Enantioselective 1,3-dipolar cycloaddition of azomethine imines with propioloylpyrazoles induced by chiral π-cation catalysts

Article abstract of DOI:10.1021/ja508441t

We developed 1,3-dipolar cycloadditions of azomethine imines with propioloylpyrazoles catalyzed by a chiral copper(II) complex of 3-(2-naphthyl)-L-alanine amide. The asymmetric environment created by intramolecular π - cation interaction and the N-alkyl group of the chiral ligand gives the corresponding adducts in high yields with excellent enantioselectivity. This is the first successful method for the catalytic enantioselective 1,3-dipolar cycloaddition of azomethine imines with internal alkyne derivatives to give fully substituted pyrazolines.

Full text of DOI:10.1021/ja508441t

Communication
pubs.acs.org/JACS
Enantioselective 1,3-Dipolar Cycloaddition of Azomethine Imines
with Propioloylpyrazoles Induced by Chiral π−Cation Catalysts
Masahiro Hori,† Akira Sakakura,*,‡ and Kazuaki Ishihara*,†,§
†Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8603, Japan
‡Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan
§Japan Science and Technology Agency (JST), CREST, Furo-cho, Chikusa, Nagoya 464-8603, Japan
S
* Supporting Information
ABSTRACT: We developed 1,3-dipolar cycloadditions of
azomethine imines with propioloylpyrazoles catalyzed by a
chiral copper(II) complex of 3-(2-naphthyl)-L-alanine
amide. The asymmetric environment created by intra-
molecular π−cation interaction and the N-alkyl group of
the chiral ligand gives the corresponding adducts in high
yields with excellent enantioselectivity. This is the first
successful method for the catalytic enantioselective 1,3-
dipolar cycloaddition of azomethine imines with internal
alkyne derivatives to give fully substituted pyrazolines.
Figure 1. Chiral π−cation catalysts 1·CuX2.
itrogen-containing five-membered heterocycles are core
N
structures that are found in many bioactive compounds.
For example, it has been reported that multisubstituted
pyrazolines show various useful bioactivities.1 Based on their
biological significance and potential as chiral building blocks,
the development of methods for the synthesis of these
heterocycles is an important issue.2 For the synthesis of chiral
pyrazolines, asymmetric 1,3-dipolar cycloaddition of azome-
thine imines with alkynes is one of the most powerful
methods.3
There are two methodologies for the 1,3-dipolar cyclo-
addition of azomethine imines with alkynes (Scheme 1): (1)
copper(I) acetylide-mediated cycloaddition4 and (2) Lewis
acid-catalyzed cycloaddition. In 2003, Fu reported the first
asymmetric CuI-catalyzed cycloaddition of azomethine imines
with terminal alkynes (method 1).4a Recently, Arai,4c,f
Kobayashi,4d and Maruoka4e also reported Cu(I) acetylide-
mediated enantioselective cycloaddition of azomethine imines.
Although these methods induce high enantioselectivity,
dipolarophiles are limited to terminal alkynes. In contrast,
Figure 2. Proposed exo- and endo-transition-state assemblies for the
reaction of 2a with 3a.
Lewis acid-catalyzed cycloaddition (method 2) could be applied
to not only terminal alkynes but also to internal alkynes, in
principal, so this method may be useful for the synthesis of fully
substituted pyrazolines. However, there have been no reports
on the asymmetric Lewis acid-catalyzed cycloaddition of
azomethine imines with internal alkynes.
