1,1′-Binaphthylazepine-based ligands for the enantioselective dialkylzinc addition to aromatic aldehydes

Article abstract of DOI:10.1016/j.tetasy.2008.07.026

The new 1,1′-binaphthylazepine ligand 1c has been prepared and tested in the enantioselective addition of Et₂Zn to arylaldehydes, allowing us to reach ee's up to 97% and giving extremely rapid reactions (10-20 min). Aminoalcohol 1c and the analogous compounds 1a and 1b were then tested in the enantioselective addition of Bu₂Zn and Me₂Zn to arylaldehydes. All of the ligands efficiently catalyze the Bu₂Zn addition to benzaldehyde, providing good yields in short reaction times (2-4 h) and high ee (up to 96%). In the enantioselective methylation of arylaldehydes ligands 1b and 1c gave high yields (88-97%) and good to high (80-90%) ee's.

Full text of DOI:10.1016/j.tetasy.2008.07.026

Tetrahedron: Asymmetry 19 (2008) 1784–1789
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
0
1
,1 -Binaphthylazepine-based ligands for the enantioselective dialkylzinc
addition to aromatic aldehydes
Laura Pisani, Stefano Superchi *
Dipartimento di Chimica, Università della Basilicata, Via N. Sauro 85, 85100 Potenza, Italy
a r t i c l e i n f o
a b s t r a c t
0
Article history:
The new 1,1 -binaphthylazepine ligand 1c has been prepared and tested in the enantioselective addition
Received 13 May 2008
Accepted 25 July 2008
Available online 9 August 2008
of Et
10–20 min). Aminoalcohol 1c and the analogous compounds 1a and 1b were then tested in the enantio-
selective addition of Bu Zn and Me Zn to arylaldehydes. All of the ligands efficiently catalyze the Bu Zn
2
Zn to arylaldehydes, allowing us to reach ee’s up to 97% and giving extremely rapid reactions
(
2
2
2
addition to benzaldehyde, providing good yields in short reaction times (2–4 h) and high ee (up to 96%).
In the enantioselective methylation of arylaldehydes ligands 1b and 1c gave high yields (88–97%) and
good to high (80–90%) ee’s.
Ó 2008 Elsevier Ltd. All rights reserved.
7
1
. Introduction
The enantioselective addition of dialkylzinc reagents to alde-
pound bear a chiral methyl carbinol moiety or can derive from
8
butyl substituted alcohols. In fact, despite the enormous number
of studies concerning the enantioselective addition of Et Zn to
2
hydes is one of the most studied and effective reactions for asym-
metric C–C bond formation. Hundreds of chiral ligands have been
aldehydes, no synthetic application of this reaction has been
reported so far while few, but significant, examples concern the
employment of the methylation and butylation reactions in the
1
employed as successful catalytic precursors in this reaction, and
detailed mechanistic studies have been undertaken, providing a
9
synthesis of bioactive compounds.
2
deep understanding of the asymmetric induction mechanism.
We also recently employed the enantioselective addition of
For these reasons this reaction ‘has become a classical test to
design new chiral ligands for catalytic enantioselective syntheses’,
as stated by Pu and Yu in their comprehensive review. However,
the large majority of the studies on the asymmetric dialkylzinc
2
Et Zn to aldehydes to test the efficiency of new chiral ligands for
asymmetric synthesis. On the basis of mechanistic considerations
1c
0
we rationally designed new 1,1 -binaphthylazepine aminoalcohols
of general formula 1 (Fig. 1) demonstrating that, by simply tuning
the size of the substituents on the C(O), with no changes on the
chiral atropisomeric binaphthyl backbone, a very high increase of
addition to aldehydes concern the use of Et
2
Zn, while the analo-
3
,4
3b,g,t,4a,i,5
2 2
gous Me Zn and Bu Zn
have been employed only spo-
1
0,11
radically, and systematic investigations of their behavior in this
the enantioselectivity could be achieved.
The further insertion
reaction are still lacking. Only some recent studies3
r–u,4f,h,j
have
of substituents on the C(N), giving rise to steric interactions with
both the chiral binaphthyl moiety and the substituents on the
C(O), provided an even better chirality transfer between these
two moieties, allowing us to obtain ee’s of up to 95% in the ethyla-
addressed the issue of investigating the reactivity of Me
2
Zn with
different aromatic aldehydes, reaching good to high enantioselec-
tivity in the methylation reaction. The scarce popularity of Me Zn
and Bu Zn in this reaction is mainly due to their reduced reactivity,
clearly established by Noyori et al.,
relative reactivity of Me Zn, Bu Zn, and Et
2
1
2,13
2
tion of several arylaldehydes with ligand 1b.
By means of these
2a,d
who reported that the
Zn in the alkylation of
benzaldehyde catalyzed by DAIB is a 1:8:21 ratio. The lower reac-
tivity of the former two reagents requires higher reaction temper-
atures and longer reaction times and often determines either lower
2
2
2
6
R
N
R
Ph
Ph
Ph
Ph
chemical yields and enantioselectivity with respect to Et
the other hand, the enantioselective alkylation with Me
Bu Zn provides a much more synthetically attractive outcome than
the Et Zn counterpart, given that a great number of bioactive com-
2
Zn. On
OH
N
OH
2
Zn and
2
2
1
1
a
b
R = H
1c
R = Me
*
Corresponding author. Tel.: +39 0971 202232; fax: +39 0971 202223.
