Preparation of enantioenriched axially chiral anilides via [2+2+2] cycloaddition of 1,6-diynes with trimethylsilylynamides

Article abstract of DOI:10.1055/s-2007-983799

The rhodium-catalyzed enantioselective [2+2+2] cycloaddition of 1,6-diynes with teimethylsilylynamides provides enantioenriched axially chiral anilides in poor to good yields with good to excellent enantioselectivity. Trimethylsilylynamides can be readily

Full text of DOI:10.1055/s-2007-983799

2920
PRACTICAL SYNTHETIC PROCEDURES
Preparation of Enantioenriched Axially Chiral Anilides via [2+2+2]
Cycloaddition of 1,6-Diynes with Trimethylsilylynamides
Preparation of
E
na
e
ntioenriche
n
d Axially Chiral
A
T
nilides anaka,* Kenzo Takeishi
Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture
and Technology, Koganei, Tokyo 184-8588, Japan
Fax +81(42)3887037; E-mail: tanaka-k@cc.tuat.ac.jp
PSP
Received 8 March 2007; revised 27 March 2007
No95
Abstract: The rhodium-catalyzed enantioselective [2+2+2] cycloaddition of 1,6-diynes with trimethylsilylynamides provides enantio-
enriched axially chiral anilides in poor to good yields with good to excellent enantioselectivity. Trimethylsilylynamides can be readily
prepared in two steps starting from commercially available bis(trimethylsilyl)acetylene.
Key words: anilides, diynes, BINAP, rhodium, ynamides
Me
Z
Me
4: Z = C(CO2Me)2
(1.0 equiv)
O
O
10 mol%
Ph
[Rh(cod)2]BF4/
(S)-xyl-BINAP
KHMDS
PhCONHPh
PhI(OAc)2
CF3SO3H
Ph
N
Ph
Ph
N
+
I
Ph
–OTf
Me
SiMe3
Me
Me3Si
SiMe3
SiMe3
CH2Cl2, r.t.
79%
54%
84%
1
2
SiMe3
Step 1
Step 2
Step 3
Z
3
5a (97% ee)
Scheme 1 Preparation of enantioenriched axially chiral anilide 5a via the rhodium-catalyzed [2+2+2] cycloaddition
Introduction
successfully extended to a practical synthesis of another
important class of axially chiral compounds, axially chiral
Axially chiral anilides are important compounds for anilides.12
asymmetric reactions and biologically active com-
The synthetic procedure, outlined in Scheme 1, consti-
pounds.1–4 Their previously reported enantioselective syn-
thesis is based on two types of palladium-catalyzed N-
functionalization of achiral ortho-tert-butyl-NH-anil-
ides.5,6 Taguchi’s group and Curran’s group reported the
first catalytic enantioselective synthesis of axially chiral
anilides with low to moderate enantioselectivity (30–53%
ee) via palladium-catalyzed N-allylation.5 Taguchi, Kita-
gawa, and co-workers reported the palladium-catalyzed
enantioselective N-arylation with high enantioselectivity
(70–96% ee), but this method is restricted to the synthesis
of N-aryl anilides.6
tutes three steps starting from commercially available
bis(trimethylsilyl)acetylene (1). Treatment of 1 with
PhI(OAc)2 and CF3SO3H furnishes (trimethylsilyl)ethy-
nyliodonium salt 2 in good isolated yield (Step 1).13 N-
Ethynylation of an NH-amide furnishes trimethylsilylyna-
mide 3 in good isolated yield (Step 2).14 Enantioselective
aromatization via [2+2+2] cycloaddition of 1,6-diyne 4
with trimethylsilylynamide 3 (1.0 equiv) in the presence
of 10 mol% of a cationic rhodium(I)/(S)-xyl-BINAP com-
plex furnishes axially chiral anilide 5a in good isolated
yield with excellent enantioselectivity (Step 3).12,15–17
In 2003, our research group first demonstrated that cation-
ic rhodium(I)/BINAP-type bisphosphine complexes are
highly effective catalysts for chemo- and regioselective Scope and Limitations
[2+2+2] cycloadditions.7 These catalysts were further ap-
plied to the synthesis of axially chiral biaryls via an enan- Chiral BINAP-type ligands (Figure 1) were extensively
tioselective [2+2+2] cycloaddition.8–11 This protocol was screened at room temperature in the enantioselective
[2+2+2] cycloaddition of malonate-derived internal 1,6-
diyne 4 with N-benzyl-N-(trimethylsilylethynyl)benz-
amide leading to axially chiral anilide 5e. The highest
SYNTHESIS 2007, No. 18, pp 2920–2923
Advanced online publication: 12.07.2007
x
x.
