1,3-Dipolar cycloaddition of diazoacetate compounds to terminal alkynes promoted by Zn(OTf)2: an efficient way to the preparation of pyrazoles

Article abstract of DOI:10.1016/j.tetlet.2009.03.030

A series of pyrazoles were prepared in good yields via 1,3-dipolar cycloaddition of diazoacetate compounds to terminal alkynes promoted by Zn(OTf)₂ under mild conditions. It was supposed that the reaction was through the intermediate of Zn alky

Full text of DOI:10.1016/j.tetlet.2009.03.030

Tetrahedron Letters 50 (2009) 2443–2445
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Tetrahedron Letters
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1,3-Dipolar cycloaddition of diazoacetate compounds to terminal alkynes
promoted by Zn(OTf)2: an efficient way to the preparation of pyrazoles
*
Sheng He, Li Chen, Yan-Ning Niu, Lu-Yong Wu, Yong-Min Liang
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of pyrazoles were prepared in good yields via 1,3-dipolar cycloaddition of diazoacetate com-
pounds to terminal alkynes promoted by Zn(OTf)2 under mild conditions. It was supposed that the reac-
tion was through the intermediate of Zn alkynilide.
Received 9 January 2009
Revised 4 March 2009
Accepted 6 March 2009
Available online 11 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Pyrazolederivatives are knownas an importantclass of heterocy-
cles which display an ample spectrum of biological activities and are
widely employed as anti-tumor, anti-inflammatory, anti-microbial,
and anti-psychotic agents.1 The most widely used method for their
synthesis is the reaction between 1,3-dicarbonyl compounds and
hydrazines,2,3 the harsh reaction conditions or the multistep se-
quences usually required to access the starting materials make its
usage limited. In last few years, the 1,3-dipolar cycloaddition of dia-
zo compounds4 and other 1,3-dipoles5 to alkynes has become popu-
lar, however, because of the increased HOMO–LUMO energy gap
between diazocarbonyl compounds and alkynes,6 1,3-dipolar cyclo-
addition of diazo compounds to alkynes is rarely reported.7 To over-
come this problem, two complementary strategies focus on
modulating the reactivity of the dipolarophile. One of the most com-
monly used approaches is to introduce Lewis acids to lower the en-
ergy of the LUMO of the dipolarophile.8 Under such conditions the
dipole reacts through its HOMO to generate the cycloaddition prod-
uct.9 Alternatively, additives that increase the electron density of the
dipolarophile can accelerate cycloaddition through a HOMO(dipol-
arophile)–LUMO(dipole) interaction.9 Here, we wish to report a
new example of dipolar cycloaddition reactions: the intermolecu-
lar1,3-dipolar cycloaddition of diazocarbonyl compounds to termi-
nal alkynes promoted by Zn(OTf)2 without solvent to synthesize
pyrazoles.
best, other amine, such as NHEt2, DABCO, DBU, and pyridine, ap-
peared to be ineffective in this reaction (Table 1, entries 8–12).
Table 1
Reaction results of ethyl diazoacetate with phenylethynea
H
N
Cat.
N
CO2Et
N2CHCO2Et
+
Ph
solvent
Ph
1a
2a
3aa
Entry
Lewis acid
Amine
Solvent
Temp (C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15g
16h
Cu(OTf)2
Cu(PPh3)Br
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Noc
No
DME
Benzene
THF
Toluene
No
No
No
No
No
100
100
Reflux
Reflux
Reflux
100
100
100
100
100
100
100
80
Dpd
Nre
55
48
35
50
78
76
28
Dp
Nr
Dp
55
18
89
28
Et3Nf
NHEt2
DABCO
Pyridine
DBU
No
No
No
No
Et3N
We began the exploration of the reaction with various catalysts
and the results are summarized in Table 1.10 It was found that other
catalysts such as Cu(OTf)2 and Cu(PPh3)Br could not promote this
reaction (Table 1, entries 1 and 2). Solventeffect on the cycloaddition
reaction was also studied. The reactions performed in solvents pro-
ceed in 35–55% yields, respectively (entries 3–6), when carried out
with no solvent, the product comes to 78% (Table 1, entry 7). Further-
more, we investigated various amines and NEt3 was found to be the
Et3N
40
100
100
Et3Nc
Et3N
No
a
Reactions were carried out in 5 mL solvent with 1.0 mmol phenylacetylene,
1.2 mmol ethyl diazoacetate, 2.0 mmol amine, and 0.2 mmol Lewis acid by heating
at the indicated temperature.
b
Isolated yields.
