A chiral cobalt(II) complex catalyzed asymmetric formal [3+2] cycloaddition for the synthesis of 1,2,4-triazolines

Article abstract of DOI:10.1039/c7cc01278k

A highly efficient catalytic asymmetric formal [3+2] cycloaddition reaction of 5-alkoxyoxazoles with azodicarboxylate compounds has been realized by a chiral N,N′-dioxide/Co(BF₄)₂·6H₂O complex. A series of poly-substituted 1,2,4-triazolines compounds were obtained in moderate to excellent yields (70-99%) with excellent enantioselectivities (82-98% ee).

Full text of DOI:10.1039/c7cc01278k

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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Chiral Cobalt(II) Complex Catalyzed Asymmetric Formal [3+2]
Cycloaddition to Synthesize 1,2,4-Triazolines
Received 00th January 20xx,
Accepted 00th January 20xx
Baiwei Ma, Weiwei Luo, Lili Lin, Xiaohua Liu* and Xiaoming Feng*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A highly efficient catalytic asymmetric formal [3+2] cycloaddition Suga,5a,b and Evans,5c respectively. Thus, realization of such a useful
reaction of 5-alkoxyoxazoles with azodicarboxylate compounds asymmetric formal [3+2] reaction to synthesize 1,2,4-trizaolines will
has been realized by a chiral N,N'-dioxide/Co(BF4)2.6H2O complex. be desirable. Herein, we report the application of chiral N,N’-
A series of poly-substituted 1,2,4-triazolines compounds were dioxide-Co(II) complex6 in the catalysis of formal [3+2] cycloaddition
obtained in moderate to excellent yields (70-99%) with excellent of azodicarboxylate with a variety of 5-alkoxyoxazoles under mild
enantioselectivities (82-98% ee).
reaction conditions.
Nitrogen-containing heterocycles are frequently found structural
motifs of pharmaceuticals and agrochemicals with various biological
functions and properties.1 Among the vast array of such
compounds, the saturated 1,2,4-triazolines remain underutilized
and their synthesis only attracts considerable attention recently.2
Especially, the asymmetric synthesis approach of 1,2,4-triazolines
compounds is very limited, only two asymmetric catalytic methods
have been reported. One convenient method for the synthesis of
1,2,4-triazolines with
a
quaternary C3 carbon containing
a
carboxylic acid functional
group was catalytic
a
hydrazination/cyclization cascade reaction of α-isocyano
esters/amides and azodicarboxylates (Scheme 1a).2i,3 The second
approach is related to 1,2,4-triazole derivatives with additional aryl
substituent at C5 carbon atom, initiated by a nucleophilic addition
of an azlactone to azodicarboxylate.2h The asymmetric version was
realized by the Huang group utilizing a cinchona alkaloid-derived
amine-amide organocatalyst (Scheme 1b).4 Nevertheless, the
heterocyclization was mediated by excessive TMSCHN2 and the
substrate scope was focus on alkyl-substitution at the quaternary
center and aryl-substitution at C5 carbon. Although ring opening of
oxazoles and formal [3+2] cycloaddition with azocompounds give
direct access to 1,2,4-triazoline derivatives,2a-d which has been
established early in 1988, none of the asymmetric version has been
described to date (Scheme 1c). Only a similar enantioselective
Aldol/cyclization process with 5-alkoxyoxazoles and aldehydes to
synthesize 2-oxazoline derivatives was reported by Ibata and
Scheme 1. Asymmetric catalytic synthesis of chiral 1,2,4-triazolines
The reaction of 5-methoxyoxazoles 1a with diethyl
azodicarboxylate 2a (DEAD) was carried out in the presence of
chiral N,N'-dioxide L-PrPr2 and various metal salts (Table 1, entries
1-4). The metal salt Co(BF4)2.6H2O could smoothly promote the
asymmetric formal [3+2] reaction process to afford 1,2,4-triazole
3aa with high reactivity and moderate enantioselectivity (97% yield
and 72% ee, entry 4). Other metal salts, such as Ni(OTf)2, Sc(OTf)3
and Zn(OTf)2 gave good to excellent yields but lower
enantioselectivities (entries 1-3). Owing to effect upon this
cycloaddition using chiral Lewis acid of N,N'-dioxide-promoted
conditions, we next alternated the substructures of N,N'-dioxides.
