G Model
CCLET 4154 No. of Pages 4
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R. Mao et al. / Chinese Chemical Letters xxx (2017) xxx–xxx
Table 1
Initial screening and optimization.a
Entry
Change from standard conditions
Yield (%)b
Fig. 1. Selected examples of aminated THF derivatives that exhibit biological
activities.
1
2
3
4
5
6
7
None
99
0
0
50
0
30
99
Reaction run in the dark
No Umemoto’s reagents
CH3CN (2.0 mL) as solvent
DMF (2.0 mL) as solvent
Toluene (2.0 mL) as solvent
No photocatalyst
Herein, we report our results inspired by the hypothesis in
Scheme 1. Our initial reaction conditions involved irradiation with
blue LEDs (lmax = 455 nm) in the presence of 2,6-dichloropurine 5a
(0.030 mmol), tetrahydrofuran (THF) (1.0 mL), Umemoto’s reagent
(0.078 mmol), photocatalyst [Ru(bpy)3](PF6)2 (0.0015 mmol) and
4 Å molecular sieves in CH2Cl2 (2.0 mL) (Table 1). When the
standard conditions were used, the desired product 4a was
obtained in nearly quantitative yield. The control experiments
demonstrated that the irradiation and the use of Umemoto’s
reagent are essential. The solvent screening experiments showed
the insignificant differences or inferior results from those obtained
using CH2Cl2. However, the irradiation without [Ru(bpy)3](PF6)2
provided the similar yield of 99%! This surprising outcome is likely
due to the formation of an electron donor-acceptor (EDA) complex
[16], in which purine and Umemoto's reagent may serve as the
electron donor and electron acceptor, respectively. Thanks to the
large conjugated system, the EDA complex could be employed
directly as a photon-absorbing EDA that would avoid using
photocatalysts.
a
Unless specified, a mixture of 5a (0.030 mmol), THF (1.0 mL), Umemoto’s
reagent (0.078 mmol), photocatalyst [Ru(bpy)3](PF6)2 (0.0015 mmol) and 4 Å
molecular sieves (200 mg) in CH2Cl2 (2.0 mL) was exposed to blue LEDs irradiation
(
lmax = 455 nm) at room temperature for 12 h.
b
Isolated yield.
After surveying various nucleobases, we turned to test the
reactions of various ethers with 2,6-di-chloropurine 5a under the
optimized reaction conditions (Table 2, entries 7–10). To our
delight, various ethers were proven to be reliable reactants as
illustrated in Table 2. Cyclic ether compounds, either five- (6a) or
six-membered ring (6b or 6c), could afford the desired products in
good yields (entries 1, 7 and 8). The sterically hindered compound
methyl tert-butyl ether (MTBE) (6d) also underwent this reaction
to yield the product 4i (entry 9). Interestingly, when the unsym-
metrical ether isochroman (6e) was used as substrate,
a
We next investigated the substrate scope of the reaction under
the reaction conditions depicted in entry 7 of Table 1. Under the
optimized high-yielding reaction conditions, various purines and
several other alkyl ethers were examined. As shown in Table 2,
various purines were employed as substrates, and different 6-
halopurine derivatives 5a–5c could react with THF smoothly
(entries 1–3). The purine derivatives with nitrogen-containing
groups at the C-6 position (5d–5f) could also afford the alkylated
products in good yields (entries 4-6). Besides, it seemed that when
the purine derivatives with C-2 position replaced by halogen atoms
(such as Cl and F) were used, the yields of products were increased
slightly (entries 1, 2 and 5).
regioselective product 4j was obtained in good yield (entry 10).
The high efficiency of this light-promoted synthesis of N-9
alkylated purine nucleoside derivatives was further highlighted
by the irradiation of sunlight. The reaction of 5a and 6a could also
give product 4a in good yield (71%, Scheme 2).
With the establishment of substrate scope, we also wished to
find some evidence to investigate the mechanism of this reaction.
It was found that when running the reaction under the optimized
reaction conditions depicted (Table 1, entry 7) in the presence of
3.0 equiv. of TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl),
barely no product was obtained even prolonged exposure to light.
Besides, the PBN (a-phenyl N-tertiary-butyl nitrone) trapped CF3
Scheme 1. Original hypothesis for the synthesis of N-9 alkylated purine nucleoside derivatives.
Please cite this article in press as: R. Mao, et al., N-9 Alkylation of purines via light-promoted and metal-free radical relay, Chin. Chem. Lett.