New, improved procedure for the synthesis of structurally diverse N-spiro C2-symmetric chiral quaternary ammonium bromides

Article abstract of DOI:10.1021/jo030032f

Selective, direct ortho magnesiation of (S)-2,2′bis(isopropoxycarbonyl)-1,1′-binaphthyl (6) has been achieved under mild conditions, using magnesium bis(2,2,6,6-tetramethylpiperamide) [Mg(TMP)₂]. In combination with the subsequent reaction with

Full text of DOI:10.1021/jo030032f

Since Ar-NAS-Br can be readily assembled under
mildly basic conditions from (S)-bis-bromide 2 and sec-
ondary amine 3, we focused our attention on the synthe-
sis of 2, which could be derivatized from the correspond-
ing (S)-bis-ester 4 by simple reduction-bromination
sequence. In considering the Suzuki-Miyaura cross-
coupling reaction3 for the introduction of aromatic sub-
stituent (Ar) to the 3,3′-position, (S)-3,3′-dibromo-1,1′-
binaphthyl-2,2′-dicarboxylic ester 5a appeared as a
requisite compound to be prepared. For a straightforward
synthesis of 5a , direct ortho metalation of (S)-1,1′-
binaphthyl-2,2′-dicarboxylic ester 6 was required, for
which we chose magnesium bis(2,2,6,6-tetramethylpip-
eramide) [Mg(TMP)2] as an appropriate base4 and opti-
mized the reaction conditions.5
New , Im p r oved P r oced u r e for th e
Syn th esis of Str u ctu r a lly Diver se N-Sp ir o
C2-Sym m etr ic Ch ir a l Qu a ter n a r y
Am m on iu m Br om id es
Takashi Ooi, Yukitaka Uematsu, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science,
Kyoto University, Sakyo, Kyoto 606-8502, J apan
maruoka@kuchem.kyoto-u.ac.jp
Received J anuary 27, 2003
Thus, (S)-1,1′-binaphthyl-2,2′-dicarboxylic acid6 was
converted to the corresponding isopropyl ester 67 in the
usual manner. Treatment of 6 with 3 equiv of freshly
prepared Mg(TMP)2 in THF at room temperature for 10
h and subsequent reaction with bromine (6 equiv) at -78
°C to room temperature furnished (S)-3,3′-dibromo-2,2′-
bis(isopropoxycarbonyl)-1,1′-binaphthyl (5a ) in 60% yield
(entry 1 in Table 1),8 and the use of 4 equiv of Mg(TMP)2
and 8 equiv of bromine improved the yield to 88% (entry
2). Further, we found that 3 h of stirring was critical for
complete magnesiation and at least 8 equiv of bromine
was optimal (entries 3-5). As expected, use of other
electrophiles such as iodine became feasible, affording an
alternative candidate for the next coupling reaction in
83% yield (entry 6). This method represents the potential
utility of relatively unfamiliar Mg(TMP)2 for the selective
metalation of aromatic compounds possessing labile
functionalities.4b
Abstr a ct: Selective, direct ortho magnesiation of (S)-2,2′-
bis(isopropoxycarbonyl)-1,1′-binaphthyl (6) has been achieved
under mild conditions, using magnesium bis(2,2,6,6-tetra-
methylpiperamide) [Mg(TMP)2]. In combination with the
subsequent reaction with the appropriate electrophiles,
bromine and iodine, this method constitutes a key step in
establishing a new and concise synthetic route to a wide
variety of N-spiro C2-symmetric chiral quaternary am-
monium bromides of type 1.
