Atropisomeric Biarylbisphosphines Derived from 2,2-Difluoro-1,3- benzodioxole

Article abstract of DOI:10.1055/s-2004-815926

Starting from the inexpensive 2,2-difluoro-1,3-benzodioxole or its 5-bromo derivative, two new atropisomeric bisphosphines have been prepared which, after racemate resolution, exhibit attractive features as ligands for enantioselective catalysts. The key step in their synthesis is a low temperature Ullmann reaction. An improved protocol secures coupling yields of 70-80%.

Full text of DOI:10.1055/s-2004-815926

326
SHORT PAPER
Atropisomeric Biarylbisphosphines Derived from 2,2-Difluoro-1,3-benzo-
dioxole
A
tropisomeric
r
Biarylb
é
d
s
D
erived fr
ér
i
-benz
o
c
dioxole Leroux, Joanna Gorecka, Manfred Schlosser*
Institut de Chimie moléculaire et biologique, Bâtiment de Chimie (BCh), Ecole polytechnique fédérale, 1015 Lausanne, Switzerland
Fax +41(21)6939365; E-mail: manfred.schlosser@epfl.ch
Received 28 October 2003; revised 15 December 2003
subsequently to convert it into the dibromo derivative 5,
Abstract: Starting from the inexpensive 2,2-difluoro-1,3-benzo-
the bisphosphine 6 or the dicarboxylic acid 9 proved un-
successful.
dioxole or its 5-bromo derivative, two new atropisomeric bisphos-
phines have been prepared which, after racemate resolution, exhibit
attractive features as ligands for enantioselective catalysts. The key
The atropisomeric bisphosphine 3 is a tetrafluoro analog
step in their synthesis is a low temperature Ullmann reaction. An
of SEGPHOS,13,14 one of the best performing ligands for
improved protocol secures coupling yields of 70–80%.
asymmetric synthesis.15–17 Its racemate resolution can be
easily accomplished by the fractional crystallization of the
Key words: atropisomers, 2,2-difluoro-1,3-benzodioxole, bromo/
lithium permutation, metalation, biarylbisphosphines
diastereomeric dibenzoyltartaric acid complexes of the
corresponding bis(phosphine oxide),18 as described for
the popular BINAP-ligand.19 The bis(phosphine oxide)
The singular electronic structure1 of 2,2-difluoro-1,3-ben-
can be made in virtually quantitative yield by the oxida-
zodioxole confers a distinctive reactivity profile to this
compound and its congeners as well.2–4 In particular, the
4- and 7-positions are strongly acidified and can be readi-
ly deprotonated. Thus, consecutive treatment of the com-
mercial 5-bromo-2,2-difluoro-1,3-benzodioxole with
lithium diisopropylamide and oxirane or carbon dioxide
tion of the bisphosphine 3 with hydrogen peroxide. A
shorter route leading to the same product in 35% overall
yield consists of the consecutive treatment of 5-bromo-
2,2-difluoro-1,3-benzodioxole with magnesium, chlo-
rodiphenylphosphine and hydrogen peroxide and the sub-
sequent reaction of the resulting 5-diphenylphosphoryl-
2,2-difluoro-1,3-benzodioxole with lithium diisopropyl-
amide and ferric chloride. After silane-promoted deoxy-
genation of the bisoxides the (+)- or (–)-bisphosphine 3
was coordinated with ruthenium salts and applied as an
amazingly enantioselective catalyst for the asymmetric
hydrogenation of a series of model substrates.20
afforded,
2-(5-bromo-2,2-difluoro-1,3-benzodioxol-4-
yl)ethanol (76%)2 or 5-bromo-2,2-difluoro-1,3-benzo-
dioxole-4-carboxylic acid (88%),2 respectively, whereas
5-bromo-2,2-difluoro-4-iodo-1,3-benzodioxole (1) was
isolated in 86% yield when the organometallic intermedi-
ate was trapped with elemental iodine. Employing an im-
proved version5 of the low temperature modification6–10 of
the Ullmann coupling,11,12 the biaryl 2 was obtained in
72% yield. This was transformed to the bisphosphine 3
(67%) by halogen/metal permutation followed by conden-
sation with two equivalents of chlorodiphenylphosphine
(Scheme 1).
