A new asymmetric tridentate carbazole ligand: Its preparation and application to Nozaki-Hiyama allylation

Article abstract of DOI:10.1055/s-2003-37535

The manuscript describes our studies on a newly designed tridentate ligand. The new ligand 1 was successfully synthesized, and it was found that the asymmetric catalysis of Nozaki-Hiyama allylation with ligand 1 affords the product with good enantioselectivity in high yield.

Full text of DOI:10.1055/s-2003-37535

570
LETTER
A New Asymmetric Tridentate Carbazole Ligand: Its Preparation and
Application to Nozaki–Hiyama Allylation
New
A
symmetr
a
ic
T
ridenta
k
te Carbazole
aLigand hiro Suzuki, Akihiro Kinoshita, Hatsuo Kawada, Masahisa Nakada*
Department of Chemistry, School of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
Fax +81(3)52863240; E-mail: mnakada@waseda.jp
Received 30 December 2002
As shown in Scheme 1, preparation of ligand 1 started
Abstract: The manuscript describes our studies on a newly de-
from the known compound, 3,6-dinitrocarbazole (2).6
Bromination of 2 in DMF afforded 1,8-dibromide-3,6-
signed tridentate ligand. The new ligand 1 was successfully synthe-
sized, and it was found that the asymmetric catalysis of Nozaki–
dinitrocarbazole (3), which was reduced, then diazotized,
and in situ reduced to afford 4. Rosenmund–von Braun re-
action of 4 gave dinitrile 5, which was followed by bis-ox-
azoline formation using (R)- or (S)-phenylglycinol with
ZnCl2 to afford ligand 1.7
Hiyama allylation with ligand 1 affords the product with good enan-
tioselectivity in high yield.
Key words: asymmetric catalysis, carbazole, chromium, allyl-
ations, Nozaki–Hiyama reaction, tridentate ligand
With ligand 1 in hand, asymmetric catalysis of Nozaki–
Hiyama allylation was investigated. We adopted Fürst-
ner’s conditions3 because metallic Mn was surmised to be
a suitable co-reducing reagent for enantioselective allyl-
ation due to its low intrinsic reactivity.3,8
Cr(II)-mediated C-C bond-forming reactions developed
by Nozaki et al.1 have been known as useful reactions due
to their high chemoselectivity and excellent compatibility
with various functional groups. Therefore, these reactions
have been used frequently in numerous total syntheses of
natural products.2
R2
R2
Recently, a catalytic redox system using CrCl2, Mn, and
TMSCl was reported by Fürstner et al. which reduces the
quantity of chromium salts making these reactions more
valuable and environmentally benign.3
e
N
H
N
R1
H
R1
O
O
N
N
2 R1=H, R2=NO2
3 R1=Br, R2=NO2
4 R1=Br, R2=H
5 R1=CN, R2=H
a
b, c
Asymmetric Cr(II)-mediated C-C bond-forming reactions
have been also reported;4 however, asymmetric catalysis
on the reactions was limited to the studies by Cozzi and
Umani–Ronchi.5 They reported the first enantioselective
Ph
Ph
d
1
Nozaki–Hiyama allylations using a commercially avail- Scheme 1 Synthesis of Ligand 1, Reagents and Conditions: (a) Br2
(10.0 equiv), NaHCO3 (5.0 equiv), DMF, r.t., 22 h, quant.; (b)
Na2S2O4 (10.0 equiv), NaOH (6.0 equiv), EtOH, H2O, 80 °C, 10 min;
(c) NaNO2 (5.0 equiv), 50% H2PO3(100 equiv), 0 °C, 20 min, 60% (2
steps); (d) CuCN (3.1 equiv), NMP, reflux, 1 h, 84%; (e) (S)-phenyl-
able salen ligand, but the enantioselectivities and yields
were not satisfactory. In addition, the formation of a con-
siderable amount of a side-product, pinacols, was also a
problem. In this paper we report the studies on a new
chiral ligand effective for the asymmetric catalysis of
Nozaki–Hiyama allylation.
glycinol (2.3 equiv), ZnCl2 (2.8 equiv), C6H5Cl, reflux, 3 days, 39%.
First, ligand 1 (10 mol%), CrCl2 (9.7 mol%), and Mn (2.0
equiv) were mixed in THF under an atmosphere of Ar at
room temperature. The Cr(II)-ligand 1 complex thus pre-
pared in situ was used for the enantioselective allylation.