In 1999 we introduced N-spiro C2-symmetric chiral
quaternary ammonium bromides of type 1 and demon-
strated the effectiveness of (S,S)-1c [(S,S)-â-Np-NAS-Br]
as a chiral phase-transfer catalyst in the enantioselective
alkylation of protected glycine derivative, providing a
practical method for the asymmetric synthesis of both
natural and unnatural R-amino acids.1 In the next year,
we also disclosed a new catalyst (S,S)-1b [(S,S)-3,4,5-
F3-Ph-NAS-Br] possessing an electron-withdrawing 3,4,5-
trifluorophenyl substituent and its successful utilization
for the catalytic asymmetric synthesis of R,R-dialkyl-R-
amino acids.2 Although these chiral quaternary am-
monium bromides can be assembled by a reliable proce-
dure we recently published,1e more than 10 steps are
required for preparation of the appropriately modified
binaphthyl subunit; this could be an impediment to
finding broad applications in academia as well as indus-
try. Further, certain structural limitations pose a critical
problem in every consideration of more precise molecular
design. Accordingly, we undertook an exploration of an
essentially new synthetic route to improve this situa-
tion. Herein we detail new procedures involving selective
ortho magnesiation of 1,1′-binaphthyl-2,2′-dicarboxylic
ester as a key step (Scheme 1), which enables the
synthesis of a variety of chiral quaternary ammonium
bromides of type 1.
With this efficient method in hand, various aromatic
substituents could be installed on the 3,3′-position of 5
(1) (a) Ooi, T.; Kameda, M.; Maruoka, K. J . Am. Chem. Soc. 1999,
121, 6519. See also: (b) Ooi, T.; Kameda, M.; Tannai, H.; Maruoka, K.
Tetrahedron Lett. 2000, 41, 8339. (c) Ooi, T.; Uematsu, Y.; Kameda,
M.; Maruoka, K. Angew. Chem., Int. Ed. 2002, 41, 1551. (d) Ooi, T.;
Takahashi, M.; Doda, K.; Maruoka, K. J . Am. Chem. Soc. 2002, 124,
7640. (e) Ooi, T.; Kameda, M.; Maruoka, K. J . Am. Chem. Soc. 2003,
125, 5139.
(2) (a) Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J . Am. Chem.
Soc. 2000, 122, 5228. See also: (b) Ooi, T.; Takeuchi, M.; Maruoka, K.
Synthesis 2001, 1716.
(3) For review, see: Suzuki, A. J . Organomet. Chem. 1999, 576, 147
and references therein.
(4) (a) Eaton, P. E.; Lee, C.-H.; Xiiong, Y. J . Am. Chem. Soc. 1989,
111, 8016. (b) Henderson, K. W.; Kerr, W. J . Chem. Eur. J . 2001, 7,
3430.
(5) Use of LiTMP in place of Mg(TMP)2 in the reaction with 6 gave
totally unsatisfactory results. For instance, treatment of 6 with 2.2
equiv of LiTMP in THF at 0 °C for 2 h and subsequent reaction with
bromine (2.2 equiv) at -78 °C to room temperature resulted in almost
total recovery of starting 6, while both attempts to use 3 equiv of
LiTMP and to perform the lithiation at room temperature gave a
deteriorated mixture.
(6) (a) Ohta, T.; Ito, M.; Inagaki, K.; Takaya, H. Tetrahedron Lett.
1993, 34, 1615. See also: (b) Seki, M.; Yamada, S.; Kuroda, T.;
Imashiro, R.; Shimizu, T. Synthesis 2000, 1677.
(7) Attempted reactions with the corresponding methyl and ethyl
esters under similar conditions afforded the desired products in less
than 20% yields (1H NMR).
(8) Concomitant formation of monobromination product was ob-
served (ca. 25%). Magnesiation of 6 under more concentrated condition
(0.62 M) or at higher temperature (50 °C) did not lead to the
improvement of the chemical yield of 5a , as long as 3 equiv of Mg-
(TMP)2 was used.
10.1021/jo030032f CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/03/2003
4576
J . Org. Chem. 2003, 68, 4576-4578

SCHEME 1
TABLE 1. Op tim iza tion of th e Rea ction P a r a m eter for
Or th o Ma gn esia tion of 6 a n d Su bsequ en t Tr a p p in g w ith
Electr op h ilesa
SCHEME 2
Mg(TMP)2
(equiv)
condition
(h)
E+
(equiv)
yieldb
(%)
entry
product
1
2
3
4
5
6
3
4
4
4
4
4
10
10
3
3
3
Br2 (6)
Br2 (8)
Br2 (8)
Br2 (6)
Br2 (9)
I2 (8)
60
88
89
76
89
83
5a
5a
5a
5a
5a
5b
3
a
The magnesiation was carried out by adding a THF solution
of 6 to Mg(TMP)2 in THF-hexane at 0 °C followed by stirring at
room temperature. Then, electrophile (E+) was introduced at -78
°C, and the mixture was allowed to warm to room temperature
b
and stirred there for 1 h. Isolated yield.