Details concerning standard operations and abbreviations are spec-
ified in previous publications21–23 from this laboratory. 1H, (1H-de-
coupled) 13C and 31P NMR spectra were recorded at 400 MHz, 101
MHz and 162 MHz, respectively. The samples were dissolved in
CDCl3 with TMS (for 1H and 13C NMR) or 85% aqueous H3PO4 (for
31P NMR) being used as the internal or external reference ( = 0
ppm). Although the rules of nomenclature would oblige us to clas-
sify compounds 4–8 as silanes, e.g. 4 as triethyl(5-bromo-2,2-di-
fluoro-1,3-benzodioxol-4-yl)silane, we have preferred to call them
benzodioxoles in order to preserve the same parent structure in all
cases.
Bisphosphine 3 was independently accessed starting from
6-bromo-4-triethylsilyl-2,2-difluoro-1,3-benzodioxole.
The same series of reactions as described above gave the
iodo derivative 4 (73%), the silyl-protected dibromobiaryl
5 (84%) and the silyl-protected bisphosphine 6 (69%).
The removal of the triethylsilyl groups was accomplished
with tetrabutylammonium fluoride hydrate.
5-Bromo-2,2-difluoro-4-iodo-1,3-benzodioxole (1)
At –75 °C, 2,2,6,6-tetramethylpiperidine (17 mL, 14 g, 0.10 mol)
and 5-bromo-2,2-difluorobenzodioxole (14 mL, 24 g, 0.10 mol)
were added consecutively to a solution of BuLi (0.10 mol) in THF
(0.20 L) and hexanes (65 mL) The mixture was kept in dry ice–
MeOH bath for 2 h before being treated with iodine (25 g, 0.10 mol)
in THF (0.10 L). The solvents were evaporated and the residue was
dissolved in Et2O (0.10 L). After washing with a 10% aq solution of
sodium thiosulfate (50 mL), the organic layer was dried and evapo-
rated. After crystallization from EtOH, colorless cubes were ob-
tained; yield: 31.2 g (86%); mp 65–67 °C.
In contrast, we failed to introduce the bromine atoms at a
later stage, i. e. after the aryl-aryl coupling. The reductive
dimerization of 2,2-difluoro-4-iodo-7-triethylsilyl-1,3-
benzodioxole (7; prepared in the usual way from 2,2-di-
fluoro-4-triethylsilyl-1,3-benzodioxole4 in 94% yield) oc-
curred smoothly to provide the bissilylated biaryl 8
(77%). However, numerous attempts to dimetalate it and
1H NMR (400 MHz, CDCl3): = 7.40 (d, J = 8.3 Hz, 1 H), 6.93 (d,
J = 8.3 Hz, 1 H).
SYNTHESIS 2004, No. 3, pp 0326–0328
Advanced online publication: 26.01.2004
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DOI: 10.1055/s-2004-815926; Art ID: T11503SS
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Atropisomeric Biarylbisphosphines Derived from 2,2-Difluoro-1,3-benzodioxole
327
SiR3
SiR3
O
O
O
O
O
O
F
F
F
F
F
F
Br
Br
Br
a
a
a
SiR3
SiR3
O
O
O
O
O
O
F
F
F
F
F
F
Br
4
7
1
I
I
I
b
b
b
SiR3
SiR3
O
O
O
F
F
F
F
F
F
O
O
O
O
O
O
Br
Br
Br
Br
F
F
F
F
F
F
O
O
O
O
O
2
5
8
SiR3
SiR3
SiR3
c
c
SiR3
O
F
F
F
F
F
F
O
O
O
O
O
O
PPh2
PPh2
PPh2
PPh2
COOH
COOH
d
F
F
F
F
F
F
O
O
O
3
6
9
SiR3
SiR3
Scheme 1 R = Et. a) (1) Lithium 2,2,6,6-tetramethylpiperidide in THF, 2 h at –75 °C; (2) Iodine in THF at –75 °C. b) (1) BuLi in Et2O, 5 min
at –75 °C; (2) Cupric bromide, 45 min at –75 °C; (3) Nitrobenzene, –75 °C → +25 °C. c) (1) BuLi in Et2O, 5 min at –75 °C; (2) Chlorodiphe-
nylphosphine. d) Tetrabutylammonium hydrate in THF, 12 h at +75 °C (reflux).