x
x
.
2
0
0
7
DOI: 10.1055/s-2007-983799; Art ID: Z05907SS
© Georg Thieme Verlag Stuttgart · New York
enantioselectivity (97% ee) was achieved using xyl-

PRACTICAL SYNTHETIC PROCEDURES
Preparation of Enantioenriched Axially Chiral Anilides
2921
BINAP as the ligand, although the use of tol-BINAP (84% Table 1 Rhodium-Catalyzed Enantioselective [2+2+2] Cycloaddi-
tion of 1,6-Diynes with Trimethylsilylynamides
ee) and BINAP (80% ee) could furnish 5e with syntheti-
cally acceptable ee values. The active catalyst can be
Entry Product
Yield
(%)a
ee
(%)
readily prepared by mixing commercially available
[Rh(cod)2]BF4 and (S)-xyl-BINAP in CH2Cl2 followed by
treatment with hydrogen (1 atm) at room temperature.
O
Ph
SiMe3
5a: Z = C(CO2Me)2
5b: Z = C(CH2OMe)2
5c: Z = NSO2(4-
BrC6H4)
1
2
3
79 (–b)
97
98
84
Ph
N
29 (56b)
50 (38b)
Me
(S)-BINAP: Ar = Ph
PAr2
(S)-tol-BINAP: Ar = 4-MeC6H4
Me
PAr2
(S)-xyl-BINAP: Ar = 3,5-Me2C6H3
Z
O
Ph
Figure 1 Chiral BINAP-type ligands
Ph
Et
N
4
SiMe3
Et
5d
62 (34b)
96
Scope of the present procedure is shown in Table 1. With
respect to 1,6-diynes, not only malonate-derived 1,6-
diyne (entries 1,5,7,8, and 9) but also 1,3-diol derivative
(entry 2), sulfonamide-linked 1,6-diynes (entries 3,6,10,
and 11), and ether linked 1,6-diyne (entry 4) furnished the
corresponding axially chiral anilides with high enantiose-
lectivity. With respect to trimethylsilylynamides, the re-
action of not only phenyl (entries 1–4) but also benzyl
(entries 5 and 6), primary alkyl (entry 7), and secondary
alkyl (entry 8) substituted N-benzoylynamides furnished
the corresponding axially chiral anilides with high enantio-
selectivity. Furthermore, not only benzoyl (entries 5 and
6) but also acetyl (entries 9 and 10), and methoxycarbonyl
(entry 11) substituted N-benzylynamides furnished the
corresponding axially chiral anilides with high enantiose-
lectivity. Interestingly, the yield of anilides highly de-
pends on the substituents of ynamides. Significantly
increased yields were observed in the case of an N-phenyl
(entries 1–4) or an N-methoxycarbonyl (entry 11) substi-
tuted anilide. The absolute configuration of (+)-5f (entry
6) was determined to be S by anomalous dispersion meth-
od. The anilides exist as an equilibrium mixture of cis and
trans rotamers between the N-substituent and amido car-
bonyl oxygen group in CDCl3 solution as shown in
Figure 2.3b The cis rotamers are typically observed as ma-
jor isomers of anilides (Table 1).
