Enantioselective synthesis of C2-symmetric spirobilactams via Pd-catalyzed intramolecular double N-arylation

Article abstract of DOI:10.1021/ol900016g

A Pd/BINAP-complex-catalyzed enantioselective intramolecular double N-arylation of malonamides bearing 2-bromoarylmethyl groups furnished C ₂-symmetric spirobi(3,4-dihydro-2-quinolone) derivatives in up to 70% ee.

Full text of DOI:10.1021/ol900016g

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1483-1486
Enantioselective Synthesis of
C2-Symmetric Spirobilactams via
Pd-Catalyzed Intramolecular Double
N-Arylation
Kazuhiro Takenaka, Noriyuki Itoh, and Hiroaki Sasai*
The Institute of Scientific and Industrial Research (ISIR), Osaka UniVersity,
Mihogaoka, Ibaraki, Osaka 567-0047, Japan
sasai@sanken.osaka-u.ac.jp
Received January 5, 2009
ABSTRACT
A Pd/BINAP-complex-catalyzed enantioselective intramolecular double N-arylation of malonamides bearing 2-bromoarylmethyl groups furnished
C2-symmetric spirobi(3,4-dihydro-2-quinolone) derivatives in up to 70% ee.
The demand for C2-symmetric spiranes has been steadily
increasing in synthetic chemistry because they contain an
entirely rigid spiro backbone, which creates an effective
asymmetric environment.1 For instance, Zhou and co-workers
have demonstrated the practicality of chiral phosphorus
ligands based on the spiro skeleton.2 A novel asymmetric
dearomatization of phenol derivatives was recently reported,
in which the use of a chiral hypervalent iodine(III) reagent
having a spirobiindane scaffold was crucial for the high
enantioselectivity.3 We have also been investigating the
utility of chiral spiro compounds as not only ligands4 but
also organocatalysts.5 Since C2-symmetric spiro skeletons
have been recognized as suitable structural cores for useful
materials, it is important to establish efficient protocols for
their synthesis. A catalytic asymmetric synthesis would
therefore provide a highly practical method for the prepara-
tion of optically active spiranes. The first example of this
approach was reported by Tamao and co-workers in 1996.6
They obtained an enantiomerically enriched 5-silaspiro[4.4]-
(4) (a) Arai, M. A.; Arai, T.; Sasai, H. Org. Lett. 1999, 1, 1795. (b)
Arai, M. A.; Kuraishi, M.; Arai, T.; Sasai, H. J. Am. Chem. Soc. 2001,
123, 2907. (c) Shinohara, T.; Arai, M. A.; Wakita, K.; Arai, T.; Sasai, H.
Tetrahedron Lett. 2003, 44, 711. (d) Muthiah, C.; Arai, M. A.; Shinohara,
T.; Arai, T.; Takizawa, S.; Sasai, H. Tetrahedron Lett. 2003, 44, 5201. (e)
Takizawa, S.; Honda, Y.; Arai, M. A.; Kato, T.; Sasai, H. Heterocycles
2003, 60, 2551. (f) Wakita, K.; Arai, M. A.; Kato, T.; Shinohara, T.; Sasai,
H. Heterocycles 2004, 62, 831. (g) Kato, T.; Marubayashi, K.; Takizawa,
S.; Sasai, H. Tetrahedron: Asymmetry 2004, 15, 3693. (h) Wakita, K.;
Bajracharya, G. B.; Arai, M. A.; Takizawa, S.; Suzuki, T.; Sasai, H.
Tetrahedron: Asymmetry 2007, 18, 372. (i) Takenaka, K.; Nakatsuka, S.;
Tsujihara, T.; Koranne, P. S.; Sasai, H. Tetrahedron: Asymmetry 2008, 19,
2492.
