FULL PAPER
of 13b with phenyl boric acid, phenyl magnesium chloride are well tolerable. Such a deoxygenation
bromide, or phenyl zinc chloride, all gave desired protocol also enables the preparation of geminally
product 15 in excellent yields. In addition, direct dideuterated alkane, by simply using DCO2D as
manipulations to azacycles of the activating group deuteride donor and D2O as co-solvent. High deute-
were also accessible. For example, Pandey’s group rium incorporation at the target sites is obtained (up to
reported the conversion of 2a into 1,4-dihydroquino- 90% for dideuteration). The proposed mechanism
line 17 through photocatalytic generation of involves the transfer hydrogenation of ketones to
amonomethyl radical and subsequent addition and alkanols and deoxygenation of alkanols via transfer
cyclization with enone 16.[23b] Wang’s group synthe- hydrogenation of the generated carbocations. Notably,
sized tetrahydroquinoline 19 through aryl iminium the deuterative deoxygenation of ketones is much
formation by treating with methylene diiodide and slower than the hydrogenative counterpart. The activat-
subsequent [4+2] cycloaddition with olefin 18.[23c]
ing 4-(N,N-disubstituted amino)aryl group have been
The 4-(N,N-disubstituted amino) aryl also emerges demonstrated to undergo a variety of useful trans-
as an important structural subunit in some medicines formations such as cross-coupling and transannulation
such as Chlorambucil (Leukeran), which is marketed reactions to synthesize azacyclic and multi-aromatic
and widely used in clinic for treating various forms of structures. A synthetic application of the deoxygena-
cancer. With our iridium-catalysed dideuteration proto- tive deuterations has also been achieved to prepare the
col, chlorambucil (24) and its 4,4-d2 counterpart (23) deuterated drug molecule Chlorambucil-4,4-d2.
were successfully synthesized (Scheme 9). Friedel-
Crafts acylation of N,N-bis(2-chloroethyl)aniline (20)
with succinic anhydride (21) gave ketone 22 in 70%
Experimental Section
yield. Submission of 22 to our deoxygenation and General Procedure for Deoxygenation of Ketones 1.
dideuteration delivered 24 and 23 in 54% and 43%
yields, respectively. Moreover, it also demonstrated the
good tolerance of chloroalkyl and carboxylic groups,
To a 5-mL tube was sequentially added ketone 1 (0.125 mmol),
and 125 μL of C8 catalyst solution (0.0005 mmol/mL for S/C=
2000; 0.0002 mmol/mL for S/C=5000; 0.00005 mmol/mL for
S/C=20000) in water, 125 μL of deionized water, 250 μL of
HFIP (in most cases) or water (only for 1ai, 1aj, and 1ak), and
HCO2H (76 μL, 2 mmol, 16 equiv.). The tube was sealed with a
rubber septum that was connected with an empty balloon. The
especially the former, which was intolerable in many
reductive conditions for deoxygenations.[1–13,15–17]
Conclusion
°
resultant reaction mixture was immersed in a preheated 80 C
heating-mantle and was stirred for 2 h. Upon cooling to room
temperature, diluting with saturated sodium bicarbonate solu-
tion (5 mL), extracting with ethyl acetate (5 mL×3), drying
over Na2SO4, concentration of the organic phase under reduced
pressure, and purification by column chromatography on silica
gel with PE and EA as eluent afforded desired products 2.
We have developed an iridium-catalysed deoxygena-
tion of ketones and aldehydes. Formic acid is used as
hydrogen source and water is used as co-solvent. At
5000 S/C ratio, a number of 4-(N,N-disubstituted
amino) aryl ketones are readily deoxygenated in
excellent yields and chemoselectivity. Numerous func-
tional groups, such as halogen atoms, ester, cyano,
nitro, phenolic and alcoholic hydroxyls, heteroaryls, General Procedure for Deoxygenative Dideutera-
secondary amine, carboxylic acids, and especially alkyl tion of Ketones 1.
To a 5-mL reaction tube was sequentially added ketone 1
(0.125 mmol), 125 μL of the C2 catalyst solution (0.005 mmol/
mL for S/C=200) in D2O, 125 μL of HFIP, and 38 μL of formic
acid-d2 (DCO2D, 1 mmol, 8 equiv.). The tube was sealed with a
rubber septum that was connected with an empty balloon. The
°
resultant reaction mixture was immersed in a preheated 80 C
heating-mantle and was stirred for 2 h. Upon cooling to room
temperature, diluting with saturated sodium bicarbonate solu-
tion (5 mL), extracting with ethyl acetate (5 mL×3), drying
over Na2SO4, concentration of the organic phase under reduced
pressure, and purification by column chromatography on silica
gel with PE and EA as eluent afforded desired products 4.
For more details of experimental procedures, analytical data,
and NMR spectra, see the Supporting Information.
Scheme 9. Synthesis of Chlorambucil-4,4-d2.
Adv. Synth. Catal. 2020, 362, 1–11
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