O
O
Ph
Ph
N
5
6
5e: Z = C(CO2Me)2 29 (66b)
5f: Z = NTs
19 (67b)
97
79
Me
SiMe3
Me
Z
O
Ph
N
N
N
7
8
5g: Z = C(CO2Me)2 15 (46b)
97
87
Me
SiMe3
Me
Z
O
Ph
Me
SiMe3
Me
5h: Z = C(CO2Me)2 40 (52b)
Z
O
Ph
Me
Me
9
10
5i: Z = C(CO2Me)2
5j: Z = NTs
21 (55b)
30 (48b)
90
88
SiMe3
O
R1
R2
R2
Me
R1
R3
N
O
R3
N
Z
SiMe3
R3
SiMe3
R3
O
Ph
MeO
Me
N
5k: Z = NSO2
(4 -BrC6H4)
11c
69 (26b)
98
SiMe3
Z
Z
cis rotamer
trans rotamer
Me
Figure 2 Cis and trans rotamers of axially chiral anilides
Z
a Yield of isolated product.
In these reactions, competetive homo [2+2+2] cycloaddi-
tions of 1,6-diynes leading to hexasubstituted benzenes 6
and 7 occur as side reactions (Figure 3). However, yn-
amides can be recovered unchanged by silica gel chroma-
tography.
b Recovery (%) of trimethylsilylynamide.
c Ligand: (R)-tol-BINAP.
Synthesis 2007, No. 18, 2920–2923 © Thieme Stuttgart · New York

2922
K. Tanaka, K. Takeishi
PRACTICAL SYNTHETIC PROCEDURES
cially available and can be handled in air. However, these com-
pounds should be stored under inert atmosphere (argon or N2), and
[Rh(cod)2]BF4 should be stored at low temperature to suppress its
decomposition. All other reagents were obtained from commercial
sources and used as received unless otherwise indicated.
Me
Me
Me
Me
Me
Z
Z
Z
Z
Z
Me
Me
Me Me
Me
6
7
Phenyl(trimethylsilylethynyl)iodonium Triflate (2)13
Under N2, PhI(OAc)2 (6.31 g, 19.6 mmol) was dissolved in CH2Cl2
[30 mL, dried over 4 Å MS (Wako Pure Chemical Industries, Ltd.)]
and the solution was cooled to 0 °C. CF3SO3H (5.60 g, 37.3 mmol)
was added to this solution by using a glass pipette. After stirring at
Figure
3
By-products of rhodium-catalyzed enantioselective
[2+2+2] cycloadditions of 1,6-diynes with trimethylsilylynamides
Coordination of carbonyl group of trimethylsilylynamides 0 °C for 30 min, bis(trimethylsilyl)acetylene (1; 3.16 g, 18.5 mmol)
was added to this solution by using a glass pipette. After stirring at
to rhodium may play an important role in obtaining high
0 °C for 2 h, the resulting solution was concentrated in vacuo at r.t.
ee values. Indeed, the use of 1,6-diynes bearing methoxy-
to give an oily residue. This oil was poured dropwise into stirred n-
carbonyl group significantly decreased enantioselectivity
hexane (100 mL) at r.t. The resulting solid materials were collected
of the corresponding anilides presumably due to the elec-
by filtration, washed with Et2O, and dried in vacuo to give phe-
tronic repulsion between carbonyl groups of 1,6-diynes
and trimethylsilylynamides (Figure 4).
nyl(trimethylsilylethynyl)iodonium triflate (2) (7.04 g, 84%) as a
colorless solid.
Note: Although workup and crystallization procedures can be car-
ried out in air, compound 2 should be stored under a dry inert atmo-
sphere to avoid its decomposition.
O
O
Ph
Ph
Ph
N
Ph
N
MeO2C
SiMe3
MeO2C
SiMe3
N-Phenyl-N-(trimethylsilylethynyl)benzamide (3)12
Under argon, KHMDS (0.5 M in toluene, 9.80 mL, 4.90 mmol) was
added to a solution of N-phenylbenzamide (0.863 g, 4.37 mmol) in
toluene [40 mL, dried over 4 Å MS (Wako Pure Chemical Indus-
tries, Ltd.)] at 0 °C. After warming to r.t., phenyl(trimethylsilyl-
ethynyl)iodonium triflate (2; 2.21 g, 4.91 mmol) was added in four
portions. The resulting mixture was stirred for 15 h at r.t. and fil-
tered through a plug of silica gel. Purification by silica gel column
chromatography (silica gel 60 N, spherical, neutral, Kanto Chemi-
cal Co.; hexane–EtOAc, 40:1) gave 3 (0.688 g, 54%) as a yellow
solid; mp 70–71 °C.