(1) For reviews, see: (a) Xie, J.-H.; Zhou, Q.-L. Acc. Chem. Res. 2008,
41, 581. (b) Bajracharya, G. B.; Arai, M. A.; Koranne, P. S.; Suzuki, T.;
Takizawa, S.; Sasai, H. Bull. Chem. Soc. Jpn. 2009, 82, in press.
(2) For recent examples, see: (a) Fan, B.-M.; Xie, J.-H.; Li, S.; Wang,
L.-X.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2007, 46, 1275. (b) Yang, Y.;
Zhu, S.-F.; Duan, H.-F.; Zhou, C.-Y.; Wang, L.-X.; Zhou, Q.-L. J. Am.
Chem. Soc. 2007, 129, 2248. (c) Huo, X.-H.; Xie, J.-H.; Wang, Q.-S.; Zhou,
Q.-L. AdV. Synth. Catal. 2007, 349, 2477. (d) Duan, H.-F.; Xie, J.-H.; Qiao,
X.-C.; Wang, L.-X.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2008, 47, 4351.
(e) Yang, Y.; Zhu, S.-F.; Zhou, C.-Y.; Zhou, Q.-L. J. Am. Chem. Soc. 2008,
130, 14052.
(5) (a) Patil, M. L.; Rao, C. V. L.; Yonezawa, K.; Takizawa, S.; Onitsuka,
K.; Sasai, H. Org. Lett. 2006, 8, 227. (b) Patil, M. L.; Rao, C. V. L.;
Takizawa, S.; Takenaka, K.; Onitsuka, K.; Sasai, H. Tetrahedron 2007,
63, 12702. (c) Patil, M. L.; Sasai, H. Chem. Rec. 2008, 8, 98.
(6) Tamao, K.; Nakamura, K.; Ishii, H.; Yamaguchi, S.; Shiro, M. J. Am.
Chem. Soc. 1996, 118, 12469.
(3) Dohi, T.; Maruyama, A.; Takenaga, N.; Senami, K.; Minamitsuji,
Y.; Fujioka, H.; Caemmerer, S. B.; Kita, Y. Angew. Chem., Int. Ed. 2008,
47, 3787.
10.1021/ol900016g CCC: $40.75
Published on Web 03/02/2009
2009 American Chemical Society

Scheme 1
.
Synthetic Approach to 1 via N-Arylation
Scheme 2. Preparation of 2a-Br
nonane derivative through an intramolecular double hydrosi-
lylation catalyzed by a Rh/chiral diphosphine complex. Since
then, asymmetric catalysis has been successfully employed
for the synthesis of C2-symmetric spiro compounds.7-9
Hence, further development of their catalytic asymmetric
synthesis may provide an efficient route to various optically
active spiranes. Herein we report an enantioselective syn-
thesis of spirobi(3,4-dihydro-2-quinolone) derivatives 110
utilizing a Pd-catalyzed N-arylation (the Buchwald-Hartwig
reaction). Such frameworks are expected to be versatile
building blocks for functional chiral molecules.10b The
present study is believed to be the first example of an
enantioselective synthesis of C2-symmetric spiranes using
the Buchwald-Hartwig reaction.11,12
synthesized racemic 1a.15 A mixture of 2a-Br and Cs2CO3
(1.4 equiv/Br) in toluene was stirred at 100 °C for 3 h in the
presence of Pd(OAc)2 (3.3 mol %/Br) and DPEPHOS (5.0
mol %/Br) to afford 1a quantitatively (Scheme 3). No special
care (e.g., high dilution or slow addition) was needed to
prevent possible intermolecular reactions.
We hypothesized that optically active spirobilactams 1
would be obtained via a Pd-catalyzed double cyclization of
malonamides 2 (Scheme 1). As a model substrate, 2,2-bis(2-
bromobenzyl)-N,N′-dimethylmalonamide (2a-Br), in which
the bromophenyl group can be reacted intramolecularly with
the secondary amide, was designed (Scheme 2). The mal-
onamide 2a-Br was readily prepared in high yield starting
with commercially available N,N′-dimethylbarbituric acid
(3a). Thus, dialkylation of 3a with 2-bromobenzyl bromide
(4a-Br) under phase transfer catalysis conditions,13 followed
by a hydrolytic ring-opening reaction,14 gave 2a-Br in 89%
yield (2 steps).