13C NMR (101 MHz, CDCl3): = 147.1 (s), 140.9 (s), 130.6 (t, J =
258.9 Hz), 127.0 (s), 123.5 (s), 110.2 (s).
Ana. Calcd for C14H4Br2F4O4 (471.98): C, 35.63; H, 0.85. Found: C,
35.92; H, 0.94.
Anal. Calcd for C7H2BrF2IO2 (362.89): C, 23.17; H, 0.56. Found: C,
23.19; H, 0.54.
5,5 -Bis(diphenylphosphanyl)-2,2,2 ,2 -tetrafluoro-4,4 -bi-1,3-
benzodioxole (3)
At –75 °C, BuLi (30 mmol) in hexanes (19 mL) was added to a so-
lution of 5,5 -dibromo-2,2,2 ,2 -tetrafluoro-4,4 -bi-1,3-benzodiox-
ole (2; 7.1 g, 15 mmol) in Et2O (75 mL) followed 45 min later by
chlorodiphenylphosphine (5.4 mL, 6.6 g, 30 mmol) in Et2O (50
mL). The mixture was treated at 25 °C with a sat. aq solution of
NH4Cl (60 mL) before being extracted with EtOAc (3 × 30 mL).
Evaporation of the solvents and crystallization from EtOAc–hex-
anes afforded colorless needles; yield: 6.85 g (67%); mp 218–220
°C.
1H NMR (400 MHz, CDCl3): = 7.3 (m, 12 H), 7.2 (m, 8 H), 7.01
(d, J = 8.1 Hz, 2 H), 6.87 (d, J = 8.3 Hz, 2 H).
31P NMR (162 MHz, CDCl3): = –12.3 (s).
5,5 -Dibromo-2,2,2 ,2 -tetrafluoro-4,4 -bi-1,3-benzodioxole (2)
At –75 °C and under vigorous stirring, BuLi (0.50 mmol) in hexanes
(33 mL) was added to a solution of 5-bromo-2,2-difluoro-4-iodo-
1,3-benzodioxole (1; 18 g, 50 mmol) in Et2O (0.25 L) followed 5
min later by copper(II) bromide (11 g, 50 mmol) and 45 min later
by nitrobenzene (5.1 mL, 6.2 g, 50 mmol). The reaction mixture was
allowed to reach 25 °C slowly in the course of 12 h. The suspension
was poured into a 12% aq solution of NH3 (0.10 L). The organic
phase was separated and the aq layer was extracted with EtOAc (2
× 50 mL). The combined organic layers were dried (over Na2SO4)
before being evaporated. The residue was purified by chromatogra-
phy on silica gel (0.50 L, 0.25 kg) using hexanes as the eluent. After
crystallization from EtOH, colorless needles were collected; yield:
8.49 g (72%); mp 89–91 °C.
Anal. Calcd for C38H24F4O4P2 (682.55): C, 66.87; H, 3.54. Found:
C, 66.70; H, 3.57.
1H NMR (400 MHz, CDCl3): = 7.46 (d, J = 8.5 Hz, 2 H), 7.07 (d,
J = 8.5 Hz, 2 H).
13C NMR (101 MHz, CDCl3): = 143.0 (s), 142.7 (s), 138.7 (s),
Bisphosphine 3 was also formed when a solution of the silylated
bisphosphine 6 (2.7 g, 3.0 mmol) and tetrabutylammonium fluoride
tetrahydrate (4.0 g, 12 mmol) in THF (10 mL) was heated for 12 h
under reflux; yield: 0.98 g (48%).
131.6 (t, J = 258.5 Hz), 127.5(s), 117.5 (s), 111.3 (s).
Synthesis 2004, No. 3, 326–328 © Thieme Stuttgart · New York

328
F. Leroux et al.
SHORT PAPER
5-Bromo-2,2-difluoro-4-iodo-7-triethylsilanyl-1,3-benzodiox-
ole (4)
2,2,2 ,2 -Tetrafluoro-7,7 -bis(triethylsilanyl)-4,4 -bi-1,3-benzo-
dioxole (8)
Starting from 6-bromo-2,2-difluoro-4-triethylsilyl-1,3-benzodi-
oxole4 (23 g, 65 mmol) compound 4 was obtained analogously as
described above for the preparation of compound 1. After crystalli-
zation from MeOH, colorless cubes were obtained; yield: 22.6 g
(73%); mp 34.0–35.5 °C.
