Group 11 metal amide-catalyzed asymmetric cycloaddition reactions of azomethine imines with terminal alkynes

Article abstract of DOI:10.1021/ja311150n

We developed a 1,3-dipolar cycloaddition reaction of azomethine imines with terminal alkynes catalyzed by group 11 metal amides to provide N,N-bicyclic pyrazolidinone derivatives. This reaction afforded the cycloadducts in a unique 5,7-disubstituted manner. Furthermore, we succeeded in applying this catalysis to asymmetric reactions, and the desired heterocycles were produced in high yields with exclusive regioselectivity and high enantioselectivity. Mechanistic studies elucidated a stepwise reaction pathway and critical features that determine the regioselectivity.

Full text of DOI:10.1021/ja311150n

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Communication
Group 11 Metal Amide-Catalyzed Asymmetric Cycloaddition
Reactions of Azomethine Imines with Terminal Alkynes
Takaki Imaizumi, Yasuhiro Yamashita, and Shu Kobayashi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja311150n • Publication Date (Web): 29 Nov 2012
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Group 11 Metal Amide-Catalyzed Asymmetric Cycloaddition
Reactions of Azomethine Imines with Terminal Alkynes
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_
Takaki Imaizumi, Yasuhiro Yamashita, and Shu Kobayashi*
Department of Chemistry, School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
KEYWORDS Metal amide, 1,3-Dipolar cycloaddition, Azomethine imine, Asymmetric catalysis
Supporting Information Placeholder
Scheme 1. General Scheme of Reactions of Azomethine
Imines with Terminal Alkynes
ABSTRACT: We developed 1,3-dipolar cycloaddition reac-
tions of azomethine imines with terminal alkynes catalyzed by
group 11 metal amides to provide N,N-bicyclic pyrazolidinone
derivatives. This reaction afforded the cycloadducts in a
unique 5,7-disubstituted manner. Furthermore, we succeeded
in applying this catalysis to asymmetric reactions, and the
desired heterocycles were produced in high yields with exclu-
sive regioselectivity and high enantioselectivity. Mechanistic
studies elucidated a stepwise reaction pathway and critical
features that determine the regioselectivity.
Metal and metalloid catalysts have attracted great interest in
the field of acid/base catalysis in the past two decades.1
Among the various acid/base catalysts that have been inten-
sively studied, Lewis acid catalysts have displayed unique
reactivity and selectivities, especially enantioselectivity.2
These catalysts have often been used for carbon–carbon bond-
forming reactions via proton transfer, which usually start from
carbanion formations using catalytic amounts of bases.3 In
many cases, external bases were employed in the presence of
Lewis acid catalysts, causing available Lewis acids to be lim-
ited because the Lewis acids should be base compatible in this
situation. Moreover, the range of substrates for the reactions
is reasonably dependent upon the basicity of the employed
bases. We envisioned that a more effective and general cata-
lytic system would be produced if metal catalysts that have
both Lewis acidic and strong Brønsted basic characters were
developed.4 As such a metal catalyst, our group recently re-
ported silver amide, which promotes the 1,3-dipolar cycload-
dition of azomethine ylides to alkenes affording pyrrolidine
derivatives in high yields with high diastereo- and enantiose-
lectivity.5 Proton transfer reactions using highly Brønsted
basic catalysts have been recognized to be difficult, because
the conjugate acids display very high pKa values. However,
silver amide can realize an effective catalytic cycle under these
conditions.
The synthesis of heterocycles is of great importance because
of their various applications as pharmaceutical, agricultural,
and engineering materials.6 Among the numerous methods for
the preparation of heterocycles, 1,3-dipolar cycloaddition reac-
tions have played important roles because various kinds of
heterocyclic compounds can be synthesized by the combina-
tion of 1,3-dipoles and dipolarophiles.7 1,3-Dipolar cycloaddi-
tions of azomethine imines 1 derived from 3-pyrazolidinone to
terminal alkynes 2 afford five-membered ring structures con-
taining nitrogen–nitrogen bonds, which are typical motifs
found in biologically active compounds.8,9 However, to our
knowledge, there had been no report on an asymmetric variant
of this reaction before Fu’s article.9b Fu et al. described cy-
cloadditions of N,N-cyclic azomethine imines 1 to terminal
alkynes catalyzed by a copper(I)–phosphaferrocene complex
to afford 5,6-disubstituted bicycle compounds 4 with high
enantioselectivity. However, there has been no report of high-
ly regioselective reactions affording 5,7-disubstituted products
3.
