Synthesis of new axially dissymmetric ligand with large perfluoroalkyl groups

Article abstract of DOI:10.1016/j.tetlet.2004.11.038

A new axially dissymmetric ligand with large perfluoroalkyl groups, 2,2′-bis(1-hydroxy-1H-perfluorooctyl)biphenyl (1c), which could not be obtained by the coupling reaction of the aryl bromide using copper powder, was synthesized successfully by the coupl

Full text of DOI:10.1016/j.tetlet.2004.11.038

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 319–322
Synthesis of new axially dissymmetric ligand
with large perfluoroalkyl groups
Masaaki Omote, Yuji Nishimura, Kazuyuki Sato, Akira Ando and Itsumaro Kumadaki*
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1, Nagaotoge-cho, Hirakata 573-0101, Japan
Received 17 September 2004; revised 1 November 2004; accepted 5 November 2004
Available online 25 November 2004
Abstract—A new axially dissymmetric ligand with large perfluoroalkyl groups, 2,20-bis(1-hydroxy-1H-perfluorooctyl)biphenyl (1c),
which could not be obtained by the coupling reaction of the aryl bromide using copper powder, was synthesized successfully by the
coupling reaction using Ni(COD)2. This ligand showed much higher asymmetric induction in the reaction of diethylzinc with benz-
aldehyde than the trifluoromethyl (1a) or pentafluoroethyl (1b) analogues.
Ó 2004 Elsevier Ltd. All rights reserved.
An asymmetric reaction to provide enantiomerically en-
riched product is of great importance to recent organic
reaction. A number of chiral ligands for the asymmetric
synthesis have been synthesized, and new methodologies
using them have been developed. Among the chiral li-
gands, 1,10-bi-2-naphthol (BINOL) is one of the most
widely used and well-studied chiral ligands with C2 sym-
metry.1 Many outstanding reports on the asymmetric
reactions with BINOL and its derivatives have been
published.2
ters, are characteristic of our ligands. The electron with-
drawing and hard Rf groups inhibit racemization of the
chiral centers on the side chains. Further, the Rf groups
increase the acidity of the hydroxyl groups near to that
of phenols. This makes the hydroxyl groups favorable as
a ligand for Lewis metals. The ligands, 1a or 1b, cata-
lyzed asymmetric addition reaction of diethylzinc to
benzaldehyde, and 1b showed higher asymmetric induc-
tion than 1a. This suggested that the larger perfluoro-
alkyl groups would give the larger asymmetric
induction. Thus, we designed a perfluoroheptyl ana-
logue of 1a (1c) expecting much higher asymmetric
induction. However, the coupling reaction with copper
powder used for the synthesis of 1a or 1b did not work
for the synthesis of 1c. In this paper, we would like to
report the synthesis of 1c using nickel complex and its
application to asymmetric synthesis.
We have already reported the synthesis of new axially
dissymmetric ligands of C2 symmetry with two chiral
centers, (R)-(R)2- and (S)-(S)2-1a and 1b, as chiral li-
gands for Lewis metals (Fig. 1).3 Concerning the repre-
sentation of stereochemistry, the first (R) indicates axial
chirality and the second (R) the chirality of side chains.
Perfluoroalkyl (Rf) groups, composing the chiral cen-
The key step for the synthesis of the ligands (1a or 1b)
was the Ullmann type coupling reaction of correspond-
ing aryl bromides using copper powder. The chiral sub-
strate (5c) for the same coupling reaction was prepared
according to the previous route as shown in Scheme 1.
Thus, enantioselective reduction of 3c4 with catechol-
borane in the presence of CBS catalyst5 gave 4c6 quan-
titatively in a high ee. Interestingly, while (S)-4a was
obtained with (R)-CBS catalyst, (R)-4c was obtained
with the (R) catalyst.7 This suggested that the order of
steric bulkiness is C7F15 ꢀ C6H5 ꢀ C2F5 > CF3. The
reduction of heptafluoropropyl analogue with the (R)
catalyst gave the (S)-product only in 60% ee, which
means that the bulkiness of C3F7 is slightly smaller than
Rf
H OH
Rf
Rf = CF3: (R)-(R)2-1a
Rf = C2F5: (R)-(R)2-1b
Rf = C7F15: (R)-(R)2-1c
HO
H
Figure 1. Structure of (R)-(R)2-1a–c.