E-mail address: stefano.superchi@unibas.it (S. Superchi).
Figure 1.
0
957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.07.026

L. Pisani, S. Superchi / Tetrahedron: Asymmetry 19 (2008) 1784–1789
1785
0
studies we also provided a qualitative rationale of the stereochem-
ical outcome of the reaction with these ligands defining the influ-
ence of the substituents carried by the aminoalcoholic moiety. The
chiral ligands 1a,b, which were the most efficient ones in the ethy-
lation reaction, were then also tested in the enantioselective addi-
tion of zinc acetylides and diphenylzinc to arylaldehydes,
providing moderate to good ee’s.14
The new 1,1 -binaphthylazepine aminoalcohol (aS,S,S)-1c was also
prepared starting from dibromide (S)-2 according to the procedure
described in Scheme 1. Dibromide (S)-2 was treated with
NH
2
OHꢀHCl in refluxing Et
3
N for 15 h obtaining hydroxylamine
(S)-3 in 65% yield. The latter was then reduced with zinc and a cat-
1
7
alytic amount of indium heating at reflux in a 1:2 solution of eth-
anol and saturated aqueous NH Cl to afford, after chromatographic
4
Our previously developed ligands 1a and 1b present the pecu-
purification, binaphthylazepine (S)-4 in 97% yield. Starting from
(S)-4 the N-nitroso dimethylazepine (aS,S,S)-6 was obtained
following a procedure described by Rychnovsky et al. Azepine
(S)-4 was dissolved in acetic acid, and was treated at room temper-
2
ature with an aqueous solution of NaNO . After neutralization with
2
liar feature of displaying only axial chirality and a pseudo-C sym-
1
5
18
metry. The enantioselectivity improvement was achieved by
ensuring an efficient chirality transfer from the chiral binaphthyl
moiety to the achiral aminoalcoholic fragment. The latter being
the moiety which provides the zinc amino alkoxide involved in
the enantioselective catalytic cycle.1a In searching for even more
efficient aminoalcoholic ligands of this family, we herein explore
a new approach to ensure such chirality transfer. We reasoned that
this effect could be similarly achieved by introducing two methyls
10 M aqueous NaOH and workup N-nitroso-azepine (S)-5 was iso-
lated in 87% yield. The latter was dimethylated by treatment with
KH in THF at room temperature and quenching the resulting dian-
ion with excess of methyl iodide at reflux. After workup the dime-
thylated N-nitroso-azepine (aS,S,S)-6 was obtained in 83% yield.
The deprotection of the N-nitroso derivative (aS,S,S)-6, originally
0
on the benzylic positions of the 1,1 -binaphthylazepine moiety.
1
8
These groups could sterically connect the chiral binaphthyl moiety
and the phenyls on the C(O) providing a chiral environment on the
aminoalcoholic fragment. The new ligand 1c, designed on the basis
of this concept, although having two additional chiral centers, still
described by Rychnovsky et al. by using gaseous HCl, was instead
more smoothly achieved by treatment with H in EtOH in the pres-
2
1
9
ence of Raney-Ni. After one night at room temperature the mix-
ture was filtered through Celite to remove the metal catalyst,
smoothly affording (aS,S,S)-7 in 80% yield. The absolute configura-
tion of the two newly formed benzylic stereocenters was con-
2
retain the peculiar pseudo-C symmetry. Herein we report the
preparation of the new binaphthylazepine-based ligand 1c and a
comparative study of this ligand in the enantioselective ethylation
of arylaldehydes. The use of aminoalcohols 1a, 1b, and 1c in the
1
1
firmed by H NMR analysis. The H NMR of 7 showed in fact a
high symmetry of the molecule, allied with a C symmetric molec-
2
Me
2
Zn and Bu
2
Zn enantioselective addition to arylaldehydes is also
ular structure, and then with a anti disposition of the two methyls.
1
described with the aim of investigating the behavior of our ligands
in these synthetically very important transformations.
The comparison of the H NMR spectrum with the literature
1
8,20
data
clearly confirmed that, among the two possible diastereo-
isomers, only the desired (aS,S,S)-7 was obtained. The dimethyl-
azepine (aS,S,S)-7 was then N-alkylated with ethyl bromoacetate,
heating at reflux in chloroform in the presence of Et N. After
3
workup and column chromatography, the aminoester (aS,S,S)-8
was obtained in 41% yield. Finally, compound (aS,S,S)-8 was treated
with PhLi in THF at ꢁ70 °C affording, after workup and chromato-
graphic purification, aminoalcohol (aS,S,S)-1c in 51% yield.
2
2
. Results and discussion
.1. Synthesis of chiral ligands
Aminoalcohols 1a,b were prepared as already described,10,12
1
0,16
starting from dibromide (S)-2, in turn obtained from (S)-BINOL.
Br
Br
.
NH OH HCl
Zn, In cat.
2
N OH
NH
Et N, reflux
3
EtOH/satd NH Cl
4
reflux
(
S)-3
(S)-4
(S)-2
KH, MeI
Raney Ni
HOAc
NaNO2, r.t.