Scheme 1. 1,3-Dipolar Cycloaddition of Azomethine Imines
with Alkynes
We previously reported that chiral π−cation catalyst 1b·
CuX2 (Figure 1) effectively promoted enantioselective cyclo-
additions with propioloylpyrazoles 3, such as the Diels−Alder
reaction, [2 + 2] cycloaddition and the 1,3-dipolar cyclo-
addition of nitrones.5−7 These cycloaddition reactions are
Received: August 18, 2014
Published: September 8, 2014
© 2014 American Chemical Society
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dx.doi.org/10.1021/ja508441t | J. Am. Chem. Soc. 2014, 136, 13198−13201

Journal of the American Chemical Society
Communication
Table 1. 1,3-Dipolar Cycloaddition of 2a with 3a Catalyzed
by 1·Cu(NTf2)2
Table 3. 1c·Cu(NTf2)2-Catalyzed 1,3-Dipolar Cycloaddition
a
a
of 2 with β-Substituted Propiolamide 3
entry
1 (R)
time (h)
yield (%)
ee (%)
entry
2
3 (R2)
time (h)
yield (%)
ee (%)
1
2
3
1a (c-C6H11)
1b (c-C5H9)
1c (c-C4H7)
1c (c-C4H7)
1c (c-C4H7)
1d (c-C3H5)
1e (i-C3H7)
1f (CH3)
26
43
73
96
95
94
98
95
92
82
54
86
95
95
94
93
60
73
1
2
2a
2a
2d
2a
2a
2d
2f
3b (ClCH2)
88
300
144
74
5, 89
6, 83
94
94
87
92
92
87
93
91
86
85
80
3c (MeOCH2)
3c (MeOCH2)
3d (MsOCH2)
3d (MsOCH2)
3d (MsOCH2)
3d (MsOCH2)
3d (MsOCH2)
3e (BzOCH2)
3f [(CH2O)2CH]
3g (PhthalNCH2)
b
2.5
24
3
7, 79
b
4
4
8, 92
c
c
5
192
10
5
48
8, 85
6
7
8
6
7
72
9, 99
43
48
10, 94
11, 95
12, 98
13, 98
14, 70
24
8
2i
24
a
9
2d
2a
2a
120
48
Reaction of 2a (1.1 equiv) with 3a (0.1 mmol) was conducted in the
presence of 1·Cu(NTf2)2 (30 mol %) and MS 4A (100 mg) in CH2Cl2
(1.2 mL). Reaction was conducted with 3a (0.3 mmol) in the
presence of 1c·Cu(NTf2)2 (10 mol %). Reaction was conducted with
3a (0.6 mmol) in the presence of 1c·Cu(NTf2)2 (2.5 mol %) in
CH2Cl2 (7.5 mL).
10
b
d
11
168
c
a
Reaction of 2 (1.1 equiv) with 3 (0.3 mmol) was conducted in the
presence of 1c·Cu(NTf2)2 (10 mol %) and MS 4A (100 mg) in
CH2Cl2 (1.2 mL). Reaction was conducted in the presence of 1c·
Cu(NTf2)2 (20 mol %). The reaction of 2a (1.1 equiv) with 3d (3
mmol) was conducted in the presence of 1c·Cu(NTf2)2 (10 mol %)
and MS 4A (0.5 g) in CH2Cl2 (12 mL). Reaction was conducted at
−20 °C.
b
c
Table 2. 1c·Cu(NTf2)2-Catalyzed 1,3-Dipolar Cycloaddition
of 2 with 3a
a
d
following transition-state assembly was proposed for the
present 1,3-dipolar cycloaddition (Figure 2). An efficient
asymmetric environment was created around the Cu(II) cation:
a 2-naphthyl group in 1b shielded the carbonyl Re face of
coordinated 3a through the intramolecular π−cation inter-
action that was supported by theoretical calculations.5b,e,10,11
Azomethine imine 2a would approach the Si face of the
coordinated 3a via the endo-TS (Figure 2B, n = 1), thus
avoiding steric repulsion between the N-cyclopentyl group of
1b and the phenyl group of 2a in exo-TS (Figure 2A) to give
(R)-4a as a major enantiomer. The steric interaction between
the N-cyclopentyl group of 1b and the ethylene group of 2a
may have decreased the reactivity.
entry
2 (R1)
4
time (h)
yield (%)
ee (%)
1
2
2b (2-MeOC6H4)
2c (3-MeOC6H4)
2c (3-MeOC6H4)
2d (4-MeOC6H4)
2e (4-NO2C6H4)
2f (4-BrC6H4)
4b
4c
4c
4d
4e
4f
69
4
80
93
89
87
94
91
94
83
98
88
91
93
90
90
93
95
87
90
b
3
9
4
5
6
7
8
9
24
66
21
48
122
25
2g (2-naphthyl)
2h (3-furyl)
4g
4h
4i
2i (PhCHCMe)
a
Therefore, we next investigated the N-alkyl group of ligand 1
to improve the reactivity and enantioselectivity. When the
reaction was conducted with 1a bearing an N-cyclohexyl group,
cycloadduct 4a was obtained with poor enantioselectivity (entry
1). On the other hand, the use of N-cyclobutyl and N-
cyclopropyl groups (ligands 1c and 1d) successfully improved
both the reactivity and enantioselectivity (entries 3 and 5).
