Aminomethylation of BINOL with methyleneiminium salts

Article abstract of DOI:10.1139/v11-100

A new method for synthesizing chiral 3,3′-bis(N,N-dialkylaminomethyl) -1,1′-bi-2-naphthols with high enantiomeric excess is described. The procedure consists of bis-lithiation of diprotected (S)-or (R)-1,1′-bis(2- naphthol) followed by treatment of the intermediate with methyleneiminium salts. Mild reaction conditions prevent racemization and provide 3,3′-bis(N,N- dialkylaminomethyl)-1,1′-bi-2-naphthols or 3-(N,N-dialkylaminomethyl)-1, 1′-bi-2-naphthols with an enantiomeric excess >99%.

Full text of DOI:10.1139/v11-100

1
319
Aminomethylation of BINOL with
methyleneiminium salts
Gennady Shustov and Vladimir Khlebnikov
Abstract: A new method for synthesizing chiral 3,3′-bis(N,N-dialkylaminomethyl)-1,1′-bi-2-naphthols with high enantio-
meric excess is described. The procedure consists of bis-lithiation of diprotected (S)- or (R)-1,1′-bis(2-naphthol) followed by
treatment of the intermediate with methyleneiminium salts. Mild reaction conditions prevent racemization and provide 3,3′-
bis(N,N-dialkylaminomethyl)-1,1′-bi-2-naphthols or 3-(N,N-dialkylaminomethyl)-1,1′-bi-2-naphthols with an enantiomeric
excess >99%.
Key words: 3,3′-bis(N,N-dialkylaminomethyl)-1,1′-bi-2-naphthols, methyleneiminium salts, chiral, enantiomeric excess.
Résumé : On décrit une nouvelle méthode de synthèse des 3,3′-bis(N,N-dialkylaminométhyl)-1,1′-bi-2-naphthols chiraux
avec des excès énantiomères élevés. Le procédé implique une bis-lithiation du (S)- ou (R)-1,1′-bis(2-naphthol) diprotégé, sui-
vie d’un traitement de l’intermédiaire avec des sels de méthylèneiminium. Les conditions douces de la réaction permettent
d’éviter la racémisation et elles permettent d’obtenir les 3,3′-bis(N,N-dialkylaminométhyl)-1,1′-bi-2-naphthols ou 3-(N,N-
dialkylaminométhyl)-1,1′-bi-2-naphthols avec des excès énantiomères de plus de 99 %.
Mots‐clés : 3,3′-bis(N,N-dialkylaminométhyl)-1,1′-bi-2-naphthols, sels de méthylèneiminium, chiral, excès énantiomère.
[
Traduit par la Rédaction]
often they are synthesized from commercial (S)- or (R)-1,1′-
bis(2-naphthol) (BINOL, 2).
Introduction
Axial C2 chirality of 3,3′-bis(N,N-dialkylaminomethyl)-
Starting from BINOL, two basic synthetic approaches are
described in the literature to prepare BINOLAMs containing
tertiary amines in the side chain. The first one is a multistep
1
,1′-bi-2-naphthols (BINOLAMs (1), see Fig. 1) and their ca-
pability to form adducts with metals and some organic com-
pounds makes them promising chiral auxiliaries in
2a
route that starts with the introduction of the carboxylic or
aldehyde8 groups into the 3,3′ positions of BINOL, followed
by the formation of amides or imines that are subsequently
reduced (a lengthier procedure from BINOL 3,3′-dialdehyde
1
asymmetric synthesis. The first use of BINOLAMs as chiral
catalysts was reported in the Michael addition of 2-(tri-
methylsilyloxy)furans to oxazolidinone enoates. Later they
c
2
were used in phase-transfer a-alkylation of iminoesters of
is sometimes used,4 since it provides higher yields ). In
,10
10
3
4
5
amino acids, aldol and nitroaldol condensations, and in
6
a
6a,6b
isolated examples the required enantiomerically pure BINOL
asymmetric addition of alkynyl- and diphenylzincs
to
3
3
,3′-dicarboxylic acid was obtained via resolution or enan-
aldehydes and ketones. The major application of BINOLAMs
so far is the ability of their complexes with metals to catalyze
and induce enantioselectivity in various reactions of cyanosi-
12
tioselective oxidative biaryl coupling. Once the appropriate
,3′-disubstituted BINOL intermediates are produced, the fol-
3
lylation,6 cyanocarbonylation, and cyano-
a,7
8
9a,9b
lowing steps are known to proceed without racemization and
provide the enantiomerically pure BINOLAMs in 10%–30%
chemical yield. The most recent publication based on this tra-
ditional approach describes a newly developed synthesis
based on bis-anionic Fries rearrangement7d of BINOL carba-
mates, and it provided BINOLAM (S)-1 (R = Et) with 63%
yield in three steps. Unfortunately, this method can hardly be
or hydroxy-
phospholylation9 of aldehydes (other examples in this area
c
1
c
are given in the review by Najera et al. )
Recently, it was reported that BINOLAMs are photocyto-
toxic to DNA, which makes them effective against certain
human tumor cell lines. This BINOLAM action is based
on their ability to undergo the elimination of dialkylamines
under UV irradiation and form highly reactive methylene-
quinoid structures; the latter are powerful DNA alkylating
and cross-linking agents.