In an initial investigation, the reaction of azomethine imine
1a with phenyl acetylene 2a was examined (Table 1). In the
presence of 10 mol% of silver bis(trimethylsilyl)amide
(AgHMDS), the reaction proceeded slowly at 20 °C to afford
the 1,2-adduct 5aa alone in poor yield (8%, entry 1). When
the reaction temperature was increased to 40 °C, the reaction
proceeded smoothly even at a lower concentration, providing a
mixture of the 1,2-adduct 5aa and cycloadduct 3aa (ca. 1:1,
entry 2). Interestingly, the regioselectivity of the cycloadduct
was the reverse of that of the previously reported reaction, and
5,7-disubstituted adduct 3aa was obtained exclusively. It is
noteworthy that this is the first known example of the regiose-
Group 11 metals are well known for their specific ability to
coordinate with carbon–carbon multiple bonds to generate π-
complexes. We therefore focused on the cooperative activa-
tion of terminal alkynes using Lewis acidity and Brønsted
basicity of group 11 metal amides to generate active acetylide
species. Herein, we describe 1,3-dipolar cycloaddition reac-
tions of azomethine imines with terminal alkynes catalyzed by
group 11 metal amides, silver amide and copper amide, in
which acetylide formation is a key step (Scheme 1).
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(0.040 mmol), rac-BINAP (0.040 mmol), and MS 5A (50 mg) in
THF (2 mL) at 40 °C for 24 h.
lective synthesis of the regioisomer 3aa. We then tested other
1
2
3
4
5
6
7
8
solvents, but the results were not promising (entries 3, 4).
Furthermore, no product was obtained by using a less basic
silver source (AgOAc, entry 5), and even the combination of
AgOTf and an external base (DBU or KOtBu) showed lower
reactivity, and no cyclized product was obtained (entries 6 and
7). Stronger basicity of AgHMDS was found to be essential
for this cyclization. The addition of molecular sieves (MS) 5A
and a decrease in the amount of the alkyne gave the cycload-
duct 3aa almost exclusively in high yield (92%, 99/1, entry 9).
We have revealed that the scope of substrates is broad for
substituents on the aromatic rings of both azomethine imines
and phenyl acetylenes (Table 2). Electron-donating substitu-
ents (para-methyl or -methoxy) and electron-withdrawing
substituents (para-chloro) on the azomethine imine part did
not affect the reactivity or regioselectivity (entries 2–4). Steric
bulkiness of the aromatic ring was tolerated for this cycliza-
tion (entry 5). With respect to substituents on phenyl acety-
lenes, various electronic and steric characters could not de-
crease the reactivity or selectivity (entries 6–9), although in
the previous report, electron-rich terminal alkynes required a
longer reaction time because of low reactivity.9b
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Table 1. 1,3-Dipolar Cycloaddition of Azomethine Imine 1a
to Alkyne 2a Using a Silver Catalysta
En-
try
Temp.
(°C)
Yield
(%)
Having established the exclusive regioselective reaction
conditions for silver amide-catalyzed cyclization of the azo-
methine imine 1 and terminal alkyne 2, we turned our atten-
tion to asymmetric catalysis (Table 3). Unfortunately, despite
the intensive screening of ligands, chiral AgHMDS displayed
poor enantioselectivity (24% ee, entry 1). Therefore, we
switched to copper amide catalysis. The desired heterocycle
was produced with moderate enantioselectivity in the presence
of 10 mol% of CuHMDS10 and (S)-BINAP (50% ee, entry
2).11 More sterically bulky BINAP ligands, namely tol-
BINAP and xylyl-BINAP, afforded the desired products with
higher enantioselectivity than that with BINAP (entries 3 and
4). (S)-DIP-BINAP led to the cycloaddition in high yield with
good enantioselectivity and exclusive regioselectivity (entry
5). Finally, the desired adduct 3aa was obtained exclusively
in 97% yield with 90% ee, when cyclopentyl methyl ether
(CPME) was used as the solvent (entry 6).12
Solv.
Conc. (M)
3aa/5aa
1
THF
THF
Et2O
20
40
40
0.4
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
8
<1/>99
45/55
42/58
<1/>99
–
2
97
87
32
n.r.