IR (neat): 2975, 2200, 1680, 1260, 840, 720 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.89–7.78 (m, 2H), 7.55–7.22 (m,
8H), 0.06 (s, 9H).
13C NMR (75 MHz, CDCl3): d = 170.7, 139.5, 133.5, 131.6, 129.04,
129.02, 127.7, 127.2, 125.0, 97.2, 75.0, –0.3.
HRMS (EI): m/z [M – CH3]+ calcd for C17H16NOSi: 278.1001;
found: 278.0956.
Me
CO2Me
Z
Z
Z = C(CO2Me)2: 50% ee
Z = C(CO2Me)2: <10% ee
Figure 4 Axially chiral anilides obtained from 1,6-diynes bearing
methoxycarbonyl groups
Axially chiral anilides inaccessible by the present method
are shown in Figure 5. Terminal 1,6-diynes failed to react
with trimethylsilylynamides due to the rapid homo
[2+2+2] cycloaddition of the diynes. Terminal ynamides
and cyclic ynamides failed to react with 1,6-diynes.
O
O
R2
R2
R1
H
N
R1
N
O
N
SiMe3
H
Me
H
Me
SiMe3
Me
Note: KHMDS should be used as a base for the synthesis of tri-
methylsilylynamides employed in Table 1. According to our exper-
iments, n-BuLi did not furnish the desired trimethylsilylynamides in
satisfactory yield.
Me
Z
Z
Z
Figure 5 Axially chiral anilides inaccessible via rhodium-catalyzed
[2+2+2] cycloaddition
(–)-5-(Benzoylphenylamino)-4,7-dimethyl-6-(trimethylsilyl)
indan-2,2-dicarboxylic Acid Dimethyl Ester
(5a, cis/trans = 60:40)12 (Scheme 1)
Under argon, (S)-xyl-BINAP (18.4 mg, 0.0250 mmol) and
[Rh(cod)2]BF4 (10.2 mg, 0.0250 mmol) were dissolved in CH2Cl2 (1
mL) and the mixture was stirred at r.t. for 5 min. H2 was introduced
to the resulting solution in a Schlenk tube. After stirring at r.t. for 30
min, the resulting solution was concentrated to dryness and redis-
solved in CH2Cl2 (1.0 mL). To this solution was added, dropwise
over 1 min, a solution of diyne 4 (59.1 mg, 0.250 mmol) and tri-
methylsilylynamide 3 (73.3 mg, 0.250 mmol) in CH2Cl2 (1 mL) at
r.t., and washed the remaining substrates away by using CH2Cl2 (3
mL). The mixture was stirred at r.t. for 42 h. The resulting solution
was concentrated and purified by silica gel preparative TLC (Wako-
gel B-5F, Wako Pure Chemical Industries, Ltd.; hexane–EtOAc–
Et3N, 10:1:2), which furnished 5a (118 mg, 79%, 97% ee) as a col-
In summary, the rhodium-catalyzed enantioselective
[2+2+2] cycloaddition of 1,6-diynes with trimethylsilyl-
ynamides allows the preparation of enantioenriched axial-
ly chiral anilides. The trimethylsilyl group of these
anilides is expected to be utilized for further functional-
ization.
Procedures
All reactions were carried out under argon or N2 in oven-dried
glassware with magnetic stirring. Anhyd CH2Cl2 (No. 27,099-7),
used for the rhodium-catalyzed [2+2+2] cycloaddition, was ob-
tained from Aldrich and used as received. BINAP-type ligands (xyl-
BINAP, tol-BINAP, and BINAP) and [Rh(cod)2]BF4 were commer-
25
orless oil; [a]D –32.6 (CHCl3, c = 1.14, 97% ee). CHIRALPAK
AD: hexane–i-PrOH (80:20); 1.0 mL/min; tR: 11.8 min (minor iso-
mer) and 23.9 min (major isomer).