Keywords: Fluorine; Chiral; Axial dissymmetry; Ligand; Coupling
reaction; Asymmetric synthesis.
*
Corresponding author. Tel.: +81 72 866 3140; fax: +81 72 850
7020; e-mail: kumadaki@pharm.setsunan.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.038

320
Br
M. Omote et al. / Tetrahedron Letters 46 (2005) 319–322
Br
O
Br
H
(S)-(R)2-1
(R)-(R)2-1
K1a= 6.8
K1b= 16
K1c = 10
Br
OH
Rf
H OMOM
Rf
Br
Boiling
toluene
Rf
a
b
c
2
(R)-4c 96%, 99% ee
(R)-5c 92%
3c Rf = C7F15 (84%)
Figure 2. Thermal equilibrium of 1.
Scheme 1. Reagents and conditions: (a) (i) BuLi, THF–Et2O, ꢁ110°C,
(ii) RfCOOEt, (b) catecholborane, THF, (R or S)-5,5-diphenyl-2-
methyl-3,4-propano-1,2,3-oxazaborolidine, ꢁ78 to ꢁ30°C, (c) NaH,
MOMCl, THF.
equilibration followed by separation. Namely, refluxing
a solution of each (S)-(R)2-ligand in toluene gave an
equilibrium mixture, where the corresponding (R)-
(R)2-ligand predominated. The efficiency of the conver-
sion depended on each equilibrium constant (K) shown
in Figure 2. The equilibrium mixture was separated by
silica-gel column chromatography to a major amount
of the desired (R)-(R)2-ligand and a minor amount of
(S)-(R)2-ligand. The large K values of 1b and 1c facili-
tated the conversion of (S)-(R)2-1b or 1c to the corre-
sponding (R)-(R)2-isomers over 90%11 in only once
equilibration followed by separation. (S)-(R)2-1a was
also converted into (R)-(R)2-1a in 93% yield by twice
equilibration and separation. (S)-(S)2-1c was obtained
similarly.
C6H5. After protection of the hydroxyl groups, (R)-5c8
was used for the next coupling reaction.
Coupling reaction of 5c using copper powder was extre-
mely difficult probably due to the strong repulsion be-
tween the large C7F15 groups. To solve this problem,
tetrakis(triphenylphosphine)nickel(0), Ni(PPh3)4, or
bis(1,5-cyclooctadiene)nickel(0), Ni(COD)2, were exam-
ined in the place of active copper powder, since they
were reported to have high activity on oxidative addi-
tion to aryl bromides.9 Results of the coupling reaction
are summarized in Table 1. The coupling reaction of
(R)-5c with Ni(COD)2 in DMF at 60°C gave 6c in total
71% yield, 59% of (R)-(R)2-6c and 12% of the axial iso-
mer (S)-(R)2-6c10 after separation by a column chroma-
tography (entry 1). The latter was easily converted to
(R)-(R)2-1c after hydrolysis as mentioned later. When
NMP was used as a solvent, the total yield was de-
creased to 30% (entry 2). Raising the reaction tempera-
ture did not improve the yield of the coupling reaction
(entry 3). When Ni(PPh3)4 was used, the total yield of
6c was decreased to 6%, and a fairly large amount of
5c was recovered. This suggested that the low reactivity
might be due to a low oxidative additivity of this nickel
complex to aryl bromide. This coupling reaction using
Ni(COD)2 in DMF gave much higher yields of 6a or
6b than the former method3 (entry 5 and 6).
Activities on asymmetric induction of 1c were evaluated
by the reaction of diethylzinc with benzaldehyde in the
presence of a stoichiometric amount of Ti(Oi-Pr)4.12
The results are summarized with the previous results
of 1a and 1b in Table 2. The trifluoromethyl analogue
1a showed a good asymmetric induction, as reported be-
fore: The product was obtained in 85% ee using 5mol%
of 1a.13 The pentafluoroethyl analogue 1b with bulkier
pentafluoroethyl groups showed higher asymmetric
induction: Ee of the product increased to 91% with the
same amount of 1b as 1a. The highest asymmetric induc-
tion was achieved by the perfluoroheptyl analogue 1c. A
5mol% of 1c catalyzed the reaction efficiently to give the
product of 97% ee. Increasing the amount of 1c to
8mol% resulted in a further improvement of the ee.
