Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Regiodivergent Synthesis of Pyrazolines with a Quaternary Carbon Center via Cycloaddition of Diazoesters to N‑Purine-Substituted Allenes Ming-Sheng Xie, Zhen Guo, Gui-Rong Qu, and Hai-Ming Guo*
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Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China S Supporting Information *
ABSTRACT: Diversity-oriented synthesis of pyrazoline derivatives that contain a quaternary carbon center has been achieved via the 1,3-dipolar cycloaddition between N-purine-substituted allenes and α-alkyl/aryl diazoesters. Using Pd2(dba)3 as a catalyst, only 1-pyrazoline derivatives are produced in a regioselective manner. When DPPB is used as a catalyst, diverse 1-pyrazolines and 2-pyrazolines are obtained in moderate to good total yields.
P
synthesis of pyrazoline derivatives.5−7 During the past few decades, alkenes or alkynes have been extensively investigated and well developed in the cycloaddition with diazo compounds (Scheme 1a).8 However, in sharp contrast, use of allenes as partners in such cycloadditions with diazo compounds has been less studied, and this is presumably due to the difficulty in controlling the regioselectivity of the two adjacent CC double bonds in allenes.9,10 In 2010, Shi’s group reported the 1,3-dipolar cycloaddition of vinylidenecyclopropane diesters with aromatic diazomethanes generated in situ from aldehydes and tosylhydrazine, affording pyrazole derivatives in good yields (Scheme 1b, top).11 In 2014, Ma and co-workers developed a regioselective 1,3-dipolar cycloaddition of electron-deficient allenic esters or ketones with trifluorodiazoethane, giving 5-(trifluoromethyl)pyrazolines or 3-(trifluoromethyl)pyrazoles in good to high yields (Scheme 1b, bottom).12 To the best of our knowledge, to date, there have been no reported examples of a 1,3-dipolar cycloaddition between α-alkyl/aryl diazoesters and allenes. In the context of our ongoing studies on modifying purines and nucleosides,13 we report herein the regioselective 1,3-dipolar cycloaddition between N-purine-substituted allenes and α-alkyl/aryl diazoesters to produce (in moderate to high yields) diverse pyrazoline derivatives that have a quaternary carbon center (Scheme 1c). Initially, the reaction between 9-allenyl-9H-purine 1a and αmethyl diazoacetate 2a was selected as the model reaction
yrazolines with a quaternary carbon center are prevalent in many biologically active molecules. Representative examples of such pyrazolines are shown in Figure 1. Mefenpyr-
Figure 1. Selected pyrazolines that have a quaternary carbon center and biological activities.
diethyl is a herbicide safener that has favorable toxicological, ecotoxicological, and environmental behavior.1 RH 3421 is an insecticide that can block both peripheral and central neuronal activities in insects.2 Pyrazoline I exhibits potent selective androgen receptor agonist activity.3 Chloroquine-derived pyrazoline II possesses promising antimalarial activity.4 Because of the variety of functions of these compounds, developing an efficient method to construct pyrazolines that have a quaternary carbon center is therefore highly desirable. The 1,3-dipolar cycloaddition of diazo compounds with olefinic dipolarophiles represents an efficient approach for the © XXXX American Chemical Society
Received: July 11, 2018
A
DOI: 10.1021/acs.orglett.8b02161 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
(Table 1). Without any catalyst, the 1,3-dipolar cycloaddition occurred in toluene at 80 °C, affording a mixture of 1pyrazoline 3aa and 2-pyrazoline 4aa in 33% total yield (entry 1). When PPh3 was used as a catalyst, the cycloaddition proceeded well and afforded a mixture of 3aa and 4aa in 73% total yield; 2-pyrazoline 4aa had a quaternary carbon center and was the major adduct with an excellent Z/E ratio (entry 2). The structure of 3aa was confirmed via the X-ray crystallographic analysis. Subsequently, other phosphine catalysts including DPPE C1, DPPB C2, P(Cy)3 C3, DPPF C4, and S-Phos C5 were examined. DPPB C2 produced the cycloadducts in a higher total yield and had a 52:33 regioselectivity (4aa/3aa) (entries 3−7). The reaction temperature was further investigated, and 100 °C was selected as the best option, giving the cycloadducts 3aa and 4aa in 91% total yield with 57:34 regioselectivity (4aa/3aa) (entries 4, 8, and 9). Interestingly, when PdCl2 was used as a catalyst, the regioselectivity (4aa/3aa) was reversed, and 1-pyrazoline 3aa was the major adduct, which indicates that metal salt can affect the regioselectivity of the reaction (entries 9 and 10). Other metal salts, including Ag2CO3, In(OTf)3, Pd(OAc)2, Pd(dba)2, and Pd2(dba)3, were evaluated, and Pd2(dba)3 was determined to be the better choice; Pd2(dba)3 gave the pyrazoline derivatives in a 83% total yield with 70:13 regioselectivity (3aa/4aa) (entries 11−15). Several solvents were then tested,
Scheme 1. Different Routes for Constructing Chiral Acyclic Purine Nucleoside Analogues
Table 1. Optimization of Reaction Conditionsa
entry
cat.