No solvent.
Decomposition.
No reaction.
Et3N (1.0 equiv)
Zn(OTf)2 (0.20 equiv) Et3N (1.5 equiv).
Zn(OTf)2 (0.05 equiv) Et3N (1.5 equiv).
c
d
e
f
g
* Corresponding author. Tel.: +86 931 8912593; fax: +86 931 8912582.
E-mail address: liangym@lzu.edu.cn (Y.-M. Liang).
h
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.030

2444
S. He et al. / Tetrahedron Letters 50 (2009) 2443–2445
Table 2
Zn(OTf)2-promoted nucleophilic addition of terminal alkynes to car-
bonyl compounds could serve as a prototype for our cycloaddition
reaction. According to the nucleophilic pathway (Scheme 1), the
complex of 1-alkyne with zinc triflate yielded zinc acetylide, which
is operative in these cases. Zinc may serve as an electron-donating
group and raise the energy of the HOMO of the alkyne. A cycloaddi-
tion that involves the LUMO of the diazocarbonyl compound gener-
ates a (pyrazolyl)Zn (a) intermediate which can tautomerize under
the reaction conditions.
In summary, we have developed a novel one-step method for
the synthesis of pyrazoles,13 which was proceeded via Zn(OTf)2-
catalyzed 1,3-dipolar cycloaddition of terminal alkynes with diazo-
carbonyl compounds. The simple reaction conditions, straightfor-
ward procedure, synthetically useful products, good yielding, and
easy manipulation make this method potentially useful in organic
synthesis.
Zn(OTf)2–Et3N-catalyzed 1,3-dipolar cycloaddition of diazocarbonyl compounds to
terminal alkynes without solventa
H
Zn(OTf)2
N
N
R1
CO2R2
+
N2CHCO2R2
NEt3,100 ºC
R1
1
2
3
Entry
Alkyne 1 (R1=)
Diazoester 2
Product 3
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a (Si(CH3)3)
2a (R2 = Et)
2a (R2 = Et)
2a (R2 = Et)
2a (R2 = Et)
2a (R2 = Et)
2a (R2 = Et)
2b (R2 = t-Bu)
2c (R2 = Bn)
2a (R2 = Et)
2a (R2 = Et)
2a (R2 = Et)
2a (R2 = Et)
2a (R2 = Et)
2a (R2 = Et)
2a (R2 = Et)
3aa
3ba
3ca
3da
3ea
3fa
3fb
3fc
3ga
3ha
3ia
3ja
3ka
3la
53
71
89
81
87
89
71
78
—
45
47
44
28
48
31
1b (4-CH3C6H4)
1c (4-Br C6H4)
1d (4-NO2 C6H4)
1e (2-Ethynylpyridine)
1f (C6H5)
1f (C6H5)
1f (C6H5)
1g Diphenylethyne
1h (CH2 C2H5)
1i (CH2CH2CH2C2H5)
1j (CH2O C2H5)
1k (CH2OCH2CHCH2)
1l (CH2OOCPh)
1m (C(CH3)2OH)
Acknowledgment
We thank the NSF (NSF-20672049) for financial support.
References and notes
3ma
a
Reaction conditions: anhydrous Zn(OTf)2 (73 mg, 20 mol %), acetylene
1
(1 mmol), diazoester 2 (1.2 equiv), and Et3N (165 mg, 1.5 mmol) were added. The
mixture was stirred for 8 h with stirring at 100 °C.