Thus, the development of synthetic methods for producing
enantiomerically pure BINOLAMs seems to be quite impor-
tant. These compounds can be obtained from racemic starting
material, for example, via photochemical transamination11b
using L-proline esters as chiral auxiliaries; however, more
1
0
1
1
13
called general, because it was reported that for some sub-
strates migration of the second carbamate group is slow, and
a significant amount of mono-rearranged by-product is
formed.
The second known approach to the enantiomerically pure
BINOLAMs utilizes the direct reaction of aminomethylation
of BINOL enantiomers with N-hydroxymethylmorpholine (3,
Fig. 2) at 110 °C, followed by enantiomeric enrichment of
1
0
Received 22 March 2011. Accepted 28 June 2011. Published at www.nrcresearchpress.com/cjc on 21 September 2011.
G. Shustov and V. Khlebnikov. NAEJA Pharmaceutical Inc, 4290 91A Street NW, Edmonton, AB T6E 5V2, Canada.
Corresponding author: V. Khlebnikov (e-mail: vkhlebnikov@naeja.com).
Can. J. Chem. 89: 1319–1324 (2011)
doi:10.1139/V11-100
Published by NRC Research Press

1320
Can. J. Chem. Vol. 89, 2011
Fig. 1. Chiral BINOLAMS and parent (S)-BINOL.
Fig. 3. Methyleneiminium salts 5a–5d.
O
R
H
N
X
R
NR2
N
H
5
5
5
5
a R+R = (CH ) O(CH ) , X = Cl
2 2 2 2
b R+R = (CH ) O(CH ) , X = CF SO
3
OH
OH
OH
OH
OH
OH
2
2
2 2
3
c R = Me X = Cl
d R = Me X = I
Scheme 1. Synthesis of methyleneiminium salts 5a and 5b.
AcCl or Tf O
NR2
N
O
O
O
O
2
H
N
(
S)-1
(S)-1a
(S)-2
N
N
Et O, RT
2
X-
H
Fig. 2. Aminomethylating agents.
5a
4
(X = Cl)
5
b (X = CF SO )
3 3
O
O
O
HO
N
N
N
Results and discussion
3
4
N,N-Dialkylmethyleneiminium salts can be easily generated
by a reaction of acyl chlorides or anydrides with methylene–
the product by recrystallization.6a,7c This is the shortest syn-
thesis of BINOLAMs and hence it looks the most conven-
ient. However, it suffers from several shortcomings.
15
bis(dialkylamines). Thus, chloride 5a was obtained in 97%
yield and triflate 5b in 99% yield by reacting 4 with acetyl
chloride or triflic anhydride accordingly (Scheme 1). Imi-
nium salts 5c and 5d are commercially available.
First, the conversion of the starting BINOLs to BINO-
LAMs in this aminomethylation reaction is not very high,
and usually a significant amount of monoaminomethylated
product is formed along with the desired BINOLAM. Appa-
rently, the yield in this reaction depends on the purity of the
aminomethylating agent 3 and, according to our experience,
the reagent 3 (normally prepared by condensation of morpho-
line with paraformaldehyde) often contains a significant
amount of unreactive N,N-methylene–bismorpholine (4). The
latter reaction is difficult to control, and the composition of
the crude mixture may vary from experiment to experiment.
