Phosphino hydrazones as suitable ligands in the asymmetric Suzuki-Miyaura cross-coupling

Article abstract of DOI:10.1021/jo300548z

Phosphino hydrazones derived from C₂-symmetric hydrazines exhibit excellent catalytic activity and provide good enantioselectivities in the asymmetric Suzuki-Miyaura cross-coupling to axially chiral biaryls, in particular for the most challenging reactions of monocyclic, functionalized aryl bromides and triflates. X-ray analysis of preformed [Pd(P/N)Cl₂] precatalysts [(P/N) = phosphino hydrazone] revealed a strong n-π conjugation in the hydrazone moiety, identified by a high planarity degree at the pyrrolidine N(sp³) atom, that makes rotations around N-N bonds inconsequential. The complexes are also characterized by an envelope-like conformation with the Pd atom placed at the opposite side to the 2-phenyl group on the nearest stereogenic center of the pyrrolidine group. The isolation and structural analysis of oxidative addition intermediates indicate that the configurational stability of Pd-C(Ar) bonds is dependent on the substitution pattern in the aryl bromide.

Full text of DOI:10.1021/jo300548z

Article
pubs.acs.org/joc
Phosphino Hydrazones as Suitable Ligands in the Asymmetric
Suzuki−Miyaura Cross-Coupling
†
‡
‡
†
,‡
́
Abel Ros, Beatriz Estepa, Antonio Bermejo, Eleuterio Alvarez, Rosario Fernandez,*
́
and Jose M. Lassaletta*,†
́
†Instituto de Investigaciones Químicas (IIQ), CSIC/US, Amer
́
ico Vespucio 49, 41092 Seville, Spain
‡Departamento de Química Organ
́
ica, Universidad de Sevilla, Apdo. de Correos No. 1203, 41071, Seville, Spain
S
* Supporting Information
ABSTRACT: Phosphino hydrazones derived from C2-sym-
metric hydrazines exhibit excellent catalytic activity and
provide good enantioselectivities in the asymmetric Suzuki−
Miyaura cross-coupling to axially chiral biaryls, in particular for
the most challenging reactions of monocyclic, functionalized
aryl bromides and triflates. X-ray analysis of preformed [Pd(P/
N)Cl2] precatalysts [(P/N) = phosphino hydrazone] revealed
a strong n−π conjugation in the hydrazone moiety, identified by a high planarity degree at the pyrrolidine N(sp3) atom, that
makes rotations around N−N bonds inconsequential. The complexes are also characterized by an envelope-like conformation
with the Pd atom placed at the opposite side to the 2-phenyl group on the nearest stereogenic center of the pyrrolidine group.
The isolation and structural analysis of oxidative addition intermediates indicate that the configurational stability of Pd−C(Ar)
bonds is dependent on the substitution pattern in the aryl bromide.
INTRODUCTION
■
Asymmetric, heterobidentate ligands with different electronic
properties constitute an important family of compounds for
their applications in catalysis. In fact, transition-metal
complexes carrying such type of ligands may reach very high
levels of activity and selectivity in some reactions as a result of
the trans-influence. Among them, P/N ligands are established
as the most popular ligand class; after the pioneering work
of the Helmchen,1 Pfaltz,2 and Williams3 groups on the use of
phosphino-oxazolines (PHOX) in Pd-catalyzed allylic sub-
stitutions,4 these compounds have found applications in many
other reactions and can therefore be considered as “privileged
ligands”5 in asymmetric catalysis. The asymmetric Suzuki−
Miyaura cross-coupling to biaryls constitutes a particularly
challenging reaction, as it requires catalysts that combine a high
activity to achieve reactions with highly hindered coupling
partners (unavoidable if the newly created Ar−Ar′ bond will
be configurationally stable) and a geometry able to drive
enantiocontrolled reactions. In this context, P/N ligands have
played a predominant role, providing good results for several
types of substrates.6 Additional studies have also been carried
out using different ligands such as mono-7 or diphosphines,8
dienes,9 phenyl-bis(oxazoline),10 or heterocyclic carbenes,11 but
the collected results are in general modest in terms of generality
and enantioselectivity. We have recently reported on the use
of phosphine-free C2-symmetric glyoxal bis-hydrazone 1 as the
ligand (Figure 1),12 which provides very good enantioselectiv-
ities at low temperatures, particularly for the synthesis of
unfunctionalized binaphthalenes. The long reaction times
required for completion, and the lower reactivity and/or enantio-
selectivities collected for some types of substrate prompted us to
Figure 1. Hydrazone-based ligands 1 and 2.
modify the structure of the catalyst. Toward this goal, we
reasoned that ligands 2 combining a hydrazone unit (that
provides an excellent chiral environment in the bis−hydrazone
case) and a phosphine donor to build the successful hetero-
bidentate P/N architecture (expected to provide a better
reactivity) would be interesting candidates for the asymmetric
Suzuki−Miyaura reaction. A survey of the pertinent literature
revealed that, in spite of their availability, only a couple of
representatives of this class of ligands have been reported.
Thus, Mino and co-workers13 have reported the use of
prolinol-derived phosphino hydrazones 3−5 in Pd-catalyzed
asymmetric allylic alkylations, and, more recently, Widhalm’s
group14 reported binaphthyl-based azepine derivatives 6 and
their use as ligands in the same reaction (Figure 2). Their use
in cross-coupling reactions (or any other applications) remains
unexplored.
Received: March 14, 2012
© XXXX American Chemical Society
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1-Amino-2,5-diisopropylpyrrolidine 9c was obtained from
commercially available 1,4-diol 8c following a similar procedure,
though higher reaction temperatures were required in the
cyclization step. In this case, the product 9c did not survive the
standard workup, and therefore, the crude reaction mixture was
made to react with 7 to afford the desired ligand 2c in 85%
overall yield from 8c. Reactions of phosphino hydrazones 2a−c
with [PdCl2(CH3CN)2] readily afforded neutral Pd(II)
1
complexes 10a−c in nearly quantitative yields. The H NMR
spectrum at 295 K of these complexes showed broad signals
attributed to slow N−N bond rotations, making it difficult to
obtain any valuable information about the geometry of the
coordinated P,N ligands in solution. In the solid state, however,
the structures of 10a and 10c could be analyzed by single-crystal
X-ray diffractometry (Figures 4 and 5).
Figure 2. Phosphino hydrazones in asymmetric catalysis.
RESULTS AND DISCUSSION
■
As in previous studies with bis-hydrazones,12,15 C2-symmetric
hydrazines were chosen as precursors of phosphino hydrazones,
as the introduction of this substructure is the key design
strategy to make N−N bond rotations inconsequential. Thus,
and in contrast with monosubstituted hydrazine derivatives, the
maintenance of an asymmetric environment around the metal
center is granted in their corresponding complexes (Figure 3).
Figure 4. ORTEP drawing of complex 10a. Thermal ellipsoids are
drawn at the 50% probability level. Hydrogen atoms are omitted for
clarity. Selected bond lengths (Å) and bond angles (deg): Pd(1)−P(1)
2.2172(9), Pd(1)−N(1) 2.086(2), Pd(1)−Cl(1) 2.401(1), Pd(1)−
Cl(2) 2.2751(9), N(1)−N(2) 1.354(4), Cl(1)−Pd(1)−Cl(2)
89.23(3), P(1)−Pd(1)−N(1) 87.72(7).
Figure 3. C2-Symmetry as the key strategy to make N−N bond
rotations inconsequential.
In order to check the suitability of the proposed phosphino
hydrazone ligands, we started synthesizing representatives 2a−c
from commercially available 2-(diphenylphosphino)benzaldehyde
7 and C2-symmetric hydrazines 9a−c. Diphenyl-substituted
pyrrolidine 9a and piperidine 9b derivatives were synthesized
from the corresponding known diols 8a,b after mesylation and
reaction with hydrazine hydrate as described previously.15,16 Then,
a simple condensation with 7 afforded the desired heterobidentate
ligands 2a and 2b in 97 and 82% yield, respectively (Scheme 1).
Figure 5. ORTEP drawing of complex 10c. Thermal ellipsoids are
drawn at the 50% probability level. Hydrogen atoms are omitted for
clarity. Selected bond lengths (Å) and bond angles (deg): Pd(1)−P(1)
2.2237(7), Pd(1)−N(1) 2.091(2), Pd(1)−Cl(1) 2.2820(7), Pd(1)−
Cl(2) 2.3645(7), N(1)−N(2) 1.363(3), Cl(1)−Pd(1)−Cl(2)
88.99(3), P(1)−Pd(1)−N(1) 88.81(6).
Scheme 1. Synthesis of Phosphino Hydrazones 2a−c and Pd
Complexes 10a−c
In both cases, as expected, an efficient n→π conjugation in the
hydrazone moiety was deduced from the low pyramidalization
degree at the N(sp3) atoms [virtual dihedral angles N(1)−
N(2)−C(8)−C(11) = 159.6° for 10a and N(1)−N(2)−C(20)−
C(23) = 162.8° for 10c]17,18 and the torsion angles C(1)−
N(1)−N(2)−C(8) = 2.3(4)° and C(7)−N(1)−N(2)−C(20) =
−18.8(4)° for 10a and 10c, respectively. Such a conjugation
should consequently increase the electronic density in the
hydrazone fragment. The longer Pd−Cl bond trans to the pho-
sphine [Pd−Cl(1) = 2.401 Å for 10a and Pd−Cl(2) = 2.365 Å
for 10c] compared to the Pd−Cl bond trans to the nitrogen
atom [Pd−Cl(2) = 2.275 Å for 10a and Pd−Cl(1) = 2.282 Å for
10c] reflects the stronger trans influence of the phosphine
terminus. Both complexes show the expected square-planar
B
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geometry in the Pd center, with the ligand-containing pallada-
cycle adopting a slightly distorted envelope-like conformation
that places the Pd atom below the plane defined by P−C(1)−
C(2)−C(3) (conformer EPd in Figure 6), the angle between this
enantioselectivities ranging from er 59:41 to 88:12 (entries
1−3). The analysis of these results indicates that, as previously
observed in related catalysts12,15 or auxiliaries,20 the pyrrolidine-
based phosphino hydrazones 2a,c provide better chiral
environments than the piperidine-based analogue 2b, a fact
that can be attributed to the higher conformational rigidity
associated with the stronger n−π conjugation. Though better
enantioselectivity (er = 95:5) was observed using the previously
reported bis-hydrazone 1 as the ligand under the same reaction
conditions, ligands 2a and 2c can be considered as promising
alternatives in terms of catalytic activity. Thus, the reaction
carried out with 1 required 7 days (versus 15 h for 2a or 2c) to
afford a lower 61% yield.21 Additional structural variability was
introduced by modification of the phosphino moiety. Thus,
ligands 2d−h with different PAr2 groups were synthesized by
reaction of the corresponding diarylphosphinobenzaldehydes
16d−h, available from a common intermediate 14 via acetals
15d−h,22 with (2S,5S)-1-amino-2,5-diphenylpyrrolidine 9a
(Scheme 2). Following a modified procedure, the synthesis of
Figure 6. Envelope-like conformations in complexes 10.
