Development of an N-heterocyclic carbene ligand based on concept of chiral mimetic

Article abstract of DOI:10.1016/j.tetlet.2005.12.098

Development of a new N-heterocyclic carbene ligand based on the concept of a chiral mimetic is described. In Pd-catalyzed enantioselective intramolecular α-arylation of N-(2-bromophenyl)-N-methyl-2-arylpropanamide, (4R,5R)-4,5-diphenyl-1,3-diadamantylmeth

Full text of DOI:10.1016/j.tetlet.2005.12.098

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1417–1420
Development of an N-heterocyclic carbene ligand based
on concept of chiral mimetic
Takafumi Arao, Kazuhiro Kondo* and Toyohiko Aoyama*
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
Received 1 December 2005; revised 15 December 2005; accepted 16 December 2005
Abstract—Development of a new N-heterocyclic carbene ligand based on the concept of a chiral mimetic is described. In Pd-cata-
lyzed enantioselective intramolecular a-arylation of N-(2-bromophenyl)-N-methyl-2-arylpropanamide, (4R,5R)-4,5-diphenyl-1,3-
diadamantylmethyl-4,5-dihydro-3H-imidazol-1-ium tetrafluoroborate is shown to function as a good N-heterocyclic carbene
precursor.
Ó 2005 Elsevier Ltd. All rights reserved.
We have recently been developing a novel chiral phos-
phine ligand 1 mimicking axial chirality, in which a chi-
ral carbon center induces a preferred conformation 2a
by rotation around an N–Ar bond which is fixed by for-
mation of a chelate structure with metal (Fig. 1).1 In
order to expand the scope of our chiral mimetic concept,
we planned to develop a novel N-heterocyclic carbene
ligand2 3. The substituent R on the N group in the car-
bene ligand 3 may be conformationally flexible, but if
the complexation of 3 and metal is reflected by the asym-
metric center in 3, a more stable complex 4a, in which
orientation of the substituent R on the N group is fixed,
is expected to be selectively formed (Fig. 2). Herein, we
would like to report our investigation on the enantio-
selective intramolecular a-arylation of amide 5 with the
novel N-heterocyclic carbene ligands 3 (Scheme 1).
Scheme 2.3 Amidation of 1-adamantanecarboxylic acid
(10) with (1R,2R)-1,2-diphenyl-1,2-ethanediamine (9),
EDCI, Et3N and DMAP in THF at 60 °C afforded the
coupling product 11. The carbonyl group in 11 was then
reduced with BH3 in THF under reflux to provide the
diamine 12 in 54% yield (two steps). Finally, treatment
of diamine 12 with CH(OEt)3 and NH4BF4 under reflux
gave the imidazolium salt 7a in 98% yield. Other imi-
dazolium salts 7b–d and 8 are prepared in the same
manner.
Hartwig4 and Glorius5 have reported the enantioselec-
tive a-arylation6 of amide 5a, giving oxindole 6a in
57% ee and 43% ee, respectively (Scheme 3). We chose
5a as a substrate and began to screen imidazolium salts
7a–d and 8 as an N-heterocyclic carbene ligand precur-
sor. The results are shown in Table 1, entries 1–5. Reac-
tions were carried out with amide 5a as a substrate,
10 mol % of Pd(OAc)2, 20 mol % of imidazolium salts
The synthesis of the imidazolium salt 7a as an N-hetero-
cyclic carbene precursor is representatively shown in
X
n
n
n
X
Free
X
M
M
N
N
Rotation
N
PPh2
PPh2
PPh2
M
>
M = metal
1
Unstable complex 2b
Stable complex 2a
Figure 1.
*
Corresponding authors. Fax: +81 52 836 3439; e-mail addresses: kazuk@phar.nagoya-cu.ac.jp; aoyama@phar.nagoya-cu.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.098

