland
S
* Supporting Information
ABSTRACT: A series of eight novel bis(oxazoline) ligands
incorporating gem-disubstitution on one of the oxazoline rings
were prepared from (S)-valine. These ligands are designed as a
cost-effective alternative to similar ligands possessing an
oxazolinyl C(5)-tert-butyl group derived from expensive (S)-
tert-leucine. Four of the ligands possess a C(4)-gem-dimethyl
group and four a C(4)-gem-diphenyl group adjacent to the
C(5)-isopropyl substituent. Zinc complexes of ligands 11a−h,
along with non-C(4)-gem-disubstituted analogues 1a−g, were
effective in the Friedel−Crafts alkylation of both indole (up to
74% ee) and 2-methoxyfuran (up to 95% ee) with a series of
nitroalkenes. Three of the ligands (11a−c), an iron dichloride
complex of ligand 11d and two zinc dichloride complexes,
were characterized by X-ray crystallography, one with ligand 11d and the second a bis-tert-butyl-substituted N-methylamine
ligand. A direct comparison of the latter structures clearly illustrates the gem-dimethyl effect.
amination as the key step, allowed for the preparation of both
C2- and C1-symmetric ligands, with varied substitution patterns
on each of the oxazoline rings. We subsequently applied these
ligands to a range of asymmetric transformations including the
Nozaki−Hiyama−Kishi allylation,7 crotylation,7 methallyla-
tion,8 and the first regio- and enantioselective homoallenylation
of aldehydes.9
Subsequently, we desymmetrized the ligand biaryl backbone
by introducing a thiophene moiety into the structure, making
ligands of type 2, and we also synthesized the first thiazoline−
oxazoline hybrid ligands of type 3 (Figure 1). Ligands of type 2
and 3 were then applied in the asymmetric Nozaki−Hiyama−
Kishi allylation of benzaldehyde10 and the asymmetric Friedel−
Crafts alkylation of indole,11 respectively. In many cases, we
observed that the C1-symmetric ligands induced higher levels of
enantioselectivity than their C2-symmetric analogues.12
The group of Du has since reported an alternative synthetic
approach to 1.13 However, this methodology is limited to the
synthesis of C2-symmetric ligands, while our approach can
furnish both C2- and non-C2-symmetric ligands.6 Du has
subsequently applied metal complexes of 1 in a wide range of
asymmetric transformations such as the Henry reaction of α-
keto esters,14 the Friedel−Crafts alkylation of arenes with
INTRODUCTION
■
Brunner reported the first example of chiral oxazoline-based
ligands in asymmetric catalysis.1 Subsequently, a diverse range
of ligands possessing one, two, or more oxazoline units have
been successfully applied in a wide range of metal-catalyzed
asymmetric reactions.2−5 The vast majority of oxazolines used
are C2-symmetric and are derived from naturally occurring
chiral amino alcohols. This places the C(5)-substituent α- to
the oxazolinyl donor nitrogen atom, thus directly influencing
the levels of asymmetric induction of the metal-catalyzed
reaction.
As part of our program on the design and application in
asymmetric catalysis of metal complexes of bis(oxazoline)
ligands, we reported the convergent synthesis of bis(oxazoline)
ligands of type 1, linked by a phenylaniline unit (Figure 1).6
Our synthetic approach, involving a Buchwald−Hartwig aryl
Received: July 30, 2015
Figure 1. Bis(oxazoline) ligands.
© XXXX American Chemical Society
A
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nitroalkenes,15−18 and the Michael addition of nitroethane to
nitroalkenes.19 Nishiyama has also applied these ligands in the
asymmetric hydrosilylation of ketones and enones,20−22 and Li
and Zhang have recently studied their use in the cationic rare-
earth metal-catalyzed quasi-living polymerization of isoprene23
and the Pd-catalyzed polymerization of norbornene.24
general, metal complexes of C-5 gem-disubstituted ligands
afforded higher levels of enantioselectivity than those with just
an isopropyl group at C-4 and approached that of their tert-
butyl counterpart.
RESULTS AND DISCUSSION
■
With the vast majority of the ligands discussed above, it was
found that one of the substituents on the oxazoline ring had to
be a tert-butyl group in order to obtain high levels of
enantioselectivity for a range of transformations. However,
the high cost of the starting material necessary for the synthesis
of these ligands, tert-leucine, is a serious drawback and therefore
limits the use of such ligands, especially in the case of the (R)-
enantiomer which would be required to provide the opposite
hand of product.25 A cheaper, alternative ligand that could
induce similar levels of enantioselectivity without compromis-
ing catalytic activity would therefore be highly desirable.
The first example of a ligand that could achieve similar levels
of enantioselectivity to a previously superior tert-butyl analogue
was reported by Corey.26 Their bis(oxazoline) ligand replaced
the tert-butyl substituent at C-4 with an isopropyl group in
conjunction with a vicinal gem-dimethyl at the C-5 position and
provided better enantioselectivity than the analogous tert-butyl
ligand (85% vs 82%).27 This gem-disubstitution effect28 was
further applied in many other areas of research,29,30 including
chiral auxiliaries,31−35 phosphinooxazoline (PHOX) li-
gands,36,37 and recently by Paquin,38,39 who explored the
gem-disubstituent effect, again with the PHOX type ligands,40,41
as did Stoltz in a very recent report on an electronically
modified PHOX ligand.42
Ligand Synthesis. Amino alcohols 7a and 7b, prepared
according to a procedure by Denmark,45 were reacted with
benzoyl chloride in the presence of Na2CO3 with vigorous
stirring in a biphasic mixture of H2O and dichloromethane (3:4
ratio) to afford the corresponding amides 8a and 8b in 98% and
93% yields, respectively. Both amides 8a and 8b were then
cyclized under acidic conditions to form the desired
bromoaryloxazolines 9a and 9b in 99% and 83% yields,
respectively. While the cyclization of amide 8a proceeded
smoothly at 40 °C, microwave irradiation was necessary to
promote the cyclization of amide 8b, where the reaction could
be carried out at 60 °C (Scheme 1).
The final step to form the desired ligands 11a−h utilized a
Buchwald−Hartwig aryl amination (Scheme 2).6,46−48 This
Scheme 2. Buchwald−Hartwig Aryl Amination of 9a/b and
10a−d Forming Bis(oxazoline) Ligands 11a−h
We have recently exploited this effect in the design of
oxazoline-containing N,O ligands 4 and P,N ligands 5 and 6,
which were applied with success in the diethylzinc and
ethylphenylzinc addition to aldehydes and the asymmetric
intermolecular Heck reaction, respectively (Figure 2).43,44 In
allowed us to access non-C2-symmetric ligands with various
combinations of substitution patterns on the oxazoline rings in
yields ranging from 40% to 52% (Table 1). The required amino
Table 1. Synthesis of Ligands 11a−h under Palladium
Catalysis with MW Irradiation
a
entry
ligand
R1
R2
yield (%)
1
2
3
4
5
6
7
8
11a
11b
11c
11d
11e
11f
i-Pr
t-Bu
Ph
Me
Me
Me
Me
Ph
49
47
45
52
52
40
45
45
Bn
i-Pr
t-Bu
Ph
Ph
11g
11h
Ph
Bn
Ph
a
Yields after column chromatography.
Figure 2. Recent oxazoline-containing ligands possessing gem-
disubstitution.
