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ChemComm
DOI: 10.1039/C3CC45449E
Reaction conditions: benzamide 1 (0.3 mmol), aldehyde 2 (1.2 mmol),
synthesis of imino/ketocarboxylic acids via aryl amide directed
CꢀH activation reaction. A range of representative biaryl imino
carboxylic acids were successfully prepared. In addition, this
methodology has also provided an alternative approach for the
45 preparation of keto carboxylic acids via cheap readily available
aldehydes.
The financial support from the National Natural Science
Foundation of China (Grant No. 21342001), Tianjin Natural
Science Foundation (Grant No. 13JCQNJC04800) and the
50 Innovation Foundation of Tianjin University (2013XJꢀ0005) are
gratefully acknowledged.
Pd(OAc)2 (10 mol%), TBHP (70% in H2O) (5.0 equiv), BF3•Et2O (0.4
o
equiv) at 130 C in DMSO:dioxane 4:1 (1.5 mL, 0.2 M), 5 h. Then conc.
a
HCl(aq) (10.0 equiv) was added, reflux for 6 h. NꢀOMe benzamide was
5
used; bNꢀOiPr benzamide was used.
The treatment of benzamides 1 with aryl aldehydes under our
standard reaction conditions followed by the introduction of
concentrated HCl solution, the corresponding aryl keto carboxylic
acids 4aꢀ4e were successfully obtained in good yields. Both
10 electron rich and poor benzamides as well as aryl aldehydes
bearing electron donating group and electron withdrawing group
are tolerated under these reaction conditions.
Notes and references
Attempts on the decarboxylication of 3a were also carried out.
Under Gooβen’s decarboxylation conditions,8 carboxylic acid 3a
15 was treated with 25 mol% of Cu2O in the presence of 1,2ꢀ
phenanthroline resulted in the corresponding aryl imine 5a in
83% yield without the detection of the hydrolysis product.
aTianjin Key Laboratory for Modern Drug Delivery & High-Efficiency,
School of Pharmaceutical Science and Technology, Tianjin University,
55 Tianjin 300072, China. Fax: 0086-22-27404031; Tel: 0086-22-
27405316; E-mail: jhuang@tju.edu.cn and kangzhao@tju.edu.cn
bTianjin University of Traditional Chinese Medicine
cSynergetic Innovation Center of Chemical Science and
Engineering(Tianjin)
60
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
65
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75
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85
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95
1
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20 Scheme 3. Cuꢀmediated decaboxylation for the synthesis of
biaryl imine 5a
In addition, a oneꢀpot procedure using benzyl alcohols was
also developed.9 The corresponding iminocarboxylic acids 3a, 3o
and 3s were isolated in useful to good yields. (Scheme 4)
25
Reaction conditions: benzamide 1a (0.3 mmol), alcohol (1.8 mmol),
Pd(OAc)2 (10 mol%), TBHP (70% in H2O) (8.0 equiv), BF3•Et2O (0.4
equiv) at 130 oC in DMSO:dioxane 4:1 (1.5 mL, 0.2 M), 2ꢀ8 h.
Scheme 4. Oneꢀpot procedure for the synthesis of
30 iminocarboxylic acid from alcohol.
2
3
To further prove our initial proposal, the subjection of
hydroxyl isoindolone 6a into the reaction system under our
standard iminocarboxylic acid forming conditions resulted in our
desired imino caroxylic acid 3a in a good yield of 88%. It is also
35 worth noting that we have observed the formation of hydroxyl
isoindolone 6a during our reaction both by TLC and NMR
analyses.
4
5
6
7
8
100
105
Scheme 5. Ring opening of hydoxyl isoindolone 6a
9
F. Xiao, Q. Shuai, F. Zhao, O. Baslé, G. Deng and CꢀJ. Li, Org.
Lett., 2011, 13, 1614.
40
In conclusion, we have reported the first Pdꢀcatalysed
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