Only 1mol% of (S)-(S)2-1c gave the (R)-product in
88% ee. These results suggest that the asymmetric induc-
tion depends significantly on the size of perfluoroalkyl
moieties of the ligands. The larger perfluoroalkyl groups
give better asymmetric induction.
Deprotection of (R)-(R)2-6a–c with TFA gave the de-
sired ligands (R)-(R)2-1a–c quantitatively. The axial iso-
mers (S)-(R)2-6a–c were also deprotected quantitatively
to (S)-(R)2-1a–c. The (S)-(R)2-ligands could be con-
verted to the corresponding (R)-(R)2-ligands by thermal
Table 1. Ni mediated homo-coupling reaction
Br
H OMOM
Rf
Rf
H
OMOM
Rf
Ni(0), DMF, 60 °C
MOMO H
(R)-5a to c
(R or S)-(R)2-6a-c
Product
Entry
Substrate
Catalyst
Yielda (%)
(S)-(R)2-6c
1
(R)-5c
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(PPh3)4
Ni(COD)2
Ni(COD)2
(R)-(R)2-6c
59
25
55
5
12
5
2b
3c
4
10
1
5
(R)-5a
(R)-5b
(R)-(R)2-6a
(R)-(R)2-6b
56
69
(S)-(R)2-6a
(S)-(R)2-6b
36
11
6
a Isolated yield.
b NMP was employed as a solvent.
c Reaction was carried out at 120°C.

M. Omote et al. / Tetrahedron Letters 46 (2005) 319–322
321
(EI) m/z: 552 (M+), 533 (M+ꢁF), 183 (M+ꢁC7F15, base
peak). HRMS calcd for C14H4O79BrF15 (M+): 551.921.
Found: 551.921.
Table 2. Asymmetric reaction of benzaldehyde with Et2Zn
H OH
Ti(Oi-Pr)4
Ligand
+
PhCHO
Et2Zn
Ph
Et
*
5. (a) Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990, 31,
611; (b) Omote, M.; Ando, A.; Takagi, T.; Koyama, M.;
Kumadaki, I.; Shiro, M. Heterocycles 1998, 47, 65–68.
6. Compound (R)-4c was prepared according to the Ref. 3a.
Compound (R)-4c: colorless crystals. Mp 43.5–44.5°C.
Ligand
Mol%
Yielda (%)
Eeb (%)
Config.c
(S)-(S)2-1a
(R)-(R)2-1a
2
2
95
97
92
94
97
97
99
96
99
92
93
97
96
91
81
82
81
85
85
63
90
91
93
88
94
96
97
98
R
S
S
S
S
S
S
S
S
R
R
R
S
S
24
½aꢂD +15.2 (c 0.92, CHCl3). 1H NMR (CDCl3): d 7.62 (1H,
3
5
d, J = 7.8Hz), 7.58 (1H, d, J = 7.8Hz), 7.36 (1H, dd,
J = 7.8, 7.8Hz), 7.24 (1H, ddd, J = 7.8, 7.8, 1.4Hz), 5.89
(1H, ddd, J = 19.8, 5.3Hz, 2.5Hz), 2.78 (1H, d,
J = 5.3Hz). LRMS (EI) m/z: 554 (M+), 185 (M+ꢁC7F15,
base peak). HRMS (EI) calcd for C14H6O79BrF15 (M+):
553.936. Found 553.937.
10
1
(R)-(R)2-1b
(S)-(S)2-1c
2.5
5
10
1
7. Absolute configurations of 4c were determined by con-
verting them to (S)-methoxyphenyl(trifluoromethyl)acetic
acid esters. The a-proton of the ester from (R)-4c was
observed at 6.98ppm, while that of the ester from (S)-
isomer at 7.07ppm. Structure optimization by MOPAC
calculation suggested that 4c has large substituents and the
Mosher rule could not be simply applied. By this
optimization, the former proton is near the benzene ring
of MTP acid, while the latter is far from it. These results
support the configurations shown in the text. The results
of asymmetric synthesis using these ligands are compar-
able to the results of 1a, the structure of which was
determined by X-ray analysis.3a
3
5
(R)-(R)2-1c
5
8
a Isolated yield.
b Ee was determined by chiral GLC analysis.
c Determined by sign of optical rotation.
