Enantioselective synthesis of axially chiral anilides through rhodium-catalyzed [2+2+2] cycloaddition of 1,6-diynes with trimethylsilylynamides

Article abstract of DOI:10.1021/ja060348f

We have developed a rhodium-catalyzed enantioselective intermolecular [2+2+2] cycloaddition of 1,6-diynes with trimethylsilylynamides for the synthesis of axially chiral anilides. The axial chirality is constructed at the formation of benzene rings with h

Full text of DOI:10.1021/ja060348f

Published on Web 03/21/2006
Enantioselective Synthesis of Axially Chiral Anilides through
Rhodium-Catalyzed [2+2+2] Cycloaddition of 1,6-Diynes with
Trimethylsilylynamides
Ken Tanaka,*,† Kenzo Takeishi,† and Keiichi Noguchi‡
Department of Applied Chemistry, Graduate School of Engineering, and Instrumentation Analysis Center,
Tokyo UniVersity of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan
Received January 17, 2006; E-mail: tanaka-k@cc.tuat.ac.jp
Table 1. Screening of Modified-BINAP Ligandsa
Axially chiral anilides are valuable structures for asymmetric
reactions and biologically active compounds, and various asym-
metric syntheses of them have been reported.1-3 These are mainly
based on a chiral pool method or an optical resolution of racemic
compounds,2 although the straightforward enantioselective synthesis
is highly desired.3
Taguchi’s group and Curran’s group reported the first catalytic
enantioselective synthesis of axially chiral anilides through Pd-cat-
alyzed N-allylation of achiral o-tert-butyl-NH-anilides, although
high enantioselectivity could not be achieved (30-53% ee).4 Re-
cently, Taguchi, Kitagawa, and co-workers reported the Pd-catal-
yzed enantioselective N-arylation of achiral o-tert-butyl-NH-anilides
with high enantioselectivity (70-96% ee).5 In this Communication,
we report an enantioselective synthesis of axially chiral anilides
through a rhodium-catalyzed intermolecular [2+2+2] cycloaddition
of 1,6-diynes with trimethylsilylynamides. It should be noted that
the present reaction employs the readily prepared trimethylsily-
lynamides starting from commercially available bis(trimethysilyl)-
acetylene and trimethylsilyl group of the product anilides is expected
to be utilized for further functionalization (Scheme 1).
entry
ligand
yield (%)b
ee (%)
1
2
3
4
5
6
(R)-BINAP
38
38
32
33
13
21
80
84
97
79
90
12
(R)-tol-BINAP
(S)-xyl-BINAP
(S)-H8-BINAP
(S)-xyl-H8-BINAP
(S)-Segphosc
a [Rh(cod)2]BF4 (0.010 mmol), ligand (0.010 mmol), 1a (0.10 mmol),
2a (0.10 mmol), and CH2Cl2 (2.0 mL) were employed. b Isolated yield.
c (4,4′-Bi-1,3-benzodioxole)-5,5′-diylbis(diphenylphosphine).
Table 2. Rhodium-Catalyzed Enantioselective [2+2+2]
Cycloaddition of 1,6-Diynes with Ynamidesa
Scheme 1
entry
1
2
R2
R3
3
yield (%)b
ee (%)
1
2
3
4
1a
1a
1a
1a
1a
1d
1b
1c
1d
1e
1e
2a
2b
2c
2d
2e
2f
2d
2d
2d
2a
2e
Ph
Ph
Ph
Ph
Me
OMe
Ph
Ph
Ph
Bn
3aa
3ab
3ac
3ad
3ae
3df
3bd
3cd
3dd
3ea
3ee
29 (66c)
15 (46c)
40 (52c)
79 (-c)
21 (55c)
69 (26c)
29 (56c)
62 (34c)
50 (38c)
19 (67c)
30 (48c)
97
97
87
97
90
98
98
96
84
79
88
n-Bu
i-Pr
Ph
Bn
Bn
Ph
Ph
Ph
Bn
Bn
Recently, we reported the synthesis of axially chiral biaryl
compounds through the cationic rhodium(I)/modified-BINAP com-
plexes-catalyzed chemo-, regio-, and enantioselective intermolecular
[2+2+2] cycloadditions.6,7 We anticipated that an intermolecular
[2+2+2] cycloaddition of 1,6-diynes with trimethylsilylynamides
would construct axial chirality upon the formation of benzene rings
(Scheme 1).8,9
5
6d
7
8
9
10
11
Ph
Me
We first investigated an intermolecular [2+2+2] cycloaddition
of malonate-derived internal 1,6-diyne 1a with trimethylsilylyna-
mide 2a, as shown in Table 1. Screening of various modified-
BINAP ligands revealed that the highest enantioselectivity was
achieved by using xyl-BINAP as ligand (entry 3). On the other
hand, a terminal 1,6-diyne failed to react with 2a due to the rapid
homo [2+2+2] cycloaddition of the diyne.