The same is true for preparation of other N-hydroxymethyl-
dialkylamines.
Second, since the described direct aminomethylation of
BINOL is carried out at elevated temperature (110 °C),
noticeable racemization could occur, resulting in the obtained
BINOLAM with an ee of about 75%.
understandable and potentially unavoidable because, as it has
been demonstrated earlier, the configurational stability of
BINOL decreases in the presence of bases. Increasing the ee
of (S)-1 by recrystallization as described by other authors6
cannot be considered to be a general method applicable to
other BINOLAMs, since the recrystallization conditions need
to be optimized for each individual compound. This could
take significant time and may not be possible in some situa-
tions.
Based on these considerations, we thought it would be
highly desirable to develop an aminomethylating agent with
better reactivity, to make it possible for the aminomethylation
reaction to proceed with higher yields and under milder con-
ditions. Since the target aminomethylated BINOLs have use-
ful practical applications and might be required in multigram
quantities, we were looking at reagents that could be easily
synthesized and purified.
The good reactivity of N,N-dialkylmethyleneiminium salts
in aromatic electrophilic substitution reactions, which was
16
17
15c
18
demonstrated for anilines, phenols, furanes, thiophenes,
pyrrols,19 and various other electron-rich heterocycles,20 en-
couraged us to try this approach in the preparation of opti-
cally active BINOLAMs.
We started our experiments on BINOL aminomethylation
with chloride 5a, trying to reproduce the conditions that
were reported in the literature for 3- and 4-methoxycarbonyl-
phenols.17 It appeared that the reaction of 2 with iminium salt
5a in dichloromethane in the presence of K CO at room
2
3
temperature did not occur. Changing the solvent to acetoni-
trile, increasing the amount of 5a to 8 equiv, and carrying
out the reaction at 60 °C for 19 h did not bring positive re-
sults either. No aminomethylation reaction for 2 was ob-
served even when stronger bases were used, such as 1 N
NaOH (CH Cl –H O, room temperature, 16 h) or NaH
6
a,7c
These results are
2
2
2
(DMF, room temperature, 19 h).
1
4
Based on these results, it was concluded that to make the
reaction of methyleneiminium salts with BINOL substrates
successful, the increase of nucleophilicity of the latter were
required. This can be done, for example, by lithiation of the
3 and 3′ positions of bis-O,O′-diprotected BINOL as de-
scribed by Snieckus and co-workers.21
a,7c
A series of experiments demonstrated that indeed MOM-
protected BINOL 6, after treatment with n-BuLi, reacted
smoothly with methyleneiminium salts 5a–5d to produce cor-
responding BINOLAMs 7a and 7b in 54%–88% yields, re-
spectively (Scheme 2 and Table 1). Small amounts of
monoaminomethyl derivatives 8a and 8b were also formed;
however, the yields of these side products were significantly
lower then in the case of the reaction of BINOL (2) with N-
hydroxymethylenemorpholine (3).6
a,7c
In this study we investigated the possibility of using the
methyleneiminium salts 5a–5b (Fig. 3) as such reagents.
In a typical aminomethylation procedure, 3.2 equiv of
methyleneiminium salt 5 relative to substrate 6 were used.
Published by NRC Research Press

Shustov and Khlebnikov
1321
Scheme 2. Synthesis of 7a and 7b and 8a and 8b.
Scheme 3. Synthesis of 3,3′-bis(N,N-dialkylaminomethyl)-1,1′-bi-2-
naphthols (BINOLAMs) 1a and 1b.
