Palladium-catalyzed asymmetric [3+3] cycloaddition of trimethylenemethane derivatives with nitrones

Article abstract of DOI:10.1002/anie.200701529

(Chemical Equation Presented) Rounding up the reactants: Functionalized 1,2-oxazines can be obtained in high yield by a palladium-catalyzed asymmetric [3+3] cycloaddition of trimethylenemethane derivatives with nitrones. The use of a modified phosphoramid

Full text of DOI:10.1002/anie.200701529

Angewandte
Chemie
DOI: 10.1002/anie.200701529
Asymmetric Catalysis
Palladium-Catalyzed Asymmetric [3+3] Cycloaddition of
Trimethylenemethane Derivatives with Nitrones**
Ryo Shintani,* Soyoung Park, Wei-Liang Duan, and Tamio Hayashi*
In memory of Yoshihiko Ito
Transition-metal-catalyzed intermolecular cycloaddition
reactions can provide rapid access to cyclic compounds in a
convergent manner with high efficiency. The development of
asymmetric variants is, therefore, of high value in synthetic
organic chemistry. In this regard, although [4+2] cycloaddi-
tions, such as the Diels–Alder reaction, have been extensively
investigated for the construction of enantioenriched six-
membered cyclic compounds,[1] transition-metal-catalyzed
asymmetric [3+3] cycloaddition reactions have been much
less studied to date.[2] Herein we describe the development of
a palladium-catalyzed asymmetric [3+3] cycloaddition of
trimethylenemethane derivatives (TMMs) with nitrones to
produce six-membered heterocycles with high stereoselectiv-
ity.[3]
intermediate A rapidly isomerizes to Pd-TMM intermediate
B, which contains a more stable benzylic anion, and this
intermediate is engaged in the subsequent cycloaddition with
Since their first introduction by Trost and Chan in 1979,[4]
Pd-TMM complexes have served as an efficient source of
three-carbon units in various cyclic frameworks, particularly
in the context of [3+2] cycloaddition reactions.[5] Unfortu-
nately, however, the application of this useful chemistry to
asymmetric catalysis is very limited. In fact, only two reports,
by Ito, Hayashi, and co-workers with ferrocene-based chiral
bisphosphine ligands in 1989[6] and by Trost et al. with chiral
phosphoramidite ligands in 2006,[7] have met with reasonable
success in the palladium-catalyzed asymmetric [3+2] cyclo-
addition of trimethylenemethane derivatives, and there have
been no reports on the corresponding [3+3] cycloaddition
reaction to date.[3,8]
2a (Scheme 1).[11]
Scheme 1. Proposed reaction pathway for the palladium-catalyzed
[3+3] cycloaddition of 1a with 2a.
In an initial investigation, we conducted a reaction of the
TMM precursor 1a with nitrone 2a in the presence of 5 mol%
[CpPd(h3-C3H5)] (Cp = cyclopentadienyl) and 10 mol% PPh3
at 408C, and found that product 3aa was obtained in 86%
yield as a mixture of two diastereomers (d.r. ꢀ 1:1), with
almost no formation of the structural isomers 4aa and 5aa
[Eq. (1)].[9,10] The observed high selectivity to generate 3aa
over 4aa or 5aa indicates that the initially formed Pd-TMM
On the basis of the result obtained using PPh3 as a ligand
[Eq. (1)], we investigated the use of (S)-MeO-mop,[12] a chiral
monodentate phosphine, as a ligand in the reaction of 1a with
2a, but the reaction was very sluggish and gave 3aa in only
17% yield with low diastereo- and enantioselectivity (Table 1,
entry 1). No reaction was observed when (S)-binap,[13] a chiral
bisphosphine ligand, was used (Table 1, entry 2). In contrast,
the reaction proceeded smoothly in the presence of dieth-
ylamino-substituted phosphoramidite ligand (S)-6a[14] to give
3aa in 83% yield, but both the diastereoselectivity and
enantioselectivity were only moderate (trans/cis 60:40 with
27% ee and 45% ee, respectively; Table 1, entry 3). Modifi-
cation of the nitrogen substituents of the phosphoramidite
ligands gave (S,R,R)-6b[14,15] and its diastereomer (S,S,S)-
6b,[14] both of which improved the diastereoselectivity for the
formation of the trans isomer (Table 1, entries 4 and 5); the
trans diastereomer was formed in 84% ee in the presence of
(S,S,S)-6b. Changing the ligand framework from 1,1’-
binaphthyl ((S,S,S)-6b) to 5,5’,6,6’,7,7’,8,8’-octahydro-1,1’-
binaphthyl ((S,S,S)-6c)[16] resulted in further improvement
in the diastereoselectivity and enantioselectivity (trans/cis
[*] Dr. R. Shintani, S. Park, W.-L. Duan, Prof. Dr. T. Hayashi
Department of Chemistry
Graduate School of Science, Kyoto University
Sakyo, Kyoto 606-8502 (Japan)
Fax: (+81)75-753-3988
E-mail: shintani@kuchem.kyoto-u.ac.jp
thayashi@kuchem.kyoto-u.ac.jp
[**] Support has been provided in part by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science,
and Technology, Japan (21 COE on Kyoto University Alliance for
Chemistry).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2007, 46, 5901 –5903
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5901