Starting from 2,2-difluoro-4-iodo-7-triethylsilanyl-1,3-benzodiox-
ole (7; 48 g, 0.12 mol) compound 8 was obtained analogously as de-
scribed above for the preparation of biaryl 2. After crystallization
from MeOH colorless platelets were obtained; yield: 25.0 g (77%);
mp 44.5–45.0 °C.
1H NMR (400 MHz, CDCl3): = 7.35 (s, 1 H), 1.0 (m, 9 H), 0.9 (m,
6 H).
1H NMR (400 MHz, CDCl3): = 7.43 (d, J = 8.0 Hz, 2 H), 7.19 (d,
J = 8.0 Hz, 2 H), 1.01 (t, J = 7.8 Hz, 18 H), 0.89 (q, J = 8.0 Hz, 12
H).
13C NMR (101 MHz, CDCl3): = 146.0 (s), 145.3 (s), 131.9 (s),
130.3 (t, J = 257.5 Hz), 123.7(s), 121.1 (s), 80.6 (s), 7.1 (s), 2.9 (s).
13C NMR (101 MHz, CDCl3): = 148.9 (s), 139.7 (s), 131.1 (t, J =
253.9 Hz), 129.4 (s), 123.6 (s), 119.4 (s), 117.8 (s), 7.2 (s), 3.1 (s).
Anal. Calcd for for C13H16BrF2IO2Si (477.16): C, 32.72; H, 3.38.
Found: C, 32.84; H, 3.41.
Anal. Calcd for C26H34F4O4Si2 (542.72): C, 57.54; H, 6.31. Found:
C, 57.32; H, 6.00.
5,5 -Dibromo-2,2,2 ,2 -tetrafluoro-7,7 -bis-(triethylsilanyl)-4,4 -
bi-1,3-benzodioxole (5)
Acknowledgment
Starting from 5-bromo-2,2-difluoro-4-iodo-7-triethylsilanyl-1,3-
benzodioxole (4; 15 g, 31 mmol) compound 5 was obtained analo-
gously as described above for the preparation of biaryl 2. After crys-
tallization from EtOH colorless needles were isolated; yield: 9.12 g
(84%); mp 99–100 °C.
1H NMR (400 MHz, CDCl3): = 7.40 (s, 2 H), 1.02 (t, J = 7.1 Hz,
18 H), 0.91 (q, J = 7.0 Hz, 12 H).
This work was financially supported by the Schweizerische Natio-
nalfonds zur Förderung der wissenschaftlichen Forschung (grant
20-63’584-00), Bern, and the Bundesamt für Berufsbildung und
Technologie (KTI-Projekt 5474.1 KTS), Bern.
References
13C NMR (400 MHz, CDCl3): = 147.4 (s), 141.4 (s), 132.4 (s),
131.2 (t, J = 256.8 Hz), 122.5(s), 118.0 (s), 117.6 (s), 7.1 (s), 3.0 (s).
(1) Castagnetti, E.; Schlosser, M. Chem.–Eur. J. 2002, 8, 799.
(2) Castagnetti, E.; Schlosser, M. Eur. J. Org. Chem. 2001, 691.
(3) Schlosser, M.; Gorecka, J.; Castagnetti, E. Eur. J. Org.
Chem. 2003, 452.
Anal. Calcd for C26H32Br2F4O4Si2 (700.51): C, 44.58; H, 4.61.
Found: C, 44.66; H, 4.73.
(4) Gorecka, J.; Leroux, F.; Schlosser, M. Eur. J. Org. Chem.
2004, in press.
(5) Leroux, F., manuscript in preparation..
(6) Krizewsky, J.; Turner, E. E. J. Chem. Soc. 1919, 115, 559.
(7) Gilman, H.; Straley, J. M. Recl. Trav. Chim. Pays-Bas 1936,
55, 821.
(8) Wittig, G.; Lehmann, G. Chem. Ber. 1957, 90, 875.