55
23
90
92
3
4
Toluene 40
5b
6c
7d
8e
9e,f
THF
THF
THF
THF
THF
40
40
40
40
40
<1/>99
<1/>99
82/18
99/1
aReaction conditions: The reaction of azomethine imine 1a
(R1=Ph, 0.40 mmol) with phenyl acetylene 2a (R2=Ph, 0.80
mmol) was conducted using AgHMDS (0.040 mmol) and rac-
BINAP (0.040 mmol) for 24 h. bAgOAc was used instead of
AgHMDS. cAgOTf and DBU were used instead of AgHMDS.
dAgOTf and KOtBu were used instead of AgHMDS eMS 5A (50
Table 3. Asymmetric 1,3-Dipolar Cycloaddition Reaction of
Azomethine 1a Imine with Terminal Alkyne 2aa
f
mg) was used. 2a (0.44 mmol) was used.
En-
try
M
Ligand
Yield
(%)
3aa/5aa ee (%,
3aa)
Table 2. Substrate Scope: Azomethine Imine and Alkynea
1
2
3
4
Ag (S)-BINAP
95
96
94
93
99/1
24
50
57
60
Cu
Cu
Cu
(S)-BINAP
>99/<1
>99/<1
>99/<1
(S)-Tol-BINAP
(S)-Xylyl-
BINAP
En R1
try
R2
Yield
(%)
3/5
5
Cu
Cu
Cu
(S)-DIP-BINAP 93
(S)-DIP-BINAP 97
(S)-DIP-BINAP 94
>99/<1
>99/<1
>99/<1
83
90
90
6b
7b,c
1
2
3
4
5
6
Ph (1a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
92
98
84
92
96
90
99/1
aReaction conditions: The reaction of azomethine imine 1a (0.40
mmol) with phenyl acetylene 2a (0.44 mmol) was conducted us-
ing metal HMDS (0.040 mmol), a ligand (0.040 mmol), and MS
5A (50 mg) in THF at 40 °C (2 mL) for 24 h. bCPME was used as
the solvent. c2a was added slowly over 16 h.
p-MeC6H4 (1b)
p-MeOC6H4 (1c)
p-ClC6H4 (1d)
1-Nap (1e)
>99/<1
>99/<1
>99/<1
>99/<1
>99/<1
Wide substrate scope was confirmed in the chiral CuHMDS-
catalyzed cycloaddition. With respect to the imine portions of
the azomethine imines, the reaction tolerated electron-
deficient and -rich aryl, alkenyl, and alkyl groups on the car-
bonyl carbons, furnishing the products in high yields with high
enantioselectivity (Table 4, entries 1–9). With regard to ter-
minal alkynes, the reactions proceeded cleanly by employing
alkynes with electron-deficient and electron-rich aromatic,
alkyl, silyl, and protected alcohol groups (entries 10–17).
Ph (1a)
p-MeC6H4
(2b)
7
Ph (1a)
p-MeOC6H4
(2c)
88
>99/<1
8
9
Ph (1a)
Ph (1a)
p-ClC6H4 (2d) 93
>99/<1
>99/<1
p-FC6H4 (2e) 96
aReaction conditions: The reaction of azomethine imine 1 (0.40
mmol) with alkyne 2 (0.44 mmol) was conducted using AgHMDS
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(2b)
For better understanding of the reaction mechanism, several
1
2
3
4
5
6
7
8
experiments were conducted. As we described above, the 1,2-
adduct 5aa was produced in the reaction of azomethine imine
1a with terminal alkyne 2a. It was confirmed that when 5aa
was treated under the reaction conditions, the cycloadduct 3aa
was obtained quantitatively (Scheme 2). In addition, the ee
values of 5aa and 3aa were almost identical under the said
conditions even using racemic ligands. On the other hand, this
transformation did not proceed without the transition metals.
Furthermore, we investigated the use of isolated copper acety-
lide. We employed a catalytic amount of copper acetylide
species instead of the metal amides in this reaction, and found
that the reactivity decreased slightly without loss of enantiose-
lectivity. When hexamethyldisilazane was added to this reac-
tion system, the reactivity was recovered.13 These results indi-
cate that the conjugate acid of the metal HMDS played an
important role in the catalytic cycle. Therefore, it was pro-
posed that the cyclized compounds were produced not via a
concerted pathway as proposed in previous reports,9 but via a
stepwise reaction mechanism: 1,2-addition of metal acetylides
to azomethine imines took place, followed by intramolecular
cyclization with alkynes activated by Lewis acid (Scheme 3).