The influence of the chiral backbone of the N,N'-dioxide ligands on
this reaction was tested, and the L-proline derived L-PrPr2 exhibited
better enantioselectivity than the ones derived from L-pipecolic
acid and L-ramipril (72% ee vs. 64% and 65% ee, entry 4 vs. 5 and 6).
Next, several L-proline derived N,N'-dioxide ligands were
investigated (see the ESI for details), and only the ligand L-PrtBu
gave better enantioselectivity than L-PrPr2 (76% ee, entry 7).
a.Key Laboratory of Green Chemistry & Technology, Ministry of Education, College
of Chemistry, Sichuan University, Chengdu 610064, People’s Republic of China.
Fax: (+)86 28 85418249 E-mail: liuxh@scu.edu.cn; xmfeng@scu.edu.cn
† Footnotes relaꢀng to the ꢀtle and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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Table 1 Optimization of the reaction conditionsa
Table 2 Substrate scope of the asymmetric formal [3 +2] reactiona
Ph
CO2R
RO2C
CO2R
L/Metal salt
N
N
N
N
(1:1, 10 mol%)
+
Ph
OMe
N
CH2Cl2, 35 o
C
PMP
CO2R
N
O
MeO2C
PMP
2
1a
3aa: R = Et 3ac: R = Bn
3ab: R = tBu 3ad: R = iPr
2a: R = Et 2c: R = Bn
2b: R = tBu 2d: R = iPr
PMP = 4-MeOC6H4
m
Entry
1
2
3
4
5
6
7
8
R1
4-MeOC6H4
3-MeOC6H4
4-EtOC6H4
4-tBuC6H4
3,5-Me2C6H3
4-BrC6H4
4-FC6H4
Ph
2-naphthyl
2-furyl
2-thienyl
Me
n-pentyl
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
Ph
R2
Yield (%)b
99 (3ab)
99 (3bb)
99 (3cb)
99 (3db)
99 (3eb)
95 (3fb)
94 (3gb)
99 (3hb)
94 (3ib)
83 (3jb)
75 (3kb)
90 (3lb)
81 (3mb)
91 (3nb)
84 (3ob)
95 (3pb)
89 (3qb)
81 (3rb)
94 (3sb)
88 (3tb)
74 (3ub)
99 (3vb)
70 (3wb)
Trace (3xb)
75 (3xa)
99 (3yb)
Ee (%)c
95
96
94
97
98
92
93
95
95
91
89
92
89
83
89
87
82
96
95
96
94
95
92
--
m
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
n
N
O
N
O
N
N
O
O
O
O
N
N
O
O
Ar
Ar
H
H
N
N
H
Ar
H
Ar
L-PiPr2: Ar = 2,6-iPr2C6H3, m = 2, n =1
L-PrPr2: Ar = 2,6-iPr2C6H3, m = 1, n = 1
L-PrtBu: Ar = 2-tBuC6H4, m = 1, n = 1
L2-PrtBu: Ar = 2-tBuC6H4, m = 1, n = 0
L2-PrPr2: Ar = 2,6-iPr2C6H3, m = 1, n = 0
L2-PrpMe: Ar = 4-MeC6H4, m = 1, n = 0
L-RaPr2: Ar = 2,6-iPr2C6H3
9
10
11
12d
13d
14
15
16
17
18
19
20
21
22
23
24
25e
26
Entry
Ligand
Metal salts
R
Yield
(%)b
93
77
99
97
98
89
88
93
97
Ee
(%)c
49
3
1
2
3
4
5
L-PrPr2
L-PrPr2
L-PrPr2
L-PrPr2
L-PiPr2
L-RaPr2
L-PrtBu
L-PrtBu
L-PrtBu
L2-PrtBu
L2-PrPr2
L2-PrPr2
L2-PrPr2
L2-PrPr2
Zn(OTf)2
Sc(OTf)3
Ni(OTf)2
Et
Et
Et
Et
Et
48
72
64
65
76
82
88
93
95
37
49
81
Me
Et
Co(BF4)2.6H2O
Co(BF4)2.6H2O
Co(BF4)2.6H2O
Co(BF4)2.6H2O
Co(BF4)2.6H2O
Co(BF4)2.6H2O
Co(BF4)2.6H2O
Co(BF4)2.6H2O
Co(BF4)2.6H2O
Co(BF4)2.6H2O
Co(BF4)2.6H2O
iPr
6
7
Et
Et
4-BrC6H4
4-FC6H4
4-ClC6H4
4-MeOC6H4
4-MeC6H4
3-ClC6H4
2-ClC6H4
2-ClC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
8
tBu
tBu
tBu
tBu
Et
9d
10d
11d,e
12d,e
13d,e
94
99
81
76
Bn
iPr
87
94
14d,e
85
4-MeOC6H4
a