(9) Wittig, G.; Klar, G. Liebigs Ann. Chem. 1967, 704, 91.
(10) Wittig, G.; Rümpler, K.-D. Liebigs Ann. Chem. 1971, 751, 1.
(11) Fanta, P. E. Synthesis 1974, 9.
(12) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003, 42,
5400; Angew. Chem. 2003, 115, 5642.
(13) Saito, T.; Yokozawa, T.; Zhang, S.-y.; Sayo, N. Takasago
Int. Corp. Eur. Pat. Appl., 850945, 1996; Chem. Abstr. 1998,
129, 124055y.
(14) Sayo, N.; Saito, T.; Yokozawa, T. Takasago Int. Corp. Eur.
Pat. Appl., 945457, 1999; Chem. Abstr. 1999, 131, 251749u.
(15) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994.
(16) Comprehensive Asymmetric Catalysis; Jacobsen, E. N.;
Pfaltz, A.; Yamamoto, H., Eds.; Springer: Berlin, 1999.
(17) Catalytic Asymmetric Synthesis, 2nd ed; Ojima, I., Ed.;
Wiley VCH: New York, 2000.
5,5 -Bis(diphenylphosphanyl)-2,2,2 ,2 -tetrafluoro-7,7 -bis(tri-
ethylsilanyl)-4,4 -bi-1,3-benzodioxole (6)
Starting from the dibromo compound 5 (3.5 g, 5.0 mmol), com-
pound 6 was obtained analogously as described above for the prep-
aration of bisphosphine 3. Upon crystallization from EtOH
colorless needles were obtained; yield : 3.14 g (69%); mp 140–141
°C.
1H NMR (400 MHz, CDCl3): = 7.3 (m, 20 H), 6.81 (t, J = 1.6 Hz,
2 H), 0.82 (t, J = 7.4 Hz, 18 H), 0.66 (q, J = 7.4 Hz, 12 H).
31P NMR (162 MHz, CDCl3): = –11.5 (s).
Anal. Calcd for C50H52F4O4P2Si2 (911.07): C, 65.92; H, 5.75.
Found: C, 66.17; H, 5.73.
2,2-Difluoro-4-iodo-7-triethylsilanyl-1,3-benzodioxole (7); Typ-
ical Procedure
A mixture of 2,2-difluoro-4-triethylsilanyl-1,3-benzodioxole4 (41
g, 0.15 mol) and sec-BuLi (0.15 mol) in THF (0.18 L) and cyclo-
hexane (0.12 L) was kept for 2 h at –75 °C before being treated with
iodine (38 g, 0.15 mol) in THF (30 mL). At 25 °C, it was washed
with a sat. aq solution of sodium thiosulfate (50 mL). Upon distilla-
tion, a colorless liquid was collected; yield: 56.1 g (94%); bp 150–
152 °C/9 Torr; nD20 = 1.5250.
(18) Michel, D.; Lonza AG, Visp, unpublished results, 2002.
(19) Takaya, H.; Akutagawa, S.; Noyori, R. Org. Synth., Coll.
Vol. VIII; Wiley: New York, 1993, 57–63.
1H NMR (400 MHz, CDCl3): = 7.35 (d, J = 8.0 Hz, 1 H), 6.83 (d,
J = 8.1 Hz, 1 H), 1.0 (m, 9 H), 0.9 (m, 6 H).
13C NMR (400 MHz, CDCl3): = 147.2, 144.7, 132.2, 130.6, 130.1
(t, J = 255 Hz), 119.0, 72.0, 7.1 (3 C), 3.0 (3 C).
(20) Mettler, H. P.; Haesakkers, P.; Lonza AG, Visp, unpublished
results, 2002/2003.
(21) Desponds, O.; Franzini, L.; Schlosser, M. Synthesis 1997,
150.
(22) Heiss, C.; Schlosser, M. Eur. J. Org. Chem. 2003, 447.
(23) Schlosser, M.; Marull, M. Eur. J. Org. Chem. 2003, 1569.
Anal. Calcd for C13H17F2IO2Si (398.26): C, 39.21; H, 4.30. Found:
C, 39.64; H, 4.83.
Synthesis 2004, No. 3, 326–328 © Thieme Stuttgart · New York