1. (a) Daidone, G.; Maggio, B.; Plescia, S.; Raffa, D.; Musiu, C.; Milia, C.; Perra, G.;
Marongiu, M. E. Eur. J. Med. Chem. 1998, 33, 375–382; (b) Tsuji, K.; Nakamura,
K.; Konishi, N.; Tojo, T.; Ochi, T.; Senoh, H.; Matsuo, M. Chem. Pharm. Bull. 1997,
45, 987; (c) Nauduri, D.; Reddy, G. B. Chem. Pharm. Bull. 1998, 46, 1254–1260;
(d) Gajare, A. S.; Bhawsar, S. B.; Shingare, M. S. Indian J. Chem. 1997, 6, 321–322;
(e) Wise, L. D.; Butler, D. E.; DeWald, H. A.; Lustgarten, D. M.; Pattison, I. C.;
Schweiss, D. N.; Coughenour, L. L.; Downs, D. A.; Heffner, T. G.; Pugsley, T. A. J.
Med. Chem. 1987, 30, 1807–1812.
2. Stanovnik, B.; Svete, J.. In Science of Synthesis; Neier, R., Ed.; Thieme: Stuttgart,
2002; Vol. 12, p 15. and references cited therein.
3. Kost, N.; Grandberg, I. Adv. Heterocycl. Chem. 1996, 6, 347.
4. Padwa, A.. In 3-Dipolar Cycloaddition Chemistry; John Wiley & Sons: New York,
1984; Vol. I.
b
Isolated yields.
Encouraged by the elementary results, we studied the effects of
temperature on the efficiency of the reaction using the same reac-
tion conditions. It revealed that the preferred temperature for the
reaction was 100 °C, higher temperature had only a minor effect
on the yield and lower temperature led to long reaction times
and lower yields (Table 1, entries 13 and 14). Further screening
demonstrated that the reaction proceeded well with 20 mol % of
Zn(OTf)2 at 100 °C (Table 1, entry 15, 89% yield). However, the yield
decreases to less than 30% after the loading of catalyst is reduced to
5 mol % (Table 1, entry 16).
5. For examples, see: Ponti, A.; Molteni, G. J. Org. Chem. 2001, 66, 5252–5255;
Washizuka, K. I.; Nagai, K.; Minakata, S.; Ryu, V.; Komatzu, M. Tetrahedron Lett.
2000, 41, 691–695.
6. Fleming, I. Frontier Orbitals and Organic Chemical Reactions; JohnWiley & Sons:
Chichester, 1976.
After optimization of the reaction conditions, it was concluded
that the reaction could proceed effectively with 0.2 mmol of
Zn(OTf)2 and 1.5 equiv of NEt3 at 100 °C without solvent. As shown
by the data collected in Table 2, the reaction proceeded well with a
wide range of terminal alkynes. Most terminal alkynes reacted effi-
ciently to afford the corresponding pyrazole compounds in med-
ium to good yields (53–89%) (Table 2, entries 1–8). But the
reaction with some other alkynes gave lower yields (Table 2, en-
tries 10–15). Obviously, aryl alkynes performed significantly better
than alkyl alkynes. In addition, no desired product was observed
when diphenylethyne performed this reaction (Table 2, entry 9).
The zinc-mediated cycloaddition of terminal alkynes with diazo-
esters is reminiscent of the silylation of 1-alkynes with chlorosilanes
catalyzed by Zn(OTf)211 and the copper-promoted cycloaddition of
diazocarbonyl compounds and acetylides.12 Accordingly, we sus-
pect a similar reaction mechanism (Scheme 1). We thought that
7. (a) Krishna, P. R.; Sekhar, E. R.; Mongin, F. Tetrahedron Lett. 2008, 49, 6768–
6772; (b) Kobayashi, K.; Igura, Y.; Imachi, S.; Masui, Y.; Onaka, M. Chem. Lett.
2007, 36, 60; (c) Nan, J.; Li, C. J. Chem. Commun. 2004, 394.
8. Gothelf, K. V.; Jøgensen, K. A. Chem. Rev. 1998, 98, 863–909.
9. (a) Sustmann, R. Tetrahedron Lett. 1971, 12, 2717–2720; (b) Bastide, J.; Henri-
Rousseau, N. C. O. Tetrahedron Lett. 1972, 13, 4225–4228; (c) Houk, K. N. Acc.