Especially, the catalytic activity of 1c·Cu(NTf2)2 was high
enough to promote the reaction with a catalyst loading of 10
mol % (entry 4). Only 2.5 mol % of 1c·Cu(NTf2)2 successfully
promoted the reaction without any decrease of enantioselec-
tivity, albeit the reaction required rather long reaction time
(entry 5). The use of sterically less-hindered N-cycloalkyl
groups would successfully avoid steric repulsion with the
ethylene group of 2a (Figure 2B, n = 0). The N-isopropyl
group of 1e has steric hindrance similar to the N-cyclohexyl
group of 1a, which may be the reason why 1e showed low
enantioselectivity (entry 7). Ligand 1f bearing N-methyl group
also showed poor enantioselectivity (entry 8), probably because
steric repulsion between the N-methyl group and the phenyl
group of 2a in exo-TS was very weak, and the reaction
proceeded via both exo- and endo-TS.
Reaction of 2 (1.1 equiv) with 3a (0.3 mmol) was conducted in the
presence of 1c·Cu(NTf2)2 (10 mol %) and MS 4A (100 mg) in
CH2Cl2 (1.2 mL). Reaction of 2c (1.1 equiv) with 3a (3 mmol) was
conducted in the presence of 1c·Cu(NTf2)2 (10 mol %) and MS 4A
(0.5 g) in CH2Cl2 (12 mL).
b
highly useful for the enantioselective synthesis of bicyclic 2,5-
diene ligands, β-lactams, and so on. We report here a significant
expansion of the scope of the enantioselective cycloadditions
with alkynes: the 1,3-dipolar cycloaddition of azomethine
imines 2 with propioloylpyrazoles 3. To the best of our
knowledge, this is the first enantioselective 1,3-dipolar cyclo-
addition of azomethine imines with internal alkynes.
In an initial investigation, we performed the enantioselective
1,3-dipolar cycloaddition of azomethine imine 2a with
propioloylpyrazole 3a in CH2Cl2 at −40 °C in the presence
of MS 4A.8 However, the reaction required a long reaction time
and showed unsatisfactory enantioselectivity, even when 30 mol
% of 1b·Cu(NTf2)2 was used as a catalyst (Table 1, entry 2).
The absolute configuration of the major enantiomer of
cycloadduct 4a was determined to be R.9 Based on the
absolute configuration of 4a and the previous results, the
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Journal of the American Chemical Society
Communication
diamine 16 as a single diastereomer, which could be isolated as
cyclic urea 17 after the reaction with triphosgene13 (82% yield,
2 steps). The stereochemistry of three contiguous stereogenic
Scheme 2. Transformation of Cycloadducts 6 and 7
1
centers of 18 was determined to be (4R,5S,6S) by H NMR
analysis. Cycloadduct 12 was also converted to the correspond-
ing cyclic urea 18 (70% yield, 4 steps). Since the benzoyl group
of 12 was removed by the methanolysis, the primary hydroxy
group was protected by TBDPS group. Since the silyloxy and
the urea groups of 18 were unstable under Ru-catalyzed
oxidation, they were protected by acetyl group (71% yield, 2
steps). Oxidation of 4-methoxyphenyl group of 19, followed by
methyl esterification, gave the corresponding trimethyl ester 20
(77% yield, 2 steps). Since methoxycarbonyl and protected
hydroxymethyl groups can be converted to various functional
groups, cyclic ureas 17 and 20 should be useful building block.
Mesyloxymethyl group of 8 could be used for a carbon chain
elongation. For example, nucleophilic substitution14 of 8 with
allyl acetoacetate and allyl methyl malonate, followed by
decarboxylation,15 gave methyl ketone 21 and methyl ester 22
in respective yields of 78 and 66%. In addition, the reduction of
the mesyloxymethyl group of 8 gave 23 with the methyl group
(89% yield).
In conclusion, we have developed a catalytic enantioselective
1,3-dipolar cycloaddition reaction of azomethine imines with
propioloylpyrazoles using chiral π−cation catalysts. The
reaction with β-substituted propioloylpyrazoles gave fully
substituted pyrazolines in high yields with high enantioselectiv-
ities. The cycloadducts could be converted to 1,3-diamines with
three contiguous stereogenic centers.
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures and full characterization of
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
ishihara@cc.nagoya-u.ac.jp
sakakura@okayama-u.ac.jp
Notes
The authors declare no competing financial interest.