1
) NaH
NR2
NR2
2
) ClCH OMe
2
O
O
OMe
OMe
OH
OH
THF
O
O
OMe
OMe
HCl
OH
OH
MeOH
(S)-2
(S)-6
NR2
NR2
1
2
) BuLi
NR2
NR2
R
N
H
)
X
(S)-7a,7b
(S)-1a,1b
R
a R+R = (CH ) O(CH )
2 2
b R = Me
2
2
O
O
OMe
OMe
O
O
OMe
OMe
H
5a-5d
+
THF
(
TLC) carried out on Macherey–Nagel Alugram SIL G/
UV254 silica gel 60 plates with a fluorescent indicator using
phosphomolybdic acid in ethanol and heat as a developing
agent. NMR spectra were recorded on a Varian Mercury 400
NR2
(S)-7a,7b
(S)-8a,8b
a R+R = (CH ) O(CH )
2 2
b R = Me
1
2
2
NMR instrument (400 MHz frequency for H) using residual
undeuterated solvent as an internal reference. Low-resolution
mass spectra were recorded on a Water Micromass ZQ mass
spectrometer with electrospray ionization (ESI). HPLC analy-
ses were performed on a Waters 600 system with a Waters
2996 photodiode array detector using a C-18 reverse-phase
column. For the ee determination, a Chiralcel OD-R column
Table 1. Aminomethylation of (S)-6 with methyleneiminium salts
a–5d (Scheme 2).
5
Ratio of 7:8
Yield
(%)
Methyleneiminium salt (mol/mol)a
b
Entry
1
2
3
4
5
5a
5b
5c
5d
5a
1:0.2
1:0.2
1:0.2
1:0.02
0.2:1
54
69
63
88
69
was used (MeCN – 0.5 N aq NaClO , 60:40 as a mobile
4
phase). All dry column chromatography purifications were
performed on silica gel 60A with a 5–15 µm particle size.
N-Methylenemorpholinium chloride (5a)
To a stirred solution of acetyl chloride (4.32 g, 55 mmol)
Note: The reaction was carried out in THF at –15 °C to room tempera-
ture (1 or 2 h) with 2.6 equiv of n-BuLi and 3.2 equiv of 5a–5d for en-
tries 1–4 and with 1.3 equiv of n-BuLi and 1.6 equiv of 5a for entry 5.
in anhydrous Et O (100 mL), a solution of methylene–
2
22
bismorpholine (9.31 g, 50 mmol) in anhydrous Et O
2
a
In the crude mixture.
Isolated yield of the major product.
(
50 mL) was added dropwise at 20–24 °C over 1.5 h. The
b
reaction mixture was stirred for an additional 0.5 h at room
temperature. The white precipitate was filtered off, washed
Reducing this amount to 1.6 equiv allowed the monomethylene-
imine compound 8 to be obtained in 69% yield.
with anhydrous Et O (3 × 40 mL), and dried in vacuum to
2
provide 6.39 g (94%) of N-methylenemorpholinium chloride
Carrying out the reaction under mild conditions (tempera-
ture from –20 to 20 °C) helped to avoid the racemization of
substrate 6 and its aminomethylated derivatives 7 and 8. The
high ee (>99%) of isolated products (S)-7a and (S)-7b and
15d
1
5
a
as a white powder. H NMR (400 MHz) in (CD ) SO
3 2
3
3
d: 3.90 (4H, t, J = 5.0 Hz, OCH ), 4.06 (4H, t, J =
.0 Hz, NCH ), 8.24 (2H, N=CH ).
2
+
5
2
2
(
S)-8a as well as BINOLAMs (S)-1a and (S)-1b, which were
N-Methylenemorpholinium triflate (5b)
obtained after removing the MOM protective groups
To a stirred solution of trifluoromethanesulfonic anhydride
(
Scheme 3), was confirmed by HPLC analysis using a col-
(
9.93 g, 35.2 mmol) in anhydrous Et O (200 mL), a solution
2
umn with a chiral stationary phase.
22
of methylene–bismorpholine (5.96 g, 32 mmol) in anhy-
drous Et O (50 mL) was added dropwise at 20–24 °C over
2
Conclusion
1
h. The reaction mixture was stirred for an additional 2 h at
room temperature. The white precipitate was filtered off,
In conclusion, the investigated reaction of lithiated MOM-
protected BINOL with methyleneiminium salts can be a con-
venient and versatile method for the synthesis of BINOLAMs
with high enantiomeric excess (>99%).
washed with anhydrous Et O (3 × 40 mL), and dried in vac-
2
uum to provide 7.90 g (99%) of N-methylenemorpholinium
triflate 5b as a highly hygroscopic white powder.2 H NMR
3 1
(
400 MHz) in (CD ) SO d: 3.90 (4H, br. t, OCH ), 4.08 (4H,
3 2 2
+
br. t, NCH ), 8.21 (2H, N=CH ).