Scheme 1. Synthesis of Bromoaryloxazoline Coupling Partners 9a and 9b
B
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coupling partners 10a−d were synthesized via a previously
reported zinc-catalyzed condensation of aminobenzonitrile and
the desired commercially available amino alcohols.11
Table 2. Asymmetric Friedel−Crafts Alkylation of Indole
Using Zinc Complexes of Ligands 11a−h
a
b
a
b
yield
ee
yield
ee
c
Catalytic Asymmetric Friedel−Crafts Reaction. The
Friedel−Crafts (FC) alkylation is a cornerstone reaction in
organic chemistry.49 Extending this reaction to include
electron-deficient alkenes as the alkylating agents has only
been made possible by the employment of Lewis acid
catalysts.50−52 The two reacting partners most widely studied
in the asymmetric Friedel−Crafts variant are indole and
nitroalkenes.11,53−62 The latter possesses one of the strongest
electron-withdrawing groups known, a feature that has also
been exploited in their use as Michael acceptors.63−66 This high
reactivity, allied to the ease of transformation of the nitro group
into a diverse range of functionalities, explains their extensive
application to date in organic synthesis.67−73
c
entry ligand
(%)
(R)
entry ligand
(%)
(R)
1
2
3
4
5
6
7
8
11a
11b
11c
11d
11e
11f
90
95
93
93
94
93
89
85
35
3
9
1a
1b
1c
1d
1e
1f
95
95
89
99
99
97
97
27
d
10
11
12
13
14
15
68
45
67
62
64
74
61
58
13
Rac
44
5
11g
11h
1g
a
b
Yields after column chromatography. Determined by chiral HPLC:
c
Chiralcel IB, (heptane/ethanol 70:30, 0.9 mL/min). Absolute
configuration determined by comparison to literature [α]D.51
d
Literature result included for comparison.15
C2-Symmetrical examples of ligands 1, first synthesized
within our group, were applied by Du in the asymmetric FC
alkylation of indole with trans-β-nitrostyrene achieving high ee’s
of up to 83%15 and in the asymmetric FC alkylation of 2-
methoxyfuran with nitroalkenes, again, achieving high ee’s of up
to 92%.16 As C2-symmetric versions of 1 have induced high
levels of enantioselectivity in both of these transformations they
are ideal reactions to evaluate our novel library of C1-symmetric
ligands 11a−h along with the analogous C1-symmetric ligands
1a−g.6
discarded. However, the study does allow a direct comparison
to be made between related ligands (11a−d vs 1a−d (gem-
dimethylisopropyl vs tert-butyl), entries 1−4 vs 9−12) and
(11e−f vs 1a−d (gem-diphenylisopropyl vs tert-butyl), entries
5−8 vs 9−12). Complexes of ligands 11a and 11c induced
higher levels of enantioselectivity of 35% ee and 61% ee versus
27% ee and 45% ee, respectively (entries 1 and 3 vs entries 9
and 11). The optimal gem-disubstituted ligand was 11c, which
afforded product (14a) in 61% ee, entry 3. Overall, the gem-
diphenyl-substituted ligands induced poor to moderate levels of
enantiodiscrimination (up to 44% ee), which was somewhat
surprising as we had envisaged that the more rigid structural
motif would have been advantageous for enhanced asymmetric
induction. The remaining series of non-C2-symmetric ligands,
1e−g, gave more promising results (62−74% ee), although still
lower than the best result (83% ee) obtained by Du using this
ligand class (R1 = R2 = Ph).15
Our initial optimization and ligand screening, in which we
applied our full range of C1-symmetric ligands, was carried out
in the reaction of indole (12) with trans-β-nitrostyrene (13a)
(Scheme 3). The reactions were carried out using 5 mol % of
Scheme 3. Asymmetric Friedel−Crafts Alkylation of Indole
(12) with trans-β-Nitrostyrene (13a) Using Ligands 1a−g
and 11a−h
However, these promising results prompted us to further test
the ligands in a similar transformation, replacing indole (12)
with 2-methoxyfuran (15). Although 2-methoxyfuran has not
received as much attention as indole (12), its inherent reactivity
makes it a very interesting substrate for this reaction (Scheme
4), and Du had already reported encouraging levels of
enantioselectivities (78−92% ee) with C2-symmetric ligands
of type 1 (R1 = R2 = i-Pr; t-Bu; Ph; Bn).16
Scheme 4. Asymmetric Friedel−Crafts Alkylation of 2-
Methoxyfuran (15) with trans-β-Nitrostyrene (13a) Using
Ligands 1a−g and 11a−h
Zn(OTf)2 and 5 mol % of ligand at −20 °C in toluene, which
were found to be optimal conditions for this type of catalysis in
our previous reports and those of both Zhou and Du.11,15,53,62
However, the reaction time was extended to 40 h in the current
study in order to achieve higher conversion levels.
Zinc complexes of the range of ligands tested in the present
study gave very good to excellent yields (85−97%) of alkylated
product (14a) (Table 2). Unsurprisingly, the levels of
enantioselectivity were highly dependent upon the ligand
substitution pattern, even more so as the ligands are non-C2-
symmetric. The existence of a background reaction due to free
zinc compounds or free triflic acid from hydrolysis cannot be
Gratifyingly, zinc complexes of ligands 11a−d,g and 1a−g
gave good to very high enantioselectivities of up to 90% ee in
this transformation (Scheme 4 and Table 3). A direct
comparison can again be made between related ligands
(11a−d vs 1a−d (gem-dimethylisopropyl vs tert-butyl), entries
1−4 vs 9−12) and (11e−f vs 1a−d (gem-diphenylisopropyl vs
tert-butyl), entries 5−8 vs 9−12). As with indole as substrate,
the gem-diphenyl-substituted ligands (11e−h) gave poor to
moderate yields and very low ee’s, with the exception of ligand
11g, which afforded the alkylated furan (16a) in 69% yield and
C
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studied, and the opposite configuration of the major
enantiomer is due to changes in CIP priority assignments.
In the proposed transition states for the FC alkylation of
indole (12) and 2-methoxyfuran (15) (Figure 3), the two
Table 3. Asymmetric Friedel−Crafts Alkylation of 2-
Methoxyfuran Using Zinc Complexes of Ligands 11a−h
a
b
c
a
b
c
entry ligand yield (%) ee (S) entry ligand yield (%) ee (S)
1
2
3
4
5
6
7
8
11a
11b
11c
11d
11e
11f
65
82
65
88
16
20
69
48
69
81
59
89
7
9
1a
1b
1c
1d
1e
1f
80
73
83
85
66
84
90
83
92
89
90
88
80
87
d
10
11
12
13
14
15
5
11g
11h
70
7
1g
a
b
Yields after column chromatography. Determined by chiral HPLC:
c
Chiralcel IB (heptane,ethanol 90:10, 1.0 mL/min). Absolute
configuration determined by comparison to literature [α]D.53
d
Literature result included for comparison.16
70% ee. Complexes of ligands 11b and 11d induced high levels
of enantioselectivity, although lower than their tert-butyloxazo-
line analogues (1a and 1d), 69% ee and 89% ee versus 83% ee
and 90% ee, respectively (entries 1 and 4 vs entries 9 and 12).
The remaining series of non-C2-symmetric ligands, 1e−g, gave
impressive results (80−90% ee), although still lower than the
best result (92% ee) obtained by Du using this ligand class
(ligand 1b, entry 10).16
It was decided to take the optimal gem-disubstituted ligand,
11d, and investigate a substrate scope in the asymmetric FC
reaction between 2-methoxyfuran and a range of nitroalkenes
(Scheme 5 and Table 4). The enantioselectivities obtained
Figure 3. Proposed transition states for the FC alkylation of indole
(12) and 2-methoxyfuran (15).
oxazolinyl nitrogen atoms are coordinated to the zinc center
and the nitro group of the nitroalkene coordinates through the
two oxygen atoms to the Lewis acid center.74 This activates the
nitroalkene to nucleophilic attack by the electron-rich arene.
The attack happens preferentially at the Si face due to the
influence of the substituents on each of the oxazoline rings,
therefore leading to an enantioenriched product with the (R)-
configuration in the case of indole (12) and (S)-configuration
in the case of 2-methoxyfuran (15). There is potential for π-
stacking between the benzyl substituent and the electron-
deficient alkene, thus promoting Si-facial attack. In contrast to
proposed transition states proposed by Du,15,16 we do not
propose that the NH is involved as a H-bond donor via an
NH···π interaction with indole or 2-methoxyfuran.
Scheme 5. Asymmetric Friedel−Crafts Alkylation of 2-
Methoxyfuran (15) with Substituted Nitroalkenes (13a−g)
Using Optimal Ligand 11d
X-ray Crystal Structural Analysis of the gem-Dimethyl
Effect. In order to determine the effect of the C(4) gem-
disubstitution on the orientation of the adjacent isopropyl
group, crystal structures for the gem-dimethyl-substituted
ligands 11a−c were obtained (Figure 4A−C). As ligand 11d
did not form crystals, we attempted to form a metal complex of
this ligand. All initial attempts to synthesize zinc complexes of
ligands 11a−d failed; however, an iron complex of ligand 11d
was amenable to crystallization and its structure was solved by
X-ray analysis (Figure 4D). The latter complex possesses a
distorted bipyramidal trigonal geometry that would differ
considerably from the expected canonical tetracoordination of
the Zn complex yet was still of interest as it allowed us to
investigate our optimal ligand from the catalytic studies
performed.