Scheme 3. Synthesis of the Racemic Spirobilactam 1a
This result prompted us to explore an efficient chiral ligand
(Table 1). When the reaction was conducted with (S)-BINAP
in N-methyl-2-pyrrolidone (NMP) solvent, 1a was obtained
in 99% yield with 55% ee (entry 1). Other axially chiral
diphosphine ligands including (S)-Tol-BINAP were less
stereoselective (entries 2-7). Pd complexes with chiral
monophosphine ligands such as (R)-MeO-MOP and (S)-
QUINAP gave the racemate in 69% and 57% yields,
respectively (entries 8 and 9). The reactions with a ferrocene-
based chiral phosphine also produced 1a, albeit with no
enantioselectivity (entries 10 and 11). A centrally chiral
diphosphine ligand (R,R)-DIOP, a phosphine-oxazoline
hybrid ligand (R)-iPr-PHOX, and a bisoxazoline ligand (S,S)-
tBu-BOX turned out to be ineffective (entries 12-14). Non-
negligible background reactions were observed under the
reaction conditions without ligand, resulting in a 19% yield
of 1a (entry 15).
To examine whether the Pd-catalyzed intramolecular
double N-arylation would be indeed operative, we initially
(7) (a) Takahashi, M.; Tanaka, M.; Sakamoto, E.; Imai, M.; Matsui,
A.; Funakoshi, K.; Sakai, K.; Suemune, H. Tetrahedron Lett. 2000, 41,
7879. (b) Tanaka, M.; Takahashi, M.; Sakamoto, E.; Imai, M.; Matsui, A.;
Fujio, M.; Funakoshi, K.; Sakai, K.; Suemune, H. Tetrahedron 2001, 57,
1197
(8) Takahashi, T.; Tsutsui, H.; Tamura, M.; Kitagaki, S.; Nakajima, M.;
Hashimoto, S. Chem. Commun. 2001, 1604
(9) Wada, A.; Noguchi, K.; Hirano, M.; Tanaka, K. Org. Lett. 2007, 9,
.
.
1295.
(10) The preparation of racemic 1 using another route was reported;
see: (a) Choi, H.-J.; Park, Y. J.; Kim, M. G.; Park, Y. S. J. Heterocycl.
Chem. 2000, 37, 1305. (b) Choi, H.-J.; Park, Y. S.; Kim, M. G.; Park, Y. J.;
Yoon, N. S.; Bell, T. W. Tetrahedron 2006, 62, 8696
.
(11) For the enantioselective Buchwald-Hartwig reaction, see: (a)
Kitagawa, O.; Takahashi, M.; Yoshikawa, M.; Taguchi, T. J. Am. Chem.
Soc. 2005, 127, 3676. (b) Kitagawa, O.; Yoshikawa, M.; Tanabe, H.; Morita,
T.; Takahashi, M.; Dobashi, Y.; Taguchi, T. J. Am. Chem. Soc. 2006, 128,
12923. (c) Kitagawa, O.; Kurihara, D.; Tanabe, H.; Shibuya, T.; Taguchi,
T. Tetrahedron Lett. 2008, 49, 471
.
After extensive optimization of reaction conditions (Pd/
BINAP ratio, base, solvent, etc.),16 we were gratified to find
(12) For examples of the Buchwald-Hartwig reaction using kinetic
resolution of racemic substrates, see: (a) Rossen, K.; Pye, P. J.; Maliakal,
A.; Volante, R. P. J. Org. Chem. 1997, 62, 6462. (b) Tagashira, J.; Imao,
D.; Yamamoto, T.; Ohta, T.; Furukawa, I.; Ito, Y. Tetrahedron: Asymmetry
2005, 16, 2307. (c) Kreis, M.; Friedmann, C. J.; Bra¨se, S. Chem. Eur. J.