x
solvent
temp (°C)
yieldb (%)
3aa yield (%)c (E/Z)d
4aa yield (%)c (Z/E)d
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20e
PPh3 C1 C2 C3 C4 C5 C2 C2 PdCl2 Ag2CO3 In(OTf)3 Pd(OAc)2 Pd(dba)2 Pd2(dba)3 Pd2(dba)3 Pd2(dba)3 Pd2(dba)3 Pd2(dba)3 Pd2(dba)3
20 20 20 20 20 20 20 20 10 10 10 10 10 10 10 10 10 10 10
toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene DCE PhCF3 mesitylene mesitylene mesitylene
80 80 80 80 80 80 80 60 100 80 80 80 80 80 80 60 60 60 100 100
33 73 80 85 75 75 56 66 91 65 65 51 68 74 83 52 36 61 70 73
17 (2.5/1) 32 (5/1) 33 (5/1) 33 (5/1) 29 (5/1) 44 (5/1) 33 (10/1) 27 (5/1) 34 (5/1) 47 (1.6/1) 48 (8/1) 27 (4/1) 33 (4.2/1) 34 (1.6/1) 70 (5/1) 26 (5/1) 17 55 (5/1) 70 (5/1) 73 (5/1)
16 (>20/1) 41 (>20/1) 47 (>20/1) 52 (>20/1) 46 (>20/1) 31 (>20/1) 23 (>20/1) 39 (>20/1) 57 (>20/1) 18 (>20/1) 17 (>20/1) 24 (>20/1) 35 (>20/1) 41 (>20/1) 13 (>20/1) 26 (>20/1) 19 (>20/1) 6 (>20/1) trace 0
a
Unless otherwise noted, reaction conditions were as follows: cat. (20 mol %), 1a (0.05 mmol), 2a (0.3 mmol) in solvent (1.0 mL) under N2 for 48 h. bTotal yield of 3aa and 4aa. cIsolated yield. dDetermined from 1H NMR spectroscopy of the crude reaction mixture. e2a and Pd2(dba)3 were added twice in mesitylene. B
DOI: 10.1021/acs.orglett.8b02161 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
To obtain 2-pyrazolines and realize the diversity-oriented synthesis of pyrazolines, 1,3-dipolar cycloaddition reactions of 9-allenyl-9H-purines and α-diazoacetates were performed with DPPB C2 as the catalyst (Table 1, entry 9). As shown in Table 2, a variety of 9-allenyl-9H-purines that had different
and mesitylene afforded a better regioselectivity (55:6 for 3aa/ 4aa) (entries 15−18). Upon increasing the reaction temperature to 100 °C and changing the sequence of material addition, a higher yield (73%) was obtained and only 1pyrazoline 3aa was formed (entries 18−20). The generality of the 1,3-dipolar cycloaddition was explored (Scheme 2) using a catalytic amount of Pd2(dba)3 (Table 1,
Table 2. Substrate Scope of 9-Allenyl-9H-purinesa
Scheme 2. Substrate Scope under Pd Catalysta
a
Reaction conditions: DPPB (20 mol %), 1a−k (0.1 mmol), 2a (0.6 mmol) in toluene (1.5 mL) under N2 for 48 h. bTotal yield of 3 and 4. cIsolated yields are reported. dDetermined by 1H NMR spectroscopy of the crude reaction mixture. a
Unless otherwise noted, the reaction conditions are as follows: Pd2(dba)3 (10 mol %), 1a−1i (0.05 mmol), 2a−g (0.3 mmol) in mesitylene (1.0 mL) at 100 °C under N2 for 48 h. 2a−g and Pd2(dba)3 were added twice. Isolated yields are reported. E/Z ratios are determined by 1H NMR spectroscopy of the crude reaction mixture.