While these crystal structures clearly illustrate the gem-
dimethyl effect for three ligands and one metal complex, it is
difficult to extrapolate to rationalizing the results in catalysis
obtained employing zinc complexes of these ligands. Therefore,
we reinvestigated the potential for forming such zinc
complexes. We felt that our initial attempts at forming zinc
complexes were not facilitated by the presence of the NH
group, and hence, we aimed to synthesize the zinc dichloride
complex of the related N-methyl ligands. As a starting point, we
prepared the C2-symmetric N-methyl-bis-tert-butyloxazoline
zinc dichloride complex (18) in 66% yield from the
Table 4. Asymmetric Friedel−Crafts Alkylation of 2-
Methoxyfuran with Nitroalkenes Using Zinc Complex of
Ligand 11d
a
b
c
entry
Ar
product
yield (%)
ee (S)
1
2
3
4
5
6
7
Ph
16a
16b
16c
16d
16e
16f
88
84
75
89
70
68
83
89
92
93
92
4-MeOC6H4
4-BrC6H4
4-MeC6H4
2-furyl
d
89
d
2-thienyl
90
3-ClC6H4
16g
95
a
b
Yields after column chromatography. Enantiomeric excess (ee) was
determined by chiral HPLC: Chiralcel IB, (heptane:ethanol 90:10, 1
c
mL/min). Absolute configuration determined by comparison to
d
literature [α]D.16 (R)-Enantiomer in excess.
ranged between 89 and 95% ee, with yields of 70−89%, with
the optimal substrate being the m-chloro-substituted nitro-
styrene, entry 7, which gave alkylated furan (16g) in 95% ee.
Employing heteroaromatic nitroalkenes (13e−f) gave rise to
slightly lower yields and similar enantioselectivities, entries 5
and 6. The sense of asymmetric induction for these nitroalkene
substrates is identical to that of the remaining nitroalkenes
D
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Figure 5. Crystal structures of zinc dichloride complex 18 (A) and
zinc dichloride complex 19 (B) and overlay of complexes 18 (red) and
19(blue) (C).
Scheme 7. Preparation of Zinc Dichloride Complex (19)
Derived from Ligand 11d
Figure 4. Crystal structures of ligands 11a−c (A−C) and FeCl2
complex of ligand 11d (D).
condensation of N-methyl-bis(benzonitrile) (17) with tert-
leucinol in the presence of a stoichiometric amount of
anhydrous zinc chloride (Scheme 6). This approach employed
Scheme 6. Preparation of C2-Symmetric N-Methyl-bis-tert-
butyloxazoline Zinc Dichloride Complex (18)
pentane solution at room temperature. As with complex 18, the
ligand coordinates through both oxazolinyl nitrogen atoms, the
aryl oxazoline units cross over each other and the NH points
away from the zinc (Figure 5B), which adds weight to our
proposed transition-state model (Figure 3) in which we do not
invoke NH···π interactions with indole or 2-methoxyfuran.
However, the key feature of the gem-dimethyl effect and its
influence on the conformation of the isopropyl group is clear as
there is almost complete overlap between the two structures
when overlaid (Figure 5C).
From the torsion angle data, we can determine the
orientation of the isopropyl group in each of the three ligands
11a−c, the iron complex of ligand 11d, and the zinc complexes
18 and 19 (Table 5). Although ligand 11a was not analyzed as a
metal complex, the dihedral angles obtained (−79° for N1−
C5−C6−C7 and 46° for N1−C5−C6−C8) closely resemble
those obtained for the iron complex of ligand 11d (−77° for
N1−C5−C6−C7 and 50° for N1−C5−C6−C8), entries 1 and 4,
confirming that the isopropyl methyl groups prefer to take up a
region in space away from the vicinal gem-dimethyl groups. In
contrast, when there is a tert-butyl (11b) or phenyl substituent
(11c) on the other oxazoline ring, the isopropyl group
positioning is quite different with dihedral angles of N1−C5−
C6−C7 and N1−C5−C6−C8 of −177°/−177° and −56°/−55°,
respectively, entries 2 and 3. This shows that not only do the
gem-dimethyl substituents have an effect on the adjacent
isopropyl unit but so too does the substituent on the other
oxazoline ring. With the zinc dichloride complexes 18 and 19 in
hand, the direct comparison of the relevant dihedral angles is
Bolm’s zinc dichloride mediated methodology for bisoxazoline
synthesis,75 which used milder reaction conditions than the
original report of Witte and Seeliger.76 Bolm also reported an
X-ray crystal structure of a bisoxazoline zinc dichloride
complex, which demonstrated the expected tetrahedral
coordination about zinc.75
To elucidate the structure of 18, a crystal was grown by
isothermal diffusion using dichloromethane/petroleum ether
(40−60 °C) as the solvent. X-ray crystallographic analysis
showed a distorted tetrahedral complex in which the ligand
coordinates to zinc in a bidentate fashion through the two
oxazolinyl nitrogen atoms with the central nitrogen atom of the
ligand being significantly removed from the metal. Contrary to
expectations, the ligand adopts an interesting nonplanar
conformation in which the central nitrogen atom has a trigonal
planar conformation and the aryl oxazoline units cross over
each other (Figure 5A). With this structure in hand, we
proceeded to prepare the key comparitor zinc dichloride
complex (19) derived from ligand 11d (Scheme 7). Gratify-
ingly, we were able to obtain crystals of suitable quality for X-
ray diffraction by the slow evaporation of an acetonitrile/
E
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are not significantly inferior to ligands 11a and 11d. A recent
meta analysis of the influence of chelate geometry on the roles
of P,N chelating ligands highlights the difficulty of extrapolating
from solid state data to rationalizing ligand efficacy in
asymmetric catalysis.77
Table 5. Comparison of Dihedral Angles of Novel Ligands
11a−c with Metal Complexes of Ligands 11d, 5, 6a,b, 20,
and 21 and Zinc Dichloride Complexes 18 and 19
dihedral angle
dihedral angle
entry ligand/complex (N1−C5−C6−C7) (deg) (N1−C5−C6−C8) (deg)
1
11a
−79
−177
−177
−77
46
−56
−55
50
CONCLUSION
2
11b
■
3
11c
Herein, we have disclosed the synthesis of eight novel
bis(oxazoline) ligands (11a−h) derived from inexpensive (S)-
valine as a cost-effective alternative to similar ligands possessing
an oxazolinyl C(5)-tert-butyl group. Four of the examples
possess a C(4)-gem-dimethyl group and four a C(4)-gem-
diphenyl group adjacent to the C(5)-isopropyl substituent. Zinc
complexes of ligands (11a−h), along with non-C2-symmetric
analogues 1a−g, were effective in the Friedel−Crafts alkylation
of both indole (12) and 2-methoxyfuran (15) with a series of
nitroalkenes, furnishing the alkylation products in high yields
and with up to 95% ee in the reaction of 2-methoxyfuran and
(m-chlorophenyl)nitrostyrene. Three of the ligands (11a−c),
an iron dichloride complex of ligand 11d, and two zinc
dichloride complexes, one formed from ligand 11d and the
other with a novel N-methyl, bis-tert-butyl-oxazoline, were
characterized by X-ray crystallography. In some cases, the novel
ligands induced levels of enantioselectivity comparable to their
tert-butyl counterparts, suggesting that this type of structural
motif can be considered a surrogate tert-butyl group. Further
investigations to probe the gem-disubstitution effect in ligand
design and application in asymmetric catalysis are currently
underway and will be reported in due course.
4
FeCl2[11d]
18
5
−58
64
6
19
−80
−76
−68
−159
−76
45
7
PdCl2[6a]43
PdCl2[6b]43
PdCl2[5]43
PdCl2[20]39
PdCl2[21]39
50
8
57
9
−38
51
10
11
−80
58
possible with the relevant dihedral angles of N1−C5−C6−C7
and N1−C5−C6−C8 being −58°/−80° and 64°/45°, respec-
tively, entries 5 and 6. This shows that there is some distortion
of the isopropyl group in 19 with conformation tending toward
mimicking the tert-butyl group, illustrating the gem-dimethyl
effect.