Communications
Table 1: Ligand effects in the palladium-catalyzed asymmetric
[3+3] cycloaddition of 1a with 2a.
Table 2: Scope of the palladium-catalyzed asymmetric [3+3] cycloaddi-
tion.
Entry Ligand
Yield [%][a] trans/cis[b] trans ee [%][c] cis ee [%][c]
1
2
3
4
5
6
7
(S)-MeO-mop
(S)-binap
(S)-6a
(S,R,R)-6b
(S,S,S)-6b
(S,S,S)-6c
(S,S,S)-6d
17 57:43
0 –
21
–
32
–
45
2
39
62
77
Entry TMM Nitrone Product Yield [%][a] trans/cis[b] trans ee [%][c]
83 60:40
79 79:21
90 85:15
85 87:13
95 89:11
27
21
84
91
92
1[d]
2[e]
3[e]
4[e]
5[e]
6[d]
7[d]
8[e]
9[d,f]
1a
1a
1a
1a
1a
1b
1c
1c
1d
2a
2b
2c
2d
2e
2a
2a
2c
2a
2c
2a
3aa
3ab
3ac
3ad
3ae
3ba
3ca
3cc
3da
3dc
3ea
95
99
98
99
92
78
91
98
85
99
90
89:11
84:16
85:15
76:24
85:15
83:17
86:14
85:15
88:12
85:15
–
92
91
91
91
92
88
90
93
89
93
1
1
[a] Yield of isolated product. [b] Determined by H NMR spectroscopy.
[c] Determined by HPLC on chiral stationary phases (AD-H + OG) with
hexane/2-propanol 95:5.
10[e,f] 1d
11[d,f] 1e
1
[a] Yield of isolated product. [b] Determined by H NMR spectroscopy.
[c] Determined by HPLC. [d] 5 mol% Pd catalyst was used. [e] 8 mol%
Pd catalyst was used. [f] Ligand (S,S,S)-6c was used.
tion of which was determined to be S,S by X-ray crystallo-
graphic analysis of its benzylamine salt (Figure 1).[19]
In summary, we have developed a palladium-catalyzed
asymmetric [3+3] cycloaddition of trimethylenemethane
derivatives with nitrones to produce the corresponding 1,2-
oxazines in high yield. The use of a modified phosphoramidite
ligand has led to the formation of these compounds with high
stereoselectivity.
87:13, trans isomer: 91% ee; Table 1, entry 6). A slightly
better result was achieved (trans/cis 89:11, trans isomer:
92% ee) by employing (S,S,S)-6d as the ligand, which has a
bis((S)-1-(2-naphthyl)ethyl)amino group[17] rather than a
bis((S)-1-phenylethyl)amino group (Table 1, entry 7).
The scope of this asymmetric [3+3] cycloaddition reaction
was investigated under these conditions using (S,S,S)-6d as
the ligand (Table 2). It was found that various aryl groups can
be tolerated on the electrophilic carbon atom of the nitrone
(Table 2, entries 1–5), with [3+3] cycloadducts obtained in
excellent yield (92–99% yield) and relatively high diastereo-
selectivity (trans/cis 76:24–89:11) and high enantioselectivity
(91–92% ee).[18] Several TMM precursors with different aryl