N
NO
NH
N
NO
H2
EtOH
THF, 18h
reflux
(
aS,S,S)-6
(aS,S,S)-7
(S)-5
O
Ph
Ph
PhLi
Et N, BrCH CO Et
3
2
2
N
OEt
N
OH
CHCl , reflux
THF, -78 ºC
3
(
aS,S,S)-8
(aS,S,S)-1c
Scheme 1.

1
786
L. Pisani, S. Superchi / Tetrahedron: Asymmetry 19 (2008) 1784–1789
2
.2. Enantioselective alkylations
than in the case of 1b is achieved. With all the ligands studied
a–c, having (S) configured binaphthyl moiety, alcohols of (S)-
1
The 1,2-aminoalcohol 1c was tested in the enantioselective
addition of diethylzinc to arylaldehydes, and the results were com-
pared with those of the parent disubstituted aminoalcohols 1a,b
Table 1). The reaction was carried out in dry toluene at 20 °C in
the presence of 8 mol % of chiral ligand and monitored by TLC
and GC–MS. When complete conversion of the aldehyde was de-
tected, the mixture was quenched by the addition of 10% aqueous
absolute configuration were obtained, revealing the same sense
of enantioinduction. Also in 1c, which has two additional stereo-
genic centers, the sense and value of the enantioselectivity ap-
peared to be determined mainly by the atropisomeric binaphthyl
system, and therefore the mechanism of enantioinduction with li-
(
0
gand 1c should be the same as suggested with the other 1,1 -
1
2
binaphthylazepine aminoalcohols.
0
HCl. After extraction with Et
2
O, drying, and evaporation of the sol-
1,1 -Binaphthylazepine aminoalcohols 1a–c were then tested as
vent, the product ratio was directly determined on the crude mix-
ture by GC–MS while the ee of the product 1-aryl-1-propanol was
measured by HPLC or GC on chiral stationary phases (Fig. 2).
catalytic precursors in the enantioselective addition of Bu
benzaldehyde and in the addition of Me Zn to differently substi-
tuted arylaldehydes (Table 2). The reaction was carried out in dry
toluene, at 0 °C in the case of Bu Zn and at room temperature with
Me Zn. In both cases 3.0 equiv of the dialkylzinc and 10 mol % of
2
Zn to
2
2
Table 1
Zn to arylaldehydes mediated by ligands 1a–ca
2
2
Enantioselective addition of Et
the chiral ligand were employed. The reactions were monitored
by TLC and GC–MS and when complete conversion of the aldehyde
was detected, the mixture was quenched by the addition of 10%
Run
1e
Ligand
Ar
Time (min)
Yieldb (%)
eec (ac)d (%)
1a
1b
1c
1a
1b
1c
1a
1b
1c
1a
1b
1c
C
C
C
6
H
6
H
6
H
5
5
5
30
45
15
90
90
15
10
10
10
20
20
20
99
99
99
99
99
99
99
99
99
99
99
99
87 (S)
95 (S)
97 (S)
80 (S)
87 (S)
93 (S)
e
2
2
aqueous HCl. After extraction with Et O, drying, and evaporation
3
e
of solvent, the product ratio was directly determined on the crude
mixture by GC–MS, and the ee of the obtained 1-aryl-carbinol was
measured by HPLC or GC on chiral stationary phases (Fig. 3).
4
4-CH
4-CH
4-CH
4-CNC
4-CNC
4-CNC
4-CF
4-CF
4-CF
3
3
3
OC
OC
OC
6
6
6
H
H
H
4
4
4
e
5
6
e
f
g
g
g
7
6
6
6
H
H
H
4
4
4
84 (S)
e
f
8
95 (S)
Table 2
f
Enantioselective addition of R
2
Zn to arylaldehydes mediated by ligands 1a–ca
9
96 (S)
e
h
g
g
1
1
1
0
1
2
3
3
3
C
6
H
4
85 (S)
Yieldb (%)
eec (ac) (%)
e
h
Run
Ligand
R
Ar
Time (h)
C
C
6
H
H
4
4
94 (S)
i
d
6
96 (S)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1a
1b
1c
1a
1b
1c
1a
1b
1c
n-Bu
n-Bu
n-Bu
Me
Me
Me
Me
Me
Me
Me
C6H5
4
3
2
29
23
14
39
30
15
8
85
84
90
42
92
96
38
88
90
91
97
94
88 (S)
96 (S)
96 (S)
36 (S)
d
C
6
C
6
C
6
C
6
C
6
H
5
H
5
H
5
H
5
H
5
a
Reaction conditions: aldehyde/ligand/Et
Chromatographic (GLC) yield. Isolated yields 2–3% lower than the chromato-
2
Zn = 1.0:0.08:2.0, in toluene at rt.
d
b
e
graphic ones were obtained after purification on a silica gel column. No traces of
benzylalcohols were detected.
80 (S)e
e
80 (S)
38 (S)
64 (S)
c
Determined by HPLC on Chiralcel OD-H.
Determined by elution order on Chiralcel OD-H.
See Refs. 11 and 12.
Determined by HPLC on Chiralcel OJ.
Determined by comparison of [
f
4-CH
4-CH
4-CH
3
3
3
OC
OC
OC
6
6
6
H
H
H
4
4
4
d
e
f
21
f
f
90 (S)
g
h
h
h
1
1
1
0
1
2
4-CF
4-CF
4-CF
3
C
6
6
6
H
4
36 (S)
80 (S)
80 (S)
g
h
i
with literature values.22
a
]
D
g
Me
Me
3
C
C
H
H
4
4.5
1
Determined by HPLC on Chiralcel OJ of its acetate.