The Lewis acidity of the metal amides was utilized for activa-
tion of carbon–carbon multiple bonds in both formation of
metal acetylides and intramolecular cyclization. It is noted
that basic reaction conditions, in which no active proton
source exists, effectively promoted the intramolecular cycliza-
tion. The conjugate acids of the bases with less Brønsted ba-
11 Ph (1a)
p-MeOC6H4
(2c)
88
>99/<1
88
12 Ph (1a)
13 Ph (1a)
14 Ph (1a)
15 Ph (1a)
16 Ph (1a)
17 Ph (1a)
p-ClC6H4 (2d) 93
>99/<1
>99/<1
>99/<1
>99/<1
>99/<1
>99/<1
90
91
90
88
93
82
p-FC6H4 (2e)
nBu (2f)
cHex (2g)
96
88
90
92
83
TESb (2h)
9
CH2OBn (2i)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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60
aReaction conditions: The reaction of azomethine imine 1 (0.40
mmol) with alkyne 2 (0.44 mmol) was conducted using CuHMDS
(0.040 mmol), (S)-DIP-BINAP (0.040 mmol), and MS 5A (50
mg) in CPME (2 mL) at 40 °C for 24 h. 2 was added slowly over
16 h. bTES = Triethylsilyl.
Scheme 2. Transformation of the 1,2-Adduct to the Cycload-
duct
Scheme 3. Proposed Catalyst Cycle
t
sicity (DBUH+, BuOH) could protonate the alkynylated in-
termediate and inhibit intramolecular cyclization (Table 1,
entries 5 and 6). This proposed pathway can also explain the
unique regioselectivity of the products.
Table 4. Reaction Scope for Asymmetric Reaction: Azome-
thine Imine and Alkynea
Finally, it was interesting to find that the regioselectivity
was changed by the ligands employed (Table 5). Complete
reversal of the regioselectivity was observed by using the bi-
soxazoline (Box)-type ligand and 2,2′-bipyridyl ligand (entries
2 and 3). Three types of BIPHEP-type ligands 6–8 were also
employed in this reaction to examine the steric and electronic
effects of ligands on the regioselectivity. BIPHEP 6 produced
a mixture of two regioisomers with 3aa/4aa = 84/16 (entry 4).
By contrast, the sterically less bulky BIPHEP analogue 7 led
to the reverse ratio of 3aa/4aa = 22/78 (entry 5). When
En R1
try
R2
Yield
(%)
3/5
ee
(%, 3)
1
2
Ph (1a)
Ph (2a)
Ph (2a)
92
98
99/1
90
92
p-MeC6H4
(1b)
>99/<1
3
4
5
p-MeOC6H4 Ph (2a)
(1c)
84
92
96
>99/<1
>99/<1
>99/<1
93
88
90
p-ClC6H4
(1d)
Ph (2a)
N,N,N′,N′-tetraphenyl-2,2′-diaminobiphenyl ligand
8
(N-
analogue of BIPHEP) was used, the reaction proceeded
smoothly to afford the cycloaddition products in high yield
with 3aa/4aa = 73/27 regioselectivity (entry 6). These results
indicate that the steric character of the ligands has much more
influence on the regioselectivity than the type of atom coordi-
nating to the metal.
p-CNC6H4
(1f)
Ph (2a)
6
7
1-Nap (1e)
Ph (2a)
Ph (2a)
87
88
>99/<1
>99/<1
93
89
PhCH=CH
(1g)
8
9
nPr (1h)
cHex (1i)
Ph (2a)
92
94
90
>99/<1
>99/<1
>99/<1
92
95
87
Table 5. Effect of the Ligands on Regioselectivitya
Ph (2a)
10 Ph (1a)
p-MeC6H4
Entry Ligand
Yield (%)
3aa/4aa
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[4] a) Rowlands, G. J. Tetrahedron 2011, 57, 18651882; b) Shiba-
saki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187-2210; c) Ma, J.-
1
2
3
4
5
6
(S)-BINAP
96
>99/<1
<1/>99
<1/>99
86/14
1
2
3
4
5
6
7
8
(S,S)-Box
>99
>99
>99
>99
98
A.; Cahard, D. Angew. Chem. Int. Ed. 2004, 43, 4566-4583. Repre-
sentative works; d) Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem.
Soc. 1986, 108, 6405-6406; e) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.;
Shibasaki, M. J. Am. Chem. Soc. 1992, 114, 4418-4420; f) Yamada,
Y. M. A.; Yoshikawa, N.; Ohshima, T.; Shibasaki, M. Angew. Chem.
Int. Ed. 1997, 36, 1871-1873; g) Trost, B. M.; Ito, H. J. Am. Chem.