plane and the Pd coordination plane [defined by P−N−Pd−
Cl(1)−Cl(2)] being 55.3° and 54.1°, respectively. As the most
significant difference, the structure of 10c exhibits an apical Pd−
H interaction with the tertiary isopropyl CH bond [Pd−H(27) =
2.677 Å]. In solution, an alternative conformation with the Pd
atom placed above the mentioned plane (PdE in Figure 6) could
in principle be considered, but it can be disregarded for the
severe steric interaction that would arise between one of the
chlorine atoms and the R group in the nearest stereogenic center
if the n−π conjugation is preserved.
a
Scheme 2. Synthesis of Phosphino Hydrazone Ligands 2d−i
Precatalysts prepared in situ from ligands 2a−c were then
tested in the asymmetric Suzuki−Miyaura reaction. To this aim,
1-bromo-2-methoxynaphthalene 11c and 1-naphthyl boronic
acid 12a (Table 1) were chosen as model substrates, a relatively
Table 1. Screening of P/N Ligands in the Reaction of 11c
a
with 12a
b
c
d
entry
precat
R in PR2
time (h) yield (%)
er
1
2
2a/[Pd]
2b/[Pd]
2c/[Pd]
2d/[Pd]
2e/[Pd]
2f/[Pd]
2g/[Pd]
2h/[Pd]
2i/[Pd]
18/[Pd]
19/[Pd]
10a
Ph
Ph
Ph
15
15
15
24
24
24
24
24
24
15
15
15
15
90
91
80
72
53
86
81
99
20
97
94
97
90
83:17
59:41
88:12
79:21
53:47
75:25
72:28
68:32
50:50
50:50
50:50
78:22
90:10
3
4
p-MeOC6H3
5
3,5-(CF3)2C6H3
6
3,5-Me2C6H4
a
Reagents and conditions: (a) acetone/H2O, p-TsOH (cat.), reflux;
7
p-FC6H4
o-tolyl
Cy
(b) toluene, rt; (c) (1) tBuLi, Et2O, −78 °C; (2) ClPCy2, −78 °C→ rt;
(3) acetone/H2O, p-TsOH (cat.), reflux; (d) 9a, toluene, rt; (e) HSiCl3,
Et3N, toluene, reflux.
8
9
10
11
12
13
Ph
Ph
e
the dicyclohexyl derivative 2i was accomplished from phosphine
oxide intermediate 17 by condensation with 9a followed by
reductive deoxygenation of the resulting product 18. Finally,
a “privileged” ligand such as (S)-4-tert-butyl-2-[2-(diphenyl-
phosphino)phenyl]-2-oxazoline 1923 was included in the study
for comparative purposes.
Ph
10c
Ph
a
Reactions were performed at room temperature on a 0.1 mmol scale.
b
c
[Pd] = PdCl2(CH3CN)2. Isolated yields after column chromatog-
d
e
raphy. Determined by HPLC on chiral stationary phases. A catalyst
loading of 1 mol % afforded 13a in 70% yield and er = 81:19 after 48 h.
The behavior of these modified ligands was analyzed using
the same model reaction for comparison. Unfortunately, a
higher steric demand by the PAr2 group had a detrimental effect
in the enantioselectivity (entries 5, 6, and 8). Taking ligand 2a
as a reference, the modulation of the donor ability of the P
atom by introduction of electron-donating (entries 4 and 8) or
-withdrawing (entries 5 and 7) functionalities in the Ar rings
demanding system for the poor reactivity of the electron-rich
bromide and the possible interferences introduced by the
neighbor methoxy group. The reactions carried out at room
temperature in toluene as the solvent and using Cs2CO3 as the
base afforded the desired coupling product 13a19 in excellent
yields (89−97%), confirming a very good catalytic activity, with
C
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was also unsuccessfully investigated. Unexpectedly, dicyclohexyl
derivative 2i showed a poor catalytic activity and afforded
the product 13a in racemic form (entry 9). This result suggests
that a much better P donor facilitated decoordination of the
hydrazone N(sp2) atom, making the ligand behave as a
monodentate achiral phosphane.24 Finally, the catalysts
prepared in situ from phosphino oxazoline 19 were shown to
be active but not selective, affording 13a in a nearly quantitative
yield but in racemic form (entry 11). Reactions carried out with
preformed complexes 10a or 10c afforded slightly improved
results (entries 12 and 13), and therefore, these precatalysts
were used in successive studies aimed to explore the scope of
the new ligands in the asymmetric Suzuki−Miyaura cross-
coupling. Thus, a variety of aryl bromides or triflates 11, 20, and
21 were made to react with boronic acids 12 or 22 (Chart 1),
a much lower enantioselectivity (er 69:31, entry 3). In general, a
moderate level of enantioselectivity was observed for other 1,1′-
binaphthyl derivatives 13b−d (entries 4−7). More interesting
results were observed for the coupling of phenyl bromides
20a,c or triflate 20b with boronic acids 12a,b,e,f to afford the
phenyl−naphthyl coupling products 23a−d (entries 8−14) in
good enantiomeric ratios (er 89:11 to 92:8). Even the more
challenging coupling of 20c with 22 afforded the biphenyl
derivative 24 in good enantiomeric ratios (er up to 91:9, entries
15−17). Finally, the coupling of cyclic indanone 21 with
boronic acids 12a and 12b afforded coupling products 25a and
25b in good yields and enantiomeric ratios of 89:11 and 86:14,
respectively (entries 18 and 19). In general, diisopropyl-
substituted derivative 10c afforded slightly better results, but
diphenyl derivative 10a afforded competitive results in some cases
(entries 6, 9, and 15), providing the coupling products in much
better yields and similar enantioselectivities. Interestingly, these
results are complementary with those observed for catalysts based
in bis-hydrazone ligand 1. Thus, while 1 proved to be a superior
catalyst for the coupling of electron-rich and unfunctionalized
naphthyl bromides,12 this system was unsuccessfully applied
to the activation of electron-poor substrates such as 20 or 21
(8−19), even at higher temperatures. In contrast with the
couplings performed with C2-symmetric bis-hydrazones as
ligands,12 two possible regioisomers of the oxidative addition
intermediates must be considered for precatalysts 10. Because of
the higher trans influence of the phosphine ligand, the naphthyl
fragment should expectedly be placed at a position trans to the
hydrazone sp2 N atom, far away from the chiral environment
generated by the pyrrolidine ring.
Chart 1. Coupling Partners 11, 12, and 20−22
As the origin of the enantioselectivity is therefore not clear,
we decided to acquire additional information by performing a
structural study of the isolated oxidative addition intermediates.
To this aim, reaction of 1 equiv of ligand 2a with 1 equiv of
1-bromonaphthalene 11a in the presence of [Pd(COD)-
(CH2SiMe3)2]26 26 (Scheme 3) afforded the expected oxidative
addition intermediate 27a in 70% yield as a 1:1 mixture of
atropoisomers (31P NMR: δ 21.7 and 22.2 ppm). Crystallization
from CH2Cl2/acetone gave good quality yellow crystals that
were analyzed by X-ray diffractometry (Figure 7). Surprisingly,
the structure of 27a exhibits characteristics very similar to those
previously discussed for precatalyst 10a or its analogue 10c. As
in these cases, a high degree of conjugation in the hydrazone
moiety was again deduced from the N(sp3) pyramidalization
degree [expressed by the virtual angle N(1)−N(2)−C(20)−
C(23) = 163.4° and the torsion angle C(7)−N(1)−N(2)−
C(20) = 7.7(5)°]. Additionally, the complex shows again the
envelope-like EPd conformation, with the Pd coordination plane
[calculated as the plane fitting through P(1)−N(1)−Pd(1)−
C(36)−Br(1)] strongly deviated from the plane containing the
benzaldimine ring and the P and N atoms [plane fitting through
P(1)−C(1)−C(2)−C(7)−N(1); dihedral angle between planes
= 64.0°], with the Pd atom again placed on the opposite side
of the Ph group at the nearest stereogenic center. Although
X-ray structural analysis shows only one of the two possible
atropoisomers in the solid state [(Sa) configuration in the
C−Pd bond], this chiral axis proved to be configurationally
labile in solution, and a free rotation around the C−Pd bond
was observed at ∼80 °C; variable-temperature 31P NMR studies
showed coalescence of 31P signals to a single peak at 21.7 ppm.
Isolated intermediate 27a was treated with 2-methoxy-1-
naphthylboronic acid 12c to afford 13a in a 65% yield and
68:32 er (70:30 er was obtained in the catalytic reaction).
Chart 2. Coupling Products 13 and 23−25
affording the expected coupling products 13 and 23−25
(Chart 2, Table 2). In addition to the already mentioned
results for the model reaction (entries 1 and 2), the synthesis of
13a was alternatively performed from aryl bromide 11a and
boronic acid 12c, substrates with exchanged substitution
patterns. This reaction, however, does not take place at room
temperature, indicating that the catalyst is more sensitive to
steric bulk on the boronic acid 12 than on the aryl bromide 11.
Heating to 80 °C for 28 h was required for the reaction to
complete, affording the product 13a in good yield, though with
D
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Table 2. Asymmetric Suzuki−Miyaura Cross−couplings to Enantiomerically Enriched Biaryls
a
b
c
entry
ArX
Ar′B(OH)2
cat.