a [Rh(cod)2]BF4 (0.025 mmol), (S)-xyl-BINAP (0.025 mmol), 1 (0.25
mmol), 2 (0.25 mmol), and CH2Cl2 (5.0 mL) were employed. b Isolated
yield. c Recovery (%) of 2. d Ligand: (R)-tol-BINAP.
Next, the scope of this cycloaddition was examined, as shown
in Table 2. With regard to trimethylsilylynamides (entries 1-6),
the reaction of benzoyl- (2a, entry 1), acetyl- (2e, entry 5), and
methoxycarbonyl- (2f, entry 6)10 substituted N-benzylynamides
furnished the corresponding axially chiral anilides with high
† Department of Applied Chemistry.
‡ Instrumentation Analysis Center.
9
4586
J. AM. CHEM. SOC. 2006, 128, 4586-4587
10.1021/ja060348f CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
In conclusion, we have developed a rhodium-catalyzed enanti-
oselective intermolecular [2+2+2] cycloaddition of 1,6-diynes with
trimethylsilylynamides for the synthesis of axially chiral anilides.
Improvement of the product yield, utilization of trimethylsilyl group
of the product anilides, and further application of the enantiose-
lective [2+2+2] cycloaddition for the synthesis of axially chiral
compounds are underway in our laboratory.
Acknowledgment. This work was supported by Asahi Glass
Foundation and a Grant-in-Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science and Technology,
Japan. We thank Takasago International Corporation for the gift
of modified-BINAP ligands and Prof. M. Hirano (Tokyo University
of Agriculture and Technology) for assistance with the X-ray
crystallographic analysis.
Figure 1. ORTEP diagram of (S)-(+)-3ea.
Scheme 2
Supporting Information Available: Experimental procedures,
compound characterization data, and X-ray crystallographic files (PDF,
CIF). This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) For the pioneering work on axially chiral N-substituted o-tert-butylanilides,
see: Curran, D. P.; Qi, H.; Geib, S. J.; DeMello, N. C. J. Am. Chem. Soc.
1994, 116, 3131-3132.
(2) (a) Kitagawa, O.; Izawa, H.; Sato, K.; Dobashi, A.; Taguchi, T.; Shiro,
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Kondo, K.; Fujita, H.; Suzuki, T.; Murakami, Y. Tetrahedron Lett. 1999,
40, 5577-5580. (d) Ates, A.; Curran, D. P. J. Am. Chem. Soc. 2001,
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(3) For asymmetric synthesis of axially chiral anilides through enantiotopic
deprotonation, see: (a) Hata, T.; Koide, H.; Taniguchi, N.; Uemura, M.
Org. Lett. 2000, 2, 1907-1910. (b) Bennett, D. J.; Pickering, P. L.;
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enantioselectivities. Furthermore, the reactions of not only benzyl-
(2a, entry 1) but also primary alkyl- (2b, entry 2), secondary alkyl-
(2c, entry 3), and phenyl- (2d, entry 4) substituted N-benzoylyna-
mides furnished the corresponding axially chiral anilides with high
enantioselectivities. Interestingly, the yield of anilides highly
depends on the substituents on the ynamides. Significantly increased
yields were observed in the case of a phenyl- (2d, entry 4) or a
methoxycarbonyl- (2f, entry 6) substituted trimethylsilylynamide.