Another characteristic of 1c is that the perfluoroalkyl
groups are comprised in the active center of the ligand,
while almost all of the catalysts designed so far for fluo-
rous extraction have perfluoroalkyl groups far from the
active center. In the latter cases, activity of the ligands is
hardly increased.
8. Compound (R)-5c was prepared according to the usual
24
procedure. Compound (R)-5c: a colorless oil. ½aꢂD +54.5 (c
1.05, CHCl3). 1H NMR (CDCl3): d 7.65 (1H, ddd, J = 7.8,
1.8, 1.8Hz), 7.60 (1H, dd, J = 8.1, 1.2Hz), 7.39 (1H, ddd,
J = 7.8, 7.8, 1.2Hz), 7.25 (1H, ddd, J = 8.1, 7.8, 1.8Hz),
5.90 (1H, dd, J = 20.3, 1.5Hz), 4.64 (1H, dd, J = 7.2,
1.5Hz), 4.52 (1H, d, J = 7.2Hz), 3.34 (3H, s). LRMS (EI)
m/z: 598 (M+), 537 (M+ꢁCH3OCH2O), 229 (M+ꢁC7F15,
base peak). HRMS calcd for C16H10O79BrF15 (M+):
597.963. Found 597.962.
In conclusion, we have succeeded in the synthesis of new
axially dissymmetric ligands, (R)-(R)2- and (S)-(S)2-1c
by coupling reaction of 5c using Ni(COD)2 in DMF.
The undesired axial diastereomer, (S)-(R)2-1c, was con-
verted efficiently into the desired ligand (R)-(R)2-1c by
the thermal equilibration and separation. This method-
ology could be used for less bulky analogue to give bet-
ter results than the conventional Ullmann reaction using
copper powder. (R)-(R)2- or (S)-(S)2-1c showed very
high asymmetric induction in the reaction of diethylzinc
with benzaldehyde to give up to 98% ee of the product.
Furthermore, the high fluorine content of 1c was ex-
pected to allow it to be recoverable by a fluorous sol-
vent. The detailed study on the recovery of the ligand
is under investigation.
9. Semmelhack, M. F.; Helquist, P. M.; Jones, L. D. J. Am.
Chem. Soc. 1971, 93(22), 5908–5910.
10. A typical procedure is as follows. To a suspension of
Ni(COD)2 (633mg, 2.3mmol) in anhydrous DMF (4mL)
was added (R)-5c (2.00g, 3.3mmol) at room temperature
and the mixture was stirred for 24h at 60°C. The reaction
was quenched by adding aqueous HCl (5%) and extracted
with ether. The organic layer was evaporated after
dehydration, and the residue was separated by silica-gel
chromatography (Et2O–hexane = 5:95–20:80) to give (R)-
(R)2-6c (1.01g, 59%) and (S)-(R)2-6c (0.21g, 12%). Com-
pound (R)-(R)2-6c: colorless crystals. Mp 108.5–111.0°C.
25
1
½aꢂD +1.8 (c 1.07, CHCl3). H NMR (CDCl3): d 7.84 (1H,
d, J = 7.6Hz), 7.44 (1H, dd, J = 7.6, 7.6Hz), 7.34 (1H, d,
J = 7.6, 7.6Hz), 7.12 (1H, dd, J = 7.6, 6.1Hz), 5.25 (1H, d,
J = 20.9Hz), 5.08 (1H, d, J = 7.0Hz), 4.57 (1H, d,
J = 7.0Hz), 3.11 (3H, s). LRMS (EI) m/z: 1038 (M+),
669 (M+ꢁC7F15), 563 (base peak). HRMS calcd for
C32H20O4F30 (M+): 1038.088. Found 1038.088. Com-
pound (S)-(R)2-6c: colorless crystals. Mp 57.0–58.0°C.
References and notes
1. (a) Pummerer, R.; Prell, E.; Rieche, A. Chem. Ber. 1926,
59, 2159; (b) Noyori, R.; Tomino, I.; Tanimoto, Y. J. Am.