groups can also be used in the [3+3] cycloaddition reaction
with similarly high efficiency (Table 2, entries 6–10). Unfortu-
nately, the use of unsubstituted TMM precursor 1e gives the
cycloadduct with almost no enantioselectivity (Table 2,
entry 11).
The ethyl ester of trans-3dc (Table 2, entry 10) was
hydrolyzed to give trans-7 [Eq. (2)], the absolute configura-
Figure 1. X-ray structure of (S,S)-7·H2NCH2Ph with thermal ellipsoids
drawn at the 50% probability level.
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Angewandte
Chemie
W. J. Moran, A. H. G. P. Prenzel, D. A. Price, J. P. A. Harrity,
Experimental Section
Synlett 2001, 1596; c) S. J. Hedley, W. J. Moran, D. A. Price,
J. P. A. Harrity, J. Org. Chem. 2003, 68, 4286; d) K. M. Good-
enough, W. J. Moran, P. Raubo, J. P. A. Harrity, J. Org. Chem.
2005, 70, 207.
General procedure for the reaction in Table 2: A solution of
[CpPd(h3-C3H5)] (2.1 mg, 9.9 mmol or 3.4 mg, 16 mmol) and ligand
(S,S,S)-6d (12.9 mg, 19.9 mmol or 20.7 mg, 32.0 mmol) in CH2Cl2
(0.30 mL) was stirred for 10 min at room temperature. Nitrone 2
(0.200 mmol), 1 (0.400 mmol), and CH2Cl2 (0.20 mL) were then
added, and the resulting mixture was stirred for 48 h at 408C. The
reaction mixture was directly passed through a pad of silica gel with
EtOAc and the solvent removed under vacuum. The residue was
purified by preparative TLC on silica gel to afford 3.
[9] The use of [Pd(PPh3)4] as the catalyst gives similar efficiency, but
a catalyst generated from [Pd2(dba)3] (dba = trans, trans-diben-
zylideneacetone) and PPh3 shows no reactivity.
[10] For examples of metal-catalyzed synthesis of 1,2-oxazines, see
a) I. S. Young, M. A. Kerr, Angew. Chem. 2003, 115, 3131;
Angew. Chem. Int. Ed. 2003, 42, 3023; b) F. Cardona, A. Goti,
Angew. Chem. 2005, 117, 8042; Angew. Chem. Int. Ed. 2005, 44,
7832; c) Ref. [2].
Received: April 8, 2007
Revised: May 11, 2007
Published online: June 20, 2007
[11] B. M. Trost, T. N. Nanninga, T. Satoh, J. Am. Chem. Soc. 1985,
107, 721.
[12] a) T. Hayashi, Acc. Chem. Res. 2000, 33, 354; b) Y. Uozumi, A.
Tanahashi, S.-Y. Lee, T. Hayashi, J. Org. Chem. 1993, 58, 1945.
[13] H. Takaya, K. Mashima, K. Koyano, M. Yagi, H. Kumobayashi,
T. Taketomi, S. Akutagawa, R. Noyori, J. Org. Chem. 1986, 51,
629.
Keywords: asymmetric catalysis · cycloaddition · nitrones ·
palladium · trimethylenemethanes
.
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