T (°C)
t (h)
product
conf
yield (%)
er
d
1
2
11c
11c
11a
11b
11d
11e
11e
20a
20b
20b
20c
20c
20c
20c
20c
20c
20c
21
12a
12a
12c
12a
12a
12a
12a
12b
12b
12b
12a
12a
12e
12f
22
10a
10c
10a
10c
10c
10a
10c
10c
10a
10c
10c
10c
10c
10c
10a
10c
10c
10c
10c
rt
rt
15
15
28
14
24
48
48
48
24
72
6
13a
13a
13a
13b
13c
13d
13d
23a
23a
23a
23b
23b
23c
23d
24
S
97
90
93
87
66
91
30
67
95
55
73
55
83
65
88
74
72
91
78:22
90:10
69:31
74:26
77:23
79:21
82:18
91:9
d
S
d
S
3
80
rt
e
4
R
g
5
rt
S
g
6
45
45
45
45
rt
S
g
7
S
f
8
S
f
9
S
90:10
92:8
f
10
11
12
13
14
15
16
17
18
19
S
g
rt
S
87:13
89:11
91:9
g
0
48
16
30
15
15
72
18
24
S
g
rt
S
g
)
rt
S
90:10
86:14
86:14
91:9
g
rt
R
R
R
g
g
22
rt
24
22
0
24
g
12b
12d
45
45
25a
25b
S
S
89:11
86:14
g
21
64
a
b
c
Reactions were performed at 0.1 mmol scale using 5 mol % of catalyst. Isolated yield after column chromatography. Determined by HPLC on
d
chiral stationary phases. The absolute configuration was assigned by comparison with literature data. See ref 19 and the Supporting Information.
e
f
The absolute configuration was assigned by comparison with literature data. See ref 25 and the Supporting Information. The absolute configuration
g
was assigned by chemical correlation after oxidation and condensation with dimethylbenzylamine. See ref 6g and the Supporting Information. The
absolute configuration was assigned by analogy.
Scheme 3. Synthesis of Oxidative Addition Intermediates
Figure 7. ORTEP drawing of intermediate 27a.
Following the same procedure as before, but using 1-bromo-2-
methoxynaphthalene 11c as the starting material, intermediate
27c was obtained as a 7:1 mixture of atropoisomers (31P NMR:
δ 25.4 and 26.1 ppm), but in this case the chiral axis proved to
be stable at temperatures up to 80 °C. Treatment of this mixture
with 1-naphthylboronic acid 12a at rt resulted in the formation
of the corresponding coupling product 13a in 92% yield
and 80:20 er (83:17 er was obtained in the catalytic reaction).
These data suggest that both the oxidative addition and the
transmetalation steps influence the stereochemical course of
the reaction. In the case of less hindered aryl bromides (as
demonstrated for 11a, proposed by analogy for 20a, 20b, and
21), a rapid interconversion of atropoisomeric C−Pd bonds
takes place in the oxidative addition step that, therefore, appears
to be irrelevant in terms of enantioselectivity. On the other
E
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7.88 (s, 2H), 7.76−7.73 (m, 1H), 7.67 (d, 3H, J = 6.4 Hz), 7.52 (t, 1H,
J = 7.6 Hz), 7.38 (t, 1H, J = 7.6 Hz), 6.94 (t, 1H, J = 6.4 Hz), 6.34 (d,
1H, J = 4 Hz), 4.06−3.95 (m, 4H); 13C NMR (100 MHz, CDCl3) δ
143.2 (d, J = 24 Hz), 140.0 (d, J = 17 Hz), 134.0, 133.0 (d, J = 19 Hz),
132.0 (d J = 6 Hz), 131.6 (m), 130.0, 129.6, 127.3 (d, J = 7 Hz), 122.9
(q, J = 271 Hz), 122.8 (m), 102.2 (d, J = 18 Hz), 65.1; 31P NMR
(161.7 MHz, CDCl3) δ −14.2. m/z (CI) 607 (M+ + 1, 75), 635 (20),
608 (20), 588 (30), 587 (100), 577 (85), 73 (45); HRMS (CI) m/z
calcd for C25H16O2F12P 607.0696, found 607.0689.
hand, the oxidative addition to more hindered aryl bromides
affords configurationally stable intermediates and the stereo-
chemical outcome in these cases could be mainly controlled by
the oxidative addition step.
CONCLUSIONS
■
In conclusion, readily available heterobidentate C2-symmetric
phosphino hydrazones from 2,5-disubstituted 1-aminopyrroli-
dines constitute a useful ligand class with interesting structural
features. As a first application, their corresponding L/PdCl2
complexes have been used in the asymmetric Suzuki−Miyaura
cross-coupling to afford functionalized biaryls in good yields
and enantioselectivities, the scope being complementary to that
of C2-symmetric bis-hydrazones.
2-(Di-3,5-dimethylphenylphosphino)benzaldehyde Ethyl-
ene Acetal (15f). Following the general procedure using
2-bromobenzaldehyde ethylene acetal 14 (3 mmol, 447 μL), t-BuLi
(6 mmol), and chlorobis(3,5-dimethylphenyl)phosphine (3.61 mmol,
1.0 g), flash chromatography (EtOAc/hexane 1:10) gave 15f (720 mg,
1
61%) as a white foam: H NMR (400 MHz, CDCl3) δ 7.69 (dd, 1H,
J = 7.2 and 3.6 Hz), 7.39 (t, 1H, J = 7.4 Hz), 7.29−7.25 (m, 1H),
7.01−6.98 (m, 1H), 6.95 (s, 2H), 6.88 (d, 4 H, J = 8 Hz), 6.44 (d, 1H,
J = 4.8 Hz), 4.13−4.01 (m, 2H), 4.00−3.97 (m, 2H), 2.25 (s, 12H);
13C NMR (100 MHz, CDCl3) δ 142.0 (d, J = 21 Hz), 137.7 (d, J = 7
Hz), 136.6 (d, J = 9 Hz), 134.2, 131.4 (d, J = 20 Hz), 130.4, 129.7,
129.1 (d, J = 21 Hz), 126.2 (d, J = 6 Hz), 101.7 (d, J = 24 Hz), 65.4,
21.3; 31P NMR (161.7 MHz, CDCl3) δ −17.2. m/z (CI) 391 (M+ + 1,
100), 390 (25); HRMS (CI) m/z calcd for C25H28O2P 391.1827,
found 391.1823.
2-(Di-4-fluorophenylphosphino)benzaldehyde Ethylene
Acetal (15g). Following the general procedure using 2-bromoben-
zaldehyde ethylene acetal 14 (3.25 mmol, 485 μL), t-BuLi (6.5 mmol),
and chlorobis(4-fluorophenyl)phosphine (3.9 mmol, 1 g), flash
chromatography (EtOAc/hexane 1:10) gave 15g (650 mg, 54%) as
a white foam. Spectroscopic and physical data matched those reported
in the literature:37 m/z (CI) 371 (M+ + 1, 50), 351 (25), 341 (100),
297 (30); HRMS (CI) m/z calcd for C21H18F2O2P 371.1012, found
371.0999.
2-(Di-o-tolylphosphino)benzaldehyde Ethylene Acetal
(15h). Following the general procedure using 2-bromobenzaldehyde
ethylene acetal 14 (4.8 mmol, 715 μL), t-BuLi (9.6 mmol), and
chlorobis(o-tolyl)phosphine (4.02 mmol, 1.0 g), flash chromatography
(EtOAc/hexane 1:10) gave 15h (950 mg, 55%) as a white foam.
Spectroscopic and physical data matched those reported in the
literature.38
General Procedure for the Synthesis of Phosphine
Aldehydes 16d−h. Ethylene acetal 15d−h (1 mmol) was dissolved
in acetone (14 mL) and H2O (0.5 mL), and a catalytic amount of
p-toluenesulfonic acid was added. The reaction mixture was heated to
reflux overnight, cooled to rt, diluted with Et2O, and washed with
H2O. The organic layer was dried, concentrated, and purified by flash
chromatography. Yields and characterization data for compounds 16
are as follows:
2-(Di-4-fluorophenylphosphino)benzaldehyde (16d). Follow-
ing the general procedure using 2-(di-4-methoxyphenylphosphino)-
benzaldehyde ethylene acetal 15d (2.01 mmol, 1.02 g), flash chromato-
graphy (EtOAc/hexane 1:7) gave 16d (614 mg, 66%) as a yellow foam.
Spectroscopic and physical data matched those reported in the
literature:37 m/z (CI) 350 (M+, 85), 352 (25), 351 (100), 321 (25),
243 (20); HRMS (CI) m/z calcd for C21H19O3P 350.1072, found
350.1081.
2-(Di-3,5-bistrifluoromethylphenylphosphino)benzaldehyde
(16e). Following the general procedure using 2-(di-3,5-
bistrifluoromethylphenylphosphino)benzaldehyde ethylene acetal 15e
(1.21 mmol, 734 mg), flash chromatography (EtOAc/hexane 1:10)
gave 16e (560 mg, 82%) as a white foam: 1H NMR (500 MHz,
CDCl3) δ 10.12 (d, 1H, J = 3.5 Hz), 8.09−8.05 (m, 1H), 7.91 (s, 2H),
7.71 (t, 1H, J = 7.5 Hz), 7.68 (d, 3H, J = 6.5 Hz), 7.61 (t, 1H, J = 7.5
Hz), 6.87 (dd, 1H, J = 7.5 and 4.6 Hz); 13C NMR (100 MHz, CDCl3)
δ 192.0−191.9 (m), 139.7 (d, J = 18 Hz), 138.6 (dd, J = 15 and 6 Hz),
136.3 (dd, J = 29 and 3 Hz), 135.6 (dd, J = 10 and 4 Hz), 134.5 (d, J =
4 Hz), 133.8 (m), 132.9−132.0 (m), 130.4, 129.9, 123.7−123.6 (m),
123.2 (q, J = 271 Hz); 31P NMR (202.4 MHz, CDCl3) δ −11.6. m/z
(CI) 563 (M+ + 1, 100), 591 (25), 564 (25), 562 (75), 544 (25),
EXPERIMENTAL SECTION
■
General Experimental Methods. Solvents were purified and
dried by standard procedures. Flash chromatography was carried out
on silica gel (40−63 μm or 15−40 μm). Melting points were recorded
in a metal block and are uncorrected. 1H NMR spectra were recorded
at 300, 400, or 500 MHz; 13C NMR spectra were recorded at 75, 100
or 125 MHz, with the solvent peak used as the internal reference. CI
and FAB mass spectra and high resolution mass spectra were recorded
in an AUTOSPEC-Q mass spectrometer (three sectors high-resolution
mass spectrometer with added quadrupole). EI mass spectra and
high-resolution mass spectra were recorded in a QTRAP mass spectro-
meter (hybrid triple quadrupole/linear ion trap mass spectrometer).
Comercially available boronic acids were used as received.