by well-established Suzuki-Miyaura cross coupling.3 For
instance, the reaction of 5a with 3,5-dimethylphenyl-
boronic acid in the presence of Pd(OAc)2, PPh3, and
K2CO3 in DMF at 90 °C for 8 h gave rise to the desired
coupling product 4a in 97% yield. Reduction of 4a with
LiAlH4 in THF at room temperature for 4 h afforded (S)-
3,3′-bis(3,5-dimethylphenyl)-2,2′-bis(hydroxymethyl)-1,1′-
binaphthyl (7a ), which without purification was treated
with PBr3 in THF at 0 °C to room temperature for 1 h,
producing the (S)-bis-bromide 2a in 91% yield (2 steps).
It should be noted that this type of bis-bromide 2 having
several benzylic protons was inaccessible by the previous
procedure because of the difficulty of selective radical
bromination.1e Assembly of 2a with 3 was conducted in
refluxing acetonitrile, using K2CO3 as a base, giving the
chiral quaternary ammonium bromide (S,S)-1a in 96%
yield (Scheme 2). Similarly, (S,S)-1b also can be prepared
as shown in Scheme 2.
facilitate large-scale access to this type of compound and
hopefully accelerate the research using them as chiral
phase-transfer catalysts.
Exp er im en ta l Section
(S)-2,2′-Bis(isop r op oxyca r bon yl)-1,1′-bin a p h th yl (6). (S)-
1,1′-Binaphthyl-2,2′-dicarboxylic acid6 (1.71 g, 5.0 mmol) was
placed in a dry two-neck flask with a stirring bar under argon
atmosphere and SOCl2 (5 mL) was introduced. The mixture was
refluxed for 4 h and excess SOCl2 was removed under reduced
pressure. Then, i-PrOH (5 mL) and pyridine (1 mL) were added
and the mixture was heated to reflux for 1 h. The resulting
solution was washed with H2O and extracted with EtOAc. The
organic layer was dried over Na2SO4 and concentrated. The
residue was purified by column chromatography on silica gel
(short-pass, EtOAc/hexane 1:4 as eluent) to give 6 (2.05 g, 4.70
mmol, 94%) as a white solid; 1H NMR (400 MHz, CDCl3) δ 8.17
(2H, d, J ) 8.7 Hz), 8.01 (2H, d, J ) 9.1 Hz), 7.92 (2H, d, J )
8.3 Hz), 7.50 (2H, ddd, J ) 1.2, 6.7, 7.9 Hz), 7.24 (2H, ddd, J )
1.2, 6.7, 7.9 Hz), 7.13 (2H, d, J ) 8.7 Hz), 4.75 (2H, sept, J ) 6.3
Hz), 0.76 (6H, d, J ) 6.3 Hz), 0.44 (6H, d, J ) 6.3 Hz) ppm; 13
C
In summary, we have developed a new synthetic route
to the structurally diverse N-spiro C2-symmetric chiral
quaternary ammonium bromide [Ar-NAS-Br] with selec-
tive, direct magnesiation of 1,1′-binaphthyl-2,2′-dicar-
boxylic esters as a key step. This procedure should
NMR (100 MHz, CDCl3) δ 166.6, 139.5, 134.6, 133.1, 128.3, 127.6,
127.6, 127.5, 127.4, 126.5, 126.0, 67.7, 21.2, 20.8 ppm.
P r ep a r a t ion of Ma gn esiu m Bis(2,2,6,6-t et r a m et h ylp i-
p er a m id e). To Mg turnings (55.0 mg, 2.25 mmol) in refluxing
THF (2.25 mL), freshly distilled from sodium benzophenoneketyl,
J . Org. Chem, Vol. 68, No. 11, 2003 4577

was added 1,2-dibromoethane (198 µL, 2.25 mmol) dropwise to
form a suspension of MgBr2. A suspension of LiTMP in THF,
prepared in a separate flask by the treatment of distilled 2,2,6,6-
tetramethylpiperidine (759 µL, 4.5 mmol) in THF (2.25 mL) with
a 1.6 M hexane solution of n-BuLi (2.81 mL, 4.5 mmol) at 0 °C
for 30 min, was successively transferred to the MgBr2 suspen-
sion. Additional stirring at 0 °C for 2 h gave a THF solution of
Mg(TMP)2 (clear brown solution). This solution of Mg(TMP)2 is
storable in a refrigerator in a Sure/Seal bottle and no loss of
activity was observed after a month.