2
2
Experimental
Instrumentation, analysis, and starting materials
(S)-2,2′-Bis(methoxymethoxy)-1,1′-binaphthol (6)
All starting materials, solvents, and reagents were used as
purchased from commercial suppliers, unless otherwise
noted. Anhydrous THF was purchased from Sigma-Aldrich.
Reactions were monitored by thin-layer chromatography
To a stirred cooled (0–5 °C) suspension of NaH (60% in
mineral oil, 15.73 g, 0.393 mol) in a mixture of anhydrous
THF (660 mL) and anhydrous DMF (330 mL), a solution of
2 (50.41 g, 0.176 mol) in anhydrous THF (200 mL) was
Published by NRC Research Press

1322
Can. J. Chem. Vol. 89, 2011
added dropwise at 5–10 °C. The resultant mixture was al-
for an additional 2 h and the reaction was quenched by addi-
tion of water (1 mL). The resultant mixture was concentrated
under reduced pressure and the oily residue was dissolved in
ethyl acetate (50 mL). The obtained solution was washed
with water (2 × 15 mL), a saturated aqueous solution of
Na S O (15 mL), and brine (20 mL). After drying over
lowed to warm up to 15 °C and chloromethyl methyl ether
(
44.73 g, 0.556 mol) was added dropwise at 15–20 °C. The
reaction mixture was stirred for 16 h at room temperature,
quenched with water (20 mL), concentrated under reduced
pressure to a volume of ~400 mL, and diluted with EtOAc
2
2
7
(
(
800 mL). The obtained mixture was washed with water
3 × 300 mL), 1 N HCl (300 mL), saturated aqueous
MgSO , the solution was filtered and concentrated under re-
4
duced pressure to provide 2.61 g of a light yellow oil, which
was subjected to dry flash chromatography on silica gel
(CH Cl to 5% MeOH–CH Cl ) to afford 2.15 g (88%) of
NaHCO3 (300 mL), and brine (300 mL) and dried over
MgSO . Filtration through a pad of silica gel and removal of
the solvent from the filtrate under reduced pressure provided
4
2
2
2
2
7b as a colourless viscous oil. Assayed at 97.99% by HPLC.
7
2.7 g of a white solid. This solid was suspended in hexanes
HPLC analysis on a column with a chiral stationary phase
1
(
300 mL) and the precipitate was filtered off and washed
showed an enantiomeric excess of >99.5%. H NMR
2
4
with hexanes (2 × 150 mL). The product 6 (63.2 g, 96%)
was obtained as white solid after drying in vacuum. 1
NMR (400 MHz) in CDCl d: 3.14 (6H, OMe), 4.98 (2H, d,
(400 MHz) in CDCl d: 2.38 (12H, NMe), 2.76 (6H, OMe),
3
3.72 (2H, d, 2J = 14.2 Hz, NCH ), 3.80 (2H, d, J =
2
H
A
2
3
14.2 Hz, NCH ), 4.51 (2H, d, J = 5.8 Hz, OCH ), 4.66
B
A
2
2
2
(2H, d, J = 5.8 Hz, OCH ), 7.20 (2H, t, J = 8.2 Hz), 7.25
J = 6.8 Hz, OCH ), 5.08 (2H, d, J = 6.8 Hz, OCH ), 7.15
B
A
B
(
2H, d, J = 8.2 Hz), 7.40 (2H, t, J = 8.2 Hz), 7.88 (2H, d,
(
2H, d, J = 8.2 Hz), 7.22 (2H, t, J = 8.2 Hz), 7.35 (2H, t,
J = 8.2 Hz), 7.58 (2H, d, J = 8.8 Hz), 7.87 (2H, d, J =
.2 Hz), 7.95 (2H, d, J = 8.8 Hz).
+
J = 8.2 Hz), 8.04 (2H). MS (electrospray), m/z: 489 (M +
1
5
). Anal. calcd for C H N O (%): C 73.74, H 7.43, N
8
30 36 2 4
.73; found: C 73.93, H 7.37, N 5.61.