2-(Diphenylphosphino)benzaldehyde, 1-bromo-2-methylnaphtalene
(90%), and (3R,6R)-2,7-dimethyl-3,6-octanediol were purchased
from commercial suppliers. (2S,5S)-1-Amino-2,5-diphenylpyrrolidine
and (2S,6S)-1-amino-2,6-diphenylpiperidine were prepared as de-
scribed previously.15 Palladium complex [Pd(CH3CN)2Cl2],26
1-bromo-2-methoxynaphthalene,27 1-naphthyl-2-methoxyboronic
acid,28 1-naphthyl-2-methylboronic acid,29 methyl 1-bromo-2-naph-
thoate,30 2-bromo-3-methylbenzaldehyde,31 7-trifluoromethanesulfon-
yl-1-indanone,32 2-acetylphenyl trifluoromethanesulfonate,33 methyl
2-trifluoromethanesulfonyloxybenzoate,34 and o-trifluoromethanesul-
fonyl salicylaldehyde35 were prepared according to the literature
procedures. Enantiomeric excesses (ee) were measured by HPLC
i
on chiral stationary phases with PrOH/n-hexane mixtures as the
eluents.
General Procedure for the Synthesis of Phosphino Ethylene
Acetals 15. A solution of 2-bromobenzaldehyde ethylene acetal 14 in
Et2O was cooled to −78 °C, and t-BuLi was added. The reaction
mixture was stirred at −78 °C for 1 h, and then the corresponding
chlorodiarylphosphine was added dropwise and the reaction was
allowed to warm slowly to room temperature and was stirred overnight.
H2O was added, and the layers were separated. The aqueous portion
was extracted with Et2O, the combined organics were dried and
concentrated, and the resulting residue was purified by flash
chromatography. Yields and characterization data for compounds 15
are as follows:
2-(Di-4-methoxyphenylphosphino)benzaldehyde Ethylene
Acetal (15d). Following the general procedure using 2-bromobenzal-
dehyde ethylene acetal 14 (2.97 mmol, 443 μL), t-BuLi (5.94 mmol),
and chlorobis(4-methoxyphenyl)phosphine (3.56 mmol, 1 g), flash
chromatography (EtOAc/hexane 1:7) gave 15d (1.04 g, 88%) as a
white foam. Spectroscopic and physical data matched those reported
in the literature:37 m/z (CI) 395 (M+ + 1, 45), 366 (20), 365 (100),
321 (35), 287 (20); HRMS (CI) m/z calcd for C23H24O4P 395.1412,
found 395.1419.
2-(Di-3,5-bistrifluoromethylphenylphosphino)benzaldehyde
Ethylene Acetal (15e). Following the general procedure using
2-bromobenzaldehyde ethylene acetal 14 (1.69 mmol, 252 μL), t-BuLi
(3.38 mmol), and chlorobis(3,5-bistrifluoromethylphenyl)phosphine
(2.03 mmol, 1 g), flash chromatography (EtOAc/hexane 1:10) gave
15e (734 mg, 72%) as a yellow foam: 1H NMR (400 MHz, CDCl3) δ
F
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543 (90), 533 (20); HRMS (CI) m/z calcd for C23H12OF12P
563.0434, found 563.0451.
(d, JC,P = 14 Hz), 136.1 (d, JC,P = 12 Hz), 133.8 (d, JC,P = 9 Hz), 133.7
(d, JC,P = 10 Hz), 133.1, 130.8 (d, JC,P = 28 Hz), 128.7, 128.5, 128.4,
128.3, 128.3, 128.1, 127.6, 126.9, 126.5, 125.9 (d, JC,P = 14 Hz), 124.2
(d, JC,P = 5 Hz), 61.1, 30.6, 18.5; 31P NMR (161.7 MHz, CDCl3)
δ −16.0; m/z (CI) 525 (M+ + 1, 10), 290 (60), 288 (20), 238 (100),
236 (70); HRMS (CI) m/z calcd for C36H34N2P 525.2460, found
525.2463.
2-(Di-3,5-dimethylphenylphosphino)benzaldehyde (16f).
Following the general procedure using 2-(di-3,5-dimethylphenyl-
phosphino)benzaldehyde ethylene acetal 15f (700 mg, 1.79 mmol),
flash chromatography (EtOAc/hexane 1:10) gave 16f (520 mg, 84%)
as a white foam. Spectroscopic and physical data matched those
reported in the literature.39
(2S,5S)-1-[2-(Diphenylphosphino)benzylideneamino]-2,5-
diisopropylpyrrolidine (2c). A solution of (3R,6R)-2,7-dimethyl-
loctane-3,6-diol (244 mg, 1.40 mmol) and Et3N (490 μL, 3.5 mmol,
2.5 equiv) in dry CH2Cl2 (3 mL) was cooled to −30 °C, and MsCl
(275 μL, 3.5 mmol) was dropwise added. The reaction mixture was
warmed to room temperature and was stirred overnight at this
temperature. NH4Cl (saturated aqueous solution, 5 mL) was added,
and the organic phase washed with water, brine, and satd NaHCO3.
The organic layer was dried (MgSO4), concentrated to dryness, and
redissolved in 2-propanol (1.5 mL). NH2NH2·H2O (2.0 mL, 42 mmol,
30 equiv) was then added, and reaction mixture was vigorously stirred
at 60 °C for 14 h. The reaction crude was cooled to rt, diluted with
Et2O (10 mL), washed with satd NaHCO3 (2 × 5 mL) and brine
(1 × 5 mL), and dried (MgSO4). The resulting crude hydrazine
(1.38 mmol, 235 mg) was used according to the general procedure for
the synthesis of hydrazones. Flash chromatography (toluene/hexane
1:2, 1% Et3N) gave 2c (519 mg, 85%) as a white foam: [α]20D −153.4
(c 1.2, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.92 (ddd, 1H, J = 7.8,
4.2, 0.6 Hz), 7.45 (d, 1H, J = 5.1 Hz), 7.36−7.25 (m, 12H), 7.00 (t,
1H, J = 7.5 Hz), 6.68 (ddd, 1H, J = 7.7, 5.5, 0.9 Hz), 3.58 (m, 2H),
2.11−2.02 (m, 2H), 1.77−1.68 (m, 2H), 1.66−1.56 (m, 2H), 0.78 (d,
6H, J = 6.9 Hz), 0.58 (d, 1H, J = 6.6 Hz); 13C NMR (100 MHz,
CDCl3) δ 136.6, 134.6, 134.3 (d, JC,P = 20 Hz), 133.9 (d, JC,P = 20 Hz),
132.8, 129.7, 128.7 (d, JC,P = 7 Hz), 128.5 (d, JC,P = 7 Hz), 128.4,
125.8, 123.3, 65.8, 28.2, 23.4, 19.4, 16.0; 31P NMR (161.7 MHz,
CDCl3) δ −12.3; HRMS (CI) m/z calcd for C29H35N2P 442.2538,
found 442.2540.
2-(Di-4-fluorophenylphosphino)benzaldehyde (16g). Follow-
ing the general procedure using 2-(di-4-fluorophenylphosphino)-
benzaldehyde ethylene acetal 15g (1.31 mmol, 638 mg), flash
chromatography (EtOAc/hexane 1:10) gave 16g (402 mg, 69%) as
1
a white foam: H NMR (500 MHz, CDCl3) δ 10.52 (d, 1H, J = 1.2
Hz), 7.99−7.95 (m, 1H), 7.88−7.84 (m, 1H), 7.60 (dd, 1H, J = 8.3
and 1.8 Hz), 7.50−7.48 (m, 3H), 7.37−7.33 (m, 3H), 7.30−7.27 (m,
2H), 6.99−6.97 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 191.7 (d,
J = 19 Hz), 138.5 (d, J = 15 Hz), 136.1 (d, J = 9.8 Hz), 134.1 (d, J =
20 Hz), 133.7 (d, J = 28.2 Hz), 130.6 (d, J = 3.9 Hz), 128.9 (d, J =
31.1 Hz), 128.7 (d, J = 7 Hz); 31P NMR (202.4 MHz, CDCl3) δ −11.6
m/z (CI) 326 (M+, 75), 327 (100), 307 (20), 297 (40); HRMS (CI)
m/z calcd for C19H13F2OP 326.0672, found 326.0671.
2-(Di-o-tolylphosphino)benzaldehyde (16h). Following the
general procedure using 2-(di-o-tolylphosphino)benzaldehyde ethyl-
ene acetal 15h (920 mg, 2.54 mmol), flash chromatography (EtOAc/
hexane 1:10) gave 16h (729 mg, 90%) as a white foam. Spectroscopic
and physical data matched those reported in the literature.38
2-(Dicyclohexylphosphoryl)benzaldehyde (17). Following the
general procedure for the lithiation/phosphonylation step and using
2-bromobenzaldehyde ethylene acetal 14 (1.15 g, 5 mmol), the
corresponding, oxidized phoshoryl acetal was obtained and used in the
acetal deprotection step without purification. Following the general
procedure for the acetal deprotection step, flash chromatography
(EtOAc/n-hexane 1:2) gave 17 (1.2 g, 80%) as a colorless viscous oil:
1H NMR (500 MHz, CDCl3) δ 10.78 (br s, 1H), 8.01 (br s, 1H),
(2S,5S)-1-[2-(Di-4-methoxyphenylphosphino)benzylideneamino]-
7.72−7.65 (m, 3H), 2.21−2.05 (m, 4H), 1.82−1.62 (m, 6H), 1.40−
1.02 (m, 12H); 13C NMR (125 MHz, CDCl3) δ 193.7, 132.7, 132.6,
131.5, 131.3, 36.3, 35.7, 26.3, 26.2, 26.1, 25.7, 25.6, 25.2; 31P NMR
(202.4 MHz, CDCl3) δ +50.8; HRMS (CI) m/z calcd for C19H27O2P
318.1749, found 318.1750.
General Procedure for the Synthesis of Hydrazones 2a−h
and 18. Aldehyde 7, 16d−h, or 17 (1 mmol) was added to a stirred
solution of the corresponding hydrazine (1.4 mmol) in toluene (2 mL).