In order to further determine the impact of C(4) gem-
disubstitution, it of interest to compare these X-ray crystal
structure data to the metal complex studies reported by Paquin
(ligand 20)39 and also our palladium complexes of ligands 5
and 6 (Figure 6).43 In addition, it is useful to compare the
dihedral angles with the palladium complex of ligand 21 (t-Bu
PHOX).39
EXPERIMENTAL SECTION
■
General Experimental Methods. All reagents were purchased
from commercial sources and used without further purification.
Anhydrous dichloromethane, diethyl ether, tetrahydrofuran, and
toluene were obtained from a Grubbs solvent system that was
checked on a monthly basis for ppm levels of water. Catalytic reactions
were repeated at least twice in order to ensure reproducibility.
Compounds 7a,b,45 8a,b,37 and 10a−d11 were prepared according to
the literature. All microwave reactions were conducted in a CEM
Discover S-class microwave reactor, which utilizes an external infrared
temperature sensor.
(S)-2-Bromo-N-(1-hydroxy-3-methyl-1,1-diphenylbutan-2-yl)-
benzamide (8b). (S)-2-Amino-3-methyl-1,1-diphenylbutan-1-ol (7b)
(336 mg, 2.56 mmol, 1 equiv) was dissolved in dichloromethane (10
mL). To this was added a solution of Na2CO3 (814 mg, 7.68 mmol, 3
equiv) in H2O (7.5 mL). The biphasic solution was stirred vigorously,
and 2-bromobenzoyl chloride (0.37 mL, 2.82 mmol, 1.1 equiv) was
added in a dropwise manner over 5 min. The mixture was allowed to
stir for 16 h before the layers were separated. The aqueous layer was
then extracted with dichloromethane (2 × 20 mL), and the combined
organic layers were treated with a 1 M methanolic solution of KOH
(15 mL) for 15 min. The solution was then neutralized to pH 7 by the
addition of 3 M HCl. H2O (25 mL) was then added, and the layers
were separated. The aqueous layer was extracted with dichloro-
methane (2 × 20 mL), and the organic layer was dried over Na2SO4.
The solvent was removed in vacuo, and the resulting residue was
purified by flash column chromatography (pentane/EtOAc, 9:1) to
yield the title compound as a white solid (1.04 g, 93%): mp 212−215
Figure 6. Literature palladium complexes of ligands 5, 6, 20, and 21.
The corresponding dihedral angles N1−C5−C6−C7 and N1−
C5−C6−C8 for the palladium complex of ligand 21 are −80°
and 58°, entry 11, in line with the dihedral angles observed for
ligand 11a (−79° and 46°), entry 1, and the iron complex of
ligand 11d (−77° and 50°), entry 4. These data are also similar
in value to the corresponding dihedral angles of the palladium
complexes derived from ligand 20 (−76° and 51°), entry 10,
ligands 6a (−76° and 50°), entry 5, and 6b (−68° and 57°),
entry 6. Palladium complexes of ligands 5 and 6a,b were
applied by us in the intermolecular asymmetric Heck reaction
with ee values of up to 97%.43 Complex 5 did induce high levels
of enantioselectivity, even with significantly different dihedral
angles of −38° and −159° to ligands of type 6. In addition, in
the present study, the two ligands 11b and 11c, which exhibit
dihedral angles of −177°/−56° and −177°/−55°, respectively,
1
°C; Rf = 0.31 (pentane/EtOAc, 9:1); H NMR (300 MHz, CDCl3) δ
7.57−7.47 (m, 5H), 7.36−7.15 (m, 8H), 6.88−6.85 (m, 1H), 6.39 (d, J
= 9.9 Hz, 1H), 5.20 (d, J = 9.9 Hz, 1H), 2.76 (br s, 1H), 1.95 (m, 1H),
1.06 (d, J = 6.9 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (126
MHz, CDCl3) δ 167.8, 146.0, 145.3, 138.5, 133.2, 130.8, 128.9, 128.5,
127.3, 127.1, 127.0, 125.4, 125.2, 119.1, 82.4, 58.4, 29.2, 22.9, 17.9;
20
[α]D = −18.2 (c = 0.5, CHCl3); IR (film) ν = 3547, 3347, 3050,
F
DOI: 10.1021/acs.joc.5b01767
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The Journal of Organic Chemistry
Article
2953, 2872, 2360, 1626, 1542, 749 cm−1; HRMS (ES+) calcd for
C24H24NO2Br 437.0990, found 437.0991.
1H), 3.45 (d, J = 8.5 Hz, 1H), 1.85−1.78 (m, 1H), 1.48 (s, 3H), 1.33
(s, 3H), 1.10 (d, J = 6.5 Hz, 3H), 0.99 (d, J = 6.5 Hz, 3H), 0.90 (s,
9H); 13C{1H} NMR (126 MHz, CDCl3) δ 162.4, 161.0, 143.7, 143.2,
131.0 (2C), 130.5, 130.3, 120.0, 119.5, 119.2, 117.7, 116.9, 116.0, 84.9,
80.9, 76.4, 67.6, 34.0, 29.2, 29.0, 25.9, 21.2, 21.0, 20.9; [α]D20 = +18.8
(c = 1.0 in CHCl3); IR (film) ν = 2956, 1641, 1579, 1518, 1458, 1318,
1277, 1227, 1053 cm−1; HRMS (ES+) calcd for C27H35N3O2 (M + H)
434.2808, found 434.2809.
(S)-2-(2-Bromophenyl)-4-isopropyl-5,5-diphenyl-4,5-dihydrooxa-
zole (9b). (S)-2-Bromo-N-(1-hydroxy-3-methyl-1,1-diphenylbutan-2-
yl)benzamide (8b) (1.750 g, 4.0 mmol) was weighed into a large
microwave vial. Dichloromethane (10 mL) was added into the vessel,
and the contents were cooled to 0 °C. Methanesulfonic acid (2.6 mL,
40 mmol) was then added to the heterogeneous mixture, and the
contents were stirred until a clear solution remained (approximately 10
min). The vial was then capped and placed in the microwave and
heated to 60 °C at 200 W for 8 h. The reaction was then allowed to
cool to room temperature and was quenched with NaHCO3 (20 mL).
The layers were separated, and the aqueous layer was extracted with
dichloromethane (2 × 15 mL), washed with H2O (15 mL) and brine
(15 mL), and dried over Na2SO4. The solvent was removed in vacuo,
and the resulting residue was purified by flash column chromatography
(pentane/EtOAc, 4:1) to yield the title compound as a clear oil (1.40
g, 83%): Rf = 0.56 (pentane/EtOAc, 4:1); 1H NMR (500 MHz,
CDCl3) δ 7.76 (dd, J = 7.6, 1.7 Hz, 1H), 7.67 (dd, J = 7.8, 1.7 Hz, 1H),
7.55 (d, J = 7.6 Hz, 2H), 7.42−7.21 (m, 10H), 4.88 (d, J = 4.4 Hz,
1H), 1.90 (m, 1H), 1.05 (d, J = 6.7 Hz, 3H), 0.71 (d, J = 6.7 Hz, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 160.8, 145.3, 140.5, 134.0, 131.7,
Crystals suitable for X-ray analysis were grown by dissolving 11b in
Et2O (3 mL), and the ether layer was carefully layered with heptane (2
mL) followed by slow evaporation of the solvents at room
temperature: C27H35N3O2, M = 433.58, orthorhombic, a =
9.54492(6) Å, b = 12.68954(7) Å, c = 19.9983(1) Å, U =
2422.21(2) Å3, T = 100 K, space group P212121 (no. 19), Z = 4,
25062 reflections measured, 5041 unique (Rint = 0.0328) which were
used in all calculations. The final wR(F2) was 0.0686 (all data).