(
S)-3,3′-Bis(N-morpholinomethyl)-2,2′-bis(methoxy-
(
S)-3-N-Morpholinomethyl-2,2′-bis(methoxy-methoxy)-
methoxy)-1,1′-binaphthol (7a)
1
,1′-binaphthol (8a)
To a stirred cooled (–5 °C to 0 °C) solution of 6 (1.87 g,
mmol) in anhydrous THF (50 mL), a 1.6 mol/L solution of
To a stirred cooled (–5 to 0 °C) solution of 6 (13.10 g,
5 mmol) in anhydrous THF (350 mL), a 1.6 mol/L solution
5
3
n-butyl lithium in hexane (8.13 mL, 13 mmol) was added
dropwise at –5 to 0 °C. The reaction mixture was stirred for
of n-butyl lithium in hexane (28.4 mL, 45.5 mmol) was
added dropwise at –5 to 0 °C. The reaction mixture was
stirred for 2 h at 0–5 °C and cooled to –15 °C. Solid 5a
2
h at 0–5 °C and cooled to about –15 °C. Avoiding expo-
sure to air, freshly prepared and dried 5b (3.99 g, 16 mmol)
was added portionwise and the reaction mixture was allowed
to warm to room temperature. The stirring was continued for
an additional 2 h, and the reaction was quenched by addition
of water (1 mL). The resultant mixture was concentrated
under reduced pressure and the oily residue was dissolved in
ethyl acetate (50 mL). The obtained solution was washed
with water (2 × 15 mL) and brine (20 mL). After drying
(7.59 g, 56 mmol) was added portionwise and the reaction
mixture was allowed to warm up to room temperature. The
stirring was continued for additional 2 h and the reaction
was quenched by addition of water (7 mL). The resultant
mixture was concentrated under reduced pressure and the
oily residue was dissolved in ethyl acetate (350 mL). The ob-
tained solution was washed with water (2 × 100 mL) and
brine (200 mL). After drying over MgSO4, the solution was
filtered and concentrated under reduced pressure to provide
16.8 g of a yellow oil, which was subjected to dry flash chro-
matography on silica gel (30% EtOAc–hexanes to 60%
EtOAc–hexanes) to afford 11.50 g (69%) of 8a as a white
solid. Assayed at 96.81% by HPLC. HPLC analysis on a col-
umn with a chiral stationary phase showed an enantiomeric
over MgSO , the solution was filtered and concentrated under
4
reduced pressure to provide 3.02 g of a light pink semisolid,
which was subjected to dry flash chromatography on silica
gel (50% EtOAc–hexanes to 100% EtOAc) to afford 1.98 g
(
69%) of 7a as a white solid. Assayed at 98.13% by HPLC.
HPLC analysis on a column with a chiral stationary phase
1
showed an enantiomeric excess of >99.5%. H NMR
1
(
400 MHz) in CDCl d: 2.62 (8H, m, NCH ), 2.70 (6H,
excess of >99.5%. H NMR (400 MHz) in CDCl3 d: 2.63
3
2
2
OMe), 3.76 (10H, m, OCH + NCH ), 3.88 (2H, d, J =
(4H, m, NCH2), 2.77 (3H, OMe), 3.16 (3H, OMe), 3.57
2
A
2
2
1
(
3.6 Hz, NCH ), 4.57 (2H, d, J = 5.6 Hz, OCH ), 4.74
(4H, m, OCH2), 3.83 (2H, NCH2Ar), 4.64 (1H, d, J =
B
A
2
2
2H, d, J = 5.6 Hz, OCH ), 7.22 (4H, m), 7.41 (2H, t, J =
5.6 Hz, OCHA), 4.71 (1H, d, J = 5.6 Hz, OCHB), 5.02 (1H,
B
2
2
8
.0 Hz), 7.88 (2H, d, J = 8.0 Hz), 8.00 (2H). MS (electro-
d, J = 7.2 Hz, OCHA′), 5.11 (1H, d, J = 7.2 Hz, OCHB′),
7.22 (4H, m), 7.37 (2H, m), 7.58 (1H,d, J = 8.8 Hz), 7.87
(2H, m), 7.96 (2H, d, J = 8.8 Hz), 7.99 (2H). MS (electro-
+
spray), m/z: 573 (M ). Anal. calcd for C H N O (%): C
3
4
40
2
6
7
1.31, H 7.04, N 4.89; found: C 71.38, H 7.10, N 4.90.