To the reaction mixture was added allylbromide (2.0
equiv), and the mixture was stirred at room temperature
for 30 minutes. Then, benzaldehyde (1.0 equiv) and
TMSCl (2.0 equiv) were added successively to the reac-
tion mixture at room temperature. After 12 h, isolated
crude products were treated with 2 N HCl to afford alco-
hol 6 in 63% yield (2 steps, 71% ee, 63%, entry 1 in
Table 1).
We have designed and synthesized a C2-symmetrical tri-
dentate bis(oxazolinyl)carbazole ligand 1, because: 1) the
allyl-Cr(III)-ligand complex will not undergo significant
dissociation due to the stabilization by three bonds, a σ-
bond with the carbazole nitrogen and two coordination
bonds with the oxazoline nitrogens; 2) ligand 1 leaves a
vacant coordination site at which an aldehyde can bind; 3)
electronic and/or steric tuning of the catalyst formed with
a metal ion and the ligand 1 will be possible when an ap-
propriate substituent is attached on the carbazole ring and/
or the oxazole ring.
It was surmised that HCl forms in the preparation of the
Cr(II)-ligand 1 complex, impeding the catalyst formation.
Hence, the effect of the base on the yield and selectivity
was next investigated. The yield was increased to 96%
when pyridine (py) (entry 2) or triethylamine (TEA)
Synlett 2003, No. 4, Print: 12 03 2003.
Art Id.1437-2096,E;2003,0,04,0570,0572,ftx,en;U15202ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
New Asymmetric Tridentate Carbazole Ligand
571
Table 1 Enantioselective Allylation of Benzaldehyde with 1
1) CrCl2 (9.7 mol %)
Mn (2.0 equiv)
Base
Allyl
1) PhCHO (1.0 equiv)
TMSCl (2.0 equiv)
Ph
Cr(III)
Ligand 1
(10 mol %)
ligand 1
complex
Temp. (°C)
2) 2N HCl
OH
Solvent, r.t.
2) Allyl-X (2.0 equiv), r.t.
6
Entry
1
X
Base (equiv)
-
Solvent
THF
Temp (°C)
r.t.
Time (h)
12
12
24
12
40
12
12
12
1
Ee (%)a,b
S (71)
S (69)
S (41)
S (71)
S (61)
–
Yield (%)c
Br
Br
Cl
Br
Br
Br
Br
Br
I
63
96
64
96
62
0
2
Py (0.2)
THF
THF
THF
THF
Et2O
CH3CN
DMF
THF
THF
THF
THF
THF
THF
THF
r.t.
3
TEA (0.2)
TEA (0.2)
TEA (0.2)
TEA (0.2)
TEA (0.2)
TEA (0.2)
TEA (0.2)
TEA (0.2)
DIPEA (0.2)
NaHCO3 (0.3)
K2CO3 (0.1)
NaH (0.1)
n-BuLi (0.1)
r.t.
4
r.t.
5
–10
r.t.
6
7
r.t.
S (24)
S (30)
S (68)
S (22)
S (68)
S (73)
S (71)
S (62)
S (61)
31d
13e
74
95
92
74
93
87
84
8
r.t.
9
r.t.
10
11
12
13
14
15
I
0
9
Br
Br
Br
Br
Br
r.t.
12
12
12
12
12
r.t.
r.t.
r.t.
r.t.
a Ee determined by HPLC. For HPLC conditions, see General Procedure.9
b Absolute configuration determined by comparison of optical rotation to known literature value.
c Isolated yields.
d 1,2-Diphenyl-1,2-ethanediol was also obtained, but not isolated.
e 1,2-Diphenyl-1,2-ethanediol (57%) was also obtained.
(entry 4) was used, but the enantioselectivity did not
change significantly.
Surprisingly, when the reaction was carried out using al-
lylbromide at –10 °C (entry 5) or allyliodide at 0 °C (entry
10), the enantioselectivity was diminished. This result is
not explained well, but could be surmised that the solubil-
ity of the Cr(II)-ligand 1 complex and/or the related allyl
complex is reduced at the low temperature,11 and the se-
lectivity is diminished again by the achiral allylmanga-
nese reagent formed.
As shown in Table 1, yield and enantioselectivity of the
asymmetric catalysis clearly depend on the solvent, and
THF was found to be the best one. Actually, the asymmet-
ric catalysis did not proceed in Et2O (entry 6), and further-
more, the enantioselectivity as well as the yield was
considerably diminished in acetonitrile or DMF (entries 7
and 8). The low yield was found to arise chiefly from the
formation of side-product, pinacols. Interestingly, no pi-
nacol formation was observed when THF was used as the
solvent.