2005, 11, 7387.
(14) Jursic, B. S. Tetrahedron Lett. 2000, 41, 5325.
(15) For related Pd-catalyzed intramolecular N-arylations, see: (a) Wolfe,
J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996, 52, 7525. (b)
Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35.
(13) Kotha, S.; Deb, A. C.; Kumar, R. V. Bioorg. Med. Chem. Lett.
2005, 15, 1039.
(16) See Supporting Information for details.
1484
Org. Lett., Vol. 11, No. 7, 2009

Table 1. Ligand Screening in the Asymmetric Intramolecular
Double N-Arylation of 2a-Bra
Table 2. Pd-Catalyzed Enantioselective Intramolecular Double
N-Arylation of 2a
entry
chiral ligand
(S)-BINAP
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
99
97
99
96
73
98
97
69
57
99
98
53
35
3
55
37
(S)-Tol-BINAP
(R)-SYNPHOS
(R)-SEGPHOS
(R)-DIFLUORPHOS
(R)-MeO-BIPHEP
(R)-C3-TUNEPHOS
(R)-MeO-MOP
(S)-QUINAP
(R)-(S)-JOSIPHOS
(R)-(R)-WALPHOS
(R,R)-DIOP
(R)-iPr-PHOX
(S,S)-tBu-BOX
none
-36d
-14d
-7d
-26d
-14d
rac
9
rac
rac
rac
rac
rac
rac
10
11
12
13
14
15
19
a All reactions were carried out in the presence of 3.3 mol %/Br of
Pd(OAc)2, 5.0 mol %/Br of chiral ligand, and 1.4 equiv/Br of Cs2CO3 at
100 °C for 24 h in N-methyl-2-pyrrolidone (0.2 M) under an argon
atmosphere. See Supporting Information for the structures of the chiral
ligands. b Determined by 1H NMR. c Determined by HPLC analysis (Daicel
Chiralpak IB). d The enantiomer opposite to that in entry 1 was preferentially
formed.
an improvement of the enantioselectivity. Thus, the employ-
ment of 6.7 mol %/Br of (S)-BINAP and 1.4 equiv/Br of
K3PO4 in N,N′-dimethylpropylene urea (DMPU) solvent led
to quantitative formation of the spirobilactam 1a, whose
enantiomeric excess reached 70% (Table 2, entry 1). The
scope of this transformation was next examined with a variety
of malonamides 2. Substrate 2a-Cl having 2-chlorobenzyl
groups was less reactive: 1a was produced in only 8% yield
with 6% ee (entry 2). Although the reaction of the iodide
analog 2a-I took place smoothly to give 1a in high yield, its
enantioselectivity was as low as 38% ee (entry 3). This might
reflect on the greater reactivity of the aryl iodide toward the
background reaction.17 Similar to 2a-Br, the reactions of 2b
(R ) Et) and 2c (R ) Bn) furnished the products 1b and 1c
in excellent yields (99%) and sufficient selectivities (52%
ee and 49% ee), respectively (entries 4 and 5). The
enantioselectivity is affected by the substituent on the
aromatic ring. Thus, moderate optical purity (48% ee) was
detected for 1d possessing Cl groups at the 5-positions,
whereas nearly racemic spirobilactams were produced for
5-MeO- and 3-NO2-substituted malonamides 2e and 2f
(entries 6-8). It was also feasible to introduce a 1,3-
benzodioxole ring to the spirobilactam, leading to quantitative
formation of 1g with 57% ee (entry 9). Unfortunately, no
selectivity was observed for the sterically more demanding
substrate 2h (entry 10). It should be emphasized that optically
a All reactions were performed at 100 °C under an argon atmosphere
for 6-24 h. The ratio of 2 (mol)/Pd(OAc)2 (mol)/(S)-BINAP (mol)/K3PO4
(mol)/DMPU (L) ) 1.0/0.066/0.13/2.8/2.5. b Isolated yield. c Determined
by HPLC analysis. Absolute configuration of the products has not been
determined yet. d The reactions were performed in toluene using Cs2CO3
as the base for 24-72 h.
pure 1a, 1b, and 1c were readily obtained by a single
recrystallization of the product. For example, addition of
MeOH (ca. 20 mL) to a solution of 1a (70% ee, 3.37 g) in
CHCl3 (ca. 20 mL) at rt afforded 1.18 g of enantiomerically
pure 1a.