The reaction mixture was stirred at rt for 3 h, and then the reaction
crude was concentrated to dryness and purified by flash chromatog-
raphy. Yields and characterization data for compounds 2a−i are as
follows:
2,5-diphenylpyrrolidine (2d). Following the general procedure,
flash chromatography (EtOAc/n-hexane 1:7) gave 2d (656 mg, 83%)
1
as a light yellow foam: [α]20 −92.0 (c 0.8, CHCl3); H NMR (400
D
MHz, CDCl3) δ 7.63 (dd, 1H, J = 7.8, 4.2 Hz), 7.40 (d, 1H, J = 5.5
Hz), 7.30−7.24 (m, 5H), 7.20 (d, 2H, J = 7.2 Hz), 7.11 (dd, 6H, J =
6.8, 1.6 Hz), 6.96 (t, 1H, J = 7.6 Hz), 6.92−6.87 (m, 4H), 6.71 (d, 2H,
J = 8.8 Hz), 6.67−6.63 (m, 1H), 5.01 (d, 2H, J = 6.8 Hz), 3.83 (s, 3H),
3.79 (s, 3H), 2.48−2.44 (m, 2H), 1.79−1.71 (m, 2H); 13C NMR (100
MHz, CDCl3): δ 159.9 (d, JC,P = 22 Hz), 143.2, 135.5 (d, JC,P = 21
Hz), 135.1 (d, JC,P = 21 Hz), 132.5, 128.4 (d, JC,P = 2 Hz), 128.3, 126.6,
126.4 (d, JC,P = 2 Hz), 126.1, 114.1 (d, JC,P = 4 Hz), 114.0 (d, JC,P = 4
Hz), 65.2, 55.2, 55.1, 31.3; 31P NMR (161.7 MHz, CDCl3) δ −17.0;
m/z (CI) 569 (M+ −1); HRMS (CI) m/z calcd for C37H34N2O2P
569.2358, found 569.2349.
(2S,5S)-1-[2-(Diphenylphosphino)benzylideneamino]-2,5-di-
phenylpyrrolidine (2a). Following the general procedure, flash
chromatography (toluene/n-hexane 1:2, 1% Et3N) gave 2a (683 mg,
1
97%) as a white foam: [α]20 −192.6 (c 1.0, CHCl3); H NMR (400
(2S,5S)-1-[2-(Di-3,5-bistrifluoromethyphenylphosphino)-
benzylideneamino]-2,5-diphenylpyrrolidine (2e). Following the
general procedure, flash chromatography (EtOAc/n-hexane 1:10) gave
D
MHz, CDCl3) δ 7.9−7.6 (m, 1H), 7.46 (d, 1H, J = 4.1 Hz), 7.32−7.09
(m, 20H), 6.94 (t, 2H, J = 7.5 Hz), 6.67 (d, 1H, J = 5.1 Hz), 5.00 (d,
2H, J = 5.9 Hz), 2.49−2.43 (m, 2H), 1.74−1.71 (m, 2H); 13C NMR
(125 MHz, CDCl3) δ 143.2, 140.7 (d, JC,P = 19 Hz), 137.1 (d, JC,P = 11
Hz), 136.1 (d, JC,P = 11 Hz), 133.9 (d, JC,P = 19 Hz), 133.6 (d, JC,P = 19
Hz), 132.9, 130.5 (d, JC,P = 26 Hz), 128.5, 128.3, 128.2, 126.6, 126.5,
126.4, 126.0, 124.3 (d, JC,P = 4 Hz), 65.2, 31.3; 31P NMR (161.7 MHz,
CDCl3) δ −14.5; m/z (CI) 511 (M+ + 1, 65), 288 (100), 222 (70);
HRMS (CI) m/z calcd for C35H31N2P 511.2303, found 511.2307.
Anal. Calcd for C35H31N2P: C, 82.35; H, 6.07; N, 5.48. Found: C,
81.90; H, 6.17; N, 5.23.
2e (973 mg, 90%) as a light yellow viscous oil: [α]20 −59.1 (c 0.8,
D
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.61 (s, 1H),
7.43−7.40 (m, 3H), 7.33 (d, 2H, J = 6.4 Hz), 7.29 (d, 1H, J = 8.4 Hz),
7.23 (d, 4H, J = 7.6 Hz), 7.19−7.14 (m, 3H), 7.06−7.00 (m, 5H), 6.50
(dd, 1H, J = 6.6, 4.4 Hz), 4.95 (d, 2H, J = 6.8 Hz), 2.47−2.42 (m-2H),
1.78−1.71 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 158.3, 142.0,
140.9, 133.7, 133.6 (m), 133.4 (m), 132.8 (m), 132.6 (m), 129.9 (q,
JC,F = 272 Hz), 129.8, 128.5, 128.4, 127.4 (d, JC,P = 11 Hz), 126.9,
125.9, 122.5−122.4 (m), 65.1, 31.1; 31P NMR (161.7 MHz, CDCl3) δ
−9.7. m/z (CI) 782 (M+); HRMS (CI) m/z calcd for C39H27F12N2P
782.1720, found 782.1717.
(2S,5S)-1-[2-(Diphenylphosphino)benzylideneamino]-2,5-di-
phenylpiperidine (2b). Following the general procedure, flash
chromatography (toluene/n-hexane 1:2, 1% Et3N) gave 2b (630 mg,
(2S,5S)-1-[2-(Di-3,5-dimethylphenylphosphino)-
benzylideneamino]-2,5-diphenylpyrrolidine (2f). Following the
general procedure, flash chromatography (EtOAc/n-hexane 1:15) gave
1
82%) as a white foam: [α]20 −148.3 (c 1.0, CHCl3); H NMR (500
D
MHz, CDCl3) δ 7.95 (d, 1H, J = 5.5 Hz), 7.49 (m, 1H), 7.39−7.29
(m, 12H), 7.25−7.20 (m, 6H), 7.14 (t, 1H, J = 7.5 Hz), 7.05 (t, 1H,
J = 7.5 Hz), 7.01 (t, 1H, J = 7.5 Hz), 6.73 (dd, 1H, J = 7.5, 5.0 Hz),
4.98 (t, 2H, J = 5.5 Hz), 2.09−2.00 (m, 4H), 1.60−1.58 (m, 2H);
13C NMR (125 MHz, CDCl3) δ 142.0, 141.0 (d, JC,P = 21 Hz), 137.1
2f (724 mg, 92%) as a light yellow viscous oil: [α]20 −125.0 (c 1.3,
D
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.66 (ddd, 1H, J = 8.0, 4.3,
1.3 Hz), 7.48 (d, 1H, J = 4.8 Hz), 7.27−7.23 (m, 4H), 7.19−7.15 (m,
2H), 7.14−7.12 (m, 4H), 6.99−6.95 (m, 2H), 6.86−6.85 (m, 1H),
G
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6.81−6.79 (m, 2H), 6.71−6.68 (m, 1H), 6.62−6.59 (m, 2H), 5.03 (d,
2H, J = 6.8 Hz), 2.54−2.37 (m-2H), 2.27 (s, 6H), 2.20 (s, 6H), 1.82−
1.74 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 143.2, 137.5 (d, JC,P = 7
Hz), 137.3 (d, JC,P = 7 Hz), 133.1, 131.8 (d, JC,P = 20 Hz), 131.3 (d, JC,P
= 19 Hz), 130.2, 128.3 (d, JC,P = 4 Hz), 128.2, 126.6, 126.5, 126.1,
124.2 (d, JC,P = 4 Hz), 65.3, 31.4, 21.3, 21.2; 31P NMR (161.7 MHz,
CDCl3) δ −14.7; m/z (CI) 782 (M+); HRMS (CI) m/z calcd for
C39H39N2P 566.2851, found 566.2847.
flask containing [PdCl2(CH3CN)2] (0.3 mmol, 75 mg). The reaction
mixture was stirred at room temperature overnight, concentrated
to dryness, washed with n-pentane, and dried in vacuo to give the
palladium dichloride complex. Yields and characterization data for
compounds 10a−c are as follows:
(2S,5S)-1-[2-(Diphenylphosphino)benzylideneamino]-2,5-di-
phenylpyrrolidine PdCl2 complex (10a). Prepared according to
the general procedure, 10a was obtained as an orange solid (167 mg,
84%). X-ray quality crystals were grown by slow diffusion of n-hexane
(2S,5S)-1-[2-(Di-4-fluorophenylphosphino)benzylideneamino]-
2,5-diphenylpyrrolidine (2g). Following the general procedure,
into a solution of 10a in CH2Cl2: mp = 206−208 °C dec; [α]20
=
D
−806.7 (c 0.3, CHCl3); 1H NMR (500 MHz, CD2Cl2, 25 °C) δ 7.46−
7.03 (m, 22H), 6.92 (dd, 1H, J = 7.5, 4.5 Hz), 6.76 (dd, 1H, J = 10.2,
8.1 Hz), 6.09 (br s, 2H), 2.61 (br s, 2H), 1.82 (br s, 2H); 13C NMR
flash chromatography (EtOAc/n-hexane 1:20) gave 2g (587 mg, 78%)
1
as a white foam: [α]20 −108.3 (c 0.9, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 7.64−7.61 (m, 1H), 7.37−7.30 (m, 2H), 7.26−7.14 (m,
6H), 7.14−7.07 (m, 6H), 7.04−6.97 (m, 4H), 6.91−6.81 (m, 3H),
6.61−6.58 (m, 1H), 5.02 (d, 2H, J = 6.8 Hz), 2.53−2.42 (m, 2H),
1.81−1.73 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 143.1, 135.9 (dd,
J = 21, 8 Hz), 135.3 (dd, J = 21, 8 Hz), 134.0 (d, J = 20 Hz), 133.7 (d,
J = 20 Hz), 133.0, 132.6, 129.9, 128.8, 128.6, 128.5, 128.4, 128.3,
128.2, 126.7, 126.6, 126.4, 126.1, 126.0, 124.8 (d, JC,P = 4 Hz), 65.2,
31.4; 31P NMR (161.7 MHz, CDCl3) δ −16.2; m/z (CI) 546 (M+);
HRMS (CI) m/z calcd for C35H29F2N2P 546.2036, found 546.2035.