2-((S)-4-Isopropyl-5,5-dimethyl-4,5-dihydrooxazol-2-yl)-N-(2-((S)-
4-phenyl-4,5-dihydrooxazol-2-yl)phenyl)aniline (11c): yellow solid
1
(0.098 g, 45%); mp 100−103.5 °C; H NMR (400 MHz, CDCl3) δ
10.78 (s, 1H), 7.91 (dd, J = 7.9, 1.6 Hz, 1H), 7.79 (dd, J = 7.9, 1.6 Hz,
1H), 7.49 (dd, J = 8.4, 0.8 Hz, 1H), 7.40 (dd, J = 8.4, 0.8 Hz, 1H),
7.37−7.21 (m, 7H), 6.98−6.94 (m, 1H), 6.88−6.84 (m, 1H), 5.41 (dd,
J = 10.1, 8.3 Hz, 1H), 4.71 (dd, J = 10.1, 8.3 Hz, 1H), 4.14 (t, J = 8.3
Hz, 1H), 3.25 (d, J = 8.7 Hz, 1H), 1.72 (m, 1H), 1.39 (s, 3H), 1.25 (s,
3H), 1.02 (d, J = 6.5 Hz, 3H), 0.88 (d, J = 6.5 Hz, 3H); 13C{1H} NMR
(101 MHz, CDCl3) δ 164.0, 161.2, 143.6, 143.1, 142.6, 131.3, 131.04,
131.6, 129.9, 128.3, 127.8, 127.7, 127.2, 127.1, 126.5, 121.9, 93.2, 79.9,
30.4, 22.0, 17.0; [α]D20 = −304.0 (c = 0.5, CHCl3); IR (film) ν = 3552,
3476, 3414, 3240, 2956, 2361, 1658, 701 cm−1; HRMS (ES+) calcd for
C24H23NOBr (M + H) 420.0963, found 420.0976.
130.6, 130.3, 128.5, 127.3, 126.8, 120.3, 120.1, 119.3, 117.2, 116.9,
General Procedure for the Synthesis of Bis(2-oxazolinyl-
phenyl)amine Ligands 11a−h. 2-(2-Bromophenyl)oxazoline 9a,b
(0.5 mmol), sodium tert-butoxide (0.0577 g, 0.6 mmol), 1,1′-
bis(diphenylphosphino)ferrocene (DPPF) (0.028 g, 0.05 mmol),
Pd2dba3 (0.023 g, 0.025 mmol), and 2-(o-aminophenyl)oxazoline
10a−d (0.6 mmol) were added to an oven-dried tube under an
atmosphere of nitrogen. Dry, degassed toluene (2 mL) was added via
syringe, and the tube was sealed under an atmosphere of nitrogen. The
reaction mixture was then heated at 190 °C for 2 h in a microwave.
After the reaction mixture was allowed to cool to room temperature,
the seal was removed and the contents were concentrated in vacuo to
afford a brown oil which was purified by flash column chromatography
on silica gel (pentane/EtOAc, 19:1).
20
115.9, 85.1, 80.7, 73.9, 70.3, 29.0, 28.8, 21.06, 20.9, 20.7; [α]D
=
+114.9 (c = 0.75 in CHCl3); IR (film) ν = 2968, 1637, 1579, 1518,
1456, 1317, 1271, 1225, 1055 cm−1; HRMS (ES+) calcd for
C29H31N3O2 (M + Na) 476.2314, found 476.2316.
Crystals suitable for X-ray analysis were grown by dissolving 11c in
Et2O (3 mL), and the ether layer was carefully layered with heptane (2
mL) followed by slow evaporation of the solvents at room
temperature: C29H31N3O2, M = 453.57, triclinic, a = 9.86627(6) Å,
b = 10.19647(8) Å, c = 13.1369(1) Å, U = 1220.632(17) Å3, T = 100
K, space group P1 (no. 1), Z = 2, 48983 reflections measured, 9742
unique (Rint = 0.0269) which were used in all calculations. The final
wR(F2) was 0.0647 (all data).
2-((S)-4-Isopropyl-4,5-dihydrooxazol-2-yl)-N-(2-((S)-4-isopropyl-
5,5-dimethyl-4,5-dihydrooxazol-2-yl)phenyl)aniline (11a): yellow
solid (0.103 g, 49%); mp 88.5−91 °C; 1H NMR (500 MHz,
CDCl3) δ 10.72 (s, 1H), 7.82 (dd, J = 7.9, 1.6 Hz, 1H), 7.79 (dd, J =
7.9, 1.6 Hz, 1H), 7.41 (dd, J = 8.3, 0.7 Hz, 1H), 7.36 (dd, J = 8.3, 0.7
Hz, 1H), 7.30−7.22 (m, 2H), 6.93−6.89 (m, 1H), 6.88−6.84 (m, 1H),
4.31 (dd, J = 9.1, 7.9 Hz, 1H), 4.09−4.04 (m, 1H), 4.01 (dd, J = 16.5,
8.7 Hz, 1H), 3.46 (d, J = 8.7 Hz, 1H), 1.87−1.80 (m, 1H), 1.79−1.73
(m, 1H), 1.50 (s, 3H), 1.33 (s, 3H), 1.11 (d, J = 6.6 Hz, 3H), 1.00 (d, J
= 6.7 Hz, 3H), 0.99 (d, J = 6.7 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 162.5, 161.1, 143.7, 143.1, 131.1,
131.0, 130.5, 130.3, 120.0, 119.5, 119.3, 117.8, 116.9, 116.1, 85.0, 80.9,
73.0, 69.4, 33.1, 29.1, 29.0, 21.2, 21.0, 20.9, 19.2, 18.4; [α]D20 = +11.7
(c = 0.53 in CHCl3); IR (film) ν = 2964, 1639, 1579, 1518, 1458,
1315, 1275, 1227, 1053 cm−1; HRMS (ES+) calcd for C26H34N3O2 (M
+ H) 420.2651, found 420.2659.
Crystals suitable for X-ray analysis were grown by dissolving 11a in
Et2O (3 mL), and the ether layer was carefully layered with heptane (2
mL) with slow evaporation of the solvents at room temperature:
C26H33N3O2, M = 419.55, hexagonal, a = 9.51079(4) Å, b =
9.51079(4) Å, c = 44.3094(2) Å, U = 3471.04(3) Å3, T = 100 K, space
group P3121 (no. 152), Z = 6, 77335 reflections measured, 4857
unique (Rint = 0.0374), which were used in all calculations. The final
wR(F2) was 0.0651 (all data).
2-((S)-4-tert-Butyl-4,5-dihydrooxazol-2-yl)-N-(2-((S)-4-isopropyl-
5,5-dimethyl-4,5-dihydrooxazol-2-yl)phenyl)aniline (11b): colorless
solid (0.102 g, 47%); mp 126−129.5 °C; 1H NMR (500 MHz,
CDCl3) δ 10.80 (s, 1H), 7.82 (dd, J = 7.9, 1.5 Hz, 1H), 7.79 (dd, J =
7.9, 1.5 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H),
7.31−7.19 (m, 2H), 6.93−6.89 (m, 1H), 6.88−6.84 (m, 1H), 4.23 (dd,
J = 9.9, 8.4 Hz, 1H), 4.11 (t, J = 8.0 Hz, 1H), 4.04 (dd, J = 9.9, 7.7 Hz,
2-((S)-4-Benzyl-4,5-dihydrooxazol-2-yl)-N-(2-((S)-4-isopropyl-5,5-
dimethyl-4,5-dihydrooxazol-2-yl)phenyl)aniline (11d): sticky yellow
solid (0.121 g, 52%); mp unattainable; 1H NMR (400 MHz, CDCl3) δ
10.71 (s, 1H), 7.81 (m, 2H), 7.44 (d, J = 8.3 Hz, 1H), 7.38 (d, J = 8.3
Hz, 1H), 7.32−7.16 (m, 7H), 6.90 (m, 2H), 4.57 (m, 1H), 4.25 (t, J =
8.8 Hz, 1H), 4.03 (t, J = 7.8 Hz, 1H), 3.40 (d, J = 8.7 Hz, 1H), 3.17
(dd, J = 13.7, 5.3 Hz, 1H), 2.71 (dd, J = 13.7, 8.5 Hz, 1H), 1.84 (m,
1H), 1.52 (s, 3H), 1.33 (s, 3H), 1.14 (d, J = 6.5 Hz, 3H), 1.00 (d, J =
6.5 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 163.1, 161.2, 143.7,
143.1, 138.1, 131.2, 131.0, 130.5, 130.3, 129.3, 128.4, 126.3, 120.1,
119.7, 119.3, 117.6, 116.9, 116.0, 85.0, 81.0, 70.8, 68.1, 41.8, 29.1, 28.9,
20
21.2, 21.1, 20.90; [α]D = +41.6 (c = 0.30 in CHCl3); IR (film) ν =
2955, 1639, 1579, 1518, 1458, 1317, 1275, 1053 cm−1; HRMS (ES+)
calcd for C30H34N3O2 (M + H) 468.2651, found 468.2648.