Unless otherwise noted, the reaction was performed with L/metal
salt (1:1, 10 mol%) and 2 (1.2 equiv) in CH2Cl2 (1.0 mL) at 35 oC for 0.5
h, then 1a (0.1 mmol) was added, the reaction mixture was stirred for
a
Unless otherwise noted, the reactions were performed with L2-PrPr2 (10
mol%), Co(BF4)2.6H2O (10 mol%), 1 (0.1 mmol) and 2b (1.2 equiv) in CH2Cl2
(1.0 mL) at 35 oC for 24 h (entries 1-25, R3 = Me; entry 26, R3 = Et). b Isolated
yield. c Determined by chiral HPLC analysis. d L2-PrpMe as the ligand instead
of L2-PrPr2. e 2a (DEAD) instead of 2b as an azodicarboxylate substrate and L-
PrtBu as the ligand.
20 h. Isolated yield. Determined by chiral HPLC analysis. d The
reaction was performed with L/metal (1:1, 10 mol%) in CH2Cl2 (1.0
mL) at 35 oC for 0.5 h, then 1a (0.1 mmol) and 2 (1.2 equiv) was
added, the reaction mixture was stirred for 20 h. e The reaction was
performed for 24 h.
b
c
substrates. The reactions of 5-methoxyoxazoles 1a-h bearing either
electron-donating or electron-withdrawing phenyl groups could
proceed smoothly, affording the corresponding 5-aryl substituted
1,2,4-triazolines 3ab-3hb in excellent yields (94-99%) and good
enantioselectivities (92-98% ee, entries 1-8). Next, we investigated
other aromatic type group R1 at C2 carbon of 5-methoxyoxazoles. 2-
Naphthyl substituted 5-methoxyoxazole 1i can also afford a good
result in 94% yield with 95% ee (entry 9), and hetero-aromatic
substituted ones 1j and 1k reacted with 2b to afford the related
1,2,4-triazolines with slightly decreased enantioselectivities and
yields (91% ee, 83% yield and 89% ee, 75% yield, respectively,
entries 10 and 11). In addition, when the type of substituent R1 at
C2 carbon of 5-methoxyoxazoles 1 was transformed into aliphatic
group, such as methyl or n-pentyl, 90% yield, 92% ee and 81% yield,
89% ee were obtained, respectively, in the condition of L2-PrPMe
instead of L2-PrPr2 as the ligand (entries 12 and 13).
However, using di-tert-butyl azodicarboxylate 2b instead of 2a as
the reaction substrate, the enantioselectivity of the corresponding
1,2,4-triazole 3ab increased to 82% ee (entry 8). Delightfully, subtle
change in experiment procedure resulted in a further increase in
enantioselectivity (97% yield, 88% ee, entry 9). To create more
compacted spatial arrangement, the linkage between the two
amine-oxides was shorten from three carbon to two carbon, and it
was found that N,N'-dioxide L2-PrtBu improved the
enantioselectivity to 93% ee (entry 10). Among several two-carbon-
linked N,N'-dioxides (see the ESI for details), L2-PrPr2 coordinated
with Co(BF4)2.6H2O afforded the corresponding product 3ab in 99%
yield and 95% ee (entry 11). Reactions conducted with other
azodicarboxylates bearing less steric hindrance resulted in lower
yields and ee values (entries 12-14).