+
spray), m/z: 474 (M ). Anal. calcd for C H NO (%): C
73.55, H 6.60, N 2.96; found: C 73.81, H 6.72, N 3.07.
29
31
5
(
S)-3,3′-Bis(N,N-dimethylaminomethyl)-2,2′-bis-
methoxymethoxy)-1,1′-binaphthol (7b)
(
To a stirred cooled (–5 to 0 °C) solution of 6 (1.87 g,
mmol) in anhydrous THF (50 mL), a 1.6 mol/L solution
(S)-3,3′-Bis(N-morpholinomethyl)-2,2′-dihydroxy-1,1′-
binaphthol (1a)
5
of n-butyl lithium in hexane (8.13 mL, 13 mmol) was added
dropwise at –5 to 0 °C. The reaction mixture was stirred for
To a stirred cooled (–5 to 0 °C) solution of 7a (1.72 g,
3 mmol) in methanol (15 mL), a 4 mol/L solution of HCl in
1,4-dioxane (15 mL, 60 mmol) was added dropwise. The re-
action mixture was allowed to warm to room temperature and
was stirred for an additional 16 h. After removal of solvent
under reduced pressure, the solid residue was triturated with
2
h at 0–5 °C and cooled to –15 °C. Solid (N,N-dimethyl)
methyleneammonium iodide (5d) (2.96 g, 16 mmol) was
added portionwise and the reaction mixture was allowed to
warm up to room temperature. The stirring was continued
Published by NRC Research Press

Shustov and Khlebnikov
1323
Et O (2 × 30 mL) and dried in vacuum to provide 1.69 g of
(40), 9335. doi:10.1016/j.tet.2006.06.049; (b) DeBerardinis,
A. M.; Turlington, M.; Pu, L. Org. Lett. 2008 10 (13), 2709.
doi:10.1021/ol8008478; (c) For asymmetric addition of diethyl-
zinc to aldehydes catalyzed by similar BINOL derivatives
bearing aromatic N-heterocycles in 3,3′ positions see Guo,
Q.-S.; Liu, B.; Lu, Y.-N.; Jiang, F.-Y.; Song, H.-N.; Li, J.-S.
Tetrahedron Asymmetry 2005 16 (22), 3667. doi:10.1016/j.
tetasy.2005.09.018; (d) Ma, L.; Jin, R.-Z.; Lü, G.-H.; Bian, Z.;
Ding, M.-X.; Gao, L.-X. Synthesis 2007 2461; (e) Milburn, R.
R.; Hussain, S. M.; Prien, O.; Ahmed, Z.; Snieckus, V. Org.
Lett. 2007 9 (22), 4403. doi:10.1021/ol071276f.
2
a white solid. The isolated solid was suspended in CH Cl2
2
(
80 mL) and saturated aqueous NaHCO (40 mL) was added
3
to the resultant suspension. After 15 min of stirring, the or-
ganic phase was separated and dried over MgSO . Filtration
4
and removal of the solvent from the filtrate under reduced
pressure provided 1.51 g of a yellow solid, which was sub-
jected to dry flash chromatography on silica gel (2%
EtOAc–CH Cl to 20% EtOAc–CH Cl ) to afford 1.31 g
2
2
2
2
7c
(
90%) of 1a as a white solid. Assayed at 96.53% by HPLC.
HPLC analysis on a column with chiral stationary phase
1
(7) (a) Casas, J.; Nájera, C.; Sansano, J. M.; Saá, J. M. Org. Lett.
showed enantiomeranic excess of >99.5%.
H NMR
2
002 4 (15), 2589. doi:10.1021/ol0262338; (b) Casas, J.;
(
400 MHz) in CDCl d: 2.64 (8H, br. m, NCH ), 3.69 (8H,
3
2
2
Nájera, C.; Sansano, J. M.; Saá, J. M. Tetrahedron 2004 60
(46), 10487. doi:10.1016/j.tet.2004.06.137; (c) Qin, Y.-C.; Liu,
L.; Pu, L. Org. Lett. 2005 7 (12), 2381. doi:10.1021/
ol050660e; (d) North, M.; Villuendas, P.; Williamson, C.