Use of allylbromide was also important to achieve the
good enantioselectivity in the reaction with ligand 1, be-
cause as shown in Table 1, use of allylchloride or allylio-
dide decreased the yield and/or the enantioselectivity
(entries 3 and 9). One reason for the low selectivity is
found in the formation of racemate by the reaction of the
achiral allylmanganese reagent formed in situ.10
O
O
O
N
O
O
N
N
N
N
i-Pr
i-Pr
Ph
Ph
pybox
DBFOX
Figure 1 Pybox12 and DBFOX13
Synlett 2003, No. 4, 570–572 ISSN 0936-5214 © Thieme Stuttgart · New York

572
T. Suzuki et al.
LETTER
(6) Grotta, H. M.; Riggle, C. J.; Bersem, A. E. J. Org. Chem.
1964, 29, 2474.
Asymmetric catalysis on the allylation with other ligands
has also been investigated. However, the enantioselectiv-
ity obtained was not satisfactory, that is, 44% ee with
pybox12 and 3.5% ee with DBFOX (Figure 1).13
(7) (a) Witte, H.; Seeliger, W. Liebigs Ann. Chem. 1974, 996.
(b) Data for 1: mp 144–145 °C; [α]D21 +757 (c 0.15, CHCl3);
1H NMR (400 MHz, CDCl3) δ = 12.26 (1 H, s), 8.24 (2 H, d,
J = 7.6 Hz), 7.98 (2 H, d, J = 7.6 Hz), 7.37–7.20 (12 H, m),
5.49 (2 H, dd, J = 10.0 Hz, 8.8 Hz), 4.86 (2 H, dd, J = 10.0
Hz, 8.3 Hz), 4.31 (2 H, dd, J = 8.8 Hz, 8.3Hz); 13C NMR
(100 MHz, CDCl3) δ = 163.7, 142.2, 139.0, 128.4, 127.1,
126.5, 125.8, 123.7, 123.4, 118.8, 110.1, 73.7, 69.8; IR
(KBr) 3368, 1642, 1618, 1604, 1500, 1428, 1327, 1298,
1286, 1210, 1170, 1138, 1062, 1052, 958, 748, 700 cm–1;
FAB-MS [M + H]+ calculated for C30H24O2N3 : 458.1869,
found : 458.1837.
The enantioselectivity of the asymmetric catalysis with
ligand 1 is not so high, and indeed lower than the selectiv-
ity obtained with the commercially available salen ligand
by Umani–Ronchi et al.5 However, the yield with ligand 1
is high, exceeding the yields obtained with the salen
ligand. Hence, modifications of ligand 1 by attaching ap-
propriate substitutents on its carbazole ring or oxazole
ring are currently being investigated to achieve high enan-
tioselectivity.
(8) (a) Cahiez, G.; Chavant, P. Y. Tetrahedron Lett. 1989,
7373. (b) Hiyama, T.; Sawahata, M.; Obayashi, M. Chem.
Lett. 1983, 1237. (c) Takai, K.; Ueda, T.; Hayashi, T.;
Moriwake, T. Tetrahedron Lett. 1996, 37, 7049.
In summary, a newly designed ligand 1 has been synthe-
sized and it was found that the asymmetric catalysis of
Nozaki–Hiyama allylation with ligand 1 affords the prod-
uct in high yield with good enantioselectivity. Studies of
the reaction mechanism with ligand 1 and further modifi-
cations of the new ligand to improve the enantioselectivity
are now under way, and the results will be reported in due
course.
(9) General Procedure: A mixture of ligand (S, S)-1 (26.9 mg,
0.059 mmol), CrCl2 (7.0 mg, 0.057 mmol), and Mn (85.3
mg, 1.55 mmol) was azeotroped three times with toluene and
dried under high vacuum, and was suspended in THF (2
mL). The color of the suspension immediately turned to
brown. To the stirred suspension was added triethylamine
(0.016 mL, 0.118 mmol), and after 30 min to the resulting
mixture was added allylbromide (0.102 mL, 1.18 mmol).
After stirring for 30 min, to the stirred mixture were added
benzaldehyde (0.060 mL, 0.59 mmol) and TMSCl (0.149
mL, 1.18 mmol) successively at room temperature. After 12
h the color of the reaction mixture turned to reddish-brown.