Under the optimized reaction conditions (Table 1, entry 11), we
next evaluated the substrate scope of the reaction by varying
substituents of the 5-alkoxyoxazole derivatives 1. As shown in Table
2, a wide range of 5-alkoxyoxazoles with varied aryl or alkyl
substituents at C2 and C4 carbons were found to be excellent
Next, we began to investigate the effect of R2 substituent at C4
carbon of 5-methxoyoxazoles on the reaction. 2-(para-
Methoxyphenyl)-5-methoxyoxazoles with
a series of aliphatic
2 | J. Name., 2012, 00, 1-3
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groups at C4-position, including H, methyl, ethyl or isopropyl groups Foundation (141115) and National Program for Support of Top-
were converted to the related products 3nb-3qb in 84-95% yields notch Young Professionals for financial support.
and 82-89% ee in the standard condition (entries 14-17).
Subsequently, the effect of the substituent on 4-aryl group of 2-
Notes and references
phenyl-5-methoxyoxazoles upon this cycloaddition reaction was
1
For selected examples, see: (a) D. G. Hall, T. Rybak and T.
Verdelet, Acc. Chem. Res., 2016, 49, 2489; (b) R. D. Taylor, M.
MacCoss and A. D. G. Lawson, J. Med. Chem., 2014, 57, 5845;
(c) E. De Clercq, Med. Res. Rev., 2013, 33, 1278; (d) I. E.
Valverde, F. Lecaille, G. Lalmanach, V. Aucagne and A. F.
Delmas, Angew. Chem. Int. Ed., 2012, 51, 718; (e) P.Valentina,
investigated (entries 18-24). When halo-substituents or electron-
donating groups at para-position on the phenyl group of 1r-1v were
introduced, good results were obtained in 74-99% yields with 94-
96% ee (entries 18-22). However, the 3-chloro substituted substrate
1w can only afford 70% yield with slightly reduced
enantioselectivity (92% ee, entry 23). It is noteworthy that 2-chloro
substituted substrate 1x nearly cannot proceed with di-tert-butyl
azodicarboxylate 2b (entry 24), which was maybe caused by the
steric hindrance. Fortunately, when less steric hindered 2a (DEAD)
instead of 2b was used as the azodicarboxylate substrate and L-
PrtBu instead of L2-PrPr2 as a ligand, the reaction of 5-alkoxyoxazole
1x can afford the corresponding product 3xa with 75% yield and
87% ee (entry 25). At last, when R3 of 5-alkoxyoxazole was changed
into ethyl group, the desired product 3yb was generated with
comparable result with methyl substituted one (99% yield and 94%
ee, entry 26).
K. Ilango and M. K. Kathiravan, Arch. Pharm. Res., 2016, 39
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1382; (f) Q. Zhang, Y. Y. Peng, X. I. Wang, S. M. Keenan, S.
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3535; (c) T. Ibata, H. Suga, Y. Isogami, H. Tamura and X. Shi,
Bull. Chem. Soc. Jpn., 1992, 65, 2998; (d) X. Shi, T. Ibata, H.
Suga and K. Matsumoto, Bull. Chem. Soc. Jpn., 1992, 65, 3315;
(e) T. Kolasa and M. J. Miller, Tetrahedron Lett., 1988, 29
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4661; (f) D. J. Anderson and W. J. Watt, Heterocycl. Chem.
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Maeda, Heterocycles, 2001, 55, 243; (h) R. S. Z. Saleem and J.
J. Tepe, J. Org. Chem., 2010, 75, 4330; (i) D. Monge, K. L.
To show the utility of the current method, a gram-scale synthesis
of 1,2,4-triazoline 3ab was carried out. In the presence of 10 mol%
of the catalyst L2-PrPr2/Co(BF4)2, 5-methoxyoxazoles 1a (3 mmol)
reacted smoothly with azodicarboxylate 2b (3.6 mmol), affording
the product 3ab in 99% yield and 94% ee (Scheme 2). Moreover,
the absolute configuration of the product 3ab was determined to
be R by X-ray single crystal analysis (see the ESI for details).7
Jensen, I. Marín and K. A. Jørgensen, Org. Lett., 2011, 13, 328.