1418
T. Arao et al. / Tetrahedron Letters 47 (2006) 1417–1420
R
R
R
R
R
R
Free
Rotation
M
>
N
N
N
N
N
N
R
R
R
R
R
R
M
M
3
Stable complex 4a Unstable complex 4b
Figure 2.
Ar
Ph
Br Me
N
Br Me
Ph
Ar
Pd-Ligand (cat)
base
Pd-Ligand (cat)
base
*
*
O
O
N
N
N
Me
Me
O
O
Me
6a
Me
6
5a
5
Scheme 3. Enantioselective intramolecular a-arylation of amide 5a.
Scheme 1. Enantioselective intramolecular a-arylation of amide 5.
7a–d and 8, and 2 mol equiv of NaOt-Bu in DME at
100 °C for 12 h. Among the imidazolium salts screened,
7a possessing an adamantyl group as R substituent gave
better asymmetric induction7 (67% ee, entries 1),
although reaction conversion was quite low. With 7a
as an N-heterocyclic carbene ligand precursor, the use
of other solvents such as 1,4-dioxane, toluene and
DMF gave less satisfactory results (entries 6–8). Other
palladium and rhodium complexes were not good metal
sources.
Table 1. Effects of ligands and solventsa
Entry Ligand Solvent
Yield
of 6a (%) 6a (%) configuration
eeb of Absolute
1
2
3
4
5
6
7
8
7a
7b
7c
7d
8
DME
DME
DME
DME
DME
14c
16c
8c
67
45
41
36
23
50
46
—
S
S
S
S
S
S
S
—
13c
7c
7a
7a
7a
1,4-Dioxane 17c
Toluene
DMF
8c
0d
Using the best Pd(OAc)2-7a catalyst in DME, we
screened various bases as shown in Table 2. As can be
seen, the choice of base played an important role in reac-
tion conversion. The use of LiOt-Bu gave the best reac-
tion conversion with 61% enantioselectivity (entry 2).8
a The reactions of 5a were performed using 10 mol % of Pd(OAc)2,
20 mol % of the imidazolium salts and 2 mol equiv of NaOt-Bu in the
shown solvent at 100 °C for 12 h.
b Determined by HPLC analysis.
c Remainder of mass balance was the unreacted starting amide 5a.
d The debrominated product 13 was obtained in 90% yield.
Finally, we examined the enantioselective a-arylation
with amides 5b and 5c possessing electron-withdrawing
and donating groups on the benzene ring as shown in
Scheme 4. The reactions with amide 5b and 5c were
found to exhibit 65% and 54% enantioselectivity7,
respectively.
Me
Ph
N
O
Me
13
In summary, we have developed a new class of N-het-
erocyclic carbene ligands for asymmetric catalysis, con-
formation of N-substituents of which was reflected by
chirality on the carbones of heterocyclic moiety and
Ph
+
Ph
7a: R=adamantyl (Adm)
BF4- 7b: R=adamantylmethyl
7c: R=t-butyl
BF4
-
+
N
N
N
N
7d: R=t-butylmethyl
R
R
Adm
Adm
Ph
8
CO2H
Ph
Ph
H2N
Ph
EDCI, Et3N
O
O
DMAP
+
o
NH HN
NH2
THF, 60 C
Adm
Adm
11
9
10
Ph
Ph
Ph
Ph
-
CH(OEt)3, NH4 BF4
reflux
BH3
THF, reflux
Adm
BF4
+
N
N
NH HN
Adm
12: y. 54% (2 steps)
Adm
Adm
7a: y. 98%
Scheme 2. Representative synthesis of imidazolium salt.