With the optimized π−cation catalyst in hand, we next
examined the reactions of various azomethine imines to explore
the generality and substrate scope of the present 1,3-dipolar
cycloaddition (Table 2). The reactions were conducted in the
presence of 1c·Cu(NTf2)2 (10 mol %) at −40 °C to give the
corresponding cycloadducts with high enantioselectivities. The
reaction tolerated both electron-donating and -withdrawing
groups on the phenyl, heteroaryl, and alkenyl groups (entries 1,
2 and 4−9). The large-scale reaction of 2c with 3a (3 mmol)
also gave 4c in 89% yield with 93% ee (entry 3).
The present cycloaddition was also effective for β-substituted
propioloylpyrazoles 3. The reaction of 2 with 3b−g proceeded
to give the corresponding fully substituted cycloadducts 5−14
in good to high yields with high enantioselectivity (Table 3). A
large-scale reaction with 3d (3 mmol) also gave 7 in 85% yield
with 92% ee (entry 5).
ACKNOWLEDGMENTS
■
Financial support for this project was provided by JSPS.KA-
KENHI (23350039) and Program for Leading Graduate
Schools “IGER program in Green Natural Sciences”, MEXT,
Japan.
REFERENCES
■
(1) For selected examples, see: (a) Jungheim, L. N.; Sigmund, S. K.;
Fisher, J. W. Tetrahedron Lett. 1987, 28, 285. (b) Boyd, D. B. J. Med.
Chem. 1993, 36, 1443. (c) Hanessian, S.; McNaughton-Smith, G.;
Lombart, H.-G.; Lubell, W. D. Tetrahedron 1997, 53, 12789. (d) Amr,
A. E. -G. E.; Abdel-Latif, N. A.; Abdalla, M. M. Bioorg. Med. Chem.
2006, 14, 373. (e) Amr, A. E.-G. E.; Mohamed, A. M.; Mohamed, S.
F.; Abdel-Hafez, N. A.; Hammam, A. E.-F. G. Bioorg. Med. Chem. 2006,
14, 5481. (f) Rostom, S. A. F. Bioorg. Med. Chem. 2006, 14, 6475.
(g) Sayyafi, M.; Soorki, A. A.; Bazgir, A. Chem. Pharm. Bull. 2008, 56,
1289. (h) Meyers, M. J.; Arhancet, G. B.; Hockerman, S. L.; Chen, X.;
Long, S. A.; Mahoney, M. W.; Rico, J. R.; Garland, D. J.; Blinn, J. R.;
Collines, J. T.; Yang, S.; Huang, H.-C.; McGee, K. F.; Wendling, J. M.;
Dietz, J. D.; Payne, M. A.; Homer, B. L.; Heron, M. I.; Reitz, D. B.; Hu,
The 1,3-dipolar cycloadducts 4−14 are useful compounds for
the synthesis of various nitrogen-containing chiral compounds.
For example, methanolysis of 6 gave the corresponding
dimethyl ester 15 in 86% yield (Scheme 2). Raney Ni-catalyzed
hydrogenation12 of 15 gave the corresponding chiral 1,3-
13200
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Communication
X. J. Med. Chem. 2010, 53, 5979. (i) Lee, M.; Brockway, O.; Dandavati,
A.; Tzou, S.; Sjoholm, R.; Satam, V.; Westbrook, C.; Mooberry, S. L.;
Zeller, M.; Babu, B.; Lee, M. Eur. J. Med. Chem. 2011, 46, 3099.
(j) Lam, K. W.; Tham, C. L.; Liew, C. Y.; Syahida, A.; Rahman, M. B.
A.; Israf, D. A.; Lajis, N. H. Med. Chem. Res. 2012, 21, 333. (k) Lam, K.
W.; Tham, C. L.; Liew, C. Y.; Syahida, A.; Rahman, M. B. A.; Israf, D.
A.; Lajis, N. H. Med. Chem. Res. 2012, 21, 333.
(2) For selected examples of asymmetric pyrazolines syntheses, see:
́ ̀
(a) Mahe, O.; Dez, I.; Levacher, V.; Briere, J.-F. Angew. Chem., Int. Ed.
2010, 49, 7072. (b) Suga, H.; Furihata, Y.; Sakamoto, A.; Itoh, K.;
Okumura, Y.; Tsuchida, T.; Kakehi, A.; Baba, T. J. Org. Chem. 2011,
76, 7377. (c) Campbell, N. R.; Sun, B.; Singh, R. P.; Deng, L. Adv.
Synth. Catal. 2011, 353, 3123. (d) Chen, J.-R.; Dong, W.-R.; Candy,
M.; Pan, F.-F.; Jorres, M.; Bolm, C. J. Am. Chem. Soc. 2012, 134, 6924.