3
(a) M. Wang, X. H. Liu, P. He, L. L. Lin and X. M. Feng, Chem.
Commun., 2013, 49, 2572; (b) M. X. Zhao, H. L. Bi, H. Zhou, H.
Yang and M. Shi, J. Org. Chem., 2013, 78, 9377.
Q. Shao, J. A. Chen, M. H. Tu, D. W. Piotrowski and Y. Huang,
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(a) H. Suga, K. Ikai and T. Ibata, Tetrahedron Lett., 1998, 39
869; (b) H. Suga, K. Ikai and T. Ibata, J. Org. Chem. 1999, 64
,
,
7040; (c) D. A. Evans, J. M. Janey, N. Magomedov and J. S.
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6
For selected examples from our group, see: (a) X. H. Liu, L. L.
Lin and X. M. Feng, Acc. Chem. Res., 2011, 44, 574; (b) X. H.
Liu, L. L. Lin and X. M. Feng, Org. Chem. Front., 2014, 1, 298;
Scheme 2 Gram-scale version of the reaction
(c) M. S. Xie, X. X. Wu, G. Wang, L. L. Lin and X. M. Feng, Acta
Chim. Sin., 2014, 72, 856; (d) K. Zheng, L. L. Lin and X. M.
Feng, Acta Chim. Sin., 2012, 70, 1785; (e) Y. L. Kuang, Y. Lu, Y.
With related to the reaction mechanism, we proposed that chiral
N,N’-dioxide-Co(II) complex could serve as a chiral Lewis acid
catalyst based on our previous study.6 The metal ion prefers to
bond the 5-alkoxyoxazole 1a, and the competitive coordination
with azodicarboxylate 2b is weaken due to the steric hindrance of
the bulky tert-butyl ester substituent. Then electron-rich C4-
position of 5-alkoxyoxazole 1a takes place a Re-face nucleophilic
attack to azodicarboxylate 2b, affording zwitterion intermediate.
Next, alkoxyoxazole ring experiences opening and cyclization
process, generating the 1,2,4-triazoline 3ab.
Tang, X. H. Liu, L. L. Lin and X. M. Feng, Org. Lett., 2014, 16
,
4244; (f) Z. L. Zhang, X. H. Liu, Z. Wang, X. H. Zhao, L. L. Lin
and X. M. Feng, Tetrahedron Lett., 2014, 55, 3797; (g) Z. G.
Yang, Z. Wang, S. Bai, X. H. Liu, L. L. Lin and X. M. Feng, Org.
Lett., 2011, 13, 596; (h) X. J. Lian, L. L. Lin, G. J. Wang, X. H. Liu
and X. M. Feng, Chem. Eur. J., 2015, 21, 17453; (i) X. Xiao, L. L.
Lin, X. J. Lian, X. H. Liu and X. M. Feng, Org. Chem. Front.,
2016, 3, 809.
CCDC 1531931 (3ab).
7
In summary, we have developed a convenient and efficient
method to build poly-substituted chiral 1,2,4-triazolines compounds
via an asymmetric formal [3+2] reaction of 5-alkoxyoxazoles with
azodicarboxylates. A variety of 5-alkoxyoxazole substrates were
tolerated very well, giving aryl or alkyl substituted 1,2,4-triazolines
in the excellent yields and enantioselectivities. And a gram-scale
preparation was also well performed without loss of the selectivity
and yield. Further, the other enantioselective formal [3+2] reaction
of 5-alkoxyoxazoles participating in is underway.
We appreciate the National Natural Science Foundation of China
(Nos: 21290182, and 21321061), the Fok Ying Tung Education
This journal is © The Royal Society of Chemistry 20xx
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DOI: 10.1039/C7CC01278K
A chiral N,N'-dioxide/Co(BF4)2.6H2O complex catalysed highly efficient asymmetric [3+2]
cycloaddition reaction of 5-alkoxyoxazoles with azodicarboxylate compounds.