T. Arao et al. / Tetrahedron Letters 47 (2006) 1417–1420
1419
Table 2. Effects of basesa
Entry
Baseb
Yield of 6a (%)
eec of 6a (%)
Absolute configuration
1
2
3
4
NaOt-Bu
LiOt-Bu
KOt-Bu
NaOH
14d
62d
5d
67
61
41
62
S
S
S
S
16d
a The reactions of 5a were performed using 10 mol % of Pd(OAc)2, 20 mol % of imidazolium salt 7a and 2 mol equiv of the shown base in DME at
100 °C for 12 h.
b LHMDS, KHMDS and LiOH gave less satisfactory results.
c Determined by HPLC analysis.
d Remainder of mass balance was the unreacted starting amide 5a.
Pd(OAc)2 (10 mol %)
Ar Ligand 5a (20 mol %)
Ar
Br Me
N
O
LiOt-Bu (2 mol equiv)
N
o
O
DME, 100 C, 12 h
Me
Me
a
5b: Ar=p-MeO-C6H4-
5c: Ar=p-F-C6H4-
6b: Ar=p-MeO-C6H4- y.59% (65% ee)
6c: Ar=p-F-C6H4- y. 51% a (54% ee)
a
Remainder of mass balance was the
unreacted starting amide 5b or5c.
Scheme 4. Enantioselective intramolecular a-arylation of amides 5b and 5c.
C. W.; Furstner, A. Chem. Eur. J. 2005, 11, 1833; (m)
¨
fixed to be C2-symmetric by complexation with metal.
Further application to other catalytic asymmetric reac-
tions is now in progress.
Clavier, H.; Coutable, L.; Guillemin, J.-C.; Mauduit, M.
Tetrahedron: Asymmetry 2005, 16, 921; (n) Van Veldhuizen,
J. J.; Campbell, J. E.; Giudici, R. E.; Hoveyda, A. H. J. Am.
Chem. Soc. 2005, 127, 6877; (o) Song, C.; Ma, C.; Ma, Y.;
Feng, W.; Ma, S.; Chai, Q.; Andrus, M. B. Tetrahedron
Acknowledgements
´
Lett. 2005, 46, 3241; (p) Cesar, V.; Bellemin-Laponnaz, S.;
Wadepohl, H.; Gade, L. H. Chem. Eur. J. 2005, 11, 2862;
(q) Chianese, A. R.; Crabtree, R. H. Organometallics 2005,
24, 4432; (r) Ma, M.; Peng, L.; Li, C.; Zhang, X.; Wang, J.
J. Am. Chem. Soc. 2005, 127, 15016, and references cited
therein.
We thank the Ministry of Education, Science and Cul-
ture, Japan for support. K.K. was financially supported
by Sankyo Award in Synthetic Organic Chemistry,
Japan.
3. Representative procedure for the synthesis of imidazolium
salt 7a: To a stirred solution of (1R,2R)-1,2-diphenyl-1,2-
ethanediamine (9) (1.50 g, 7.07 mmol) in THF (30.0 mL)
were added 1-adamantanecarboxylic acid (10) (3.18 g,
17.7 mmol), DMAP (173 mg, 1.41 mmol), Et3N (2.46 mL,
1.79 g, 17.7 mmol) and EDCI (3.39 g, 17.7 mmol) at 0 °C.
The reaction mixture was stirred for 2 h at 60 °C, diluted
with water, and extracted with EtOAc. The organic extracts
were successively washed with 10% HCl, water, saturated
aq NaHCO3, water and brine, dried (Na2SO4), and
concentrated. Purification by silica gel column (CHCl3/
hexane, 1:2) gave a mixture (2.86 g) of coupling product 11
and small amounts of impurities. This mixture was used for
the next step without further separation. This mixture was
dissolved in THF (20.0 mL), and to this mixture BH3
(26.7 mL, 26.7 mmol, 1.0 M solution in THF) was added at
0 °C. The reaction mixture was heated under reflux for 4 h.
After being cooled to 0 °C, MeOH was carefully poured
into the reaction mixture. The whole mixture was heated
under reflux overnight and concentrated. The residue was
dissolved in water and extracted with EtOAc. The organic
extracts were washed with brine, dried (Na2SO4), and
concentrated. Purification by silica gel column (CHCl3)
gave diamine 12 (1.96 g, 54% in two steps) as colorless
References and notes
1. (a) Kondo, K.; Kazuta, K.; Fujita, H.; Sakamoto, Y.;
Murakami, Y. Tetrahedron 2002, 58, 5209; (b) Horibe, H.;
Kazuta, K.; Kotoku, M.; Kondo, K.; Okuno, H.; Mura-
kami, Y.; Aoyama, T. Synlett 2003, 2047; (c) Horibe, H.;
Fukuda, Y.; Kondo, K.; Okuno, H.; Murakam, Y.;
Aoyama, T. Tetrahedron 2004, 60, 10701; (d) Suzuki, K.;
Ishii, S.; Kondo, K.; Aoyama, T. Synlett, in press.
2. For reviews of chiral N-heterocyclic carbene ligands: (a)
Perry, M. C.; Burgess, K. Tetrahedron: Asymmetry 2003,
´
14, 951; (b) Cesar, V.; Bellemin-Laponnaz, S.; Gade, L. H.
Chem. Soc. Rev. 2004, 33, 619; (c) Herrmann, W. A. Angew.
Chem., Int. Ed. 2002, 41, 1291; For selected examples of
chiral N-heterocyclic carbene ligands: (d) Perry, M. C.; Cui,
X.; Powell, M. T.; Hou, D.-R.; Reibenspies, J. H.; Burgess,
K. J. Am. Chem. Soc. 2003, 125, 113; (e) Duan, W.-L.; Shi,
M.; Rong, G.-B. Chem. Commun. 2003, 2916; (f) Bonnet, L.
G.; Douthwaite, R. E.; Kariuki, B. M. Organometallics
2003, 22, 4187; (g) Gischig, S.; Togni, A. Organometallics
2004, 23, 2479; (h) Arnold, P. L.; Rodden, M.; Davis, K.
M.; Scarisbrick, A. C.; Blake, A. J.; Wilson, C. Chem.
Commun. 2004, 1612; (i) Catalano, V. J.; Malwitz, M. A.;
Etogo, A. O. Inorg. Chem. 2004, 43, 5714; (j) Tominaga, S.;
Oi, Y.; Kato, T.; An, D. K.; Okamoto, S. Tetrahedron Lett.
2004, 45, 5585; (k) Focken, T.; Rudolph, J.; Bolm, C.
Synthesis 2005, 429; (l) Kremzow, D.; Seidel, G.; Lehmann,
23
needles of mp 146 °C (CHCl3–hexane). ½aꢀD ꢁ5 (c 3.30,
THF). IR (nujol): m = 3315 cmꢁ1 1H NMR (CDCl3):
.
d = 1.44–2.16 (m, 36H), 3.47 (s, 2H), 6.92–7.02 (m, 4H),
7.04–7.16 (m, 6H). 13C NMR (CDCl3): d = 28.64, 33.85,
37.40, 40.95, 60.44, 70.67, 126.39, 127.53, 127.75, 142.03.