2-((S)-4-Isopropyl-4,5-dihydrooxazol-2-yl)-N-(2-((S)-4-isopropyl-
5,5-diphenyl-4,5-dihydrooxazol-2-yl)phenyl)aniline (11e): pale yel-
low solid (0.141 g, 52%); mp 67−70 °C; 1H NMR (500 MHz, CDCl3)
δ 10.86 (s, 1H), 8.04 (dd, J = 7.9, 1.6 Hz, 1H), 7.81 (dd, J = 7.9, 1.6
Hz, 1H), 7.58−7.51 (m, 2H), 7.47−7.39 (m, 2H), 7.36−7.34 (m, 2H),
7.33−7.19 (m, 8H), 6.92 (m, 2H), 4.81 (d, J = 4.7 Hz, 1H), 4.26 (dd, J
= 9.2, 7.9 Hz, 1H), 4.03−3.96 (m, 1H), 3.93 (t, J = 8.0 Hz, 1H), 1.82
(m, 1H), 1.67 (m, 1H), 0.99 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 6.7 Hz,
3H), 0.83 (d, J = 6.7 Hz, 3H), 0.57 (d, J = 6.7 Hz, 3H); 13C{1H} NMR
(126 MHz, CDCl3) δ 162.4, 160.6, 145.8, 144.0, 143.0, 140.9, 131.3,
131.0, 130.5 (2C), 128.2, 127.6 (2C), 127.1, 127.0, 126.3, 120.2, 119.4,
118.1, 117.1, 115.4, 91.1, 80.6, 73.0, 69.4, 33.0, 30.4, 21.9, 19.1, 18.4,
17.2; [α]D20 = −234.4 (c = 0.60 in CHCl3); IR (film) ν = 2958, 1647,
1579, 1518, 1458, 1352, 1315, 1273, 1223, 1051 cm−1; HRMS (ES+)
calcd for C36H38N3O2 (M + H) 544.2964, found 544.2954.
2-((S)-4-tert-Butyl-4,5-dihydrooxazol-2-yl)-N-(2-((S)-4-isopropyl-
5,5-diphenyl-4,5-dihydrooxazol-2-yl)phenyl)aniline (11f): off-white
G
DOI: 10.1021/acs.joc.5b01767
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The Journal of Organic Chemistry
Article
solid (0.111 g, 40%); mp 84−86.5 °C; 1H NMR (500 MHz, CDCl3) δ
10.96 (s, 1H), 8.04 (dd, J = 7.9, 1.5 Hz, 1H), 7.81 (dd, J = 7.9, 1.5 Hz,
1H) 7.56−7.54 (m, 2H), 7.46 (d, J = 8.3 Hz, 1H), 7.41 (d, J = 8.3 Hz,
1H), 7.37−7.34 (m, 2H), 7.33−7.19 (m, 8H), 6.93−6.89 (m, 2H),
4.81 (d, J = 4.6 Hz, 1H), 4.19 (dd, J = 9.5, 8.1 Hz, 1H), 4.07−4.03 (m,
1H), 4.01 (dd, J = 9.5, 8.1 Hz, 1H), 1.85−1.76 (m, 1H), 0.99 (d, J =
6.7 Hz, 3H), 0.84 (s, 9H), 0.55 (d, J = 6.7 Hz, 3H); 13C{1H} NMR
(126 MHz, CDCl3) δ 162.2, 160.4, 145.8, 144.1, 143.0, 140.9, 131.3,
131.0, 130.5 (2C), 128.2, 127.6, 127.6 (2C), 127.1, 127.0, 126.3, 120.1,
119.4, 119.3, 118.0, 117.1, 115.3, 91.01, 80.4, 76.4, 67.6, 33.9, 30.4,
resulting yellow oil was purified using flash column chromatography
on silica gel (pentane/EtOAc, 5:1).
(R)-3-(2-Nitro-1-phenylethyl)-1H-indole (14a): Rf = 0.20 (pentane/
EtOAc, 5:1); [α]D20 = −18.4 (c = 1.00 in CH2Cl2, 61% ee (R)) (lit.78
[α]D20 = +25.3 (c = 0.9 in CH2Cl2, 84% ee (S))); 1H NMR (500 MHz,
CDCl3) δ 8.06 ppm (br s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.35−7.30
(m, 5H), 7.26−7.23 (m, 1H), 7.19 (t, J = 8.0 Hz, 1H), 7.07 (app. t, J =
8.0 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 5.18 (t, J = 8.0 Hz, 1H), 5.05
(dd, J = 12.5, 7.5 Hz, 1H), 4.93 (dd, J = 12.5, 7.5 Hz, 1H); 13C{1H}
NMR (125 MHz, CDCl3) δ 139.2, 136.5, 128.9 (2C), 127.8 (2C),
127.6, 126.1, 122.7, 121.6, 120.0, 118.9, 114.5, 111.4, 79.5, 41.6. The
enantioselectivity was determined by HPLC: Chiralcel IB (heptane/
EtOH, 70:30, 0.9 mL/min). Retention times: tminor = 10.8 min (S),
tmajor = 12.1 min (R).
General Procedure for the Catalytic Enantioselective
Friedel−Crafts Reaction between 2-Methoxyfuran (15) and
trans-β-Nitrostyrenes 13a−f. To a flame-dried Schlenk tube were
added Zn(OTf)2 (9.3 mg, 0.025 mmol) and ligand (1a−g, 11a−h)
(0.0275 mmol) under nitrogen, followed by addition of toluene (3.0
mL). The solution was stirred at room temperature for 2 h, and trans-
β-nitrostyrene (13a−f) (37.0 mg, 0.25 mmol) was added. The mixture
was stirred for 15 min before the addition of 2-methoxyfuran (24.5 mg,
24.0 μL, 0.25 mmol). After being stirred for 24 h, the mixture was
filtered through a pad of silica, concentrated, and purified by flash
column chromatography on silica gel (pentane/EtOAc, 9:1) to yield
the title compound as a colorless oil.
20
25.8, 21.8, 17.1; [α]D = −228.4 (c = 0.75 in CHCl3); IR (film) ν =
2956, 1649, 1579, 1518, 1456, 1313, 1275, 1225, 1051 cm−1; HRMS
(ES+) calcd for C37H40N3O2 (M + H) 558.3121, found 558.3123.
2-((S)-4-Isopropyl-5,5-diphenyl-4,5-dihydrooxazol-2-yl)-N-(2-((S)-
4-phenyl-4,5-dihydrooxazol-2-yl)phenyl)aniline (11g): pale yellow
solid (0.130 g, 45%); mp 87−89.5 °C; 1H NMR (500 MHz, CDCl3) δ
10.90 (s, 1H), 8.07 (dd, J = 7.9, 1.5 Hz, 1H), 7.90 (dd, J = 7.9, 1.5 Hz,
1H), 7.51−7.46 (m, 3H), 7.43 (d, J = 7.9 Hz, 1H), 7.37−7.15 (m,
15H), 6.98−6.92 (m, 2H), 5.37−5.33 (m, 1H), 4.65 (m, 2H), 4.07 (t,
J = 8.4 Hz, 1H), 1.78−1.72 (m, 1H), 0.88 (d, J = 6.7 Hz, 3H), 0.51 (d,
J = 6.7 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 162.4, 160.6,
145.8, 144.0, 143.0, 140.9, 131.3, 131.0, 130.5 (2C), 128.2, 127.6 (2C),
127.1, 127.0, 126.3, 120.2, 119.4, 118.1, 117.1, 115.4, 91.1, 80.6, 73.0,
20
69.4, 33.0, 30.4, 21.9, 19.1, 18.4, 17.2; [α]D = −125.3 (c = 0.33 in
CHCl3); IR (film) ν = 2922, 1645, 1579, 1516, 1454, 1271, 1051
cm−1; HRMS (ES+) calcd for C39H36N3O2 (M + H) 578.2809, found
578.2803.