Chem. Res. 1975, 8, 361–369.
10. Experimental
procedure:
anhydrous
Zn(OTf)2
(73 mg,
20 mol %),
phenylacetylene (102 mg, 1 mmol), and ethyl diazoacetate (137 mg,
1.2 mmol) were added to a flame dried bottle, then Et3N (165 mg, 1.5 mmol)
was added. The mixture was stirred for 8 h with stirring at 100 °C. The reaction
mixture was quenched with
a saturated aqueous solution of ammonium
chloride, and the mixture was extracted with CH2Cl2. The combined organic
extracts were washed with water and saturated brine. The organic layer was
dried (Na2SO4) and concentrated in vacuo. Crude product was purified by
chromatography on silica gel (hexane/AcOEt = 8:1).
11. Jiang, H.; Zhu, V. Tetrahedron Lett. 2005, 46, 517–519.
12. Qi, X.; Ready, J. M. Angew. Chem., Int. Ed. 2007, 46, 3242–3244.
13. Characterization data for pyrazole compounds:
Compound 3aa: Yellow oil, 1H NMR (400 MHz, CDCl3, J/Hz) = 0.22 (s, 9H), 1.24
(t, J = 7.2, 3H), 4.27 (q, J = 7.2, 2H), 6.86 (s, 1H), 11.78 (br s, NH). 13C NMR
(100 MHz, CDCl3) = À1.4, 14.2, 60.7, 115.2, 143.8, 144.7, 162.6. FTIR (thin film):
3176, 2958, 1726, 1466, 1249, 1160, 1096, 1026, 844, 780 cmÀ1. EI-MS (m/z):
212 [M]+.
Zn(OTf)2
R
Zn-(OTf)
[3+2]
R
Compound 3ba: White solid, mp 138–140 °C, 1H NMR (400 MHz, CDCl3, J/
Hz) = 1.35 (t, J = 6.8, 3H), 2.37 (s, 3H), 4.35 (q, J = 6.8, 2H), 7.05 (s, 1H), 7.22 (d,
J = 7.2, 2H), 7.62 (d, J = 7.2, 2H), 11.74 (br s, NH). 13C NMR (100 MHz,
CDCl3) = 14.2, 21.3, 61.2, 105.1, 125.5, 127.0, 129.5, 138.5, 140.5, 146.3,
160.8. FTIR (thin film): 3141, 2981, 1726, 1419, 1272, 1243, 1138, 1025, 819,
777 cmÀ1. EI-MS (m/z): 230 [M]+.
Et3N
R'
N2
H
R
R'
N
N
Compound 3ca: White solid, mp 141–143 °C, 1H NMR (400 MHz, CDCl3, J/
Hz) = 1.33 (t, J = 7.2, 3H), 4.33 (q, J = 7.2, 2H), 7.03 (s, 1H), 7.52 (d, J = 8.0, 2H),
7.62 (d, J = 8.0, 2H), 12.38 (br s, NH). 13C NMR (100 MHz, CDCl3) = 14.2, 61.4,
105.4, 122.5, 124.0, 127.2, 132.0, 140.2, 147.5, 160.1. FTIR (thin film): 3199,
2924, 1729, 1461, 1377, 1257, 1176, 1096, 1026, 846, 764 cmÀ1. EI-MS (m/z):
294 [M]+.
N
H
R'
N
Zn-(OTf)
Zn-(OTf)
R
b
a
Compound 3da: Yellow solid, mp 151–153 °C, 1H NMR (400 MHz, CDCl3, J/
Hz) = 1.49 (t, J = 7.2, 3H), 4.50 (q, J = 7.2, 2H), 7.65 (s, 1H), 8.30 (d, J = 8.0, 2H),
Scheme 1. Proposed cycloaddition reaction of alkynes with diazocarbonyl
compounds.