Chem. Soc. 1979, 101, 3129–3131.
2. Chen, Y.; Yekta, S.; Yudin, A. K. Chem. Rev. 2003,
103(8), 3155–3211.
3. (a) Omote, M.; Kominato, A.; Sugawara, M.; Sato, K.;
Ando, A.; Kumadaki, I. Tetrahedron Lett. 1999, 40, 5583–
5585; (b) Omote, M.; Hasegawa, T.; Sato, K.; Ando, A.;
Kumadaki, I. Heterocycles 2003, 59, 501–504; (c) Hase-
gawa, T.; Omote, M.; Sato, K.; Ando, A.; Kumadaki, I.
Chem. Pharm. Bull. 2003, 51, 265–267.
25
½aꢂD ꢁ41.2 (c 1.03, CHCl3). 1H NMR (CDCl3): d 7.8 (2H,
m), 7.51–7.42 (6H, m), 5.36 (2H, d, J = 21.1Hz), 4.73 (4H,
d, J = 1.9Hz), 3.30 (6H, s). LRMS (EI) m/z: 1038 (M+),
669 (M+ꢁC7F15), 563 (base peak). HRMS calcd for
C32H20O4F30 (M+): 1038.088. Found 1038.088.
11. Deprotection of (R)-(R)2-6c (1.01g) by TFA (5mL) and
water (0.5mL) gave (R)-(R)2-1c (894mg, 96%). Treatment
of (S)-(R)2-6c (210mg) with TFA (1mL) and water
(0.1mL) gave its axial diastereomer (S)-(R)2-1c (183mg,
95%). (S)-(R)2-1c (183mg) was converted to (R)-(R)2-1c by
refluxing in toluene for 4h. The equilibrium mixture was
4. Compound 3c was prepared according to Ref. 3a. Com-
1
pound 3c: a colorless oil. H NMR (CDCl3): d 7.76–7.70
(1H, m), 7.56–7.50 (1H, m), 7.49–7.41 (2H, m). LRMS

322
M. Omote et al. / Tetrahedron Letters 46 (2005) 319–322
separated by silica-gel chromatography (Et2O–hex-
ꢁ59.6 (2F, d, J = 295.3Hz), ꢁ60.0 (2F, d, J = 303.9Hz),
ꢁ59.9 (2F, d, J = 303.9Hz), ꢁ61.8 (2F, d, J = 286.6Hz),
ꢁ63.5 (2F, d, J = 303.9Hz), ꢁ63.7 (2F, d, J = 303.9Hz).
LRMS (EI) m/z: 950 (M+), 669 (M+ꢁC7F15), 563 (base
peak). HRMS calcd for C28H12O2F30 (M+): 950.036.
Found 950.036.
ane = 1:9–3:7) to give (R)-(R)2-1c (166mg) in 91% con-
version. For further purification, (R)-(R)2-1c was
recrystallized by toluene, dissolving the crystal under
60°C so as to avoid the axial isomerization. (R)-(R)2-1c:
25
colorless crystals. Mp 82.0–83.0°C. ½aꢂD +13.6 (c 0.99,
CHCl3). 1H NMR (CDCl3): d 7.76 (2H, d, J = 7.5Hz),
7.53 (2H, ddd, J = 7.5, 7.5, 1.5Hz), 7.48 (2H, ddd, J = 7.5,
7.5, 1.5Hz), 7.24 (2H, d, J = 7.5Hz), 4.88 (2H, dd,
J = 19.1, 7.0, 7.0Hz), 3.34 (2H, d, J = 7.0Hz). 19F NMR
(CDCl3, BTF): d ꢁ18.0 (6F, t, J = 10.8Hz), ꢁ54.9 (2F, d,
J = 286.6Hz), ꢁ58.4 (2F, d, J = 285.3Hz), ꢁ59.3 (8F, s),
12. (a) Mori, M.; Nakai, T. Tetrahedron Lett. 1997, 38(35),
6233–6236; (b) Balsells, J.; Davis, T. J.; Carroll, P.;
Patrick, J. W. J. Am. Chem. Soc. 2002, 124(35), 10336–
10348.
13. Ee was determined by GLC analysis using GAMMA DEX
capillary column.