(2S,5S)-1-[2-(Di-o-tolylphosphino)benzylideneamino)-2,5-di-
phenylpyrrolidine (2h). Following the general procedure, flash
chromatography (toluene/n-hexane 1:2) gave 2h (635 mg, 85%) as a
light yellow foam: [α]20D −138.2 (c 1.2, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.70 (dd, 1H, J = 7.3 and 4.3 Hz), 7.50 (d, 1H, J = 5.5 Hz),
7.24−7.23 (m, 5H), 7.20−7.17 (m, 4H), 7.12−7.10 (m, 3H), 7.07−
7.05 (m, 1H), 6.95 (t, 2H, J = 7.3 Hz), 6.68 (dd, 1H, J = 6.8, 4.3 Hz),
6.60 (dd, 1H, J = 7.0, 4.5 Hz), 6.54 (dd, 1H, J = 6.8, 4.3 Hz), 5.02 (d,
2H, J = 6.5 Hz), 2.49−2.45 (m-2H), 2.27 (s, 3H), 2.06 (s, 3H), 1.78−
(125 MHz, CD2Cl2, 25 °C) δ 140.3 (d, JC−P = 8 Hz), 138.5 (d, JC−P
=
14 Hz), 134.7, 134.6, 134.0 (d, JC−P = 11 Hz), 133.7 (d, JC−P = 9 Hz),
133.1, 132.8 (d, JC−P = 11 Hz), 132.4, 131.7, 130.5 (d, JC−P = 8 Hz),
129.5 (d, JC−P = 12 Hz), 129.3, 129.1, 128.8 (d, JC−P = 12 Hz), 128.2
(d, JC−P = 11 Hz), 128.0, 127.8, 126.4, 124.6 (d, JC−P = 51 Hz), 117.8
(d, JC−P = 51 Hz), 67.4 (br s), 32.2; 31P NMR (202.4 MHz, CD2Cl2)
δ +28.1. m/z (CI) 616 (M+ − 2 Cl, 4), 511 (13), 288 (100); HRMS
(CI) m/z calcd for C35H31N2PPd 616.1260, found 616.1274.
(2S,5S)-1-[2-(Diphenylphosphinobenzylideneamino]-2,5-di-
phenylpiperidine PdCl2 Complex (10b). Prepared according to the
general procedure, starting from 2b (0.23 mmol, 118 mg) and
[PdCl2(CH3CN)2] (0.23 mmol, 59 mg), 10b was obtained as an
orange solid (147 mg, 91%): mp = 178−180 °C; [α]20D = −261.8 (c 0.3,
CHCl3); 1H NMR (300 MHz, CDCl3, 25 °C): δ 7.67−6.95 (m, 24H),
6.72 (dd, 1H, J = 9.9, 7.8 Hz), 6.50 (br s, 1H), 2.10−1.92 (m, 2H),
1.70−1.55 (m, 2H), 1.50−1.36 (m, 2H); 13C NMR (75 MHz, CDCl3,
25 °C): δ 148.0 (d, JC−P = 9 Hz), 141.5, 136.8 (d, JC−P = 11 Hz), 134.2
(d, JC−P = 10 Hz), 134.0, 133.2 (d, JC−P = 10 Hz), 132.8 (d, JC−P = 12
Hz), 132.3 (d, JC−P = 20 Hz), 131.5, 131.0 (d, JC−P = 8 Hz), 129.0,
128.8, 128.1, 127.9 (d, JC−P = 13 Hz), 126.9 (br s), 126.0 (d, JC−P = 25
Hz), 125.2, 124.5 (d, JC−P = 51 Hz), 118.7 (d, JC−P = 51 Hz), 64.3, 29.6,
18.1; 31P NMR (161.7 MHz, CDCl3, 25 °C) δ + 28.5. m/z (FAB) 665
(M+ − Cl, 24), 629, 154; HRMS (FAB) m/z calcd for C36H33N2PClPd
665.1105, found 665.1112.
1.77 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 143.1, 142.4 (d, JC,P
26 Hz), 141.3 (d, JC,P = 17 Hz), 134.8 (d, JC,P = 46 Hz), 133.4 (d, JC,P
=
=
33 Hz), 132.9, 129.9 (d, JC,P = 5 Hz), 128.6, 128.4, 128.3, 126.8, 126.6,
126.1, 126.0, 125.9, 125.8, 124.2, 65.3, 31.4, 26.9; 31P NMR (202.4
MHz, CDCl3) δ −31.2. m/z (EI) 538 (M+); HRMS (EI) m/z calcdfor
C37H35N2P 538.2538, found 538.2540.
(2S,5S)-1-[2-(Dicyclohexylphosphoryl)benzylideneamino]-
2,5-diphenylpyrrolidine (18). Following the general procedure,
(2S,5S)-1-[2-(Diphenylphosphino)benzylideneamino]-2,5-
isopropylpyrrolidine PdCl2 Complex (10c). Prepared according to
the general procedure, 10c was obtained as an orange solid (160 mg,
89%). X-ray quality crystals were grown by slow diffusion of diethyl
flash chromatography (EtOAc/n-hexane 1:2) gave 18 (491 mg, 66%)
1
as a light yellow foam: [α]20 −100.0 (c 0.8, CHCl3); H NMR (500
D
MHz, CDCl3) δ 7.39−7.36 (m, 4H), 7.32−7.27 (m, 9H), 7.14 (br s,
1H), 5.26 (br s, 2H), 2.62−2.56 (m, 2H), 1.90−1.81 (m, 4H), 1.77−
1.45 (m, 8H), 1.42−0.85 (m, 12H); 13C NMR (125 MHz, CDCl3) δ
130.6, 128.5, 126.8, 126.4, 126.2, 125.2 (d, JC,P = 9 Hz), 65.3 (br s),
37.3 (d, JC,P = 67 Hz), 31.3, 26.5 (d, JC,P = 12 Hz), 26.4, 26.3, 26.2,
26.2, 26.1, 24.8; 31P NMR (202.4 MHz, CDCl3) δ + 50.5; HRMS (EI)
m/z calcd for C35H43N2OP 538.3113, found 538.3112.
ether into a solution of 10c in CH2Cl2: mp = 153−155 °C; [α]20
=
D
1
−1036.0 (c 0.4, CHCl3); H NMR (500 MHz, CDCl3, 25 °C) δ 7.60
(br s, 2H), 7.50−7.37 (m, 10H), 7.23 (t, 1H, J = 7.0 Hz), 7.09 (m,
1H), 6.68 (dd, 1H, J = 9.5, 8.1 Hz), 2.33 (br s, 2H), 1.89 (br s, 2H),
1.75 (br s, 2H), 1.65 (br s, 2H), 0.84 (br d, J = 5.4 Hz, 12 H); 13C
NMR (75 MHz, CDCl3, 25 °C) broad signals were observed at 295 K;
some peaks were not observed, δ 134.8 (d, JC−P = 10 Hz), 134.1, 133.1,
132.9, 132.6 (d, JC−P = 10 Hz), 132.0, 131.8, 129.9 (d, JC−P = 8 Hz),
(2S,5S)-1-[2-(Dicyclohexylphosphino)benzylideneamino]-
2,5-diphenylpyrrolidine (2i). To a stirred solution under argon of
18 (0.5 mmol, 269 mg) in dry toluene (8 mL) were added dry Et3N
(15 mmol, 2.1 mL) and HSiCl3 (7.5 mmol, 750 μL). The reaction
mixture was stirred at 110 °C for 24 h, satd NaHCO3 (1 mL) was
added, and the reaction crude was filtered through Celite and
concentrated to dryness. Flash chromatography (EtOAc/n-hexane
129.3 (d, JC−P = 11 Hz), 128.1 (d, JC−P = 12 Hz), 22.7, 19.6, 16.0; 31
P
NMR (161.7 MHz, CDCl3) δ +28.1; m/z (CI) 548 (M+ − 2Cl, 20),
442 (100); HRMS (CI) m/z calcd for C29H35N2PPd (M+ − 2Cl)
547.9210, found 547.9203.
Isolation of Intermediate 27a. Following a described procedure,6g
a Schlenk tube was charged inside a drybox with ligand 2a (0.1 mmol,
39 mg) and [Pd(cod)(CH2TMS)2] (0.1 mmol, 39 mg). The Schlenk
tube was placed outside the drybox, and after cycles of vacuum−argon,
a solution of 1-bromonaphthalene (0.1 mmol, 28 μL) in dry and
deoxygenated THF (3 mL) was transferred via cannula. The reaction
mixture was stirred overnight at rt, and the precipitation of a yellow solid
was observed. The mixture was concentrated to dryness, and the yellow
solid was washed with dry, deoxygenated n-hexane and dried in vacuum
to obtain 58 mg (70%) of product. X-ray quality crystals were obtained
by slow evaporation of a solution of 27a in CH2Cl2/acetone mixture:
mp = 160−162 °C dec; [α]20D = −267.0 (c 0.3, CHCl3); 1H NMR (400
MHz, CDCl3, 25 °C) a 1:1 mixture of diastereoisomers in the C−Pd
bond was observed at this temperature, δ 8.56 (t, 1H, J = 7.6 Hz), 7.52−
6.93 (m, 27H), 6.88 (br s, 1H), 6.73 (br s, 2H), 6.45−6.36 (br s, 2H),
6.21 (t, 1H, J = 8.8 Hz), 2.70 (br s, 2H), 1.80 (br s, 2H); 13C NMR
(75 MHz, CDCl3, 25 °C) broad signals were observed at 25 °C and
1:20) gave 2i (150 mg, 57%) as a yellow foam: [α]20 −82.2 (c 0.9,
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.85 (d, 1H, J = 5.0 Hz), 7.75
(dd, 1H, J = 7.6, 3.0 Hz), 7.35−7.32 (m, 4H), 7.29−7.26 (m, 4H),
7.22−7.20 (m, 3H), 7.12 (t, 1H, J = 7.6 Hz), 7.05 (d, 1H, J = 7.6 Hz),
5.22 (d, 2H, J = 6.5 Hz), 2.61−2.52 (m, 2H), 1.88−1.72 (m, 4H),
1.70−1.55 (m, 4H), 1.53−1.39 (m, 4H), 1.36−1.15 (m, 8H), 1.05−
0.85 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 143.7, 131.9 (d, JC,P
=
35 Hz), 128.4, 128.2, 126.6, 126.3, 125.5, 124.0 (d, JC,P = 4 Hz), 65.0,
34.0 (d, JC,P = 15 Hz), 32.1 (d, JC,P = 12 Hz), 31.4, 30.0 (br s), 29.7,
29.3, 34.0 (d, JC,P = 8 Hz), 27.9, 27.4 (d, JC,P = 14 Hz), 27.1 (d, JC,P = 8
Hz), 27.0 (d, JC,P = 13 Hz), 26.8 (d, JC,P = 9 Hz), 26.4, 26.1; 31P NMR
(202.4 MHz, CDCl3) δ −18.7; HRMS (EI) m/z calcd for C35H43N2P
522.3164, found 522.3162.