̈
(e) Zhang, Z.; Wang, D.; Wei, Y.; Shi, M. Chem. Commun. 2012, 48,
́
9607. (f) Fernandez, M.; Reyes, E.; Vicario, J. L.; Badía, D.; Carrillo, L.
Adv. Synth. Catal. 2012, 354, 371. (g) Wang, G.; Liu, X.; Huang, T.;
Kuang, Y.; Lin, L.; Feng, X. Org. Lett. 2013, 15, 76. (h) Tripathi, C. B.;
Mukherjee, S. Org. Lett. 2014, 16, 3368.
(3) For reviews of asymmetric 1,3-dipolar cycloadditions, see:
(a) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863.
(b) Pellissier, H. Tetrahedron 2007, 63, 3235. (c) Stanley, L. M.; Sibi,
M. P. Chem. Rev. 2008, 108, 2887.
(4) (a) Shintani, R.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 10778.
́
(b) Suarez, A.; Downey, C. W.; Fu, G. C. J. Am. Chem. Soc. 2005, 127,
11244. (c) Arai, T.; Ogino, Y. Molecules 2012, 17, 6170. (d) Imaizumi,
T.; Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2012, 134, 20049.
(e) Hashimoto, T.; Takiguchi, Y.; Maruoka, K. J. Am. Chem. Soc. 2013,
135, 11473. (f) Arai, T.; Ogino, Y.; Sato, T. Chem. Commun. 2013, 49,
7776.
(5) (a) Ishihara, K.; Fushimi, M. Org. Lett. 2006, 8, 1921. (b) Ishihara,
K.; Fushimi, M.; Akakura, M. Acc. Chem. Res. 2007, 40, 1049.
(c) Ishihara, K.; Fushimi, M. J. Am. Chem. Soc. 2008, 130, 7532.
(d) Sakakura, A.; Hori, M.; Fushimi, M.; Ishihara, K. J. Am. Chem. Soc.
2010, 132, 15550. (e) Sakakura, A.; Ishihara, K. Chem. Soc. Rev. 2011,
40, 163.
(6) For a recent review of π−cation interaction, see: Mahadevi, A. S.;
Sastry, G. N. Chem. Rev. 2013, 113, 2100.
(7) For our contributions to n−cation catalysis, see: Sakakura, A.;
Kondo, R.; Matsumura, Y.; Akakura, M.; Ishihara, K. J. Am. Chem. Soc.
2009, 131, 17762.
(8) MS 4A activated 1·Cu(NTf2)2 and inhibited the hydrolysis of 3.
(9) See Supporting Information for details.
(10) The intramolecular π−cation interaction was observed in the
crystal structure of bis(L-tyrosinato)copper(II) complex. (a) Nasci-
mento, O. R.; Costa-Filho, A. J.; DeMorais, D. I.; Ellena, J.; Delboni, L.
F. Inorg. Chem. Acta 2001, 312, 133. (b) Costa-Filho, A. J.;
Nascimento, O. R.; Calvo, R. J. Phys. Chem. B 2004, 108, 9549.
(11) The spectral evidence for the π−cation interaction between
Cu2+ and tryptophan residue in peptides in aqueous solution was
reported. Yorita, H.; Otomo, K.; Hiramatsu, H.; Toyama, A.; Miura,
T.; Takeuchi, H. J. Am. Chem. Soc. 2008, 130, 15266.
(12) Koptelov, Y. B.; Saik, S. P. Russ. J. Org. Chem. 2006, 42, 1501.
(13) Hernan
Phys. Org. Chem. 2005, 18, 792.
́ ́
dez-Rodríguez, M.; Melgar-Fernandez, R.; Juaristi, E. J.
(14) (a) Takimoto, M.; Kawamura, M.; Mori, M.; Sato, Y. Synlett
2011, 1423. (b) Prashar, D.; Shi, Y.; Bandyopadhyay, D.; Dabrowiak, J.
C.; Luk, Y.-Y. Bioorg. Med. Chem. Lett. 2011, 21, 7421. (c) Teller, H.;
Corbet, M.; Mantilli, L.; Gopakumar, G.; Goddard, R.; Thiel, W.;
Furstner, A. J. Am. Chem. Soc. 2012, 134, 15331.
̈
(15) (a) Casy, G.; Taylor, R. J. K. J. Chem. Soc., Chem. Commun.
1988, 454. (b) Zhang, H.; Reddy, M. S.; Phoenix, S.; Deslongchamps,
P. Angew. Chem., Int. Ed. 2008, 47, 1272.
13201
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