(S)-2-Methoxy-5-(1-phenyl-2-nitroethyl)furan (16a): Rf = 0.42
(pentane/EtOAc, 9:1); 1H NMR (300 MHz, CDCl3) δ 7.35−7.23 (m,
5H), 5.95 (d, J = 3.2 Hz, 1H), 5.03 (d, J = 3.2 Hz, 1H), 4.94 (dd, J =
16.2, 11.5 Hz, 1H) 4.79−4.71 (m, 2H), 3.78 (s, 3H); 13C{1H} NMR
(126 MHz, CDCl3) δ 161.5, 141.5, 136.8, 129.0, 128.0, 127.8, 108.8,
79.9, 78.0, 57.7, 43.6; [α]D20 = −50.4 (c = 1.0 in CHCl3, 89% ee) (lit.16
2-((S)-4-Benzyl-4,5-dihydrooxazol-2-yl)-N-(2-((S)-4-isopropyl-5,5-
diphenyl-4,5-dihydrooxazol-2-yl)phenyl)aniline (11h): pale yellow
solid (0.133 g, 45%); mp 73−76.5 °C; 1H NMR (500 MHz, CDCl3) δ
10.75 (s, 1H), 8.08 (dd, J = 7.9, 1.6 Hz, 1H), 7.79 (dd, J = 7.9, 1.6 Hz,
1H), 7.57−7.55 (m, 2H), 7.42 (app t, J = 8.6 Hz, 2H), 7.33−7.19 (m,
9H), 7.17−7.14 (m, 4H), 7.10−7.06 (m, 1H), 6.97−6.90 (m, 2H),
6.94−6.90 (m, 1H), 4.75 (d, J = 4.8 Hz, 1H), 4.49 (dtd, J = 8.8, 7.4,
5.4 Hz, 1H), 4.19 (t, J = 8.8 Hz, 1H), 3.97 (dd, J = 8.2, 7.4 Hz, 1H),
3.07 (dd, J = 13.8, 5.4 Hz, 1H), 2.58 (dd, J = 13.8, 8.6 Hz, 1H), 1.88−
1.79 (m, 1H), 1.00 (d, J = 6.7 Hz, 3H), 0.58 (d, J = 6.7 Hz, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 163.1, 160.8, 145.7, 143.9, 143.0,
20
[α]D = −63.2 (c = 1.4 in CHCl3, 94% ee (S))); HRMS (ES+) calcd
for C13H13NO4 247.0845, found 247.0857; The enantioselectivity was
determined by HPLC: Chiralcel IB, (heptane:/EtOH, 90:10, 1.0 mL/
min). Retention times: tminor = 8.5 min (R), tmajor = 10.0 min (S).
(S)-2-Methoxy-5-(1-(4-methoxyphenyl)-2-nitroethyl)furan (16b):
1
Rf = 0.24 (pentane/Et2O, 85:15); H NMR (400 MHz, CDCl3) δ
7.21 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 5.93 (d, J = 3.2 Hz,
1H), 5.03 (d, J = 3.2 Hz, 1H), 4.92 (dd, J = 15.4, 10.9 Hz, 1H), 4.78−
4.67 (m, 2H), 3.80 (s, 3H) 3.78 (s, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 161.4, 159.2, 141.9, 128.9, 128.7, 114.3, 108.5, 79.9, 78.2,
140.9, 138.1, 131.4, 131.3, 130.6, 130.5, 129.2, 128.3, 128.2, 127.6
(2C), 127.1 (2C), 126.3, 120.2, 119.6, 119.5, 118.2, 116.9, 115.6, 91.2,
20
80.8, 70.9, 68.0, 41.7, 30.4, 22.0, 17.3; [α]D = −173.1 (c = 0.65 in
16
20
CHCl3); IR (film) ν = 2956, 2927, 1643, 1579, 1456, 1352, 1317,
1272, 1221, 1135, 1051 cm−1; HRMS (ES+) calcd for C40H38N3O2 (M
+ H) 592.2964, found 592.2969.
57.7, 55.2, 42.8; [α]D = −65.5.3 (c = 0.32 in CHCl3, 92% ee) (lit.
20
[α]D = −40.7 (c = 1.7 in CHCl3, 94% ee (S))); HRMS (ES+) calcd
for C14H15NO5 277.0950, found 277.0949. The enantioselectivity was
determined by HPLC: Chiralcel IB (heptane/EtOH, 90:10, 1 mL/
min). Retention times: tminor = 9.5 min (R), tmajor = 11.0 min (S).
(S)-2-(1-(4-Bromophenyl)-2-nitroethyl)-5-methoxyfuran (16c): Rf
= 0.39 (pentane/EtOAc, 9:1); 1H NMR (400 MHz, CDCl3) δ 7.47 (d,
J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 5.97 (d, J = 3.3 Hz, 1H),
5.05 (d, J = 3.3 Hz, 1H), 4.93 (dd, J = 15.8, 10.8 Hz, 1H), 4.80−4.68
Synthesis of FeCl2 Complex of Ligand 11d. Ligand 11d (72.8
mg, 0.22 mmol) was added under inert conditions to an oven-dried
Schlenk tube. Acetonitrile (2.5 mL) was added, and the solution was
allowed to stir under nitrogen for 5 min. FeCl2 (25 mg, 0.2 mmol) was
then added, and the solution was allowed to stir for 3 h at room
temperature, after which time any residual particulate matter was
removed by filtration. The filtrate was concentrated in vacuo to yield a
green solid residue. This residue was dissolved in Et2O (3 mL) and the
ether layer was carefully layered with heptane (2 mL). Crystals suitable
for X-ray analysis were grown by the slow evaporation of the solvents
at room temperature: C30H32Cl2FeN3O2, M = 593.34, monoclinic, a =
8.4077(1) Å, b = 17.5482(3) Å, c = 9.4560(2) Å, U = 1390.95(4) Å3, T
= 100 K, space group P21, Z = 2, 26571 reflections measured, 7971
unique (Rint = 0.0300) which were used in all calculations. The final
wR(F2) was 0.0575 (all data).
General Procedure for the Catalytic Enantioselective
Friedel−Crafts Reaction between Indole (12) and trans-β-
Nitrostyrene (13a). To an oven-dried Schlenk tube under nitrogen
were added Zn(OTf)2 (9.3 mg, 0.025 mmol) and ligand (1a−g, 11a−
h) (0.025 mmol) followed by the addition of toluene (2 mL). The
solution was stirred at room temperature for 30 min, and the trans-β-
nitrostyrene (74.5 mg, 0.5 mmol) was added. The mixture was allowed
to stir for a further 15 min and cooled to −20 °C before indole (57
mg, 0.5 mmol) was added. After being stirred for 40 h at −20 °C, the
mixture was filtered through a pad of silica and concentrated. The
(m, 2H), 3.81 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 161.6,
20
140.8, 135.8, 132.2, 129.5, 122.1, 109.0, 80.0, 77.7, 57.8, 43.0; [α]D
=
−68.2 (c = 0.37 in CHCl3, 92% ee); HRMS (ES+) calcd for
C13H12NO4Br 324.9950, found 324.9952. The enantioselectivity was
determined by HPLC: Chiralcel IB (heptane/EtOH, 90:10, 1 mL/
min). Minor retention times: tminor = 9.6 min (R), tmajor = 10.6 min (S).
(S)-2-Methoxy-5-(2-nitro-1-(p-tolyl)ethyl)furan (16d): Rf = 0.47
(pentane/EtOAc, 9:1); 1H NMR (300 MHz, CDCl3) δ 7.21−7.11 (m,
4H), 5.95 (d, J = 3.2 Hz, 1H), 5.03 (d, J = 3.2 Hz, 1H), 4.94 (dd, J =
15.2, 10.7 Hz, 1H), 4.79−4.69 (m, 2H), 3.80 (s, 3H), 2.32 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 161.5, 141.8, 137.8, 133.8, 129.7,
20
127.7, 108.6, 79.9, 78.1, 57.7, 43.2, 21.1; [α]D = −28.0 (c = 0.29 in
CHCl3, 92% ee) (lit.16 [α]D = −38.4 (c = 1.4 in CHCl3, 94% ee
20
(S))); HRMS (ES+) calcd for C14H15NO4 261.1001, found 261.0995.
The enantioselectivity was determined by HPLC: Chiralcel IB,
(heptane/EtOH, 90:10, 1 mL/min). Minor retention times: tminor
7.4 min (R), tmajor = 8.7 min (S).