(S)-3,3′-Dibr om o-2,2′-bis(isopr opoxycar bon yl)-1,1′-bin aph -
th yl (5a ). To a THF solution of Mg(TMP)2 prepared as described
above (0.31 M, 6.5 mL, 2.0 mmol) was added 6 (213 mg, 0.5
mmol) in THF (2.0 mL) dropwise at 0 °C under argon atmo-
sphere and the mixture was stirred for 3 h at room temperature.
After being cooled to -78 °C, Br2 (205 µL, 4.0 mmol) was added
and stirring was continued for 1 h at room temperature. This
mixture was then poured into cooled 1 N HCl, washed with
saturated Na2SO3, and extracted with EtOAc. The organic layer
was dried over Na2SO4 and concentrated. Purification of the
residue by column chromatography on silica gel (EtOAc/hexane
1:20 to 1:10 as eluent) gave 5a (260 mg, 0.445 mmol, 89%) as a
white solid; 1H NMR (400 MHz, CDCl3) δ 8.24 (2H, s), 7.82 (2H,
d, J ) 8.3 Hz), 7.53 (2H, ddd, J ) 1.2, 7.1, 8.3 Hz), 7.34 (2H,
ddd, J ) 1.2, 7.1, 8.3 Hz), 7.19 (2H, d, J ) 7.9 Hz), 4.78 (2H,
sept, J ) 6.3 Hz), 0.78 (6H, d, J ) 6.3 Hz), 0.67 (6H, d, J ) 6.3
Hz) ppm; 13C NMR (100 MHz, CDCl3) δ 165.3, 134.1, 134.0,
133.8, 132.1, 131.4, 127.9, 127.6, 127.1, 126.8, 115.8, 69.0, 21.1,
20.8 ppm.
h at room temperature. Then, Et2O (3 mL) was added and the
reaction was quenched by the sequential treatment with H2O
(142 µL), 15% NaOH (142 µL), and H2O (284 µL). After being
stirred for 1 h at room temperature, this mixture was filtered
through a pad of Celite and the filtrate was concentrated.
Without further purification, this crude (S)-3,3′-bis(3,5-dimeth-
ylphenyl)-2,2′-bis(hydroxymethyl)-1,1′-binaphthyl (7a ) was used
for the subsequent bromination. An analytical sample was
obtained by recrystallization from THF/hexane: 1H NMR (400
MHz, CDCl3) δ 7.92 (2H, s), 7.91 (2H, d, J ) 7.5 Hz), 7.49-7.45
(2H, m), 7.30 (4H, s), 7.27-7.23 (2H, m), 7.07 (2H, s), 7.04 (2H,
d, J ) 8.7 Hz), 4.45 (2H, d, J ) 11.7 Hz), 4.13 (2H, d, J ) 11.7
Hz), 2.41 (12H, s) ppm; 13C NMR (100 MHz, CDCl3) δ 141.5,
140.9, 137.5, 136.3, 135.8, 132.8, 132.3, 129.5, 128.9, 127.9, 127.5,
126.4, 126.3, 126.2, 60.1, 21.5 ppm.
A THF (ca. 3 mL) solution of 7a (523 mg, 1.0 mmol) was cooled
to 0 °C and PBr3 (52.8 µL, 0.5 mmol) was added dropwise. The
reaction mixture was stirred at room temperature for 1 h and
poured into H2O. Extractive workup was performed with EtOAc
and the combined extracts were dried over Na2SO4. Removal of
volatiles and purification of the residue by column chromatog-
raphy on silica gel (EtOAc/hexane 1:10 as eluent) furnished 2a
(590 mg, 0.91 mmol, 91% in two steps) as a white solid: 1H NMR
(400 MHz, CDCl3) δ 7.90 (2H, d, J ) 7.5 Hz), 7.89 (2H, s), 7.50
(2H, m), 7.28 (2H, m), 7.24 (4H, s), 7.15 (2H, d, J ) 7.5 Hz),
7.08 (2H, s), 4.30 (2H, d, J ) 10.1 Hz), 4.27 (2H, d, J ) 10.1
Hz), 2.41 (12H, s) ppm; 13C NMR (100 MHz, CDCl3) δ 141.1,
140.2, 137.5, 136.3, 133.1, 132.2, 131.7, 130.0, 129.0, 127.7, 127.3,
127.2, 127.0, 126.2, 32.2, 21.5 ppm.