The reaction was quenched with saturated aqueous NaHCO3
(1 mL), filtered through Celite, and evaporated under
vacuum. The crude product was dissolved in THF (5 mL),
and the stirred mixture was treated with 2 N HCl (1 mL) for
20 min. The reaction was quenched with adding saturated
aqueous NaHCO3 (3 mL), and the aqueous layer was
extracted with CH2Cl2 (10 ml × 4). The combined organic
layer was dried over Mg2SO4, and evaporated. The residue
was purified by flash chromatography (hexane/ethyl
acetate = 10:1) to afford the known compound, (S)-1-
phenyl-3-buten-1-ol (64.7 mg, 71% ee, 96%): ee was
determined by HPLC (254 nm); Daicel Chiral Cell OD-H
0.46 cm φ × 25 cm; hexane/iso-propanol = 19:1; flow
rate=0.3 mL/min); retention time: 26.4 min for (R)-1-phen-
yl-3-buten-1-ol, 28.7 min for (S)-1-phenyl-3-buten-1-ol.
(10) In the absence of CrCl2 and ligand 1, the allylated products
were obtained in 8% yield under the conditions of entry 1
(Table 1). Aliphatic aldehydes are surmised to be rather inert
to the allylmanganase reagent. Cf. ref.3
Acknowledgment
This work was financially supported in part by Waseda University
Grant for Special Research Projects (Individual Research, 2002A-
539), and also in part by 21COE ‘Practical Nano-Chemistry’. We
thank Messrs. Takashi Sawada and Yoshiharu Miyake for early
experiments.
References
(1) (a) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am.
Chem. Soc. 1977, 99, 3179. (b) Okude, Y.; Hiyama, T.;
Nozaki, H. Tetrahedron Lett. 1977, 3829.
(2) Recent reviews: (a) Takai, K.; Nozaki, H. Proc. Jpn. Acad.,
Ser. B 2000, 76B, 123. (b) Fürstner, A. Chem. Rev. 1999,
99, 991. (c) Wessjohann, L. A.; Scheid, G. Synthesis 1999,
1. (d) Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J. L.;
Palacios, J. C. Chem. Soc. Rev. 1999, 28, 169.
(3) (a) Fürstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118,
12349. (b) Fürstner, A.; Shi, N. J. Am. Chem. Soc. 1996,
118, 2533.
(4) (a) Sugimoto, K.; Aoyagi, S.; Kibayashi, C. J. Org. Chem.
1997, 62, 2322. (b) Chen, C.; Tagami, K.; Kishi, Y. J. Org.
Chem. 1995, 60, 5386. (c) Cazes, B.; Verniere, C.; Goré, J.
Synth. Commun. 1983, 13, 73.
(5) (a) Bandini, M.; Cozzi, P. G.; Melchiorre, P.; Morganti, S.;
Umani-Ronchi, A. Org. Lett. 2001, 3, 1153. (b) Bandini,
M.; Cozzi, P. G.; Umani-Ronchi, A. Pure Appl. Chem. 2001,
73, 325. (c) Bandini, M.; Cozzi, P. G.; Umani-Ronchi, A.
Tetrahedron 2001, 57, 835. (d) Bandini, M.; Cozzi, P. G.;
Umani-Ronchi, A. Polyhedron 2000, 19, 537. (e) Bandini,
M.; Cozzi, P. G.; Umani-Ronchi, A. Angew. Chem., Int. Ed.
2000, 39, 2327. (f) Bandini, M.; Cozzi, P. G.; Melchiorre,
P.; Morganti, S.; Umani-Ronchi, A. Angew. Chem., Int. Ed.
1999, 38, 3357.
(11) The relationship between the reaction temperature and the
solubility of the Cr(II)-ligand 1 complex and/or the related
allyl complex was hard to observe under the described
reaction condition because insoluble manganese powder was
in the flask. Further investigation of the chromium
complexes formed in situ is now under investigation.
(12) Nishiyama, H.; Sakaguchi, H.; Nakamura, T.; Horihata, M.;
Kondo, M.; Itoh, K. Organometallics 1989, 8, 846.
(13) Kanemasa, S.; Oderaotoshi, Y.; Yamamoto, H.; Tanaka, J.;
Wada, E.; Curran, D. P. J. Org. Chem. 1997, 62, 6454.
Synlett 2003, No. 4, 570–572 ISSN 0936-5214 © Thieme Stuttgart · New York