Determined by GC on Hydrodex-b-3P chiral column.
g
3
4
a
Reaction conditions: aldehyde/ligand/R
Zn and at rt with Me Zn.
Chromatographic (GLC) yield. Isolated yields 2–3% lower than the chromato-
2
Zn = 1.0:0.1:3.0, in toluene at 0 °C with
1
a-c (0.08 equiv)
OH
Bu
2
2
b
Ar CHO
Ar
H
*
Et Zn (2.0 equiv)
toluene, RT
graphic ones were obtained after purification on a silica gel column. No traces of
benzylalcohols were detected.
2
Et
c
Determined by HPLC on Chiralcel OD-H.
d
e
f
23
24
2d
Determined by comparison of [
Determined by comparison of [
Determined by comparison of [
a
a
a
]
D
]
D
]
D
with literature values.
with literature values.
with literature values.
Figure 2.
2
The results listed in Table 1 show that the addition of Et Zn to
g
h
Determined by GC on Hydrodex-b-3P chiral column.
benzaldehyde catalyzed by ligand 1c provides, with complete con-
version, the corresponding (S)-carbinol in 97% ee (run 3), a value
slightly higher than the one achieved with ligand 1b and much bet-
ter than the result given by 1a. Also, in the ethylation of differently
substituted aromatic aldehydes, ligand 1c provided ee’s that were
always higher than the previous ligands 1a and 1b, confirming the
result obtained in the case of benzaldehyde. By using 1c, an
improvement in enantioselectivity of up to 6% with respect to 1b
was observed (run 6), and the ee values obtained, in the 93–97%
range, were almost independent of both the steric and electronic
nature of the carbonyl substrates. Notably, 1c also provided much
faster reactions (10–20 min) than the other aminoalcohols with all
the aldehydes studied, including the usually less reactive para-
methoxy substituted benzaldehyde. This result then looked
encouraging toward the use of this aminoalcohol in catalyzing
the addition to aldehydes of the less reactive alkylzinc reagents
3v
Determined by comparison of [ with literature values.
a]
D
OH
1a-c (0.1 equiv)
*
Ar CHO
Ar
H
R
R Zn (3.0 equiv)
2
toluene, RT
Figure 3.
As inferred from Table 2, ligands 1a–c efficiently catalyze the
addition of Bu Zn to benzaldehyde, providing good to high (84–
2
90%) conversion of the substrate in 2–4 h, that is, in a reaction time
significantly shorter than those reported in the literature with
5
other catalysts (usually from 15 h to some days). Compound 1a
afforded a high 88% ee, while both aminoalcohols 1b and 1c pro-
vided an excellent 96% ee, which is, to the best of our knowledge,
among the highest values ever obtained in this reaction.5
2 2
Me Zn and Bu Zn. This study also points out that in 1c, the pres-
ence of the two benzylic methyls on the binaphthylazepine frag-
ment ensures an efficient chirality transfer from the latter chiral
moiety to the achiral aminoalcoholic counterpart. The higher levels
of enantioselectivity and the higher reaction speed achieved sug-
gest that within this ligand a chirality transmission even better
2
Also, in the addition of Me Zn to benzaldehyde ligands 1b and 1c
led to the 1-phenylethanol with high conversion (92–96%) and good
80% ee, while the parent ligand 1a afforded a modest 36% ee and a
low 42% yield. The same results were obtained in the Me
2
Zn addition
to 4-CF benzaldehyde, where 1b and 1c gave almost complete
3

L. Pisani, S. Superchi / Tetrahedron: Asymmetry 19 (2008) 1784–1789
1787
conversion and 80% ee, while 1a provided again a moderate 36% ee.
Interestingly, in the Me Zn addition to 4-OMe benzaldehyde larger
Phenyllithium (1.8 M solution in dibutylether), diethylzinc (1.0 M
in hexane), dibutylzinc (1.0 M in heptane), and dimethylzinc
(2.0 M in toluene) were used as purchased (Aldrich). Commercially
available (Aldrich) benzaldehyde, 4-anisaldehyde, and 4-trifluoro-
methylbenzaldehyde were distilled prior to their use, and were
stored under a nitrogen atmosphere. Unless otherwise specified,
the reagents were used without any purification. Enantiopure
2
differences among the three ligands tested were instead observed.
In fact, 1a was again the worse one, providing modest yield and
ee, while 1b, albeit giving good 88% yield, allowed us to reach a
moderate 64% ee. Conversely, ligand 1c afforded a similar 90% yield,
but an excellent 90% ee, among the highest ever reached in this reac-
tion. We can then conclude that in the methylation reaction, ligand
0
0
(S)-2,2 -bis(bromomethyl)-1,1 -binaphthalene 2 was prepared as
1
0
1
c always provided the fastest reactions, the highest yields and ee’s,
previously described.
All the 1-aryl-1-alkanols obtained by
reaching 90% ee in the addition to p-anisaldehyde. Ligand 1b gave
rise to slower reactions, but provided yields and ee’s comparable
with 1c, except for p-anisaldehyde. Finally, ligand 1a was, as ob-
served in the ethylation reaction, the worst of three, always provid-
ing low yields and ee’s and much slower reactions.