(S)-3,3′-Diiod o-2,2′-bis(isop r op oxyca r bon yl)-1,1′-bin a p h -
th yl (5b). H NMR (400 MHz, CDCl3) δ 8.52 (2H, s), 7.78 (2H,
(S)-2,2′-Bis(h ydr oxym eth yl)-3,3′-bis(3,4,5-tr iflu or oph en yl)-
1,1′-bin a p h th yl (7b): H NMR (400 MHz, CDCl3) δ 7.94 (2H,
1
1
d, J ) 8.3 Hz), 7.51 (2H, m), 7.34 (2H, m), 7.17 (2H, d, J ) 8.7
Hz), 4.76 (2H, sept, J ) 6.3 Hz), 0.76 (6H, d, J ) 6.3 Hz), 0.69
(6H, d, J ) 6.3 Hz) ppm; 13C NMR (100 MHz, CDCl3) δ 166.4,
139.3, 136.9, 134.2, 133.6, 131.8, 127.7, 127.6, 127.3, 126.5, 88.2,
69.0, 21.0, 20.8 ppm.
d, J ) 8.7 Hz), 7.93 (2H, s), 7.54-7.51 (2H, m), 7.45-7.42 (4H,
m), 7.31-7.27 (2H, m), 6.97 (2H, d, J ) 8.3 Hz), 4.32 (2H, d, J
) 11.1 Hz), 4.15 (2H, d, J ) 11.1 Hz), 1.59 (2H, br) ppm; 13C
NMR (100 MHz, CDCl3) δ 150.5 (ddd, J C-F ) 249, 9.8, 4.1 Hz),
139.3 (dt, J C-F ) 252, 15.2 Hz), 138.5, 136.8, 136.7 (m), 134.6,
(S)-2,2′-Bis(isop r op oxyca r b on yl)-3,3′-b is(3,5-d im et h yl-
p h en yl)-1,1′-bin a p h th yl (4a ). A mixture of 5a (635 mg, 1.0
mmol), 3,5-dimethylphenylboronic acid (360 mg, 2.4 mmol),
Pd(OAc)2 (11.6 mg, 0.05 mmol), PPh3 (40.1 mg, 0.15 mmol), and
K2CO3 (419 mg, 3.0 mmol) in DMF (5.0 mL) was degassed and
backfilled with argon. This mixture was heated at 90 °C for 8 h.
After being cooled to room temperature, the resulting mixture
was poured into saturated NH4Cl and extracted with Et2O. The
organic extracts were dried over Na2SO4. Evaporation of solvents
and purification of the residue by column chromatography on
silica gel (EtOAc/hexane 1:20 to 1:10 as eluent) afforded 4a (616
mg, 0.97 mmol, 97%) as a white solid: 1H NMR (400 MHz,
CDCl3) δ 7.94 (2H, s), 7.90 (2H, d, J ) 7.9 Hz), 7.52-7.48 (2H,
m), 7.34-7.29 (4H, m), 7.16 (4H, s), 6.99 (2H, s), 4.50 (2H, sept,
J ) 6.3 Hz), 2.34 (12H, s), 0.57 (6H, d, J ) 6.3 Hz), 0.55 (6H, d,
J ) 6.3 Hz) ppm; 13C NMR (100 MHz, CDCl3) δ 167.3, 140.9,
137.5, 134.3, 133.1, 132.9, 131.9, 128.9, 128.8, 127.6, 127.6, 127.0,
126.5, 126.4, 67.8, 21.4, 20.9, 20.7 ppm.