Synthesis 2007, No. 18, 2920–2923 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Preparation of Enantioenriched Axially Chiral Anilides
2923
IR (neat): 2900, 1720, 1640, 1430, 1230, 840, 710 cm–1.
Dobashi, Y.; Taguchi, T. J. Am. Chem. Soc. 2006, 128,
12923.
(7) For our first report on the cationic rhodium(I)/modified-
BINAP-catalyzed inter- and intramolecular [2+2+2]
cycloadditions, see: Tanaka, K.; Shirasaka, K. Org. Lett.
2003, 5, 4697.
1H NMR (300 MHz, CDCl3): d = 7.58–6.91 (m, 10 H, cis; 8 H,
trans), 6.68–6.56 (m, 2 H, trans), 3.84–3.70 (m, 6 H, cis and trans),
3.70–3.38 (m, 4 H, cis and trans), 2.32 (s, 3 H, trans), 2.25 (s, 3 H,
cis), 2.18 (s, 3 H, trans), 1.95 (s, 3 H, cis), 0.22 (s, 9 H, trans), 0.16
(s, 9 H, cis),
(8) For the enantioselective synthesis of axially chiral biaryls,
see: (a) Tanaka, K.; Nishida, G.; Wada, A.; Noguchi, K.
Angew. Chem. Int. Ed. 2004, 43, 6510. (b) Tanaka, K.;
Nishida, G.; Ogino, M.; Hirano, M.; Noguchi, K. Org. Lett.
2005, 7, 3119. (c) Tanaka, K.; Wada, A.; Noguchi, K. Org.
Lett. 2005, 7, 4737. (d) Nishida, G.; Suzuki, N.; Noguchi,
K.; Tanaka, K. Org. Lett. 2006, 8, 3489. (e) Tanaka, K.;
Suda, T.; Noguchi, K.; Hirano, M. J. Org. Chem. 2007, 72,
2243. (f) Nishida, G.; Noguchi, K.; Hirano, M.; Tanaka, K.
Angew. Chem. Int. Ed. 2007, 46, 3951. (g) Tanaka, K.;
Otake, Y.; Wada, A.; Hirano, M. Org. Lett. 2007, 9, 2203.
(9) For the enantioselective synthesis of axially chiral spiranes,
see: Wada, A.; Noguchi, K.; Hirano, M.; Tanaka, K. Org.
Lett. 2007, 9, 1295.
(10) For the synthesis of cyclophanes, see: (a) Tanaka, K.;
Toyoda, K.; Wada, A.; Shirasaka, K.; Hirano, M. Chem. Eur.
J. 2005, 11, 1145. (b) Tanaka, K.; Sagae, H.; Toyoda, K.;
Noguchi, K. Eur. J. Org. Chem. 2006, 3575. For
enantioselective synthesisof planar-chiral metacyclophanes,
see: (c) Tanaka, K.; Sagae, H.; Toyoda, K.; Noguchi, K.;
Hirano, M. J. Am. Chem. Soc. 2007, 129, 1522.
(11) For the enantioselective construction of central chiralities,
see: (a) Tanaka, K.; Wada, A.; Noguchi, K. Org. Lett. 2006,
8, 907. (b) Tanaka, K.; Suzuki, N.; Nishida, G. Eur. J. Org.
Chem. 2006, 3917. (c) Tanaka, K.; Osaka, T.; Noguchi, K.;
Hirano, M. Org. Lett. 2007, 9, 1307. (d) Tanaka, K.;
Nishida, G.; Sagae, H.; Hirano, M. Synlett 2007, 1426.
(12) Tanaka, K.; Takeishi, K.; Noguchi, K. J. Am. Chem. Soc.
2006, 128, 4586.