On the other hand, no reaction was observed in the case of a
terminal ynamide.
The generality of this cycloaddition was subsequently examined
with regard to 1,6-diynes. Thus, not only malonate-derived 1,6-
diyne 1a (entries 1-5) but also 1,3-diol derivative 1b (entry 7), ether-
linked 1,6-diyne 1c (entry 8), and sulfonamide-linked 1,6-diynes
1d,e (entries 6 and 9-11) gave the corresponding axially chiral
anilides with high enantioselectivities. Although competetive homo
[2+2+2] cycloaddition of 1,6-diynes proceeded as the major side
reaction, unreacted ynamides could be recovered by silica gel
chromatography. The absolute configuration of (+)-3ea was deter-
mined to be S by the anomalous dispersion method (Figure 1).
Scheme 2 depicts a plausible mechanism of the selective forma-
tion of (S)-3ea. Enantioselectivity is determined by preferential for-
mation of intermediate A, due to the coordination of the carbonyl
group of 2a to rhodium and the steric interaction between the benzyl
group of 2a and the PAr2 group of (S)-xyl-BINAP. Reductive elim-
ination of rhodium gives (S)-3ea and regenerates the rhodium catalyst.
Indeed, the use of methoxycarbonyl-substituted 1,6-diyne 1f de-
creased the ee of the corresponding anilide 3fa, presumably due to
the electronic repulsion between carbonyl groups of 1f and 2a (eq
1).11
(4) (a) Kitagawa, O.; Kohriyama, M.; Taguchi, T. J. Org. Chem. 2002, 67,
8682-8684. (b) Terauchi, J.; Curran, D. P. Tetrahedron: Asymmetry 2003,
14, 587-592.
(5) Kitagawa, O.; Takahashi, M.; Yoshikawa, M.; Taguchi, T. J. Am. Chem.
Soc. 2005, 127, 3676-3677.
(6) For Rh(I)+/modified-BINAP-catalyzed chemo- and regioselective inter-
molecular alkyne cyclotrimerization, see: (a) Tanaka, K.; Shirasaka, K.
Org. Lett. 2003, 5, 4697-4699. (b) Tanaka, K.; Toyoda, K.; Wada, A.;
Shirasaka, K.; Hirano, M. Chem. Eur. J. 2005, 11, 1145-1156.
(7) Enantioselective syntheses of axially chiral biaryl compounds through
[2+2+2] cycloaddition have been reported. For Co, see: (a) Gutnov, A.;
Heller, B.; Fischer, C.; Drexler, H.-J.; Spannenberg, A.; Sundermann, B.;
Sundermann, C. Angew. Chem., Int. Ed. 2004, 43, 3795-3797. For Ir,
see: (b) Shibata, T.; Fujimoto, T.; Yokota, K.; Takagi, K. J. Am. Chem.
Soc. 2004, 126, 8382-8383. For Rh, see: (c) Tanaka, K.; Nishida, G.;
Wada, A.; Noguchi, K. Angew. Chem., Int. Ed. 2004, 43, 6510-6512.
(d) Tanaka, K.; Nishida, G.; Ogino, M.; Hirano, M.; Noguchi, K. Org.
Lett. 2005, 7, 3119-3121. (e) Tanaka, K.; Wada, A.; Noguchi, K. Org.
Lett. 2005, 7, 4737-4739.
(8) For a recent review of ynamides, see: Zificsak, C. A.; Mulder, J. A.;
Hsung, R. P.; Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57, 7575-
7606.
(9) Witulski et al. reported the rhodium-catalyzed [2+2+2] cycloaddition of
ynamides for the synthesis of nitrogen heterocycles: (a) Witulski, B.;
Stengel, T. Angew. Chem., Int. Ed. 1999, 38, 2426-2430. (b) Witulski,
B.; Alayrac, C. Angew. Chem., Int. Ed. 2002, 41, 3281-3284.
(10) The ee’s of the product anilides derived from ynamide 2f and 1,6-diynes
1a-c,e could not be determined by chiral HPLC analysis.
(11) No regioisomer was generated other than 3fa.
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