General Procedure for the Synthesis of Palladium Complexes
10a−c. A solution of 2a−c (0.3 mmol) in dry CH2Cl2 (5 mL) under
argon was transferred via cannula to a deoxygenated round-bottom
H
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some peaks were not observed, δ 139.8, 139.1, 138.6, 138.0, 135.4, 134.6,
134.0, 133.8, 133.6, 133.4, 133.2, 132.6, 132.5, 132.4, 131.9, 131.8, 131.4,
131.3, 130.7, 130.5, 129.3, 129.1, 128.8, 128.7, 128.6, 128.5, 128.2, 127.4,
127.3, 127.2, 127.0, 126.8, 126.2, 125.5, 124.3, 123.7, 123.4, 122.9, 122.7,
122.5, 65.7 (br s), 31.5, 31.2; 31P NMR (161.7 MHz, CDCl3) δ +22.2,
21.7 (31P signals coalesce to only one peak at 21.7 ppm at 80 °C);
HRMS (CI) m/z calcd for C45H38BrN2PPd 822.0991, found 822.0989.
General Procedure for the Suzuki Coupling Reactions. In a
typical run, a dried Schlenk tube containing a magnetic stir bar was
charged with Cs2CO3 (2 equiv, 65.2 mg), 5 mol % of catalyst, and
boronic acid (0.15 mmol). After cycles of vacuum−argon (three times),
dry solvent (0.5 mL) and aryl bromide or triflate (0.1 mmol) were
added (solid aryl bromides or triflates were added during the initial
charge). The Schlenk tube was sealed, and the reaction mixture was
stirred at rt−80 °C until consumption of the aryl bromide (by TLC).
The reaction mixture was filtered through Celite and concentrated
under reduced pressure, and the crude was purified by flash
chromatography using n-hexane or n-hexane/EtOAc mixture as solvents.
Yields and characterization data for compounds 13, and 23−25 are as
follows:
3.1 mg) and toluene (0.5 mL) as solvent, after 48 h at 45 °C, flash
chromatography (n-hexane → n-hexane/EtOAc 100:1) gave 16.5 mg
(67%) of the title compound as a white solid: [α]20 −21.0 (c 1.1,
D
CHCl3) for 82% ee; 1H NMR (400 MHz, CDCl3) δ 9.50 (s, 1H), 8.13
(d, 1H, J = 8.0 Hz), 7.85 (t, 2H, J = 8.0 Hz), 7.72 (t, 1H, J = 7.5 Hz),
7.58 (t, 1H, J = 7.0 Hz), 7.46−7.43 (m, 2H), 7.37−7.32 (m, 2H), 7.19
(d, 1H, J = 9.5 Hz) 2.17 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
192.1, 143.8, 134.7, 134.2, 133.3, 133.2, 131.8, 131.5, 128.3, 128.2,
128.1, 127.9, 127.2, 126.5, 125.7, 125.2, 20.8; m/z (EI) 246 (M+, 100);
HRMS (EI) m/z calcd for C18H14O 246.1045, found 246.1049; HPLC
(Daicel Chiralpak IC, 2-propanol/n-hexane 1:99, flow 1.0 mL/min,
T = 30 °C) tR 7.9 min (major) and 9.3 min (minor).
3-Methyl-2-naphthylbenzaldehyde (23b) (Table 2, Entry 13).
Following the general procedure, using the catalyst 10c (5 mol %,
3.1 mg) and toluene (0.5 mL) as solvent, after 48 h at 0 °C, flash
chromatography (n-hexane → n-hexane/EtOAc 100:1) gave 14.0 mg
(55%) of the title compound as a colorless oil: [α]20 + 242.0
D
1
(c 0.55, CHCl3) for 79% ee; H NMR (300 MHz, CDCl3) δ 9.46 (d,
1H, J = 0.9 Hz), 7.93−7.96 (m, 3H), 7.60−7.48 (m, 4H), 7.40−7.27
(m, 3H), 1.99 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 192.5, 143.6,
138.3, 135.4, 135.2,134.4, 133.5, 132.5, 128.5, 128.4, 128.0, 127.9,
126.8, 126.2, 125.6, 125.2, 124.6, 19.5; m/z (EI) 246 (M+, 100);
HRMS (EI) m/z calcd for C18H14O 246.1045, found 246.1048. HPLC
(Daicel Chiralpak IC, 2-propanol/n-hexane 1:99, flow 1.0 mL/min,
T = 30 °C) tR 11.1 min (major) and 11.8 min (minor).
(S)-2-Methoxy-1,1′-binaphthyl (13a) (Table 2, Entry 2).
Following the general procedure, using the catalyst 10c (5 mol %,
3.1 mg) and toluene (0.5 mL) as solvent, after 15 h at room temp-
erature, flash chromatography (n-hexane → n-hexane/EtOAc 200:1)
gave 25.6 mg (90%) of the title compound as a white solid: [α]20
D
+8.0 (c 1.0, CHCl3) for 80% ee [lit.40 [α]25D= −31.4 (c 2.1, THF) for
(R)-enantiomer with 99% ee]. Spectroscopic and physical data
matched those reported in the literature.12 HPLC (Chiracel OJ,
2-propanol/n-hexane 5:95, flow 1.0 mL/min, T = 30 °C) tR 10.76 min
(major) and 21.08 min (minor).
3-Methyl-2-acenaphthalenebenzaldehyde (23c) (Table 2,
Entry 14). Following the general procedure, using the catalyst 10c
(5 mol %, 3.1 mg) and toluene (0.5 mL) as solvent, after 16 h at room
temperature flash chromatography (toluene/n-hexane 1:2) gave
22.5 mg (83%) of the title compound as a colorless oil: [α]20 +44.0
D
1
(c 1.65, CHCl3) for 82% ee; H NMR (500 MHz, CDCl3) δ 9.52 (d,
(R)-2-Methyl-1,1′-binaphthyl (13b) (Table 2, Entry 5).
Following the general procedure, using the catalyst 10c (5 mol %,
3.1 mg) and toluene (0.5 mL) as solvent, after 14 h at room temp-
erature, flash chromatography (n-hexane → n-hexane/EtOAc 200:1)
1H, J = 0.8 Hz), 7.93 (dd, 1H, J = 7.8, 0.7 Hz), 7.58 (dd, 1H, J = 7.5,
0.6 Hz), 7.39−7.36 (m, 2H), 7.32 (d, 1H, J = 6.8 Hz), 7.28 (d, 1H, J =
7.0 Hz), 3.48 (s, 4H), 2.03 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
192.9, 146.5, 146.4, 143.5, 139.2, 138.5, 135.4, 135.3, 130.9, 129.7,
129.6, 128.6, 127.8, 124.6, 120.7, 119.8, 118.8, 30.6, 30.2, 19.7; HRMS
(EI) m/z calcd for C20H16O 272.1201, found 272.1203; HPLC
(Daicel Chiralpak IC, 2-propanol/n-hexane 1:99, flow 1.0 mL/min,
T = 30 °C) tR 9.68 min (major) and 10.20 min (minor).
gave 23.4 mg (87%) of the title compound as a white solid: [α]20
D
−15.0 (c 0.9, CHCl3) for 49% ee [lit.25 [α]20D= −43.9 (c 1.0, CHCl3)
for (R)-enantiomer with 99% ee]. Spectroscopic and physical data
matched those reported in the literature.25 HPLC (Chiracel OJ,
2-propanol/n-hexane 5:95, flow 1.0 mL/min, T = 30 °C) tR 6.78 min
(major) and 11.19 min (minor).
3-Methyl-2-acenaphthalenebenzaldehyde (23d) (Table 2,
Entry 15). Following the general procedure, using the catalyst 10c
(5 mol %, 3.1 mg) and toluene (0.5 mL) as solvent, after 30 h at room
temperature, flash chromatography (toluene → n-hexane 1:2) gave
Methyl (1,1′-Binaphthyl)-2-carboxaldehyde (13c) (Table 2,
Entry 6). Following the general procedure, using the catalyst 10c
(5 mol %, 3.1 mg) and toluene (0.5 mL) as solvent, after 24 h at
room temperature, flash chromatography (n-hexane/toluene 2:1) gave
16.8 mg (65%) of the title compound as a colorless oil: [α]20 +51.0
D
1
18.6 mg (66%) of the title compound as a colorless oil: [α]20 +54.0
(c 0.55, CHCl3) for 80% ee; H NMR (500 MHz, CDCl3) δ 9.48 (d,
D
1
1H, J = 1 Hz), 8.10 (d, 1H, J = 8.5 Hz), 7.94 (dd, 1H, J = 7.8, 0.8 Hz),
7.59−7.53 (m, 2H), 7.49 (t, 1H, J = 6.8 Hz), 7.42−7.38 (m, 2H), 7.30
(dd, 1H, J = 8.0, 0.5 Hz), 7.23 (d, 1H, J = 7.0 Hz), 2.79 (s, 3H), 1.99
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 192.7, 144.0, 138.5, 135.4,
135.3,134.8, 132.6, 132.5, 132.4, 127.9, 127.6, 126.3, 126.2, 126.0,
124.6, 124.5; HRMS (EI) m/z calcd for C19H16O 260.1201, found
260.1203; HPLC (Daicel Chiracel OJ, 2-propanol/n-hexane 1:99, flow
1.0 mL/min, T = 30 °C) tR 6.83 min (major) and 8.96 min (minor).
3-Methyl-2-(o-tolyl)benzaldehyde (24) (Table 2, Entry 18).
Following the general procedure, using the catalyst 10c (5 mol %,
3.1 mg) and toluene (0.5 mL) as solvent, after 72 h at room temp-
erature, flash chromatography (n-hexane → n-hexane/EtOAc 100:1)
(c 1.1, CHCl3) for 54% ee; H NMR (500 MHz, CDCl3) δ 9.69 (d,
1H, J = 1.0 Hz), 8.16 (d, 1H, J = 8.5 Hz), 8.05 (d, 1H, J = 3.5 Hz),
8.03 (d, 1H, J = 3.5 Hz), 7.98 (t, 2H, J = 7.5 Hz), 7.66−7.59 (m, 2H),
7.52−7.49 (m, 2H), 7.39−7.37 (m, 1H), 7.35−7.30 (m, 2H), 7.22 (d,
1H, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 192.5, 144.9, 136.1,
133.5, 133.3, 133.0, 132.9,132.1, 129.2, 128.9, 128.8, 128.7, 128.3,
128.2, 127.7, 127.0, 126.8, 126.3, 126.2,125.0, 122.1; HRMS (CI) m/z
calcd for C21H14O 282.1045, found 282.1046; HPLC (Daicel Chiralpak
IC, 2-propanol/n-hexane 1:99, flow 1.0 mL/min, T = 30 °C) tR 9.86 min
(minor) and 10.55 min (major).