In both butylation and methylation, carbinols of (S)-absolute
configuration were obtained, such as in the corresponding ethyla-
tion reaction, then allowing us to envisage that the same induction
mechanism is operative in all these transformations.
dialkylzinc addition to arylaldehydes showed NMR spectra in full
agreement with the literature data. Enantiomeric excesses of the
optically active 1-aryl-1-alkanols were determined by HPLC analy-
sis performed on a JASCO PU-1580 pump with a Varian 2550 UV
detector and Daicel Chiralcel OD-H or OJ columns. Enantiomeric
excesses of 1-(4-trifluoromethylphenyl)-1-alkanols were deter-
mined by GC analyses on a Hewlett Packard 6890 chromatograph
equipped with a flame ionization detector (FID) using a hydro-
dex-b-3P column (25 m ꢂ 0.25 mm, [heptakis(2,6-di-O-methyl-3-
O-pentyl)]-b-cyclodextrin) and nitrogen as carrier gas.
3
. Conclusions
0
0
4
.2. (S)-(+)-3,5-Dihydro-4H-dinaphth[2,1-c:1 2 -e]azepine-N-
hydroxide 3
In conclusion, we have described herein the synthesis of the
0
new pseudo-C
2
symmetric 1,1 -binaphthylazepine aminoalcohol
0
0
A solution of (S)-2,2 -bis(bromomethyl)-1,1 -binaphthalene (2)
1
c. This compound proved to be an efficient ligand for the enantio-
(
2.0 g, 4.54 mmol) and hydroxylamine hydrochloride (0.96 g,
selective addition of Et Zn to arylaldehydes allowing us to obtain
2
1
3.8 mmol) in triethylamine (35 mL), under nitrogen, was stirred
ee’s up to 97% and giving extremely rapid reactions (10–20 min).
Aminoalcohol 1c and the analogous compounds 1a and 1b, previ-
ously described by us, were then tested in the enantioselective
at reflux for 15 h. The resulting suspension was filtered, the solid
residue washed with diethyl ether, and the collected organic phases
were evaporated to dryness. The recovered solid residue was
washed with petroleum ether, affording hydroxylamine 3 (1.27 g,
addition of Bu
ciently catalyze the Bu
good yields in shorter reaction times (2–4 h) and higher ee (up to
2
2
Zn and Me Zn to arylaldehydes. All ligands effi-
2
Zn addition to benzaldehyde, providing
9
1
0%), which was used without further purification. Mp 180.0–
2
0
1
82.7 °C; ½
a
ꢃ
¼ þ354:7 (c 1.02, CHCl
3 3
); H NMR (500 MHz, CDCl ):
D
9
6%) than in the examples reported in the literature.
In the enantioselective methylation of arylaldehydes, ligands 1b
d (ppm) 2.80 (br s, 1H); 3.38 (d, J = 8.8 Hz, 1H); 3.88 (d, J = 14.3 Hz,
H); 4.08 (d, J = 14.3 Hz, 1H); 4.19 (d, J = 8.8 Hz, 1H); 7.3 (d,
J = 7.5 Hz, 2H); 7.48 (dd, J = 8.0 Hz; J = 7.5 Hz, 4H); 7.63 (d,
J = 8.0 Hz, 2H); 7.96 (m, 4H); C NMR (125 MHz, CDCl ): d (ppm)
05.0; 126.2; 126.6; 127.7; 127.8; 128.6; 128.8; 133.6; 133.8;
43.4; 159.9. Anal. Calcd for C22 17NO: C, 84.86; H, 5.50; N, 4.50.
1
and 1c gave high yields (88–97%) and good to high (80–90%) ee’s.
Particularly interesting is the Me Zn addition to p-anisaldehyde,
1
2
2
1
3
3
where ligand 1c allowed us to reach a 90% ee, which is an excellent
result for this reaction.
These results show that ligands 1b and 1c can be then consid-
ered efficient chiral catalytic precursors for the enantioselective
1
1
H
Found: C, 84.81; H, 5.48; N, 4.56.
2 2
addition of both Bu Zn and Me Zn, which is a reaction endowed
0
0
4
.3. (S)-(+)-3,5-Dihydro-4H-dinaphth[2,1-c:1 2 -e]azepine 4
with interesting synthetic applications. Some synthetic applica-
tions of the enantioselective alkylation of aldehydes catalyzed by
N-Hydroxy-azepine 3 (1.27 g, 4.1 mmol) was added to a 2:1
solution of EtOH and saturated aqueous NH Cl. Indium powder
23.5 mg, 0.2 mmol) and zinc (533 mg, 8.2 mmol) were than added,
0
these 1,1 -binaphthylazepine ligands is currently under investiga-
4
tion in our laboratory.
(
and the mixture was stirred under reflux for 20 h. After cooling, the
mixture was filtered through Celite and concentrated. A saturated
Na CO solution was added, and the solution was extracted with
2 3
4
4
. Experimental
.1. General procedures
ethyl acetate. The organic phase was dried over anhydrous Na SO4
2
and the solvent evaporated in vacuo. The crude was purified by col-
1H NMR and 13C NMR spectra were recorded in CDCl
on a Var-
3
umn chromatography (SiO ; diethyl ether/methanol 9:1) affording
2
ian INOVA 500 MHz spectrometer using TMS as internal standard.