A plausible catalytic cycle for the asymmetric N-arylation
is depicted in Scheme 4. As in the conventional Buchwald-
Hartwig reaction,18 the formation of 1 seems to be initiated
by the oxidative addition of one of the bromoarenes in 2 to
a catalytically active Pd0 complex. Desymmetrization of the
amide groups in the resulting PdII complex A proceeds to
(17) The conversion of 2a-Br was 10% in the absence of (S)-BINAP
after 3 h, whereas that of 2a-I reached >95% under the same conditions.
Org. Lett., Vol. 11, No. 7, 2009
1485

Scheme 4
.
Plausible Catalytic Cycle
Scheme 5. Pd-Catalyzed Enantioselective Intramolecular
N-Arylation of Racemic Intermediate 1a′
45% conversion (Scheme 5). However, these results evidently
support the postulated reaction pathway shown in Scheme
4.
In summary, we have developed an efficient synthetic
method toward spirobilactams 1, where the Pd-catalyzed
enantioselective intramolecular double N-arylation of mal-
onamides 2 is included as the key step. Optically active 1a
was obtained in 88% overall yield from the starting material,
N,N′-dimethylbarbituric acid, without chromatographic pu-
rification. Further study on the synthetic utility of 1 is
currently in progress.
give palladacycle B. The following C-N bond-forming
reductive elimination yields monocyclized compound 1′ and
regenerates the Pd catalyst. A subsequent intramolecular
N-arylation of 1′ furnishes the desired spirobilactam 1.
Enantioselectivity is determined in the first cyclization,
namely, the formation of the intermediate 1′ by way of B. It
is accordingly conceivable that a kinetic resolution process
would be involved in the second cyclization (1′ to 1). To
confirm this possibility, racemic intermediate 1a′, which was
prepared by the N-arylation of 2a-Br under milder condi-
tions,19 was subjected to the Pd catalysis.
Acknowledgment. We gratefully acknowledge Takasago
International Corporation for supplying chiral phosphine
ligands. This research was partly supported by a Grant-in-
Aid for Scientific Research on Priority Areas “Advanced
Molecular Transformation of Carbon Resources” from the
Ministry of Education, Culture, Sports, Science, and Tech-
nology, Japan. We also thank the technical staff of the
Materials Analysis Center of ISIR for their assistance.
Contrary to our expectations, no enantioselectivities were
observed for both the formed 1a and the unreacted 1a′ at
(18) (a) Shekhar, S.; Ryberg, P.; Hartwig, J. F.; Mathew, J. S.;
Blackmond, D. G.; Strieter, E. R.; Buchwald, S. L. J. Am. Chem. Soc. 2006,
128, 3584. (b) Fujita, K.; Yamashita, M.; Puschmann, F.; Alvarez-Falcon,
M. M.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 9044.
(c) Ikawa, T.; Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. J. Am. Chem.
Soc. 2007, 129, 13001.
Supporting Information Available: Experimental pro-
cedures, details for optimization of the reaction conditions,
and compound characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(19) Racemic 1a′ was obtained by mixing 2a-Br, Pd(OAc)2 (3.3 mol
%/Br), DPEPHOS (5.0 mol %/Br), and Cs2CO3 (1.4 equiv/Br) in toluene
at 50 °C for 48 h. For details, see Supporting Information.
OL900016G
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Org. Lett., Vol. 11, No. 7, 2009