substituents at the C2 or C6 positions were evaluated. For 6-ethoxy- or 6-chloropurine-derived allenes (1b,c), the corresponding pyrazoline derivatives were generated in 71− 84% total yields, and the 2-pyrazolines 4ba and 4ca were the major products (Table 2, entries 2 and 3). In the case of 6amino-substituted purine-derived allenes (1d−f), the 1,3dipolar cycloaddition proceeded well and afforded the pyrazoline derivatives in 61−78% total yields. The 1-pyrazolines 3da−fa were the major products (Table 2, entries 4−6). In addition, N-propargyladenine-derived allene 1j was also a suitable reactant, giving the [3 + 2] cycloadducts 3ja and 4ja in 56% total yield; 1-pyrazoline 3ja was the major adduct with a 10:1 E/Z ratio (Table 2, entry 7). When 6-propylthiopurinederived allene 1k was used, the pyrazoline derivatives were produced in 56% yield, and 1-pyrazoline 3ka was the major product with a 5:1 E/Z ratio (Table 2, entry 8). The 1,3dipolar cycloadditions of 9-allenyl-9H-purines with either an amino (1g,h) or alkoxy (1i) group at the C2 position of purine were then performed. These reactions gave the pyrazoline derivatives in 72−85% total yields (Table 2, entries 9−11). Subsequently, a variety of α-diazoesters were explored in the 1,3-dipolar cycloaddition reactions using DPPB C2 as the catalyst; diverse 1-pyrazolines and 2-pyrazolines (Table 3) were generated. When several α-alkyl diazoesters with different ester groups were examined, the corresponding pyrazolines
entry 20). For 6-ethoxypurine-derived allene 1b, 1-pyrazoline 3ba was generated in 72% yield and had a 5:1 E/Z ratio. In the case of 6-chloropurine-derived allene 1c, only 46% yield of 3ca was obtained with a 4:1 E/Z ratio. When 6-amino-substituted purine-derived allenes (1d−f) were used, the 1,3-dipolar cycloaddition reactions proceeded well and afforded 1pyrazolines 3da−fa in 56−72% yields with 2:1−5:1 E/Z ratios. Meanwhile, these 9-allenyl-9H-purines with either a chloro or alkoxy substituent at the C2 position were also suitable partners, affording 1-pyrazolines 3ga−ia in 57−66% yields with 4:1−5:1 E/Z ratios. Several α-alkyl diazoesters (2b−e) that had different ester groups and alkyl groups were then examined, and the desired 1-pyrazolines 3ab−ae were afforded in 53−67% yields. α-Phenyl diazoesters (2f,g) were also tolerated in these reactions and generated the desired 1pyrazolines 3af−ag in 48−53% yields. It should be noted that the 1,3-dipolar cycloaddition proceeded in a regioselective manner, and only 1-pyrazolines were obtained in all of the cases, for which a catalytic amount of Pd2(dba)3 was used. C
DOI: 10.1021/acs.orglett.8b02161 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Table 3. Substrate Scope of Diazoestersa
entry
2
R
R1
yieldb (%)
1 2 3 4 5 6 7
2a 2b 2c 2d 2e 2f 2g
Me Et Et Et nC5H11 Ph Ph
Et iPr tBu Me Me Et Me
91 72 67 72 73 47 53
3 yield (%)c (E/Z)d 34 29 30 25 35 47 53
(5/1) (5/1) (5/1) (5/1) (5/1) (5/1) (5/1)
alkyl/aryl diazoesters. When Pd2(dba)3 was used as a catalyst, only 1-pyrazoline derivatives were afforded in a regioselective manner. When DPPB was used as a catalyst, diverse 1pyrazolines and 2-pyrazolines were obtained in moderate to good total yields.
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57 43 37 47 38
ASSOCIATED CONTENT
S Supporting Information *
4 yield (%)c (Z/E)d
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02161. Experimental procedures and compound characterization data (PDF)
(>20:1) (>20:1) (>20:1) (>20:1) (>20:1) 0 0
Accession Codes
CCDC 1848157 and 1848165 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
a
Reaction conditions: DPPB (20 mol %), 1a (0.1 mmol), 2a−g (0.6 mmol) in toluene (1.5 mL) under N2 for 48 h. bTotal yield of 3 and 4. cIsolated yields are reported. dDetermined by 1H NMR spectroscopy of the crude reaction mixture.
were produced in 67−91% total yields, and 2-pyrazolines 4aa− ad were the major products (Table 3, entries 1−4). In the case of methyl 2-diazoheptanoate 2e, the desired pyrazolines (3ae and 4ae) were obtained in 73% total yield (Table 3, entry 5). For α-phenyl diazoesters 2f,g, the 1,3-dipolar cycloaddition reactions proceeded in a regioselective manner, and only 1pyrazolines 3af,ag were produced (Table 3, entries 6 and 7). It was proposed that the steric repulsion between the bulky phenyl group and the substituent in the exocyclic CC double bond might affect the regioselectivity, resulting the formation of 1-pyrazolines 3 exclusively (Table 3, entries 6 and 7). Structure derivatization of the pyrazoline derivatives was studied (Scheme 3). Using Pd/C as a catalyst, hydrogenation
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Hai-Ming Guo: 0000-0003-0629-4524 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for financial support from the NSFC (Nos. 21472037 and U1604283), the Program for Science & Technology Innovation Talents in Universities of Henan Province (19HASTIT036), and the 111 Project (No. D17007).
Scheme 3. Structure Derivatization of Pyrazolines
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REFERENCES
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DOI: 10.1021/acs.orglett.8b02161 Org. Lett. XXXX, XXX, XXX−XXX
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DOI: 10.1021/acs.orglett.8b02161 Org. Lett. XXXX, XXX, XXX−XXX