Soc. 2000, 122, 12003-12004; h) Kumagai, N.; Matsunaga, S.; Yoshi-
kawa, T.; Ohshima, T.; Shibasaki, M. Org. Lett. 2001, 3, 1539-1542.
[5] a) Yamashita, Y.; Guo, X.-X.; Takashita, R.; Kobayashi, S. J.
Am. Chem. Soc. 2010, 132, 3262-3263; b) Yamashita, Y.; Imaizumi,
T.; Guo, X.-X.; Kobayashi, S. Chem. Asian J. 2011, 6, 2550-2559; c)
Yamashita, Y.; Imaizumi, T.; Kobayashi, S. Angew. Chem. Int. Ed.
2011, 50, 4893-4896.
[6] a) Sisko, J.; Henry, J. R.; Weinreb, S. M. J. Org. Chem. 1993,
58, 4945-4951; b) Kolodziej, S. A.; Nikiforovich, G. V.; Skeean, R.;
Lignon, M. F.; Martinez, J.; Marshall, G. R. J. Med. Chem. 1995, 38,
137-149; c) Waid, P. P.; Flynn, G. A.; Huber, E. W.; Sabol J. S. Tet-
rahedron Lett. 1996, 37, 4091-4094; d) Bianco, A.; Maggini, M.;
Scorrano, G.; Toniolo, C.; Marconi, G.; Villani, C.; Rrato M. J. Am.
Chem. Soc. 1996, 118, 4072-40080; e) Pearson, W. H. in Studies in
Natural Product Chemistry, Vol .1 (Ed.: Atta-Ur-Rahman), Elsevier,
New York, 1998, p. 323; f) Overman, L. E.; Tellew, J. E. J. Org.
Chem. 1996, 61, 8338-8340; g) Alvarez-Ibarra C.; Csaky, A. G.; Lu-
pez, I.; Quiroga, M. L. J. Org. Chem. 1996, 61, 8338-8340; h)
Denhart, D. J.; Griffith, D. A.; Heathcock, C. H. J. Org. Chem. 1998,
63, 9616-9617; i) Obst, U.; Betschmann, P.; Lerner, C.; Seiler, P.;
Diederich, F. Helv. Chim. Acta 2000, 83, 855-909; j) Sebahar, P. R.;
Williams, R. M. J. Am. Chem. Soc. 2000, 122, 5666-5667.
[7] For recent reviews on catalytic asymmetric [3+2] cycloaddi-
tions, see: a) Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products (Ed.: Padwa,
A.; Pearson, W. H.), Wiley, New York, 2002; b) Gothelf, K. V.;
Jørgensen, K. A. Chem. Rev. 1998, 98, 865-910; d) Pandy, G.;
Banerjee, P.; Gadre, S. R. Chem. Rev. 2006, 106, 4484-4517; e)
Pellissier, H. Tetrahedron 2007, 63, 3235-3285; f) Stanley, L. M.;
Sibi, M. P. Chem. Rev. 2008, 108, 2887-2902;
[8] a) Jungheim, L. N.; Sigmund, S. K. J. Org. Chem. 1987, 52,
4007-4013; b) Jungheim, L. N.; Sigmund, S. K.; Fisher, J. W. Tetra-
hedron Lett. 1987, 28, 285-288; c) Jungheim, L. M.; Sigmund, S. K.;
Jones, N. D.; Swartzendruber, J. K. Tetrahedron Lett. 1987, 28, 289-
292; d) Indelicato, J. M.; Pasini, C. E. J. Med. Chem. 1988, 31, 1227-
1230.
[9] a) Turk, C.; Steve, J.; Golic, L.; Gradadnik, S. G.; Golobic, A.;
Selic, L. Helv. Chem. Acta 2001, 84, 146-156; b) Shintani, R.; Fu G.
C. J. Am. Chem. Soc. 2003, 125, 10778-1-10779; c) Chen, W.; Du,
W.; Yang, S.-Y.; Chen Y.-C. Angew. Chem. Int. Ed. 2007, 46, 7667-
7670; d) Sibi, M. P.; Rane, D.; Stanley, L. M.; Soeta, T. Org. Lett.