S. He et al. / Tetrahedron Letters 50 (2009) 2443–2445
2445
8.43 (d, J = 8.0, 2H), 14.50 (br s, NH). 13C NMR (100 MHz, CDCl3) = 14.2, 60.8,
107.1, 124.2 126.2, 139.3, 141.5, 146.8, 148.3, 161.2. FTIR (thin film): 3422,
2253, 1655, 1517, 1419, 1343, 1247, 1049, 1027, 825, 763, 629 cmÀ1. EI-MS (m/
z): 261 [M]+.
61.0, 106.5, 140.8, 148.7, 161.6. FTIR (thin film): 3189, 2926, 1725, 1460, 1233,
1163, 1110, 1024, 838, 781 cmÀ1. EI-MS (m/z): 182 [M]+.
Compound 3ia: Yellow oil, 1H NMR (400 MHz, CDCl3, J/Hz) = 0.80 (t, J = 7.6, 3H),
1.23 (m, 6H), 1.50 (t, J = 7.2, 3H), 2.61 (t, J = 7.6, 2H), 4.28 (q, J = 7.2, 2H), 6.50 (s,
1H), 12.20 (br s, NH). 13C NMR (100 MHz, CDCl3) = 13.8, 14.2, 22.3, 25.9, 28.4,
28.7, 31.2, 60.7, 106.1, 141.6, 147.7, 162.1. FTIR (thin film): 3186, 2958, 1728,
1452, 1301, 1239, 1162, 1112, 1026, 841, 780, 732 cmÀ1. EI-MS (m/z): 210 [M]+.
Compound 3ja: Yellow oil, 1H NMR (400 MHz, CDCl3, J/Hz) = 1.14 (t, J = 7.6, 3H),
1.30 (t, J = 7.2, 3H), 3.47 (t, J = 7.6, 3H), 4.29 (t, J = 7.2, 2H), 4.53 (s, 2H), 6.73 (s,
1H), 12.49 (br s, NH). 13C NMR (100 MHz, CDCl3) = 14.2, 15.0, 61.0, 64.3, 66.0,
107.4, 139.9, 145.8,161.2. FTIR (thin film): 3197, 2979, 1725, 1450, 1374, 1231,
1171, 1097, 1025, 841, 781 cmÀ1. EI-MS (m/z): 198 [M]+.
Compound 3ea: Yellow solid, mp 112–113 °C, 1H NMR (400 MHz, CDCl3, J/
Hz) = 1.40 (t, J = 7.2, 3H), 4.42 (q, J = 7.2, 2H), 7.26 (s, 1H), 7.70 (d, J = 7.6, 1H),
7.79 (d, J = 7.6, 2H), 8.70 (d, J = 7.6, 2H), 13.63 (br s, NH). 13C NMR (100 MHz,
CDCl3) = 14.1, 61.0, 106.2, 120.4 123.2, 123.4, 137.3, 149.1, 149.3, 161.8. FTIR
(thin film): 3444, 3097, 2979, 2804, 2647, 1742, 1597, 1406, 1232, 1000, 896,
765, 622 cmÀ1. EI-MS (m/z): 217 [M]+.
Compound 3fa: White solid, mp 120–122 °C, 1H NMR (400 MHz, CDCl3, J/
Hz) = 1.16 (t, J = 7.2, 3H), 4.14 (q, J = 7.2, 2H), 6.96 (s, 1H), 7.31 (t, J = 7.4, 1H),
7.36 (t, J = 7.6, 2H), 7.70 (d, J = 7.6, 2H), 10.60 (br s, NH). 13C NMR (100 MHz,
CDCl3, d/ppm) = 13.9, 60.9, 104.9, 125.6, 128.4, 128.8, 130.2, 140.8, 146.8,
161.1. FTIR (thin film): 3140, 2981, 1726, 1465, 1417, 1275, 1243, 1140, 1026,
763, 691 cmÀ1. EI-MS (m/z): 216 [M]+.