Optical rotations were measured with a JASCO DIP-370 digital
polarimeter. Melting points were taken using a Kofler Reichert-
Jung Thermovar apparatus, and are uncorrected. GC–MS analyses
were performed on a Hewlett Packard 6890 chromatograph
equipped with a HP-5973 mass detector. Column chromatography
was carried out using Macherey-Nagel Silica Gel 60 (70–
binaphthylazepine 4 as a white solid (1.19 g, 98%). Mp 147–149 °C
2
5
20
D
25,26
(lit. mp 147–149 °C); ½
a
ꢃ
¼ þ543:7 (c 0.54, CHCl ) {lit.
3
2
D
0
1
½
aꢃ
¼ þ574:8 (c 0.8, CHCl )}; H NMR (500 MHz, CDCl ): d
3
3
(ppm) 2.12 (br s, 1H); 3.53 (d, J = 11.7 Hz, 2H), 3.85 (d,
J = 11.7 Hz, 2H); 7.23–7.31 (m, 2H); 7.43–7.50 (m, 4H); 7.58 (d,
1
3
J = 8.3 Hz, 2H); 7.94–8.02 (m, 4H); C NMR (125 MHz, CDCl ): d
3
(ppm) 48.4; 125.2; 125.6; 126.8; 127.1; 128.1; 128.7; 131.2;
2
30 mesh). Analytical thin-layer chromatography (TLC) was per-
132.8; 134.6; 134.8. Anal. Calcd for C22H17N: C, 89.46; H, 5.80; N,
4.74. Found: C, 89.52; H, 5.86; N, 4.69.
formed on Macherey-Nagel aluminum sheets precoated with silica
gel (0.25 mm). Toluene and THF were freshly distilled prior to their
use on sodium benzophenone ketyl and were stored under a nitro-
0
0
4.4. (S)-(ꢁ)-N-Nitroso-3,5-dihydro-4H-dinaphth[2,1-c:1 ,2 -
e]azepine 5
gen atmosphere. CHCl
3
2
was freshly distilled over CaH prior to its
use. Triethylamine was distilled over CaH
2
and stored under nitro-
gen on KOH. The addition of organometallics was performed using
a syringe-septum cap technique under a nitrogen atmosphere.
To a solution of 4 (0.79 g; 2.68 mmol) in acetic acid (28 mL)
was added dropwise a solution of NaNO2 (533 mg; 7.73 mmol)

1
788
L. Pisani, S. Superchi / Tetrahedron: Asymmetry 19 (2008) 1784–1789
in H
2
O (8 mL). The mixture was stirred at rt for 2 h, and then
3.54 mmol). The mixture was heated at reflux for 24 h, then cooled
at rt, diluted with CHCl , and extracted with 10% aqueous HCl. The
aqueous phase was neutralized with 10% aqueous NaOH, and was
extracted with CHCl . The organic phase was dried over anhydrous
Na SO and evaporated, providing a solid residue. After chromato-
graphic purification (SiO , CHCl /ethyl acetate 97:3), compound 8
was recovered as white solid (153 mg, 41%).
(500 MHz; CDCl ): d (ppm) 0.68 (d, J = 7.5 Hz, 6H); 1.31 (t,
was poured into an ice bath cooled flask. The mixture was basi-
fied by the addition of 10 M aqueous NaOH, then extracted with
toluene. The collected organic phases were washed with brine
3
3
and dried over Na
2
SO
4
. After evaporation of the solvent, product
2
4
5
was obtained as a yellow solid (760 mg, 87%), and was used
2
3
2
D
5
1
without further purification. Mp 57.5–57.7 °C; ½
a
ꢃ
¼ ꢁ212:3 (c
a
H NMR
1
8
25
D
1
0
(
.68; CHCl
500 MHz; CDCl
J = 13.5 Hz, 1H); 5.67 (d, J = 15.0 Hz, 1H), 5.72 (d, J = 13.5 Hz,
3
) {lit.
½
aꢃ
¼ ꢁ195:1 (c 0.99; CHCl
3
)}; H NMR
3
3
): d (ppm) 3.65 (d, J = 15.0 Hz, 1H); 4.74 (d,
J = 7.0 Hz, 3H); 3.64 (d, J = 17 Hz, 1H); 3.68 (d, J = 17 Hz, 1H);
4.18–4.25 (m, 4H); 7.26 (t, J = 7.5 Hz, 2H); 7.39 (d, J = 9.0 Hz, 2H);
7.45 (t, J = 7.5 Hz, 2H); 7.52 (d, J = 8.5 Hz, 2H); 7.92–7.95 (m, 4H).
1
7
H); 7.28–7.34 (m, 2H); 7.40–7.45 (m, 2H); 7.54–7.57 (m, 3H);
.70 (d, J = 8.5 Hz, 1H); 7.99–8.05 (m, 4H). 13C NMR (125 MHz,
Anal. Calcd for C28
2
H27NO : C, 82.12; H, 6.65; N, 3.42. Found: C,
CDCl
28.2, 129.1, 129.6, 130.4, 131.1, 131.7, 133.4, 133.9. Anal. Calcd
for C22 O: C, 81.46; H, 4.97; N, 8.64. Found: C, 81.52; H,
.05; N, 8.62.