2008, 10, 2971-2074; e) Keller, M.; Sido, A. S. S.; Pale, P.; Sommer
J. Chem. Eur. J. 2009, 15, 2810-2817; f) Tanaka, K.; Kato, T.; Fujin-
ami, S.; Ukaji, Y.; Inomata, K. Chem. Lett. 2010, 39, 1036-1038; g)
Suga, H.; Arikawa, T.; Itoh, K.; Okumura, Y.; Kakehi, A.; Shiro, M.
Heterocycles, 2010, 81, 1669-1688; h) Oishi, T.; Yoshimura, K.;
Yamaguchi, K.; Mizuno N. Chem. Lett. 2010, 39, 1086-1087; i) Yo-
shimura, K.; Oishi, T.; Yamaguchi, K.; Mizuno N. Chem. Eur. J.
2011, 17, 3827-3831.
[10] a) Miele, P.; Foulon, J. D.; Hovnanian, N.; Durand, J.; Cot, L.
Eur. J. Inorg. Solid State Chem., 1992, 29, 573-579; b) James, A. M.;
Laxman, R. K.; Fronczek, F. R.; Maverick, A. W. Inorg. Chem.,
1998, 37, 3785-3791.
[11] To the best of our knowledge, this is the first example of reac-
tions (not only asymmetric reactions but also racemic reactions) using
CuHMDS as a catalyst. We have also found that chiral CuHMDS is
an excellent catalyst for asymmetric Mannich-type reactions.
[12] The absolute configuration of the product 3aa was determined
to be S. Details are shown in Supporting Information.
2,2′-Bipyridine
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aReaction conditions: The reaction of azomethine imine 1a (0.40
mmol) with alkyne 2a (0.44 mmol) was conducted using
CuHMDS (0.040 mmol), a ligand (0.040 mmol), and MS 5A (50
mg) in CPME (2 mL) at 40 °C for 24 h. 2a was added slowly
over 16 h.
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In conclusion, we have developed silver amide-catalyzed cy-
cloaddition reactions of azomethine imines 1 with terminal
alkynes 2 to afford 5,7-disubstituted adducts 3 in high yields
with excellent selectivities. To our knowledge, this is the first
description of the synthesis of 5,7-disubstituted cycloadducts
with exclusive regioselectivity. We have also succeeded in
applying this catalysis to asymmetric reactions, and the de-
sired cycloadducts were obtained in high yields with high re-
gio- and enantioselectivity using CuHMDS and the DIP-
BINAP ligand. Mechanistic studies revealed that the reactions
proceeded via a stepwise pathway, and that the steric character
of the ligands controlled the reaction pathway to determine the
regioselectivity. Further investigations of the detailed reaction
mechanism and expansion of the scope of substrates are ongo-
ing.
ASSOCIATED CONTENT
Supporting Information
Mechanistic study and experimental details are available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
shu_kobayashi@chem.s.u-tokyo.ac.jp
ACKNOWLEDGMENT
This work was partially supported by a Grant-in-Aid for Scientific
Research from the Japan Society for the Promotion of Science
(JSPS), the Global COE Program (Chemistry Innovation through
Cooperation of Science and Engineering), the University of To-
kyo, and MEXT (Japan). T. I. thanks the JSPS Research Fellow-
ship for Young Scientists.
REFERENCES
[1] a) Heathcock, C. H. Comprehensive Organic Synthesis (Ed.:
Trost B. M.), Pergamon Press, Oxford, 1991, vol. 2, 133-179; b)
Rosini, G. Comprehensive Organic Synthesis (Ed.: Trost B. M.), Per-
gamon Press, Oxford, 1991, vol. 2, 321-340; c) Kleinman, E. F. Com-
prehensive Organic Synthesis (Ed.: Trost B. M.), Pergamon Press,
Oxford, 1991, vol. 2, 893-951; d) Jung, M. E. Comprehensive Organ-
ic Synthesis (Ed.: Trost B. M.), Pergamon Press, Oxford, 1991, vol. 4,
1-67.
[2] a) Lewis Acid Reagents: A Practical Approach (Ed.: Yamamoto
H.), Oxford, New York, 1999; b) Lewis Acid in Organic Synthesis
(Ed.: Yamamoto H.), Wiley-VCH, Weinheim, 2000; c) Acid Catalysis
in Modern Organic Synthesis (Eds.: Yamamoto H., Ishihara K.),
Wiley-VCH, Weinheim, 2008.
[13] See Supporting Information (Table S-1).
[3] Kobayashi, S.; Matsubara, R. Chem. Eur. J. 2009, 15, 10694-
10700.
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