Compound 3ka: Yellow oil, 1H NMR (400 MHz, CDCl3, J/Hz) = 1.38 (t, J = 6.8,
3H), 4.03 (d, J = 5.6, 2H), 4.37(d, J = 6.8, 2H), 4.62 (s, 2H), 5.22 (dd, J = 6.8, 10.4,
1H), 5.31 (dd, J = 6.8, 10.4, 1H), 5.93 (m, 1H), 6.81 (s, 1H),13.11 (br s, NH). 13C
NMR (100 MHz, CDCl3) = 14.2, 61.1, 63.8, 71.3, 107.5, 117.7, 134.0, 139.8,
148.0, 161.1. FTIR (thin film): 3198, 2926, 1729, 1451, 1378, 1231, 1169, 1087,
1025, 929, 838, 781 cmÀ1. EI-MS (m/z): 210 [M]+.
Compound 3fb: White solid, mp 125–127 °C, 1H NMR (400 MHz, CDCl3, J/
Hz) = 1.43 (s, 9H), 6.91 (s, 1H), 7.24 (t, J = 7.2 1H), 7.29 (t, J = 7.2, 2H), 7.67 (d,
J = 7.2, 2H), 12.80 (br s, NH). 13C NMR (100 MHz, CDCl3) = 28.1, 82.2, 105.2,
125.6, 128.3, 128.8, 131.1, 140.2, 149.3, 160.0. FTIR (thin film): 2924, 1721,
1460, 1414, 1370, 1278, 1252, 1139, 1007, 842, 763, 691 cmÀ1 EI-MS (m/z): 244
[M]+.
Compound 3la: Yellow oil, 1H NMR (400 MHz, CDCl3, J/Hz) = 1.27 (t, J = 7.2, 3H),
4.28 (q, J = 7.2, 2H), 5.36 (s, 2H), 6.86 (s, 1H), 7.32 (t, J = 7.4, 1H), 7.46 (t, J = 7.6,
2H), 7.95 (d, J = 7.6, 2H), 12.24 (br s, NH). 13C NMR (100 MHz, CDCl3) = 14.1,
58.7, 61.3, 108.8, 128.3, 129.4, 129.7, 133.2, 142.0, 145.8, 160.6, 166.5. FTIR
(thin film): 3266, 3146, 2983, 1730, 1601, 1451, 1370, 1273, 1176, 1102, 1026,
840, 780, 712 cmÀ1. EI-MS (m/z): 274 [M]+.
Compound 3fc: White solid, mp 126–128 °C, 1H NMR (400 MHz, CDCl3, J/
Hz) = 5.20 (s, 2H), 6.98 (s, 1H), 7.28 (m, 8H), 7.63 (d, J = 7.6, 2H), 11.80 (br s,
NH). 13C NMR (100 MHz, CDCl3) = 67.0, 105.7, 125.7, 128.3, 128.4, 128.5, 128.6,
135.3, 140.0, 148.5, 160.9. FTIR (thin film): 3104, 3013, 1727, 1415, 1236, 1136,
1008, 760, 693 cmÀ1. EI-MS (m/z): 278 [M]+.
Compound 3ma: Yellow oil, 1H NMR (400 MHz, CDCl3, J/Hz) = 1.28 (t, J = 7.2,
3H), 1.52 (s, 6H), 4.27 (q, J = 7.2, 2H), 6.54 (s, 1H), 12.89 (br s, NH). 13C NMR
(100 MHz, CDCl3) = 14.2, 30.2, 30.6, 61.1, 68.9, 103.9, 141.1, 154.8, 161.9. FTIR
(thin film): 3234, 2980, 1723, 1467, 1378, 1242, 1155, 1093, 1024, 885, 781,
732 cmÀ1. EI-MS (m/z): 198 [M]+.
Compound 3ha: Yellow oil, 1H NMR (400 MHz, CDCl3, J/Hz) = 0.96 (t, J = 7.6,
3H), 1.38 (t, J = 7.2, 3H), 1.70 (m, 2H), 2.66 (t, J = 7.6, 2H), 4.37 (q, J = 7.2, 2H),
6.61 (s, 1H), 12.12 (br s, NH). 13C NMR (100 MHz, CDCl3) = 13.6, 14.3, 22.4, 28.4,