3
): d 47.4, 54.2, 126.3, 126.4, 126.5, 127.1, 127.5, 127.8,
82.15; H, 6.67; N, 3.48.
1
H
16
N
2
4.8. (aS,S,S)-(+)-N-(2,2-Diphenyl-2-hydroxyethyl)-3,5-dihydro-
3,5-dimethyl-4H-dinaphth[2,1-c:1 ,2 -e]azepine 1c
0
0
5
4
.5. (aS,S,S)-(ꢁ)-N-Nitroso-3,5-dihydro-3,5-dimethyl-4H-
To a solution of 8 (140 mg; 0.34 mmol) in anhydrous THF
(40 mL) was added at ꢁ78 °C, under nitrogen, PhLi (1.8 M,
0
0
dinaphth[2,1-c:1 ,2 -e]azepine 6
1
.32 mL, 2.38 mmol). The mixture was stirred for 4 h at ꢁ78 °C,
To a solution of 5 (610 mg; 1.88 mmol) in anhydrous THF
then quenched with 10% aqueous HCl. The aqueous phase was
extracted with Et O, and the collected organic phases were dried
over anhydrous Na SO . After evaporation of the solvent, the crude
was purified by column chromatography (SiO ; petroleum ether/
Et O 95:5) to afford compound 1c as a white solid (90 mg, 51%).
Mp 77.0–80.0 °C; ½
CDCl ): d (ppm) 0.47 (d, J = 7.0 Hz, 6H); 3.62 (d, J = 13.5 Hz, 1H);
(
69 mL) under nitrogen was added KH (30% dispersion in mineral
oil, 1.04 g, 26.00 mmol) previously washed with anhydrous hex-
ane. The mixture was stirred at rt for 30 min, then CH I (1.9 mL;
0.00 mmol) was added, causing the formation of a white precipi-
tate. The mixture was heated at reflux for 18 h and then, after cool-
ing in an ice bath, H O was added to dissolve the precipitate. The
aqueous phase was separated and extracted with Et O. The col-
lected organic phases were washed with brine and dried over
anhydrous Na SO . After filtration and evaporation of the solvent,
compound 6 was recovered as a yellow solid (560 mg, 84%). Mp
2
2
4
3
2
3
2
2
D
5
1
aꢃ
¼ þ3:2 (c 0.57, CHCl
3
); H NMR (500 MHz;
2
3
2
3.81 (q, J = 7.0 Hz, 2H); 3.89 (d, J = 13.5 Hz, 1H); 7.22–7.25 (m,
4H); 7.28–7.31 (m, 3H); 7.33–7.38 (m, 5H); 7.45 (t, J = 7.2 Hz,
2H); 7.61 (d, J = 8.0 Hz, 2H); 7.72 (d, J = 8.0 Hz, 2H); 7.91–7.93
2
4
1
3
3
(m, 4H). C NMR (125 MHz, CDCl ): d (ppm) 18.5, 63.6, 65.6,
2
D
5
1
2
CDCl
25.8 °C; ½
aꢃ
¼ ꢁ175:1 (c 0.94; CHCl
3
); H NMR (500 MHz,
73.8, 125.3, 125.5, 125.8, 125.9, 126.6, 127.1, 128.0, 128.1, 128.2,
128.9, 132.6, 132.8, 134.1, 139.8, 146.9, 147.6. Anal. Calcd for
3
): d (ppm) 0.176 (d, J = 6.5 Hz, 3H), 1.09 (d, J = 7.5 Hz, 3H),
6
7
8
2
1
5
.09 (q, J = 7.0 Hz, 1H), 6.17 (q, J = 7.5 Hz, 1H), 7.38–7.27 (m, 4H),
C
2.75.
38
H
33NO: C, 87.83; H, 6.40; N, 2.70. Found: C, 87.78; H, 6.44; N,
.54–7.49 (m, 3H), 7.63 (d, J = 8.5 Hz, 1H), 7.97 (t, J = 7.0 Hz, 3H),
1
3
.02 (d, J = 8.5 Hz, 1H); C NMR (125 MHz, CDCl
1.4, 55.6, 64.9, 126.6, 126.7, 127.4, 127.5, 127.8, 128.4, 128.5,
29.7, 129.9, 132.8, 133.5. Anal. Calcd for C24 O: C, 81.79; H,
.72; N, 7.95. Found: C, 81.83; H, 5.68; N, 7.91.
3
): d (ppm) 17.7,
4.9. Typical procedure for the diethylzinc addition to
arylaldehydes
20 2
H N
To a solution of the ligand (0.05 mmol) in dry toluene (3 mL)
4
.6. (aS,S,S)-(+)-3,5-Dihydro-3,5-dimethyl-4H-dinaphth[2,1-
2
under a nitrogen atmosphere at rt was added a solution of Et Zn
0
0
c:1 ,2 -e]azepine 7
in hexane (1.0 M, 1.25 mL, 1.25 mmol). The mixture was stirred
for 30 min, then a solution of arylaldehyde (0.62 mmol) in dry
toluene (1.3 mL) was added. The mixture was monitored by
GC–MS, and when no more traces of the aldehyde were detected
the reaction was quenched by addition of 10% aqueous HCl. The
To a solution of 6 (550 mg, 1.56 mmol) in anhydrous ethanol
was added activated Raney-Ni under nitrogen atmosphere, and a
stream of hydrogen was bubbled overnight in the mixture. The tur-
bid white suspension was filtered over a short path of Celite, and
the solid residue was washed with ethanol. The collected solution
was evaporated to dryness affording amine 7 as a yellow solid
mixture was extracted with Et
washed with brine, and dried over anhydrous Na
2
O, and the organic phase was
SO . After
2
4
evaporation of solvent, the crude was directly analyzed by GC–
MS to determine the yield and by either HPLC or GC to establish
the ee.