(S)-2,2′-Bis(isop r op oxyca r b on yl)-3,3′-b is(3,4,5-t r iflu o-
r op h en yl)-1,1′-bin a p h th yl (4b): 1H NMR (400 MHz, CDCl3)
δ 7.93 (2H, d, J ) 9.1 Hz), 7.92 (2H, s), 7.57 (2H, ddd, J ) 1.2,
6.7, 7.9 Hz), 7.38 (2H, ddd, J ) 1.2, 6.7, 7.9 Hz), 7.28 (2H, d, J
) 8.3 Hz), 7.16-7.13 (4H, m), 4.55 (2H, sept, J ) 6.3 Hz), 0.61
(6H, d, J ) 6.3 Hz), 0.54 (6H, d, J ) 6.3 Hz) ppm; 13C NMR (100
MHz, CDCl3) δ 166.6, 150.8 (ddd, J C-F ) 249, 9.8, 4.1 Hz), 139.3
(dt, J C-F ) 252, 14.7 Hz), 136.8 (dt, J C-F ) 8.2, 4.9 Hz), 134.6,
134.3, 132.9, 132.2, 132.0, 129.3, 127.9, 127.8, 127.4, 112.9 (dd,
J C-F ) 15.5, 5.8 Hz), 68.5, 20.9, 20.7 ppm.
132.7, 132.5, 129.9, 128.1, 127.2, 127.1, 126.0, 114.2 (dd, J C-F )
15.6, 5.7 Hz), 59.7 ppm.
Ch ir a l Am m on iu m Sa lt (S,S)-1a . A mixture of 2a (324 mg,
0.5 mmol), chiral secondary amine 3 (147 mg, 0.5 mmol), and
K2CO3 (139 mg, 1.0 mmol) in CH3CN (3.0 mL) was heated and
refluxed for 6 h. This mixture was poured into H2O and extracted
with CH2Cl2. The organic extracts were dried over Na2SO4 and
concentrated. The residue was purified by column chromatog-
raphy on silica gel (MeOH/CH2Cl2 1:20 to 1:10 as eluent) to give
(S,S)-1a (414 mg, 0.48 mmol, 96%) as a white solid: [R]27.3D 16.6°
(c 0.50, CHCl3); 1H NMR (400 MHz, CD2Cl2) δ 8.36 (2H, s), 8.15
(2H, d, J ) 8.3 Hz), 7.93 (2H, d, J ) 7.9 Hz), 7.70-7.22 (4H, br),
7.70-7.66 (2H, m), 7.57-7.53 (2H, m), 7.45 (2H, s), 7.42 (2H, d,
J ) 8.3 Hz), 7.38-7.34 (2H, m), 7.26-7.22 (2H, m), 7.15 (4H, d,
J ) 7.9 Hz), 6.37 (2H, d, J ) 7.9 Hz), 4.99 (2H, d, J ) 13.9 Hz),
4.06 (2H, d, J ) 13.9 Hz), 3.98 (2H, d, J ) 12.9 Hz), 3.63 (2H, d,
J ) 12.9 Hz), 2.88-1.18 (12H, br) ppm; 13C NMR (100 MHz,
CDCl3) δ 139.9, 139.4, 139.2, 139.2, 136.2, 133.9, 133.8, 132.3,
130.9, 130.8, 130.3, 128.8, 128.6 (br), 128.3, 128.3, 128.0, 127.5,
127.4, 127.3, 127.3, 126.7, 125.0, 122.5, 62.1, 57.4, 21.7 ppm.
Melted at 230 °C with decomposition.
Ack n ow led gm en t. This work was partially sup-
ported by the Asahi Glass Foundation and a Grant-in-
Aid for Scientific Research from the Ministry of Edu-
cation, Culture, Sports, Science and Technology, J apan.
Su p p or tin g In for m a tion Ava ila ble: Full spectroscopic
characterization of all new compounds. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(S)-2,2′-Bis(br om om eth yl)-3,3′-bis(3,5-d im eth ylp h en yl)-
1,1′-bin a p h th yl (2a ). To a suspension of LiAlH4 (142 mg, 3.0
mmol) in THF (3.0 mL) was added 4a (635 mg, 1.0 mmol)
portionwise at 0 °C and the reaction mixture was stirred for 4
J O030032F
4578 J . Org. Chem., Vol. 68, No. 11, 2003