Methyl (1,1′-Binaphthyl)-2-carboxylate (13d) (Table 2, Entry
7). Following the general procedure, using the catalyst 10a (5 mol %,
3.4 mg) and toluene (0.5 mL) as solvent, after 48 h at 45 °C, flash
chromatography (n-hexane → n-hexane/EtOAc 200:1) gave 28.4 mg
gave 15 mg (72%) of the title compound as a colorless oil: [α]20
+37.0 (c 0.59, CHCl3) for 82% ee; H NMR (300 MHz, CDCl3) δ
D
1
(91%) of the title compound as a white solid: [α]20 −18.0 (c 0.9,
9.61 (d, 1H, J = 0.6 Hz), 7.86 (d, 1H, J = 7.2 Hz), 7.54 (dd, 1H, J =
7.5, 0.6 Hz), 7.43−7.27 (m, 4H), 7.10 (d, 1H, J = 7.2 Hz), 2.04 (s,
3H), 1.99 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 192.7, 145.1,
137.3, 136.3, 136.2, 135.5, 134.1, 130.1, 129.6, 128.1, 127.6, 125.9,
124.6, 19.9, 19.4; m/z (EI) 210 (M+, 100); HRMS (EI) m/z calcd
for C15H14O 210.1045, found 210.1042; HPLC (Daicel Chiralpak IB,
2-propanol/n-hexane 0.1:99.9, flow 1.0 mL/min, T = 30 °C) tR 8.9
(minor) and 9.5 min (major).
D
1
CHCl3) for 59% ee; H NMR (400 MHz, CDCl3) δ 7.88−7.73 (m,
5H), 7.40−7.22 (m, 3H), 7.16−6.98 (m, 5H), 3.22 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 168.0, 140.2, 136.9, 134.8, 133.2, 133.1, 132.9,
128.6, 128.2, 128.1, 128.0, 127.8, 127.8, 127.6, 126.9, 126.7, 126.0,
126.0, 125.7, 125.7, 125.1, 51.8; m/z (CI) 313 (M+ + 1, 100); HRMS
(CI) m/z calcd for C22H17O2 313.1228, found 313.1226; HPLC
(Chiracel OJ, 2-propanol/n-hexane 5:95, flow 1.0 mL/min, T = 30 °C)
tR 11.17 min (major) and 14.08 min (minor).
7-(2′-Methylnaphthyl)-1-indanone (25a) (Table 2, Entry 19).
Following the general procedure, using the catalyst 10c (5 mol %,
3.1 mg) and toluene (0.5 mL) as solvent, after 12 h at 45 °C, flash
2-(2′-Methylnaphthyl)benzaldehyde (23a) (Table 2, Entry 9).
Following the general procedure, using the catalyst 10c (5 mol %,
I
dx.doi.org/10.1021/jo300548z | J. Org. Chem. XXXX, XXX, XXX−XXX

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chromatography (n-hexane → n-hexane/EtOAc 100:1) gave 24.8 mg
Notes
(91%) of the title compound as a white solid: [α]20 +296.0 (c 1.06,
D
The authors declare no competing financial interest.
1
CHCl3) for 78% ee; H NMR (300 MHz, CDCl3) δ 7.83 (t, 2H, J =
8.1 Hz), 7.69 (t, 1H, J = 7.5 Hz), 7.57 (dd, 1H, J = 7.8, 0.9 Hz), 7.42
(d, 1H, J = 8.4 Hz), 7.37 (ddd, 1H, J = 8.0, 6.8, 1.2 Hz), 7.25 (ddd, 1H,
J = 8.4, 6.8, 1.5 Hz), 7.18 (dd, 1H, J = 7.5, 0.8 Hz), 7.13 (d, 1H, J = 8.4
Hz), 3.22 (t, 2H, J = 6.0 Hz), 2.64−2.60 (m, 2H), 2.14 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 205.0, 155.9, 138.5, 135.2, 134.6, 134.0,
132.9, 132.6, 131.9, 130.0, 128.4, 127.9, 127.4, 125.9, 125.6, 125.2,
124.5, 36.5, 25.5, 20.4; m/z (EI) 272 (M+, 100); HRMS (EI) m/z
calcd for C20H16O 272.1201, found 272.1201; HPLC (Daicel
Chiralpak IC, 2-propanol/n-hexane 10:90, flow 1.0 mL/min, T =
30 °C) tR 14.2 min (minor) and 25.5 min (major).
ACKNOWLEDGMENTS
■
We thank the Spanish “Ministerio de Ciencia e Innovacion
́
”
(Grant Nos. CTQ2010-15297 and CTQ2010-14974 and a
fellowship to B.E.), the European FEDER funds, and the Junta
́
de Andalucia (Grant Nos. 2008/FQM-3833 and 2009/FQM-
4537) for financial support. A.R. thanks the European Union
for a Marie Curie Reintegration Grant (FP7-PEOPLE-2009-
RG-256461).
7-(2′-Cyclohexylnaphthyl)-1-indanone (25b) (Table 2, Entry
20). Following the general procedure, using the catalyst 10c (5 mol %,
3.1 mg) and toluene (0.5 mL) as solvent, after 12 h at 45 °C, flash
chromatography (n-hexane → n-hexane/EtOAc 100:1) gave 22 mg
REFERENCES
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(64%) of the title compound as a white solid: [α]20 +135.0 (c 0.96,
D
1
CHCl3) for 72% ee; H NMR (400 MHz, CDCl3) δ 7.88 (d, 1H, J =
6.8 Hz), 7.83 (d, 1H, J = 6.8 Hz), 7.67 (td, 1H, J = 6.0, 1.6 Hz), 7.58
(d, 1H, J = 6.0 Hz), 7.55 (dd, 1H, J = 6.8, 1.2 Hz), 7.34 (t, 1H, J = 5.6
Hz), 7.23 (t, 1H, J = 6.2 Hz), 7.16 (d, 1H, J = 6.0 Hz), 7.02 (d, 1H, J =
6.8 Hz), 3.24 (t, 2H, J = 4.2 Hz), 2.63−2.60 (m, 2H), 2.27 (t, 1H, J =
9.0 Hz), 1.73−1.71 (m, 4H), 1.63 (d, 1H, J = 10.4 Hz), 1.55−1.49 (m,
2H), 1.25−1.20 (m, 1H), 1.11−1.03 (m, 2H), 0.9−0.89 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 204.9, 155.6, 142.1, 138.4, 135.5, 133.8,
133.6, 132.6, 131.7, 130.1, 127.8, 125.8, 125.6, 125.5, 124.6, 124.3, 41.8,
36.5, 34.4, 32.0, 29.6, 26.7, 26.1, 25.5; m/z (EI) 341 (M++1, 100);
HRMS (EI) m/z calcd for C25H25O 341.1912, found 341.1908; HPLC
(Daicel Chiralpak AD-H, 2-propanol/n-hexane 5:95, flow 1.0 mL/min,
T = 30 °C) tR 8.6 min (major) and 10.4 min (minor).
(S)-2-(2-Methyl-1-naphthyl)-N-(2-phenyl-2-propyl)benzamide.
A solution of NaClO2 (0.145 mmol) in H2O (0.5 mL) was dropwise
added (for 1 h at room temperature) to a stirred solution containing
23a (25.5 mg, 0.104 mmol) in acetonitrile (0.4 mL), NaH2PO4
(0.03 mmol), and H2O2 35% (10 μL) in H2O (0.1 mL). The reaction
mixture was stirred at 10 °C for 2 h, and then a small amount of
Na2SO3 was added to destroy the unreacted HOCl and H2O2. The
organic phase was washed with 10% aqueous HCl, dried over MgSO4,
filtered, and concentrated under reduced pressure. Purification by flash
chromatography (n-hexane/EtOAc 2:1) gave 2-(2-methylnaphthalen-
1-yl)benzoic acid (19 mg, 70%). A mixture of this material (17.3 mg,
0.066 mmol) and SOCl2 (105 μL, 1.45 mmol) was heated 6 h at
60 °C, cooled, and concentrated to dryness. The residue was dissolved
in CH2Cl2 (0.1 mL) and added to a solution containing cumylamine
(11.4 μL, 0.079 mmol), Et3N (14 μL, 0.099 mmol), and DMAP
(1.2 mg, 15 mol %) in CH2Cl2 (0.2 mL). The mixture was stirred at
room temperature for 12 h, and then it was diluted with ether, washed
with 1 N HCl, NaHCO3, and brine, dried over MgSO4, filtered,
and concentrated to dryness. Purification by flash chromatography
(n-hexane/EtOAc 10:1) gave (S)-2-(2-methyl-1-naphthyl)-N-(2-phe-
nyl-2-propyl)benzamide (20 mg, 82%). Spectroscopic and physical
data matched those reported in the literature:6g [α]20D = +10.7 (c 0.4,
CHCl3) for a sample with er 87:1341 [lit.6g [α]D = −30.5 (c 0.33,
CHCl3) for (R)-enantiomer with er 96.5:3.5].
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra for compounds 15e−g, 16e,g,
2a−i, 18, 10a−c, 27a, 13c,d, 23a−d, 24, and 25a,b; HPLC
chromatograms for compounds 13c,d, 23a−d, 24, and 25a,b;
crystallographic data for compounds 10a, 10c, and 27a. This
information is available free of charge via the Internet at http://
pubs.acs.org.
́
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Asymmetry 2000, 11, 2455.
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has also been observed by X-ray crystallography: Brown, K. L.; Damm,
L.; Dunitz, J. D.; Eschenmoser, A.; Hobi, R.; Kratky, C. Helv. Chim.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ffernan@us.es, jmlassa@iiq.csic.es.
J
dx.doi.org/10.1021/jo300548z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
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NOTE ADDED IN PROOF
■
After submission of this paper, two reports on the asymmetric
Suzuki-Miyautra reaction have appeared: (a) Wang, S.; Li, J.;
Miao, T.; Wu, W.; Li, Q.; Zhuang, Y.; Zhou, Z.; Qiu, L. Org.
Lett. 2012, 14, 1966. (b) Tang, W.; Patel, N. D.; Xu, G.; Xu, X.;
Savoie, J.; Ma, S.; Hao, M.-H.; Keshipeddy, S.; Capacci, A. G.;
Wei, X.; Zhang, Y.; Gao, J. J.; Li, W.; Rodriguez, S.; Lu, B. Z.;
Yee, N. K.; Senanayake, C. H. Org. Lett. 2012, 14, DOI:
10.1021/ol300659d.
K
dx.doi.org/10.1021/jo300548z | J. Org. Chem. XXXX, XXX, XXX−XXX