(13) Stang, P. J. In Modern Acetylene Chemistry; Stang, P. J.;
Diederich, F., Eds.; Wiley-VCH: Weinheim, 1995, 67.
(14) Martinez-Esperón, M. F.; Rodriguez, D.; Castedo, L.; Saá,
C. Org. Lett. 2005, 7, 2213.
(15) 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.
(16) For the RhCl(PPh3)3-catalyzed [2+2+2] cycloadditions of
ynamides leading to amide-substituted chiral biaryls, see:
Tracey, M. R.; Oppenheimer, J.; Hsung, R. P. J. Org. Chem.
2006, 71, 8629.
(17) For the RhCl(PPh3) 3-catalyzed [2+2+2] cycloadditions of
ynamides for the synthesis of nitrogen heterocycles, see:
(a) Witulski, B.; Stengel, T. Angew. Chem. Int. Ed. 1999, 38,
2426. (b) Witulski, B.; Alayrac, C. Angew. Chem. Int. Ed.
2002, 41, 3281.
13C NMR (75 MHz, CDCl3): d = 172.6, 172.1, 172.0, 169.8, 169.0,
146.3, 145.3, 143.1, 142.9, 141.6, 141.5, 139.5, 139.0, 138.8, 138.2,
137.7, 136.6, 136.1, 135.6, 130.3, 130.0, 129.8, 129.3, 129.0, 128.2,
128.0, 127.9, 127.4, 125.0, 124.4, 124.3, 123.9, 58.9, 53.1, 40.7,
40.5, 40.2, 21.0, 20.3, 15.3, 15.1, 2.2.
HRMS (ESI): m/z [M + Na]+ calcd for C31H35NO5Si + Na:
552.2182; found: 552.2241.
Acknowledgment
Support of this work by Asahi Glass Foundation and a Grant-in-Aid
for Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan is gratefully acknowledged.
Gift of chiral ligands from Takasago International Corporation is
also gratefully acknowledged. We thank Prof. K. Noguchi for the
X-ray crystallographic analysis.
References
(1) For the pioneering work on axially chiral N-substituted
ortho-tert-butyl anilides, see: Curran, D. P.; Qi, H.; Geib, S.
J.; DeMello, N. C. J. Am. Chem. Soc. 1994, 116, 3131.
(2) For the synthesis of axially chiral anilides, see:
(a) Kitagawa, O.; Izawa, H.; Sato, K.; Dobashi, A.; Taguchi,
T.; Shiro, M. J. Org. Chem. 1998, 63, 2634. (b) Hughes, A.
D.; Price, D. A.; Simpkins, N. S. J. Chem. Soc., Perkin
Trans. 1 1999, 1295. (c) Kondo, K.; Fujita, H.; Suzuki, T.;
Murakami, Y. Tetrahedron Lett. 1999, 40, 5577. (d) Ates,
A.; Curran, D. P. J. Am. Chem. Soc. 2001, 123, 5130.
(3) For the asymmetric synthesis of axially chiral anilides
through enantiotopic deprotonation, see: (a) Hata, T.;
Koide, H.; Taniguchi, N.; Uemura, M. Org. Lett. 2000, 2,
1907. (b) Koide, H.; Hata, T.; Yoshihara, K.; Kamikawa, K.;
Uemura, M. Tetrahedron 2004, 60, 4527. (c) Bennett, D. J.;
Pickering, P. L.; Simpkins, N. S. Chem. Commun. 2004,
1392.
(4) For the stereoselective synthesis of axially chiral N-aryl
indoles, see: Kamikawa, K.; Kinoshita, S.; Matsuzaka, H.;
Uemura, M. Org. Lett. 2006, 8, 1097.
(5) (a) Kitagawa, O.; Kohriyama, M.; Taguchi, T. J. Org. Chem.
2002, 67, 8682. (b) Terauchi, J.; Curran, D. P. Tetrahedron:
Asymmetry 2003, 14, 587.
(6) (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.;
Synthesis 2007, No. 18, 2920–2923 © Thieme Stuttgart · New York