Tetrahedron 2010 66 (10), 1915. doi:10.1016/j.tet.2010.01.
br. m, OCH ), 3.89 (2H, d, J = 14.0 Hz, NCH ), 4.12 (2H,
2
A
2
d, J = 14.0 Hz, NCH ), 7.29–7.12 (6H, m), 7.66 (2H), 7.78
B
+
(
2H, d, J = 8.4 Hz). MS (electrospray), m/z: 483 (M – 1).
(
S)-3,3′-Bis(N,N-dimethylaminomethyl)-2,2′-dihydroxy-
0
04.
1
,1′-binaphthol (1b)
(
8) (a) Casas, J.; Baeza, A.; Sansano, J. M.; Najera, C.; Saa, J. M.
To a stirred cooled (–5 to 0 °C) solution of 7b (1.02 g,
.1 mmol) in methanol (2 mL), a 4 mol/L solution of HCl in
Tetrahedron Asymmetry 2003 14 (2), 197. doi:10.1016/S0957-
2
4
166(02)00824-8; (b) Baeza, A.; Casas, J.; Nájera, C.;
methanol (10 mL, 40 mmol) was added dropwise. The reac-
tion mixture was allowed to warm up to room temperature
and was stirred for an additional 16 h. After removal of the
solvent under reduced pressure, the solid residue was tritu-
Sansano, J. M.; Saá, J. M. Eur. J. Org. Chem. 2006 1949.
doi:10.1002/ejoc.200500939; (c) Gou, S.; Liu, X.; Zhou, X.;
Feng, X. Tetrahedron 2007 63 (33), 7935. doi:10.1016/j.tet.
2
007.05.060; (d) Baeza, A.; Najera, C.; Sansano, J. M.; Saa, J.
rated with Et O (2 × 20 mL) and dried in vacuum to provide
2
M. Tetrahedron Asymmetry 2005 16 (14), 2385. doi:10.1016/j.
tetasy.2005.05.031.
0
.96 g of a white solid. The solid was suspended in CH Cl2
2
(
50 mL) and saturated aqueous NaHCO (25 mL) was added
3
(9) (a) Baeza, A.; Casas, J.; Najera, C.; Sansano, J. M.; Saa, J. M.
Angew. Chem. Int. Ed. 2003 42 (27), 3143. doi:10.1002/anie.
200351552; (b) Baeza, A.; Najera, C.; Sansano, J. M.; Saa, J.
M. Chemistry 2005 11 (13), 3849. doi:10.1002/chem.
to the resultant suspension. After 15 min of stirring, the or-
ganic phase was separated and dried over MgSO . Filtration
4
and removal of the solvent from the filtrate under reduced
pressure provided 0.81 g of a yellow solid, which was sub-
2
00401290; (c) Gou, S.; Zhou, X.; Wang, J.; Liu, X.; Feng,
jected to dry flash chromatography on silica gel (CH Cl to
2
2
X. Tetrahedron 2008 64 (12), 2864. doi:10.1016/j.tet.2008.01.
022.
2
a
6
% MeOH–CH Cl ) to afford 0.78 g (93%) of 1b as a white
2
2
solid. Assayed at 97.45% by HPLC. HPLC analysis on a col-
umn with a chiral stationary phase showed an enantiomeric
(10) Doria, F.; Richter, S. N.; Nadai, M.; Colloredo-Mels, S.; Mella,
M.; Palumbo, M.; Freccero, M. J. Med. Chem. 2007 50 (26),
6570. doi:10.1021/jm070828x.
(11) (a) Richter, S. N.; Maggi, S.; Colloredo-Mels, S.; Palumbo,
M.; Freccero, M. J. Am. Chem. Soc. 2004 126 (43), 13973.
doi:10.1021/ja047655a; (b) Colloredo-Mels, S.; Doria, F.;
Verga, D.; Freccero, M. J. Org. Chem. 2006 71 (10), 3889.
doi:10.1021/jo060227y.
1
excess of >99.5%. H NMR (400 MHz) in CDCl d: 2.36
12H, NMe), 3.76 (2H, d, J = 13.6 Hz, NCH ), 4.10 (2H,
3
2
(
A
2
d, J = 13.6 Hz, NCH ), 7.26–7.13 (6H, m), 7.61 (2H), 7.76
B
+
(
2H, d, J = 7.6 Hz). MS (electrospray), m/z: 400 (M ).
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