1420
T. Arao et al. / Tetrahedron Letters 47 (2006) 1417–1420
EIMS m/z = 508 (M+), 373, 254 (bp). Anal. Calcd for
dihydro-indol-2-one (6a) (29.3 mg, 62%, 61% ee). The
spectral data of 6a were comparable to those reported.4
4. Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402.
5. Glorius, F.; Altenhoff, G.; Goddard, R.; Lehmann, C.
Chem. Commun. 2002, 2704.
6. For Pd-catalyzed a-arylation of cabonyl compounds, see:
(a) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M.
Angew. Chem., Int. Ed. 1997, 36, 1740; (b) Muratake, H.;
Natsume, M. Tetrahedron Lett. 1997, 38, 7581; (c) Palucki,
M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108;
(d) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997,
119, 12382.
C36H48N2: C, 84.98; H, 9.51; N, 5.51. Found: C, 85.05; H,
9.50; N, 5.26. A suspension of diamine 12 (965 mg,
1.90 mmol) and NH4BF4 (239 mg, 2.28 mmol) in (EtO)3CH
(2.0 mL) was refluxed overnight. The suspension was
cooled to rt and concentrated. Purification by silica gel
column (MeOH/CHCl3, 1:30) gave (4R,5R)-4,5-diphenyl-
1,3-diadamantylmethyl-4,5-dihydro-3H-imidazol-1-ium tet-
rafluoroborate (7a) (1.13 g, 98%) as a colorless amorphous.
24
½aꢀD +127 (c 1.21, THF). IR (nujol): m = 1634 cmꢁ1
.
1H
NMR (CDCl3): d = 1.42–1.84 (m, 12H), 1.58 (d,
J = 12.7 Hz, 6H), 1.70 (d, J = 12.7 Hz, 6H), 1.99 (s, 6H),
2.78 (d, J = 14.7 Hz, 2H), 3.54 (d, J = 14.7 Hz, 2H), 5.02 (s,
7. The absolute configurations of oxindoles 6a–c were deter-
mined by comparison with the CD spectrum of 15 derived
from 14, whose absolute configuration was known.9
2H), 7.23–7.32 (m, 4H), 7.48–7.58 (m, 6H), 8.86 (s, 1H). 13
C
NMR (CDCl3): d = 27.96, 34.98, 36.41, 40.25, 57.53, 75.90,
126.2, 130.1, 130.2, 135.1, 160.1. FABMS: m/z = 520
(Mþ ꢁ BFꢁ4 þ 1). Anal. Calcd for C37H47N2BF4: C, 73.26;
H, 7.81; N, 4.62. Found: C, 73.31; H, 7.56; N, 4.51.
Representative procedure for the enantioselective intramo-
lecular a-arylation of amide 5a with imidazolium salt 7a
(Table 2, entry 2). To a stirred solution of N-(2-bromo-
phenyl)-N-methyl-2-phenylpropanamide (5a) (63.6 mg,
0.200 mmol) in DME (1.0 mL) were added imidazolium
salt 7a (24.3 mg, 0.0400 mmol), Pd(OAc)2 (4.5 mg,
0.0200 mmol) and LiOt-Bu (48.0 mg, 0.600 mmol) at rt
and the mixture was stirred for 12 h at 100 °C. After being
cooled to rt, the mixture was filtered through a layer of
silica gel and evaporated. Purification by silica gel column
(EtOAc/hexane, 1:8) gave (3S)-1,3-dimethyl-3-phenyl-1,3-
Ph
Ph
H2, Pd/C
EtOH
O
O
N
N
Me
Me
14
15
8. The good reaction conversion with a weaker base such as
LiOt-Bu might be due to the suppression of decomposition
of carbene ligand 7a.
9. Trost, B. M.; Frederiksen, M. U. Angew. Chem., Int. Ed.
2005, 44, 308.