18
(
300 mg, 59%). Mp 137.4–137.7 °C 23(lit.
mp 137–138 °C);
¼ þ365 (c 1.0, CH Cl ));
): d (ppm) 0.79 (d, J = 7.5 Hz, 6H), 2.4
br s, 1H); 4.37 (q, J = 7.2 Hz, 2H), 7.21 (ddd, J = 7.5, 7.2, 1.0 Hz,
2
D
0
20
½
a
ꢃ
¼ þ369:8 (c 0.86, CHCl
3
) (lit.
½
a
ꢃ
2
2
D
1
H NMR (500 MHz, CDCl
3
(
4.10. Typical procedure for the dibutyl and dimethyl addition
to arylaldehydes
2
H), 7.31 (d, J = 8.5 Hz, 2H), 7.43 (t, J = 7.5 Hz, 2H), 7.48 (d,
1
3
J = 8.5 Hz, 2H), 7.90 (d, J = 7.5 Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H);
C
NMR (125 MHz, CDCl
3
): d (ppm) 140.3, 134.4, 133.3, 133.1, 129.2,
28.5, 128.4, 128.3, 126.1, 125.8, 57.2, 22.4. Anal. Calcd for
21N: C, 89.12; H, 6.54; N, 4.33. Found: C, 89.16; H, 6.50; N,
.37.
To a solution of the ligand (0.06 mmol) in dry toluene (3 mL)
under a nitrogen atmosphere at rt was added a solution of the dial-
kylzinc (1.80 mmol). The mixture was stirred for 30 min at rt or at
0 °C, then a solution of arylaldehyde (0.60 mmol) in dry toluene
1
C
4
24
H
(
1.3 mL) was added. The mixture was monitored by GC–MS, and
4
.7. (aS,S,S)-(+)-N-Ethoxycarbonylethyl-3,5-dihydro-3,5-
when no more traces of the aldehyde were detected the reaction
was quenched by the addition of 10% aqueous HCl. The mixture
0
0
dimethyl-4H-dinaphth[2,1-c:1 ,2 -e]azepine 8
was extracted with Et
brine, and dried over anhydrous Na
2
O, and the organic phase was washed with
SO . After evaporation of the
To a solution of amine 7 (300 mg; 0.90 mmol) in anhydrous
2
4
CHCl
3
(28.5 mL), under nitrogen, were added anhydrous Et
3
N
L,
solvent, the crude was directly analyzed by GC–MS to determine
the yield and by either HPLC or GC to establish the ee.
(
3.51 mL, 25.32 mmol) and ethyl bromoacetate (390
l

L. Pisani, S. Superchi / Tetrahedron: Asymmetry 19 (2008) 1784–1789
1789
Org. Lett. 2007, 9, 1927; Cr: (i) Jones, G. B.; Heaton, S. B. Tetrahedron: Asymmetry
993, , 4, 261; (j) Cozzi, P. G.; Kotrusz, P. J. Am. Chem. Soc. 2006, 128, 4940.
Acknowledgments
1
5
.
(a) Corey, E. J.; Hannon, F. J. Tetrahedron Lett. 1987, 28, 5233; (b) Noyori, R.;
Suga, S.; Kawai, K.; Okada, S.; Kitamura, M. Pure Appl. Chem. 1988, 60, 1597; (c)
Yoshioka, M.; Kawakita, T.; Ohno, M. Tetrahedron Lett. 1989, 30, 1657; (d) Soai,
K.; Watanabe, M.; Yamamoto, A. J. Org. Chem. 1990, 55, 4832; (e) Shibata, T.;
Hayase, T.; Aiba, Y.; Tabira, H.; Soai, K. Heterocycles 1997, 46, 235; (f) Soai, K.;
Konishi, T.; Shibata, T. Heterocycles 1999, 51, 1421; (g) Bringmann, G.; Pfeifer, R.
M.; Rummey, C.; Hartner, K.; Breuning, M. J. Org. Chem. 2003, 68, 6859; (h)
Hatano, M.; Miyamoto, T.; Ishihara, K. Adv. Synth. Catal. 2005, 347, 1561.
Although the numerical value of the reactivity ratio among these reagents may
depend on the ligand structure, temperature, and solvent, the order of
reactivity is always maintained.
Financial support from MIUR and Università della Basilicata
Potenza) is gratefully acknowledged. We thank Dr. M. G. Pizzuti
for preliminary studies on the synthesis of ligand 1c.
(
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0
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4
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3
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2
2
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.
For addition of Me
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Zn catalyzed by metal complexes see: Ti: (a) Takahashi, H.;
(
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1
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Sokeirik, Y. S.; Mori, H.; Omote, M.; Sato, K.; Tarui, A.; Kumadaki, I.; Ando, A.