=
(R)-2-(1-(Furan-2-yl)-2-nitroethyl)-5-methoxyfuran (16e): Rf
=
1
0.37 (pentane/Et2O, 85:15); H NMR (400 MHz, CDCl3) δ 7.37
H
DOI: 10.1021/acs.joc.5b01767
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(d, J = 1.9 Hz, 1H), 6.32 (dd, J = 3.2, 1.9 Hz, 1H), 6.20 (d, J = 3.3 Hz,
1H), 6.05 (d, J = 3.3 Hz, 1H), 5.07 (d, J = 3.3 Hz, 1H), 4.92 (dd, J =
8.7, 6.3 Hz, 1H), 4.85 (dd, J = 7.1, 5.0 Hz, 2H), 3.82 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 161.5, 149.6, 142.5, 139.0, 110.5, 109.4,
107.9, 80.1, 76.1, 57.8, 37.6; [α]D20 = −30.9 (c = 0.75 in CHCl3, 89%
30100 reflections measured, 6912 unique (Rint = 0.0336) which were
used in all calculations. The final wR(F2) was 0.0502 (all data).
ASSOCIATED CONTENT
* Supporting Information
■
S
ee) (lit.16 [α]D = −24.1 (c = 0.20 in CHCl3, 86% ee (S))); HRMS
20
(ES+) calcd for C11H11NO5 237.0637, found 237.0640. The
enantioselectivity was determined by HPLC: Chiralcel IB, (hepta-
ne:EtOH, 99:1, 1 mL/min). Major retention times: tmajor = 12.3 min
(R), tminor = 13.3 min (S).
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01767.
CCDC 1415749−1415751, 1425893−1425894 contain the
supplementary crystallographic data for this paper. This data
can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
(S)-2-Methoxy-5-(2-nitro-1-(thiophene-2-yl)ethyl)furan (16f): Rf =
0.37 (pentane/Et2O, 85:15); 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J
= 1.9 Hz, 1H), 6.32 (dd, J = 3.3, 1.9 Hz, 1H), 6.20 (d, J = 3.3 Hz, 1H),
6.05 (d, J = 3.3 Hz, 1H), 5.07 (d, J = 3.3 Hz, 1H), 4.92 (dd, J = 8.7, 6.3
Hz, 1H), 4.85 (dd, J = 7.1, 5.0 Hz, 2H), 3.82 (s, 3H); 13C{1H} NMR
(101 MHz, CDCl3) δ 161.5, 140.7, 139.2, 127.1, 126.0, 125.3, 109.1,
X-ray data (CIF)
Full analysis of all new compounds including NMR, X-
ray, and chromatographic data (PDF)
20
80.1, 78.5, 57.8, 38.8; [α]D = −40.3 (c = 0.85 in CHCl3, 90% ee)
(lit.16 [α]D20 = −33.7 (c = 2.3 in CHCl3, 89% ee (S))); HRMS (ES+)
calcd for C11H11NO4S 253.0409, found 253.0397. The enantioselec-
tivity was determined by HPLC: Chiralcel OD-H (heptane/EtOH,
95:5, 1 mL/min). Retention times: tmajor = 11.1 min (R), tminor = 12.3
min (S).
AUTHOR INFORMATION
Corresponding Author
*E-mail: p.guiry@ucd.ie.
■
(S)-2-(1-(3-Chlorophenyl)-2-nitroethyl)-5-methoxyfuran (16g): Rf
1
Notes
= 0.39 (pentane/EtOAc, 9:1); H NMR (400 MHz, CDCl3) δ 7.33−
The authors declare no competing financial interest.
7.22 (m, 4H), 5.96 (d, J = 3.3 Hz, 1H), 5.04 (d, J = 3.3 Hz, 1H), 4.93
(dd, J = 17.0, 12.0 Hz, 1H), 4.80−4.68 (m, 2H), 3.80 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 161.6, 140.9, 135.3, 134.0, 129.2, 129.2
(3C), 109.0, 80.0, 77.8, 57.8, 42.9; [α]D20 = −84.2 (c = 0.28 in CHCl3,
95% ee); HRMS (ES+) calcd for C13H12NO4Cl 281.0455, found
281.0455. The enantioselectivity was determined by HPLC: Chiralcel
ACKNOWLEDGMENTS
■
S.O’R. acknowledges financial support from the Irish Research
Council through the Enterprise Partnership Scheme for the
award of a Ph.D scholarship cofunded by Henkel Ireland, Ltd.
M.A. thanks the Irish Research Council for Science, Engineer-
ing and Technology (RS/2006/6) for a Ph.D. Scholarship.
C.K.-H. acknowledges the School of Chemistry and Chemical
Biology for the award of a Research Demonstratorship. B.F.
acknowledges financial support from the Irish Research Council
through the Enterprise Partnership Scheme for the award of a
Ph.D scholarship cofunded by Henkel Ireland, Ltd. We
acknowledge the facilities provided by the Centre for Synthesis
and Chemical Biology (CSCB), funded by the Higher
Education Authority’s Programme for Research in Third-
Level Institutions (PRTLI). We thank Dr. Yannick Ortin and
Geraldine Fitzpatrick for NMR spectroscopy and Adam
Coburn and Kevin Conboy for mass spectrometry.
IB (heptane/EtOH, 90:10, 1 mL/min). Minor retention times: tminor
=
9.2 min (R), tmajor = 9.9 min (S).
Dichlorozinc Bis[2-((4S)-4-tert-butyl-4,5-dihydrooxazol-2-yl)-
phenyl]methylamine (18). An oven-dried Schlenk tube was charged
with bis(2-cyanophenyl)methylamine (0.500 g, 2.14 mmol), (S)-tert-
leucinol (0.842 g, 6.42 mmol), and anhydrous zinc chloride (0.642 g,
4.71 mmol). Chlorobenzene (anhydrous) (2 mL) was then added, and
the resulting suspension was heated at reflux temperature under an
atmosphere of nitrogen for 4 d. The reaction mixture was concentrated
in vacuo to give a brown oil which was then purified by flash column
chromatography on silica gel (3 × 30 cm) using either CH2Cl2 or ethyl
acetate as the eluent to afford the title compound (0.81 g, 66%) as a
1
yellow/green solid: H NMR (300 MHz, CDCl3) δ 7.89 (dd, J = 7.8,
1.5 Hz, 2H), 7.63 (ddd, J = 8.5, 7.8, 1.5 Hz, 2H), 7.24 (dd, J = 8.5, 1.0
Hz, 2H), 7.15 (dt, J = 7.8, 1.0 Hz, 2H), 4.17 (dd, J = 9.1, 3.7 Hz, 2H),
3.89 (dd, J = 9.7, 3.7 Hz, 2H), 3.53 (s, 3H), 3.23 (app t, J = 9.3 Hz,
2H), 0.95 (s, 18H); 13C{1H} NMR (75 MHz, CDCl3) δ 172.2, 147.4,
134.3, 133.1, 122.5, 121.2, 116.4, 70.1, 67.2, 42.5, 35.0, 25.7; IR (KBr)
ν = 3455, 2964, 1652, 1479, 1254, 945 cm−1; MS-ES+ m/z 539 (M+ −
Cl, 17), 434 (M+-ZnCl2 + 1, 100). Anal. Calcd for C27H35Cl2N3O2Zn:
C, 56.89; H, 6.19; Cl, 12.44; N, 7.40; Zn, 11.47. Found: C, 57.04; H,
6.22; Cl, 11.47; N, 7.33; Zn, 10.36.
Crystals of 18 suitable for X-ray analysis were grown by isothermal
diffusion using dichloromethane/petroleum ether (40−60 °C):
C27H35N3O2Cl2Zn, M = 654.78, monoclinic, a = 9.9185(8) Å, b =
10.6832(9) Å, c = 14.5573(12) Å, U = 1538.1(2) Å3, T = 293 K, space
group P21P21P21 (#4), Z = 2, 13999 reflections measured, 7493
unique (Rint = 0.0171) which were used in all calculations. The final
wR(F2) was 0.0962 (all data).
Synthesis of ZnCl2 Complex (19). Ligand 11d (72.8 mg, 0.22
mmol) was added under inert conditions to an oven-dried Schlenk
tube. Acetonitrile (2.5 mL) was added, and the solution was allowed to
stir under nitrogen for 5 min. ZnCl2 (0.20 mL, 0.2 mmol) was then
added, and the solution was allowed to stir for 5 min at room
temperature, after which time pentane (0.30 mL) was added to the
solution.
Crystals of 19 suitable for X-ray analysis were grown by the slow
evaporation of the solvents at room temperature: C27H35N3O2Cl2Zn,
M = 569.85, orthorhombic, a = 9.3141(2) Å, b = 11.2722(2) Å, c =
26.2759(4) Å, U = 2758.72 Å3, T = 100 K, space group P212121, Z = 6,
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